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SRT2104 Sirtris Pharmaceuticals, Inc.

1

Clinical Study Report SRT-2104-013 31-MAY-2012

TITLE PAGE

Protocol Number:

SRT-2104-013

Study Title:

A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe PlaqueType Psoriasis

Name of Product:

SRT2104

Indication Studied:

Plaque-Type Psoriasis

Development Phase of Study:

IIa

Brief Description of Study Design:

Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation

Name of Sponsor:

Sirtris Pharmaceuticals, Inc. 200 Technology Square Cambridge, MA 02139, USA

Study Initiation Date:

07 June 2010 (First subject informed consent signed)

Date of Early Termination (if applicable):

Not applicable

Study Completion Date:

09 November 2011 (Last subject visit) MD, PhD

Name & Affiliation of Principal or Coordinating Investigator(s) or Sponsor’s Medical Monitor:

Name of Company/Sponsor Signatory:

MD Chief Medical Officer Sirtris Pharmaceuticals, Inc. 200 Technology Square Cambridge, MA 02139, USA

GCP Statement:

This study was performed in compliance with Good Clinical Practice (GCP)

Date of Report:

31-May-2012

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SRT2104 Sirtris Pharmaceuticals, Inc.

2

Clinical Study Report SRT-2104-013 31-MAY-2012

SYNOPSIS

Name of Sponsor/Company: Sirtris Pharmaceuticals, Inc.

Individual Study Table Referring to Part of the Dossier

Name of Finished Product: SRT2104

Volume:

Name of Active Ingredient:

Page:

(For National Authority Use Only)

Title of Study: A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis Investigators: Nine investigators in centers located in the United States participated in this clinical trial. The Principal Investigator was MD; Study Centers: This study was conducted at eight centers in the United States: (1); (1); (1); (1)

(2);

(1);

(1);

Publication (reference): Not applicable Studies period: 17 months Date of first subject : 07 June 2010 Date of last subject visit: 09 November 2011

Phase of development: Iia

Objectives: Primary: 1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure. 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis. Secondary: 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg, and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis. 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaquetype psoriasis.

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SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013 31-MAY-2012

Name of Sponsor/Company: Sirtris Pharmaceuticals, Inc.

Individual Study Table Referring to Part of the Dossier

Name of Finished Product: SRT2104

Volume:

Name of Active Ingredient:

Page:

(For National Authority Use Only)

Objectives (continued): Exploratory: 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. 2. To assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire 9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Menter Psoriasis Instrument, PQOL-12. Methodology: SRT-2104-013 was a randomized, double-blind, placebo-controlled, Phase IIa, multi-center study with three dosing cohorts of ten subjects each. Subjects within each cohort were randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects was dosed sequentially. Dosing in the second and third cohort did not commence until subjects in the previous cohort completed at least 28 days of dosing, and a review of safety parameters (physical examination findings, vital signs, electrocardiograms, AEs and laboratory values) was completed by an Internal Safety Review Committee (ISRC). Subjects received either SRT2104 or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety was assessed on an ongoing basis. The study consisted of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Subjects selfadministered study drug in between the clinic visits. Number of subjects (planned and analyzed): Planned: 30 (3 cohorts of 10 subjects each) A total of 40 subjects were randomized into the study as follows: • • • • •

Seven subjects (18%) received at least one dose of placebo Nine subjects (23%) received at least one dose of 250 mg SRT2104 Twelve subjects (30%) received at least one dose of 500 mg SRT2104 Eleven subjects (28%) received at least one dose of 1000 mg SRT2104 One subject (3%) received no treatment

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SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013 31-MAY-2012

Name of Sponsor/Company: Sirtris Pharmaceuticals, Inc.

Individual Study Table Referring to Part of the Dossier

Name of Finished Product: SRT2104

Volume:

Name of Active Ingredient:

Page:

(For National Authority Use Only)

Number of subjects (planned and analyzed) - continued: Analysed for demographics and baseline medical history: •

Randomized Set (RS): The RS included in all subjects randomized into the study.

Analyzed for efficacy: Efficacy Analysis Set (EAS): The EAS included all randomized subjects who received at least one dose of IP, had at least one activity measurement at baseline, at least one post-baseline study visit. Total N=39; Placebo: 7; SRT2104 250 mg: 9; SRT2102 500 mg: 12; SRT2104 1000 mg: 11. Analyzed for safety: •

Safety Analysis Set (SAF): the population for all safety analyses was the Safety Analysis Set (SAF). It included all subjects who received at least one dose of IP. Total N=39; Placebo: 7; SRT2104 250 mg: 9; SRT2102 500 mg: 12; SRT2104 1000 mg: 11. Analyzed for PK: •

•

PK Population: The PK population included all subjects who received at least one dose of SRT2104 and for whom a pharmacokinetic sample was obtained and analyzed. Total N=31; SRT2104 250 mg: 9; SRT2102 500 mg: 11; SRT2104 1000 mg: 11

Diagnosis and main criteria for inclusion: Males or females aged 18 to 80 years (inclusive) with a diagnosis of clinically confirmed, stable plaque-type psoriasis for at least 6 months involving >10% of body surface area. Test product, dose and mode of administration, batch number: SRT2104 was supplied as 250 mg capsules with matching placebo which were taken orally once daily. The SRT2104 IP was prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged as one, two or four capsules in dosing bottles. The SRT2104 manufacturing lot number was 60321B0. For the placebo study drug, 250 mg microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 IP was packed into identical appearing size 00 opaque gelatin capsules. The placebo manufacturing lot number was 60321A0. Criteria for Evaluation: Primary Endpoints • Clinical Activity: The primary clinical activity outcome was an Improvement Score using the Krueger criteria which are based on histological assessment of skin biopsies after 12 weeks of exposure • Safety and tolerability parameters following multiple doses of SRT2104 including adverse events, physical examination, clinical laboratory results, ECGs and vital signs assessments

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SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013 31-MAY-2012

Name of Sponsor/Company: Sirtris Pharmaceuticals, Inc.

Individual Study Table Referring to Part of the Dossier

Name of Finished Product: SRT2104

Volume:

Name of Active Ingredient:

Page:

(For National Authority Use Only)

Criteria for Evaluation - continued: Secondary Endpoints • Psoriasis Area and Severity Index (PASI) after 4, 8, and 12 weeks of exposure • Physician’s Global Assessment (PGA) score after 4, 8, and 12 weeks of exposure • Pharmacokinetics of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects • Pharmacodynamic effects of SRT2104 as measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation in blood samples collected on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21. Exploratory Endpoints • Genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways • Patient Health Questionnaire 9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) to assess the effects of SRT2104 on sense of depression and anxiety after 4, 8, and 12 weeks of exposure • Koo-Mentor Psoriasis Instrument, PQOL-12 to assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure Statistical Methods: Demographic data, medical history, and concomitant medications were summarized by treatment group for the randomized population. The estimated AUCs, using a Population PK approach were performed by, or under the direct auspices of, Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline; the details are described in a separate analysis plan. Since previous studies have indicated that the PK exposure of SRT2104 is relatively variable, the imputed AUCs from the active treatment were combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs were natural log transformed prior to selecting the mid-point. AUC by exposure group were summarized. Using the Efficacy Analysis Set population, the treatments were combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs were natural log transformed prior to selecting the mid-point. Point estimates and 90% exact confidence intervals (CIs) based on Blyth-StillCasella method were constructed for the proportion of responses, defined as “good” or “excellent” Krueger improvements score for each of the exposure groups and all SRT2104-treated, along with a p-value for the comparison to a historical null placebo response of 5% using a one-sided, one sample binomial test. Point estimates and 90% exact CIs were constructed for the differences between the proportion of responses, defined as “good” or “excellent” Krueger improvements score, for each of the exposure groups and all SRT2104-treated relative to the actual placebo group. The exact CI on the difference of two binomial proportions is based on the standardized statistics and inverting a 2-sided test. Point estimates and 90% exact CIs were also constructed for the secondary endpoints of clinical activity (PASI-25, PASI-50, PASI75, and PGA of “minimal” or “not clear”) for the difference between the proportion of responders for each of the exposure groups, all SRT2104-treated and the actual Placebo response. The clinical activity endpoints were also summarized by treatment group, as a secondary analysis. 5 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013 31-MAY-2012

Name of Sponsor/Company: Sirtris Pharmaceuticals, Inc.

Individual Study Table Referring to Part of the Dossier

Name of Finished Product: SRT2104

Volume:

Name of Active Ingredient:

Page:

(For National Authority Use Only)

SUMMARY-CONCLUSIONS EFFICACY, PHARMACODYNAMIC, AND PHARMCOKINETIC CONCLUSIONS: •

SRT2104 appears to have positive activity in patients with moderate to severe plaque type psoriasis

•

Across all dose groups, approximately 35% of patients treated with SRT2104 achieved good to excellent improvement on skin biopsies at Day 84, based on the Krueger scoring; skin biopsy outcomes did not show positive correlation with dose group or drug exposure levels

•

There appeared to be a dose-dependent improvement in PASI scores and PGA scores for patients treated with SRT2104 compared to placebo; mean PASI improvements approached 40% at Day 84 in the higher SRT2104 dose groups; approximately 25% of patients achieved minimal to clear PGA scores at Day 84 in the higher SRT2104 dose groups

•

No meaningful conclusions could be drawn with regard to the biomarkers FGF21 or hsCRP

•

Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104; distinct differences in Cmax and AUC were observed between the low exposure group and high exposure group

SAFETY CONCLUSIONS: •

Daily doses of 250 mg, 500 mg, and 1000 mg doses of SRT2104 were generally safe and well tolerated in subjects with moderate to severe plaque psoriasis.

•

Across all treatment groups, a total of 27 subjects (69%) experienced at least one treatment emergent AE; as the dose of SRT2104 increased, both the rate and severity of treatment-emergent AEs increased.

•

AEs leading to permanent discontinuation of IP occurred in 4 subjects (10%) in the SRT2104 treatment arms: 2 subjects (22%) in the 250 mg dose group, 1 subject (8%) in the 500 mg dose group, and 1 subject (9%) in the 1000 mg dose group.

•

Serious adverse events were reported for 3 subjects (8%): 2 subjects (22%) in the SRT2104 250 mg dose group (pneumonitis and pancreatitis) and 1 subject (9%) in the SRT2104 1000 mg dose group (increased bilirubin and AST). All SAEs were considered either likely related or related to IP.

•

No deaths occurred in the study.

•

There were some individual laboratory changes noted for indirect bilirubin and creatinine that were typically mild and self-limiting and of unclear clinical relevance.

•

There were several patients on SRT 2104 that experienced elevations in LFTs leading to study drug discontinuation. LFTs resolved after study drug discontinuation. The relevance of these changes is unclear.

•

No clinically relevant changes in vital signs or ECG parameters were observed.

Date of the report: 31-MAY-2012

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Clinical Study Report SRT-2104-013 31-MAY-2012

TABLE OF CONTENTS

VOLUME 1 1 TITLE PAGE ............................................................................................................. 1 2 SYNOPSIS .................................................................................................................. 2 3 TABLE OF CONTENTS .......................................................................................... 7 4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 13 5 ETHICS .................................................................................................................... 15 5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ............ 15 5.2 Ethical Conduct of the Study ......................................................................................... 15 5.3 Subject Information and Consent ................................................................................. 16

6 7

INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........... 16 INTRODUCTION ................................................................................................... 18 7.1 Disease and Scientific Background ............................................................................... 18 7.2 SRT2104 Non-Clinical Experience................................................................................ 19 7.3 Clinical Studies with SRT2104 ...................................................................................... 20

7.3.1

Safety .......................................................................................................... 20

7.4 Pharmacokinetics............................................................................................................ 20 7.5 Study Rationale ............................................................................................................... 20

8

STUDY OBJECTIVES............................................................................................ 21 8.1 Primary ............................................................................................................................ 21 8.2 Secondary ........................................................................................................................ 21 8.3 Exploratory ..................................................................................................................... 21

9

INVESTIGATIONAL PLAN ................................................................................. 22 9.1 Overall Study Design and Plan-Description................................................................. 22 9.2 Discussion of Study Design, Including the Choice of Control Groups ...................... 22 9.3 Selection of Study Population ........................................................................................ 22

9.3.1 9.3.2 9.3.3

Inclusion Criteria ........................................................................................ 22 Exclusion Criteria ....................................................................................... 23 Removal of Patients from Therapy of Assessment ..................................... 24

9.4 Treatments ...................................................................................................................... 25

9.4.1 9.4.2 9.4.3 9.4.4 9.4.5 9.4.6 9.4.7 9.4.8

Treatments Administered ............................................................................ 25 Identity of Investigational Product(s) ......................................................... 25 Method of Assigning Patients to Treatment Groups .................................. 26 Selection of Doses in the Study .................................................................. 26 Selection and Timing of Dose for Each Patient .......................................... 26 Blinding ...................................................................................................... 26 Prior and Concomitant Therapy .................................................................. 27 Treatment and Compliance ......................................................................... 27

9.5 Safety, Pharmacokinetic, and Pharmacodynamic Variables...................................... 27

9.5.1

Safety, Pharmacodynamic, and Pharmacokinetic Measurements Assessed 27

9.5.2 9.5.3

Appropriateness of Measurements .............................................................. 35 Efficacy Variable(s) .................................................................................... 35

9.5.4

Drug Concentration Measurements ............................................................ 37

9.5.1.1 9.5.1.2

Study Schedule ...................................................................................................... 30 Safety Assessments ................................................................................................ 32

9.5.3.1

Pharmacodynamic (PD) Assessments.................................................................... 35 7

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SRT2104 Sirtris Pharmaceuticals, Inc.

9.5.4.1

Clinical Study Report SRT-2104-013 31-MAY-2012

Pharmacokinetic (PK) Assessments ...................................................................... 37

9.5.5

Health Outcomes ......................................................................................... 38

9.6.1

Audits .......................................................................................................... 38

9.5.5.1 Patient Health Questionnaire (PHQ-9) and Hospital Anxiety and Depression Scale (HADS) 38 9.5.5.2 Psoriasis Quality of Life Questionnaire (PQOL-12).............................................. 38 9.6 Data Quality Assurance ................................................................................................. 38 9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size ..... 39

9.7.1

Statistical and Analytical Plans................................................................... 39

9.7.2

Determination of Sample Size .................................................................... 47

9.7.1.1 9.7.1.2 9.7.1.3 9.7.1.4 9.7.1.5 9.7.1.6 9.7.1.7

Planned Analyses ................................................................................................... 39 Analyses Populations ............................................................................................. 39 Hypothesis and Treatment Comparisons ............................................................... 40 Premature Withdrawal and Missing Data .............................................................. 41 Randomization and Stratification .......................................................................... 41 Imputation Strategy................................................................................................ 41 Statistical Methods ................................................................................................. 41

9.8 Changes in the Conduct of the Study or Planned Analyses ........................................ 48

9.8.1 Changes in the Conduct of the Study.......................................................... 48 9.8.2 Changes in the Planned Analyses ............................................................... 49 10 STUDY SUBJECTS ................................................................................................. 50 10.1 Disposition of Subjects ................................................................................................... 50 10.2 Protocol Deviations: Inclusion/Exclusion Criteria ...................................................... 51 10.3 Unblinding ....................................................................................................................... 51

11 EFFICACY, PHARMACODYNAMIC, PHARMACOKINETIC, AND HEALTH OUTCOMES EVALUATION ....................................................................................... 52 11.1 Data Sets Analyzed ......................................................................................................... 52 11.2 Demographic and Other Baseline Characteristics ...................................................... 52

11.2.1 Demographic Characteristics ...................................................................... 52 11.2.2 Medical and Surgery History ...................................................................... 53 11.2.3 Concomitant Medications ........................................................................... 54

11.3 Measurements of Treatment Compliance .................................................................... 55 11.4 Efficacy Results and Tabulations of Individual Subject Data .................................... 56

11.4.1 Clinical Activity Results ............................................................................. 56 11.4.1.1 11.4.1.2 11.4.1.3 11.4.1.4 11.4.1.5

Results of Primary Analyses .................................................................................. 56 Psoriasis Area and Severity Index (PASI) ............................................................. 59 Physicians Global Assessment (PGA) ................................................................... 63 Use of Rescue Medications.................................................................................... 66 Biomarkers: hsCRP and FGF21............................................................................. 66

11.4.2 Drug Dose, Drug Concentration, and Relationships to Response .............. 67 11.4.3 By-Subject Displays ................................................................................... 67 11.4.4 Efficacy, Pharmacodynamic, and Pharmacokinetic Conclusions ............... 67 11.5 Health Outcomes............................................................................................................. 69

11.5.1 11.5.2 11.5.3 11.5.4

Patient Health Questionnaire (PHQ-9) ....................................................... 69 Hospital Anxiety and Depression Scale (HADS) ....................................... 70 Psoriasis Quality of Life Questionnaire (PQOL-12) .................................. 71 Health Outcomes Conclusions .................................................................... 72 8

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SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013 31-MAY-2012

11.6 Gene Expression Data .................................................................................................... 73

12 SAFETY EVALUATION........................................................................................ 76 12.1 Extent of Exposure ......................................................................................................... 76 12.2 Adverse Events (AEs) ..................................................................................................... 76

12.2.1 12.2.2 12.2.3 12.2.4

Brief Summary of Adverse Events ............................................................. 76 Display of Adverse Events ......................................................................... 77 Analysis of AEs .......................................................................................... 77 Listing of Adverse Events by Subject ......................................................... 79

12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events ....... 80

12.3.1 12.3.2 12.3.3 12.3.4

Deaths ......................................................................................................... 80 Other Serious Adverse Events .................................................................... 80 Other Significant Adverse Events ............................................................... 80 Pregnancies ................................................................................................. 80

12.4 Clinical Laboratory Evaluations ................................................................................... 81

12.4.1 Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value ........................................................................................ 81 12.4.2 Evaluation of Each Laboratory Parameter .................................................. 81

12.4.2.1 Laboratory Values over Time ................................................................................ 81 12.4.2.2 Individual Subject Changes ................................................................................... 81 12.5 Vital Signs, Physical Findings and Other Observations Related to Safety ............... 83

12.5.1 Vital Signs................................................................................................... 83 12.5.2 Electrocardiograms ..................................................................................... 83

12.6 Safety Conclusions .......................................................................................................... 83

13 DISCUSSION AND OVERALL CONCLUSIONS .............................................. 85 14 TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT ...................................................................................................................... 87 14.1 Demographic Data .......................................................................................................... 87 14.2 Efficacy Data ................................................................................................................... 88 14.3 Safety Data ...................................................................................................................... 89

14.3.1 Displays of Adverse Events ........................................................................ 90 14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events............ 91 14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events.......................................................................................................... 92 15 REFERENCE LIST ................................................................................................. 96 16 APPENDICES .......................................................................................................... 98 16.1 Study Information .......................................................................................................... 98

17 STUDY RELATED INDICIES ............................................................................ 125 17.1 17.2 17.3 17.4 17.5 17.6 17.7

Psoriasis Area and Severity Index (PASI) .................................................................. 125 Physician’s Global Assessment (PGA) ........................................................................ 126 Patient Health Questionnaire (PHQ-9) – Sample Questionnaire ............................. 128 Hospital Anxiety and Depression Scale (HADS)........................................................ 129 Psoriasis Quality of Life Questionnaire (PQOL-12).................................................. 130 Recommendations for Meals ....................................................................................... 132 Population PK Modeling .............................................................................................. 133

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Clinical Study Report SRT-2104-013 31-MAY-2012

VOLUME 2 14 TABLES FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT 14.1 Demographic Data 14.2 Efficacy Data 14.3 Safety Data 14.3.1 Displays of Adverse Events 14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events 14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 14.3.4 Abnormal Laboratory Value Listing (each subject) 15 REFERENCE LIST VOLUME 3 16 APPENDICES 16.1 Study Information 16.1.1 Protocol and Protocol Amendments 16.1.2 Sample Case Report Form 16.1.3 List of IECs or IRBs 16.1.4 List and Description of Investigators and Other Important Participants in the Study 16.1.5 Signatures of Principal or Coordinating Investigator(s) 16.1.6 Listing of Patients Receiving Test Drug(s) 16.1.7 Randomization Scheme and Codes 16.1.8 Audit Certificates 16.1.9 Documentation of Statistical Methods 16.1.10 Documentation of Inter-laboratory Standardization Methods and Quality Assurance Procedures 16.1.11 Publications Based on the Study 16.1.12 Important Publications Referenced in the Report 16.2 Patient Data Listings 16.2.1 Discontinued Patients 16.2.2 Protocol Deviations 16.2.3 Patients Excluded from the Efficacy Analysis 16.2.4 Demographic Data 16.2.5 Compliance and/or Drug Concentration Data 16.2.6 Individual Efficacy Response Data 16.2.7 Adverse Event Listings 16.2.8 Listing of Individual Laboratory Measurements by Patient 16.3 Case Report Forms 16.3.1 CRFs for Deaths, Other Serious Adverse Events and Withdrawals for AE 16.3.2 Other CRFs Submitted 16.4 Individual Patient Data Listings 10 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Clinical Study Report SRT-2104-013 31-MAY-2012

LIST OF IN-TEXT TABLES Table 5.1-1 List of IRBs for SRT-2104-013 ...................................................................... 15 Table 6.0-1 List of Clinical Study Sites for SRT-2104-013 .............................................. 16 Table 6.0-2 Administrative Information for SRT-2104-13 ............................................... 17 Table 9.5.1-1 Schedule of Events for SRT-2104-013 ....................................................... 29 Table 9.5.1.2.2-1 Clinical Laboratory Assessments for SRT-2104-013 ............................. 34 Table 9.5.3.1.1-1 Krueger Criteria for Skin Biopsy1 .......................................................... 36 Table 9.7.1.7.3-1 Laboratory Values of PCI Range ........................................................... 45 Table 9.7.1.7.3-1 Laboratory Values of PCI Range (continued) ........................................ 45 Table 9.7.1.7.3-2 Vital Signs Values of PCI Range ........................................................... 46 Table 9.7.1.7.3-3 Vital Signs Change from Baseline Values of PCI Range ....................... 46 Table 9.7.1.7.3-4 ECG Values of PCI Range ..................................................................... 46 Table 9.7.1.7.3-5 ECG Change from Baseline Values of PCI Range................................. 47 Table 9.7.2 Sample Size Sensitivity Modelling ................................................................ 48 Table 10.1-1 Summary of Subject Disposition (Randomized Set Population, N=40) .... 50 Table 10.1-2 Reasons for Withdrawal by Subject (Randomized Set Population, N=40) 50 Table 10.2-1 Subjects with Inclusion/Exclusion Criteria Deviations (Randomized Set Population, N=40) .................................................................................................................. 51 Table 11.1-1 Summary of Analysis Populations (Randomized Set Population, N=40) .. 52 Table 11.2.1-1 Summary of Demographic Characteristics (Randomized Set Population, N=40) 53 Table 11.2.3-1 Summary of Concomitant Medications by ACT Level 2 Classification Received by >1 Subjects Across Treatment Groups (Randomized Set Population, N=40) ... 55 Table 11.4.1.1-1 Summary of the Improvement Score based on the Krueger Criteria with Comparison to Historical 5% Placebo Rate Actual Visita: Day 84 (Efficacy Analysis Set Population) 57 Table 11.4.1.1-2 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo – Actual Visita: Day 84 (Efficacy Analysis Set Population)......................................................................................... 58 Figure 11.4.1.1-1 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo - Day 84 (Efficacy Analysis Set Population) 58 Table 11.4.1.2-1 Summary of Percent Change from Baseline for PASI Scores (Total Score) (Efficacy Analysis Set Population) ............................................................................. 60 Table 11.4.1.2-2 Proportion of Subjects with Clinical Activity in the PASI score(≥PASI 25, ≥PASI 50, ≥PASI 75) (Efficacy Analysis Set Population) ............................................. 61 Table 11.4.1.2-3 Summary of Results of Repeated Measures Analysis of PASI Score (Efficacy Analysis Set Population)......................................................................................... 62 11 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Clinical Study Report SRT-2104-013 31-MAY-2012

Table 11.4.1.6-1 Summary of FGF21 and hsCRP Change from Baseline (Efficacy Analysis Set Population) ........................................................................................................ 66 Table 11.4.2-1 Summary of SRT2104 Pharmacokinetic Parameters by Treatment (PK Population) 67 Table 11.5.1-1 Summary Statistics of PHQ-9 Total Score Change from Baseline (Efficacy Analysis Set Population) ........................................................................................................ 69 Table 11.5.2-1 Summary Statistics of HADS Depression Score - Change from Baseline (Efficacy Analysis Set Population)......................................................................................... 70 Table 11.5.2-2 Summary Statistics of HADS Anxiety Score - Change from Baseline (Efficacy Analysis Set Population)......................................................................................... 71 Table 11.5.3 Summary Statistics of the PQOL-12 Total Score Change from Baseline on Visit Day 84 (Efficacy Analysis Set Population) ................................................................... 71 Table 11.6-1 Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 1 of 3) ....................................... 73 Table 11.6-1 Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 2 of 3) ....................................... 74 Table 11.6-1 Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 3 of 3) ....................................... 75 Table 12.1-1 Summary of SRT2104 Exposure (Safety Analysis Set Population)........... 76 Table 12.2.1-1 Overall Summary of AEs (Safety Analysis Set Population) ...................... 77 Table 12.2.3-1 Summary of AEs Regardless of Relationship to Treatment in >1 Subject (Preferred Term) Across Treatment Groups (Safety Analysis Set Population) ..................... 78 Table 12.2.4-1 Summary of Treatment-Related (Possibly Related and/or Related AEs (Safety Analysis Set Population) ............................................................................................ 79 Table 12.3.2-1 Subjects with SAEs Reported for Study SRT-2104-013 (Safety Analysis Set Population) 80 Table 12.3.3-1 Subject with AEs Leading to Permanent Discontinuation of IP (Safety Analysis Set Population) ........................................................................................................ 80 Table 12.4.2-1 Summary of Subjects with Clinical Chemistry Values Reported as AEs (Safety Analysis Set Population) ............................................................................................ 82 LIST OF IN-TEXT FIGURES Figure 11.4.1.2-1 Plot of Mean ( +/- SE) Percent Change from Baseline in PASI Total Score vs. Time (Efficacy Analysis Set Population) ............................................................... 61 Figure 11.4.1.2-2 Plot PASI LS Mean Difference (90% CI) between SRT2104 Treatment Groups and Placebo by Visit (Efficacy Analysis Set Population)......................................... 62

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4

Clinical Study Report SRT-2104-013 31-MAY-2012

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

AE ALT AST AUC BMI C CD CI Cmax CPMS CR CRA CRP CRF CRO CSR CTC CYP DBP DSM-IV DSS EAS EAE ECG FAS FGF21 FOXO GCP GSK HADS HCV HIV hr hsCRP ICF IEC IL IP IRB ISRC IV LOCF LPS NAD MedDRA NCI NCoR

Adverse Event Alanine Aminotransferase Aspartate Aminotransferase Area Under the Plasma Concentration Time Curve Body mass index Degrees Celsius Compact disc Confidence Interval Maximum (plasma) Concentration Clinical Pharmacology Modeling and Simulation Calorie Restriction Clinical Research Associate C-reactive Protein Case Report Form Contract Research Organization Clinical Study Report Common Toxicity Criteria Cytochrome P450 enzymes Diastolic Blood Pressure Diagnostic and Statistical Manual of Mental Disorders Dextran Sulphate Sodium Efficacy Analysis Set Experimental Autoimmune Encephalitis Electrocardiogram Full Analysis Set Fibroblast Growth Factor 21 Forkhead Transcription Factors Good Clinical Practice GlaxoSmithKline Hospital Anxiety and Depression Scale Hepatitis C Virus Human Immunodeficiency Virus Hour High sensitivity C-reactive protein Informed consent form Independent Ethics Committee Interleukin Investigational Product Institutional Review Board Internal Safety Review Committee Intravenous Last Observation Carried Forward Lipopolysaccharide Nicotinamide adenine dinucleotide Medical Dictionary for Regulatory Activities National Cancer Institute Nuclear Receptor Co-repressor 13

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NF NFκβ NOAEL PASI PCI PD PE PGA PGC-1α PGx PHQ-9 PK PPS PQOL-12 PT PUVA QOL QTc QTcB QTcF RS SAE SAF SBP SIRT SIRT1 SRT2104 SD SOC SUSAR T2DM TGF TNF ULN UVB WBC

Clinical Study Report SRT-2104-013 31-MAY-2012

QTc method calculated on the Nihon Kohden products: QTc = QT +(1000-RR)/7 [msec] Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells No Observable Adverse Effect Level Psoriasis Area and Severity Index Potential Clinical Importance Pharmacodynamics Physical exam Physician’s Global Assessment PPAR Gamma Coactivator-1α Pharmacogenetics Patient Health Questionnaire Pharmacokinetics Per-Protocol Analysis Set Koo-Menter Psoriasis Quality of Life Instrument Preferred term Psoralen and Ultraviolet Light A Quality of Life QT interval corrected for heart rate QT interval corrected for heart rate using Bazett’s formula QT interval corrected for heart rate using Fridericia’s formula Randomized set Serious Adverse Event Safety Analysis Set Systolic Blood Pressure Silent Information Regulator Transcript; Sirtuin Sirtuin Enzyme 1 A SIRT1 Activator Standard Deviation System organ class Suspected Unexpected Serious Adverse Reaction Type 2 diabetes mellitis Transforming Growth Factor Tumor Necrosing Factor Upper Limit of Normal Ultraviolet light B White Blood Cell

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5

ETHICS

5.1

Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, one protocol amendment and Informed Consent Form (ICF) were submitted for approval to the Institutional Review Boards (IRBs) associated with the participating clinical study sites (Section 6). The IRBs used in this study are listed in Table 5.1-1. Table 5.1-1

List of IRBs for SRT-2104-013

IRB Information

Associated Clinical Study Site(s)

The original protocol (Version 2.0, dated 19 March 2010) and the one protocol amendment (Amendment number 1.0, dated 22 October 2010), are provided in Appendix 16.1.1. The ICF and letters of approval from the IRBs are provided in Appendix 16.1.3. 5.2

Ethical Conduct of the Study

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki (version October, 2008), and the relevant regulations under 21 CFR parts 312, 50 and 56. This study was also conducted in compliance with the study protocol and designated Standard Operating Procedures (SOPs). 15 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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5.3

Clinical Study Report SRT-2104-013 31-MAY-2012

Subject Information and Consent

Potential subjects were provided with the ICF for their review during the Screening Visit. Following an explanation of the nature and requirements of the study, a signed ICF was obtained from each potential subject prior to performing any study related procedures. 6

INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

Sirtris Pharmaceuticals, Inc., a GSK Company, 200 Technology Square, Cambridge, MA 02139, USA (hereafter referred to as Sirtris) sponsored this clinical study at eight study sites, listed in Table 6.0-1. Table 6.0-1

List of Clinical Study Sites for SRT-2104-013

Primary Investigator

Site Number

Site Address

(Until 5/16/11)

MD

As the Sponsor, Sirtris was responsible for planning and appropriate outsourcing in order to conduct and report the results of the SRT-2104-013 study. The administrative information for the study is presented in Table 6.0-2. Curricula vitae of the Principal Investigator is provided in Appendix 16.1.4. 16 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Table 6.0-2

Clinical Study Report SRT-2104-013 31-MAY-2012

Administrative Information for SRT-2104-13

Name Canfield Scientific, Inc.

Eliassen Group

GlaxoSmithKline Simbec Research Limited Quest Diagnostics Clinical Trials

Address 253 Passaic Avenue Fairfield, NJ 07004-2524 30 Audubon Road Wakefield, MA 01880 and 603 West Street Mansfield MA 02048 5 Moore Drive RTP, NC 27712 Merthyr Tydfil Ind. Park Cardiff Road Merthyr Tydfil South Wales, CF48 4DR UK 26081 Avenue Hall #150 Valencia, CA 91325 USA

Responsibilities Photography Case Report Form (CRF)/ Data Management Statistical Analysis PK/FGF-21 Analysis Central Laboratory Skin Biopsy

Biopsy Laboratory Bilcare GCS Trio Clinical Resourcing an Aptiv Solutions Company

300 Kimberton Road Phoenixville, PA 19460-2123 8045 Arco Corporate Drive, Ste 200 Raleigh, NC 27617

MD, MPH CRA CRA CRA

SRT2104 Manufacturing/ Packaging/ Labeling/ Shipping Medical Writing – CSR SAE Medical Monitor

PharmHandClinical Consulting, LLC 15 Monarch Lane Freehold, NJ 07728 Dyad Systems, LLC 222 Third Street, Ste 3211 Cambridge, MA 02142 Moon Ridge Clinical 25113 S Ridge Rd Beavercreek, OR 97004

Monitor/ Site

&

Monitor/ Site Monitor/ Site

CRA

Monitor/ Site

CRA

Monitor/ Site

and

&

Sirtris ensured that the Investigational Product (IP) and placebo were manufactured and prepared in accordance with Good Manufacturing Practice (GMP). The IP and matching placebo capsules were manufactured, packaged and labeled by Bilcare GCS. (Table 6.0-2) and were stored either in the institutional pharmacy or in the clinic under prescribed storage conditions (at 15 to 25°C protected from light).

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7 INTRODUCTION Members of the sirtuin (silent information regulator transcript [SIRT]) family of nicotinamide adenine dinucleotide (NAD) dependent protein deacetylases, which belong to class III histone/protein deacetylases (HDACs), have emerged as important regulators of chronic inflammatory diseases, cancer, and aging [Lavu 2008; Michan 2007]. The founding member, yeast silent information regulator 2 (ySIR2), the homologue of human sirtuin 1 (SIRT1), is essential for maintaining silent chromatin via the deacetylation of histones. There are seven human sirtuins (SIRT1 to SIRT7) with different subcellular compartmentalization and downstream targets [Blander 2004]. SIRT1 is predominantly nuclear and is upregulated in tissues of calorie restricted (CR) animals [Cohen 2004]. It has been shown that SIRT1 plays an important role in a wide variety of cellular processes, including stress resistance, metabolism, apoptosis, senescence, differentiation, and aging [Michan 2007]. A number of cellular substrates for SIRT1 have been identified including PGC-1α, NCoR, p300, NF B, FOXO, and p53 [Lavu 2008]. In particular, SIRT1 may participate in the regulation of myogenesis, mitochondrial biogenesis and glucose uptake, suggesting a possible role in skeletal muscle function and inflammatory conditions [Lavu 2008; Freyssenet 2007; Breen 2008]. SRT2104 is a potent selective small molecule activator of SIRT1, being developed to treat a number of inflammatory conditions, including psoriasis, inflammatory bowel disease (IBD), and uveitis; metabolic disorders including diabetes; and other diseases associated with aging. 7.1 Disease and Scientific Background Psoriasis is a chronic inflammatory skin disorder that impacts approximately 2-3% of the world’s population. [Schon 2005; Koo J 1996]. It is typically characterized by sharply demarcated, raised, erythematous plaques covered by silvery white scales. Psoriasis impacts both the physical and emotional well-being of the patient. Its effect on quality of life is comparable to that of other chronic medical disorders [Rapp 1999]. Significant unmet medical need remains for safe, effective, and convenient treatments. Psoriasis is a complex, immune-mediated disease in which T-lymphocytes, neutrophils, and dendritic cells play a major role. Numerous cytokines are over-expressed in psoriatic skin lesions including TNF-α, IL-17, and IL-23 [Krueger JG 2007]. Several growth factors are also over-expressed including transforming growth factor type alpha (TGF-α). The result is an epidermis characterized by hyperproliferation, inflammatory cell infiltrates, and vascular changes. Current treatments are primarily geared at reducing the excessive cellular proliferation and/or blocking the inflammatory response. One novel therapeutic approach to treating psoriasis and other diseases of inflammation has come from the study of aging and calorie restriction (CR). CR is a dietary regimen in which 30%-40% fewer calories than those required to maintain ideal body weight are consumed and is associated with SIRT1 activation. It has been demonstrated that CR extends lifespan in lower organisms and mammals and improves a number of metabolic and inflammatory parameters [Heilbronn 2003; Roth 2001, Fontana 2009]. As such the molecular components of the aging pathways downstream of CR may provide relevant intervention points for the development of therapeutic drugs to treat inflammatory and metabolic disease [Weindruch 2001; Ingram 2006]. 18 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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7.2 SRT2104 Non-Clinical Experience SRT2104 has shown efficacy following once daily oral administration in a number of in vivo inflammation models including LPS-induced TNF-α production, dextran sulphate sodium (DSS) - and trinitrobenzesulphonic acid-induced colitis, cecal ligation and puncture-induced sepsis as well as in experimental autoimmune encephalomyelitis (EAE). The efficacy of SRT2104 in these inflammation studies was seen at doses of 10 – 300 mg/kg/day given orally once daily for five to twenty eight days depending on the model studied. In the DSS and EAE models SRT2104 was given therapeutically, that is after the diseases had been induced in the mice. SRT2104 was tested in vitro in counter-receptor binding studies and showed no significant inhibitory activity against 39 common receptors. SRT2104 was not an inhibitor of five major cytochrome P450 isoforms tested (CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), and is not a significant inducer of cytochrome P450 isoforms CYP1A and CYP3A4 at the concentrations tested. The non-clinical safety of SRT2104 was investigated in the Ames and mouse micronucleus genetic toxicology models, and in safety pharmacology studies in rats and dogs. SRT2104 was not genotoxic at the doses investigated. No central nervous system (CNS), cardiovascular system (CVS), or pulmonary effects were observed in the safety pharmacology studies at the doses tested (300-2000 mg/kg). SRT2104 was dosed up to 2000 mg/kg/day in two species (rat and dog) for 28 days. The compound was well tolerated at all doses in both species. SRT2104 was also dosed in rat and dog for 90 days. In the 90 day studies no toxicologically relevant adverse events (AEs) were seen at the highest doses tested in rats (2,000 mg/kg/day males, 1,000 mg/kg/day females) and in dogs (300 mg/kg/day in fed males and females). In the 90 day rat study there were reductions in mean body weights primarily due to a reduction in food consumption during the first week of the study. There were reversible increases in bilirubin in both male and female rats with no corresponding histopatho-logical changes in the liver. Minor histopathology findings of increased acinar cell apoptosis in the pancreas and accumulation of amorphous material in the basal pits of the stomach were judged to be non-adverse since neither were associated with overt degenerative changes and/or were also seen in control rats. In the 90 day dog study there were mild, reversible increases in serum total/direct/indirect bilirubin in males and females at 300 mg/kg/day and reversible mild increases in serum alkaline phosphatase (males) or cholesterol (females) at 300 mg/kg/day. The increased serum bilirubin levels corresponded with pigment accumulation in the canaliculi of the liver on Day 91 for the 100 and 300 mg/kg/day males and females. However, the pigment accumulation and increased serum bilirubin, suggestive of impaired excretion or stasis, were not associated with any microscopic effect (degeneration or necrosis) on bile duct epithelium or hepatocytes. Furthermore, the clinical pathology results were reversible and well within the normalized historical control ranges. The findings seen in the 90 day studies reflect what was seen in the 28 day studies with an increase in bilirubin being the most notable finding in both the dog and rat studies. The stasis finding at 2000 mg/kg/day in female dogs was judged to be adverse in the 28 day study but not adverse in the 90 day study due to the 19 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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observation that there was no progression from 28 to 90 days and no evidence of necrosis, inflammation or any damage associated with the stasis. From a safety perspective, the 1000 mg/day dose, the highest dose tested in this SRT-2104013 protocol, was supported by the pre-clinical safety toxicology package and by the cumulative human safety experience gathered to date. From the pre-clinical 90-day toxicology studies, the safety intervals are 1.3-3.6 based on Cmax and 1.9-6.8 based on AUC at the NOAELs. There were no adverse findings at the highest doses tested in the 90-day studies so these safety intervals may be an under-estimate of the true values. 7.3

Clinical Studies with SRT2104

7.3.1 Safety As of 30 June 2011, a total nine clinical studies have been completed using SRT2104: seven Phase I studies, one Phase IIa study, and one Phase II study. Of the 446 subjects randomized into these completed studies, 331 subjects have been exposed to at least one dose of SRT2104, including 119 healthy subjects, 17 of whom were elderly (60 to 80 years of age), and 212 subjects with Type 2 Diabetes Mellitus (T2DM). The most frequently observed AEs occurring in more than 20% of subjects who received at least one dose of SRT2104 2000 mg, (the highest dose proposed to be used in future clinical studies) in completed studies were: headache (22%), nausea (11%), and nasopharyngitis (6%). The rates of these AEs were comparable to the placebo group. No dose-limiting AEs have been observed to date, and no deaths considered related to SRT2104 have occurred. Seven serious adverse events (SAEs) have occurred, two of which (pneumonitis and pancreatitis) have been assessed as possibly related to SRT2104 by the investigator. 7.4 Pharmacokinetics The pharmacokinetic parameters of SRT2104 are well characterized in healthy human volunteers. From the clinical studies conducted to date, SRT2104 exposure (in terms of AUC and Cmax) increases in a dose-dependent (but not fully proportional) manner from 30 to 2000 mg in the fasted state and from 250 mg to 2000 mg in the fed state. There is no effect of gender on exposure, nor is there any difference between capsule and suspension formulations. There is, however, a pronounced food effect (2-4 fold increase in bioavailability), which has been noted at multiple dose levels. Bioavailability varies according to dose and feeding state. In subjects given a single dose of 2000 mg, the bioavailability is approximately 5% in the fasted state and 14% in the fed state. In subjects given a single dose of 500 mg in the fed state, the bioavailability is 26% in males and 31% in females. Drug accumulation is observed after repeat administration of SRT2104, where an approximate two-fold increase in AUC and 1.5-fold increase in Cmax is observed after dosing 2000 mg daily for seven days. Exposure across studies has been relatively comparable when dose and feeding state are the same. 7.5 Study Rationale The SRT-2104-013 study was designed to investigate the effects of escalating doses of oral SRT2104 compared with placebo on clinical activity in subjects with moderate to severe plaque-type psoriasis. As discussed previously, SRT2104 is a potent small molecule activator of SRIT1. A direct role for SIRT1 in promoting keratinocyte differentiation was 20 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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elucidated [Blander 2004] and is supportive of earlier findings that resveratrol, a natural plant-derived polyphenol that has been shown to activate SIRT1, inhibited the proliferation of human keratinocytes in vitro [Holian, 2001] and suppressed angiogenesis [Brakenhielm 2001]. Taken together with the finding that SIRT1 activators are potent inhibitors of cytokine production, including TNF-α [Smith 2009], the therapeutic potential for the SIRT1 activator SRT2104 in the treatment of psoriasis were explored as part of this clinical study. We hypothesize that SIRT1 activators may demonstrate anti-psoriatic action by promoting keratinocyte differentiation, reducing inflammation and/or inhibiting angiogenesis. 8

STUDY OBJECTIVES

8.1 3.

Primary To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis.

4. 8.2 1. 2. 3. 4. 8.3 1.

2.

3.

Secondary To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg, and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque-type psoriasis. Exploratory To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. To assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire 9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the KooMenter Psoriasis Instrument, PQOL-12.

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9

Clinical Study Report SRT-2104-013 31-MAY-2012

INVESTIGATIONAL PLAN

9.1 Overall Study Design and Plan-Description SRT-2104-013 was a randomized, double-blind, placebo-controlled, Phase IIa, multi-center study with three dosing cohorts of ten subjects each. Subjects within each cohort were randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects was dosed sequentially. Dosing in the second and third cohort did not commence until subjects in the previous cohort completed at least 28 days of dosing, and a review of safety parameters (physical examination findings, vital signs, electrocardiograms, AEs and laboratory values) was completed by an Internal Safety Review Committee (ISRC). Subjects received either SRT2104 or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety was assessed on an ongoing basis. The study consisted of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Subjects self-administered study drug in between the clinic visits. Subjects were asked to sign the ICF at the Screening visit, which was to occur within 21 days prior to administration of the first dose of study drug on Day 1. Subjects who fulfilled the inclusion/exclusion criteria (Section 9.3) were eligible for randomization into the study. The dosing phase of the study, started on Day 1, subjects were randomized on approximately Day -6 to receive 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo once daily for 84 consecutive days. 9.2 Discussion of Study Design, Including the Choice of Control Groups The SRT-2104-013 study was designed to investigate if SRT2104 can demonstrate antipsoriatic action by promoting keratinocyte differentiation, reducing inflammation and/or inhibiting angiogenesis, in subjects with moderate to severe plaque-type psoriasis. SRT2104 has been well tolerated at doses up to 2000 mg/day for 28 days in subjects with T2DM. In this study, oral doses of 250 mg, 500 mg, or 1000 mg SRT2104 were administered to subjects for up to 84 days. Placebo was the control of choice for this study. The use of a placebo control served to assess if there was a difference in effectiveness and to investigate the safety profile of SRT2104 when compared to the placebo control. 9.3

Selection of Study Population

9.3.1 Inclusion Criteria Subjects were eligible for inclusion in this study only if all of the following Screening and baseline PASI criteria were met: 1. Able and willing to provide written informed consent to participate in the study. 2. Male or female aged 18 to 80 years (inclusive). 3. Had a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving >10% of body surface area. 4. Had a baseline PASI of >10. 22 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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5. Candidate for systemic psoriasis therapy, in the opinion of the investigator. 6. A female subject of child-bearing potential, was willing to use reliable contraception for the duration of the study, through the 30 day safety follow up visit (a female of childbearing potential was defined as any female, regardless of her age with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. Females with oligomenorrhea or were perimenopausal, and young females who had begun to menstruate were considered to be of child-bearing potential). 7. Willing and able to comply with the protocol for the duration of the study. 9.3.2 Exclusion Criteria Subjects were not eligible for inclusion in this study they met any of the following criteria: 1. Received systemic non-biologic psoriasis therapy or Psoralen and Ultraviolet Light A (PUVA) phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or Ultraviolet light B (UVB) phototherapy within 2 weeks prior to the Screening Visit. 2. Received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life was unknown) prior to the first dose of SRT2104. 3. Received a live vaccination within 4 weeks prior to the Screening Visit or intended to have a live vaccination during the course of the study. 4. Used any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period was prohibited. 5. Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit. 6. Received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104. 7. Active infection (e.g., sepsis, pneumonia, abscess, etc.) or at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104. 8. History of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that could not be attributed to a prior BCG inoculation. 9. Positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit. 10. Positive test for HIV antibody. 11. Abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, precluded entry into the trial. 12. A 12-lead electrocardiogram (ECG) with changes considered clinically significant on medical review including prolonged QTc intervals as defined below: • QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period) • QTcB ≥480 msec in subjects with Bundle Branch Block.

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13. Renal or liver impairment, defined as: • Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males • AST and ALT ≥ 2xULN or • Alkaline phosphatase and bilirubin > 1.5xULN (an isolated bilirubin >1.5xULN was acceptable if bilirubin was fractionated and direct bilirubin was <35%). 14. Active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which were definitively treated with standard of care approaches). 15. Pregnant or breast-feeding. Confirmation that a female subject was not pregnant was established by negative pregnancy tests at Screening and Day 1. 16. Significant history of alcoholism or drug/chemical abuse, or consumed more than 3 standard units/day of alcohol. A standard unit of alcohol was defined as 250 ml of beer, 25 ml of spirit, or 125 ml of wine. 17. History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicated their participation 18. Acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. 9.3.3 Removal of Patients from Therapy of Assessment Subjects were informed that they had the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The Investigator had the right to withdraw subjects from the study for an AE, subject request, failure to return for follow-up, administrative reasons, and/or general non-compliance with the protocol. Abnormal Liver Chemistries Subjects were to have been withdrawn during the treatment period or in the follow-up period of this study if they met one or more of the following liver chemistry thresholds designed to assure subject safety and to evaluate the liver event etiology. 1. ALT ≥3x upper limit of normal (ULN) and bilirubin ≥2x ULN. Serum bilirubin fractionation was to have been performed if it was available. If fractionation was unavailable, urinary bilirubin was to have been measured via dipstick (a measurement of direct bilirubin, which would have suggested liver injury). 2. ALT ≥5x ULN. 3. ALT ≥3x ULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia). 4. ALT ≥3x ULN that persisted for ≥four weeks. 5. ALT ≥3x ULN and could not be monitored weekly for four weeks. 6. Subjects with ALT ≥3x ULN and <5x ULN and bilirubin <2x ULN who were not exhibiting hepatitis symptoms or rash could have continued study drug as long as they could be monitored for four weeks.

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Abnormal QTc Interval on ECG Subjects were to have been withdrawn during the treatment period or in the follow-up period of this study if they met one or more of the following QTc criteria based on an average QTc value of triplicate ECGs. If an ECG demonstrated a prolonged QT interval, two more ECGs were obtained over a brief period and then the average QTc interval of the three ECGs was used to determine whether the subject should have been withdrawn: • QTcB or QTcF >500 ms or uncorrected QT >600 ms (machine or manual over read) • If a subject had bundle branch block, the criterion was QTcB or QTcF >530 msec All subjects withdrawn from the study prior to the study assessments on Day 84 underwent End of Study safety assessment. A subject who withdrew from the study or was noncompliant, could be replaced by another subject at the discretion of the Investigator, Medical Monitor, and Sponsor. The Sponsor reserved the right to terminate the study at any time for administrative reasons. 9.4

Treatments

9.4.1 Treatments Administered Study drug Study drug was dispensed to eligible subjects under the supervision of the Investigator or sub-Investigator. All subjects were provided with one dosing bottle per day that contained one, two or four capsules for oral ingestion. Subjects were instructed to store investigational product at room temperature away from direct light. A trained investigative site member administered the investigational product (IP) to subjects at the clinic visits that occurred during the dosing period (Table 9.5.1-1, Schedule of Events). On all other dosing days, subjects self-administered IP with 250 to 500 ml water, approximately 15 minutes following the consumption of a standardized meal, at the same time every dosing day. Subjects were instructed to refrain from eating or drinking anything other than water for one hour after dosing. 9.4.2 Identity of Investigational Product(s) The SRT2104 IP was prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged as one, two or four capsules in dosing bottles. The SRT2104 manufacturing lot number was 60321B0. For the placebo study drug, 250 mg microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 IP was packed into identical appearing size 00 opaque gelatin capsules. The placebo manufacturing lot number was 60321A0. All kit numbers used in this study are listed by subject according to treatment group in Listing 16.2.5.2. Acknowledgment of receipt for all blinded study drug shipments sent from Bilcare GCS. (Table 6.0-2) study drug accountability records, and dispensing records for study drug were maintained by the Investigator, designated pharmacist, or other site personnel. The drug accountability records included the study drugs’ delivery dates to the site, inventory at the site, the study drug dispensing logs, and record of return to Sirtris (or designee) or 25 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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destruction. A monitor performed study drug accountability at the site during the course of the study. 9.4.3 Method of Assigning Patients to Treatment Groups All subjects who completed the Screening procedures and who met all of the inclusion and exclusion criteria were eligible for randomization. Subjects were randomized to receive 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo in a 4:1 ratio prior to Day 1 dosing by the pharmacist using a randomization scheme prepared by Bilcare GCS (Table 6.0-2) and provided by Sirtris. Treatments were administered as follows for the duration of the study: • Arm 1: 250 mg/day administered as one 250 mg capsule (active or placebo) • Arm 2: 500 mg/day administered as two 250 mg capsules (active or placebo) • Arm 3: 1000 mg/day administered as four 250 mg capsules (active or placebo) 9.4.4 Selection of Doses in the Study In order to obtain different systemic exposures of SRT2104, three doses of SRT2104 were selected in the SRT-2104-013 study: 250 mg/day, 500 mg/day, and 1000 mg/day. Comparison of these doses will provide information regarding the pharmacokinetic/pharmacodynamic relationship for SRT2104 and investigate the possibility of a SRT2104 dose effect in the psoriatic efficacy parameters being tested. From a safety perspective, the 1000 mg/day dose, the highest dose tested in this SRT-2104013 protocol, is supported by the pre-clinical safety toxicology package and by the cumulative human safety experience gathered to date. 9.4.5 Selection and Timing of Dose for Each Patient Subjects were randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects was dosed sequentially. Dosing in the second and third cohort did not commence until subjects in the previous cohort completed at least 28 days of dosing, and a review of safety parameters was completed by an ISRC. Subjects received either SRT2104 or matching placebo once daily for 84 days. Study drugs were administered orally with 250 to 500 ml water, approximately 15 minutes following the consumption of a standardized meal, at the same time every dosing day. Subjects were instructed to refrain from eating or drinking anything other than water for one hour after dosing. 9.4.6 Blinding This randomized, double-blind, placebo-controlled trial had three dosing cohorts. Subjects within each cohort were randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. The randomization schedule was prepared by Bilcare GCS (Table 6.0-2); subjects were assigned to study treatment accordingly. SRT2104 and placebo capsules were identical in appearance. The study site was supplied with individual unblinding envelopes that contained the randomization sequence, treatment kit number, treatment group, and description of the treatment. The unblinding envelopes were stored in a restricted area according to the institution’s procedures. All study team, site personnel and subjects were blinded with respect to the subjects’ dosing assignment. An independent data analysis team received 26 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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unblinded treatment information for incorporation into the ISRC reports. ISRC members were also unblinded to treatment arm. If it was medically imperative to know the dosing assignment that the subject was receiving, the Investigator was to contact the Medical Monitor and discuss the rationale for breaking the blind. If the Medical Monitor agreed and the blind was broken for a subject, the Investigator was to record the date and the reasons for breaking the blind in the CRF, in the subject’s medical records, and on the opened unblinding envelope within 24 hours of the code break. If the Investigator exercised due diligence and was unable to locate the Medical Monitor, or if the clinical situation was such that immediate action was warranted, the Investigator could contact the pharmacist on duty at the study site to break the blind. 9.4.7 Prior and Concomitant Therapy Subjects were not to have received an IP within 30 days of the first dosing day in this study. Subjects were not to have used prescription or nonprescription drugs and herbal and dietary supplements within seven days prior to the start of this trial, unless the medication was deemed not to interfere with study procedures or to compromise subject safety. No concomitant medications or herbal products were permitted during this trial, with the following exceptions: • medications administered to treat an AE. • topical Class 6 and/or 7 “rescue” corticosteroid treatment for psoriasis flares could be used, but use was limited to the face, axillae and groin regions. Subjects were instructed not to apply topical treatments to other areas, in particular the plaque being assessed for efficacy, at or near the biopsy site. • Any chronically prescribed non-psoriatic medication or herbal or dietary supplements administered at a stable dose for at least 6 weeks prior to enrollment. The use of anti-inflammatory, analgesic medications, and protein pump inhibitors was prohibited. If the Investigator wanted to initiate therapy with a prescription medication (e.g., in the event of a newly diagnosed medical condition) during the dosing period, s/he contacted the Medical Monitor to discuss the new therapy prior to initiating it. All medications that were administered during the study were recorded in the source documents and on the CRF. 9.4.8 Treatment and Compliance Study drug was administered by site personnel at the clinic visits that occurred during the dosing period (Table 9.5.1-1, Schedule of Events) and compliance on these dosing days was assessed by visual examination of the subject’s mouth after administration. For assessment of compliance on all other dosing days, all bottles of study drug given to a subject, including all unused capsules, were returned to the study site. Treatment compliance was assessed by questioning the subject regarding compliance and by counting all returned, unused capsules. 9.5 Safety, Pharmacokinetic, and Pharmacodynamic Variables 9.5.1 Safety, Pharmacodynamic, and Pharmacokinetic Measurements Assessed A schematic diagram of the study design is provided in Figure 9-1; study assessments are listed in Table 9.5.1-1. Details of procedures performed during the study are provided herein and in the protocol (Appendix 16.1.1). 27 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Placebo X 84 days (N=2)

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Table 9.5.1-1 Schedule of Events for SRT-2104-013 Clinic Visit Number Study Day(s)

Screening 1 2 -21 to -6 18 Assessments:

3 14

Visits During Dosing 4 5 6 7 28 42 56 70

8 8410

Follow Up 114

Informed Consent Medical History1 X Viral Serology X Photographs (total body surface area X X X X involvement) 2 Randomization X Investigational Product Dispensed X X X Physical Examination3 (including height at X X X X X X Screening and weight at all subsequent visits) Vital Signs X X X X X X X X X Chest X-Ray X 12-lead ECG X X X X X Clinical Chemistry/Hematology4 X X X X X X X X X Urinalysis X X X X X X X X X Pregnancy Test5 X X X X X X Tuberculosis Test X AE/Concomitant Medication Assessment X X X X X X X X PK Sampling6 X X X PASI & PGA X X X X X QOL assessments (PHQ-9, HADS, PQOL-127) X X X X Biomarkers X X X X Pharmacogenetics Sample9 X Skin Biopsy (Immunohistochemistry and Gene X X Expression Profiling) 1. Medical events occurring prior to the first dose were collected on the medical history CRF. AEs occurring after the first dose were recorded on the AE CRF. AEs and concomitant medications were followed for 30 days after the last dose of study drug. 2. Subjects were randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of investigational product. 3. A complete physical examination (PE) was conducted at the Screening Visit. A symptom-driven, directed PE was performed as needed at all other timepoints. 4. See Section 9.5.1.2.2 for a complete listing of safety lab parameters measured/analyzed. Lipid profiling and coagulation studies were performed on fasting samples at Screening, and on Days 1, 42 and 84 only. 5. Serum pregnancy test was performed at Screening; urine screen for pregnancy at all other timepoints. 6. PK sampling was performed according to the schedule described in Section 9.5.4.1. 7. PQOL-12 was performed on Days 1 and 84 only 8. The investigator could at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1. 9. See Appendix 2 of the Protocol for a description of the pharmacogenetic assessment. 10. Subjects withdrawing from the study prior to the study assessments on Day 84 underwent all Day 84 assessments and returned for a follow-up visit 30 days following the last dose of investigational product.

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9.5.1.1 Study Schedule The SRT-2104-013 schedule of events is provided in Table 9.5.1-1. Subjects underwent Screening assessments at Visit 1 and the first dose of study drug was administered at Visit 2. Subsequent Visits occurred every 14 days for a total of 84 days for subjects to undergo scheduled assessments, and to receive more study drug. A Follow-up Visit occurred 30 days following discontinuation of IP. The assessments performed during each study visit are detailed below.

9.5.1.1.1

Visit 1 and Visit 2

Visit 1/Screening (Day -21 to Day -6) Potentially eligible subjects were given the ICF for review. Subjects had Screening assessments at the study site on the day of the Screening visit, which was conducted within 21 days prior to administration of the first dose of study drug. Prior to performing any studyrelated procedures at the Screening visit, all subjects signed and dated an ICF and assigned a unique screening number. The following procedures were performed at the Screening visit after a signed ICF had been obtained: • Medical history, drug and alcohol history, demographics • Prior/concomitant medications assessment • Physical examination (including height and body weight measurements) • Vital signs • Chest X-Ray • 12-lead ECG • Clinical laboratory tests (clinical chemistry, hematology, urinalysis, tuberculosis test, viral serology) • Pregnancy test • Eligibility determined Subjects were randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of IP. Visit 2 (Day -1 or Day 1) Randomized subjects came to the clinic on Day -1 or Day 1, as the investigator could choose to conduct a portion of the Day 1 visit procedures (exclusive of IP administration) on Day -1. The following procedures were performed: • Photograph of the body surface area affected by psoriatic lesions • Physical examination (including height and body weight measurements) • Vital signs • 12-lead ECG • Clinical laboratory tests (clinical chemistry, hematology, urinalysis) • Pregnancy test • AE assessment • Concomitant medications (prior and current documented) • PASI and PGA • QoL assessments (PHA-9, HADS, PQOL-12) • Biomarkers 30 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Pharmacogenetics sample Skin biopsy of psoriatic lesion First dose of study medication was administered after consumption of a meal; note the subjects were to follow recommendations for meals provided by the site (Appendix 17.6). Subjects received a kit containing study medication and were instructed to continue once daily dosing after breakfast, and to store the study medication under ambient conditions (between 15 and 25 ºC), protected from direct light for the remainder of the dosing period. • • •

9.5.1.1.2

Visits 3, 4, 5, 6, 7, and 8

Visit 3 (Day 14), Visit 5 (Day 42), and Visit 7 (Day 70) The following procedures were performed: • Vital signs • Clinical laboratory tests (clinical chemistry, hematology, urinalysis) • AE assessment • Concomitant medications (check for changes) • Study medication was administered after consumption of a standardized meal. Visit 4 (Day 28), Visit 6 (Day 56), and Visit 8 (Day 84) The following procedures were performed: • Photograph of the body surface area affected by psoriatic lesions • Vital signs • Prior/concomitant medication assessment • Assessment of any changes in health since the Screening visit • Physical examination (including height and body weight measurements) • Vital signs • 12-lead ECG • Clinical laboratory tests (clinical chemistry, hematology, urinalysis) • Pregnancy test • AE assessment • PK Sampling • Concomitant medications (prior and current documented) • PASI and PGA • QoL assessments (PHA-9, HADS, PQOL-12) • Biomarkers: High sensitivity C-reactive protein (hsCRP) and Fibroblast growth factor 21 (FGF21) • Skin biopsy of psoriatic lesion (Visit 8/Day 84 only) • Study medication was administered after consumption of a standardized meal. Wherever possible, based on scheduling of the subject visits, investigational product was administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times.

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9.5.1.1.3

Clinical Study Report SRT-2104-013 31-MAY-2012

Follow-Up Visit (Day 114)

The following procedures were performed: • Physical examination (including height and body weight measurements) • Vital signs • Clinical laboratory tests (clinical chemistry, hematology, urinalysis) • Pregnancy test • AE assessment • Concomitant medications (check for changes) • PASI and PGA 9.5.1.2 Safety Assessments A primary objective of the SRT-2104-013 study was to assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis. The safety assessments performed during the study are described in the following sections.

9.5.1.2.1

Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a subject administered a pharmaceutical product which does not necessarily have a causal relationship with the study drug. An AE could be any unfavorable and unintended sign (eg, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not it was considered related to the study drug. This included any newly occurring event or previous conditions that increased in severity or frequency since the administration of study drug. All AEs, SAEs, and deaths were recorded on the CRFs throughout the study from the time of first dose until the final follow-up contact. However, any SAEs assessed as related to study participation (e.g., IP, protocol-mandated procedures, invasive tests, or change in existing therapy) were recorded from the time a subject consented to participate in the study up to and including any follow-up contact. All SAEs were to be monitored until resolution or clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Any SAE that occurred at any time after completion of the study including the designated follow-up period, which the investigator considered to be related to study medication, were reported to Sirtris. The nature of each AE, date and time of onset and resolution, intensity, frequency, seriousness, relationship to study drug, action taken with study drug, other action taken, and outcome were established by the Investigator and recorded on the appropriate page of the CRF. If an AE changed in the frequency or severity, a new record of that event was initiated. Intensity for each AE was determined using the NCI CTC (Version 4.0) as a guideline wherever possible. Dose-limiting toxicities were defined as those AEs of Grade 3 or greater that were seen to occur with an evident temporal relationship to study drug administration. In those cases where NCI CTC criteria did not apply, intensity was assigned according to the following scale:

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• • • • •

Clinical Study Report SRT-2104-013 31-MAY-2012

Mild: An AE causing awareness of sign or symptom, but easily tolerated Moderate: An AE sufficiently discomforting to interfere with normal daily activities Severe: An AE preventing normal activities Life-Threatening or disabling: An AE posing an immediate risk of death Death: The event resulted in death

Causality was assigned by the Investigator according to the following categories: • Not related: No relationship between the experience and the administration of study drug; related to other etiologies such as concomitant medications or subject’s clinical state • Unlikely related: The current state of knowledge indicates that a relationship is unlikely • Possibly related: A reaction that follows a plausible temporal sequence from administration of the study drug and follows a known response pattern to the suspected study drug. The reaction might have been produced by the subject’s clinical state or other modes of therapy administered to the subject • Related: A reaction that follows a plausible temporal sequence from administration of the study drug and follows a known response pattern to the suspected study drug and could be confirmed with a positive re-challenge test or supporting laboratory data. The outcome of AEs was rated as: • Recovered/Resolved • Recovered/Resolved with sequelae • Not recovered/Not resolved • Fatal • Recovering/Resolving • Unknown An SAE was defined as any event which is: • Fatal (resulted in death) • Life threatening • Resulted in persistent or significant disability/incapacity • Required inpatient hospitalization or prolongation of existing hospitalization • Associated with a congenital anomaly/birth defect • An important medical event, defined as an event that may not have met any of the above criteria for seriousness but, based on appropriate medical judgment, it may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definitions of SAEs. Subjects were monitored by the Investigator for AEs throughout the study. Subjects were queried on AEs and evaluated for AEs by observation, physical examination or other diagnostic procedures. Subjects could also have spontaneously reported an AE. All clinically significant alterations in laboratory tests as judged by the Investigator or other clinical findings were to have been recorded as an AE. When possible, signs and symptoms indicating a common underlying pathology were to be noted as one comprehensive event. All SAEs were to have been monitored until they resolved or were clearly determined to have been due to a subject’s stable or chronic condition or intercurrent illness. Subjects 33 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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underwent a review of any new and/or follow-up of ongoing AEs and SAEs through 30 days after last dose of study drug. AEs requiring therapy were treated by recognized standards of medical care to protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines were made available to ensure the best possible treatment of an emergency situation. It was the responsibility of the Investigator to document all AEs occurring during the study. AEs reported from the time of ICF up to prior to the first dose of study drug were recorded in the Medical History CRF. AEs reported from time of administration of the first dose of study drug through 30 days following the last dose of study drug were recorded on the AE CRF and are considered treatment emergent AEs.

9.5.1.2.2

Clinical Laboratory Assessments

Safety (e.g., hematology, chemistry, and urinalysis) and screening (e.g., serum β-HCG and serology) samples were analyzed by a central laboratory. A subset of samples (e.g., PK and FGF21 samples) could be transferred for analysis to Sirtris, GlaxoSmithKline (GSK), or other designated representative working with GSK and/or Sirtris. Hematology and Clinical Chemistry: The hematology and clinical chemistry laboratory parameters are presented in Table 9.5.1.2.2-1; the time points for collection are specified in Table 9.5.1-1). Table 9.5.1.2.2-1

Clinical Laboratory Assessments for SRT-2104-013

Hematology Hemoglobin Hematocrit Red blood cell count (RBC) Red Cell Distribution Width Mean corpuscular volume Mean Corpuscular Hemoglobin Concentration Mean Corpuscular Hemoglobin Platelets White blood cell count (WBC) Complete WBC differential Clinical Chemistry Alanine aminotransferase Aspartate aminotransferase Albumin Alkaline phosphatase Amylase Bicarbonate Blood Urea Nitrogen Calcium Chloride Creatine Kinase Gamma-glutamyl transferase Lactate dehydrogenase Magnesium Phosphate Potassium Plasma Glucose Sodium Serum creatinine Total, direct, and indirect bilirubin Uric acid Activated Partial Thromboplastin Time1 Prothrombin Time/International Normalized Ratio1 Lipid Profile (Total Cholesterol, Low Density Lipoprotein, High Density Lipoprotein, Free Fatty Acids, Triglycerides)2 1. Coagulation studies were performed at Screening and on Days 1, 42 and 84 only. 2. Lipid profiles were performed in fasting samples at Screening, Days 1, 42 and 84 only.

Urinalysis: Urinalysis was performed by dipstick. If the dipstick blood and protein results were abnormal, a microscopic examination was performed.

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Pregnancy Testing: Serum β-HCG pregnancy test was performed at the Screening Visit; at all other timepoints (Table 9.5.1-1) urine screen for pregnancy was performed. Viral Serology: • Hepatitis C virus (HCV) antibody • Hepatitis B surface antigen (HbsAg) • Human Immunodeficiency Virus (HIV) 1 & 2

9.5.1.2.3

Other Safety Assessments

Other safety assessments included: • Physical examination (including height and body weight measurements) • Vital signs • Chest X-Ray • 12-lead ECG • Pregnancy test • Concomitant medications For details regarding the timing for the other safety assessments performed in this study, see Table 9.5.1-1 and Section 9.5.1.1 9.5.2 Appropriateness of Measurements Standard assessments were used in this study and were considered to be reliable measurements to evaluate safety and effectiveness of SRT2104 when compared to placebo in subjects with moderate to severe plaque-type psoriasis. In addition, novel assessments were conducted on the skin biopsy tissues, which have been used in other psoriasis trials, to identify the potential efficacy of experimental treatments. 9.5.3 Efficacy Variable(s) 9.5.3.1 Pharmacodynamic (PD) Assessments A primary objective of the SRT-2104-013 study was to assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure. The following sections discuss the PD assessments used to evaluate clinical activity of SRT2104 in subjects with moderate to severe plaque-type psoriasis.

9.5.3.1.1

Skin Biopsy Evaluation and Scoring

The primary clinical activity endpoint was the assessment of change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks as measured by an Improvement Score according to the criteria defined in Section 9.5.3.1.1. This criteria was modified based on the histology score discussed by Zaba, etal [Zaba 2007]. Skin biopsies were obtained from the same designated plaque on Days 1 and 84. A central reader at (blinded to treatment assignments) evaluated the biopsy tissue for general appearance, epidermal thickness, total inflammatory infiltrate and keratinocyte expression of K-16. RT-PCR was used to assess for expression of specific genes which could include, but was not limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL35 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPARα, PPAR-delta, and p53. Other assessments planned, but not performed were: specific cell numbers (CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells) and ICAM-l. Skin biopsies were assigned an improvement score according to the Krueger criteria defined in Table 9.5.3.1.1-1. Table 9.5.3.1.1-1

Krueger Criteria for Skin Biopsy1

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

1. Modified from Zaba, et al 2007

9.5.3.1.2

Psoriasis Area and Severity Index (PASI)

A secondary clinical activity endpoint was assessment of the PASI score to quantify the extent of psoriasis and the degree of plaque erythema, scaling and thickness on the four body areas: head, trunk, upper limbs, and lower limb. Disease assessments using the PASI score were conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. Possible scores range from 0 (no disease) to 72 (maximal disease) (See Appendix 17.1).

9.5.3.1.3

Physicians Global Assessment (PGA)

A secondary clinical activity endpoint was completion of the PGA score to quantify the effects of SRT2104 on psoriasis activity. Disease assessments using a PGA score were completed by the Investigator or designee on Days 1 (prior to first dose of IP), 28, 56, 84, and 114 (Follow-up). A 6-point grading scale of the PGA was used (See Appendix 17.2).

9.5.3.1.4

Use of Rescue Medications

The following is the permitted list of rescue medications allowed per protocol, to be used during a psoriatic flare and limited to the face, axillae, and groin only: Class 6 steroids: • Alclometasone dipropionate 0.05% cream and 0.05% ointment • Desonide 0.05% cream, 0.05% foam, 0.05% gel and 0.05% lotion • Fluocinolone acetonide 0.01% shampoo and 0.01% solution • Flurandrenolide 0.025% cream • Triamcinolone acetonide 0.025% cream and 0.025% lotion Class 7 steroids: • Hydrocortisone 0.5% cream and 0.5% ointment • Hydrocortisone 1% cream, 1% lotion and 1% ointment • Hydrocortisone 2.5% cream, 2.5% lotion and 2.5% ointment 36 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Note: Topical treatments were not allowed to be applied to areas other than those listed above, and in particular, were not allowed to be applied at out near the site of biopsy.

9.5.3.1.5

Biomarkers: hsCRP and FGF21

A secondary objective of the study was to assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque-type psoriasis. These effects were measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation. Blood samples for these biomarkers were collected on Days 1, 28, 56 and 84 and could include, but were not limited to, hsCRP and FGF21. 9.5.4

Drug Concentration Measurements

9.5.4.1 Pharmacokinetic (PK) Assessments A secondary objective of the study was to determine the PK of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis. A sparse sampling approach was used to estimate PK parameters based on a population PK model. PK measurements were required for all subjects at all participating centers. The actual dosing and sample collection times were recorded in the CRF. PK Sampling A total of five blood samples (6 ml each) were obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. In order to improve subject convenience for sampling at the later time points, the protocol provided flexible options for scheduling of most PK samples. The samples could be taken over the course of Visits 4, 6, and 8. Alternatively, multiple PK samples could be taken during one visit provided the sampling windows as described below were observed and no two samples were separated by less than 1 hour. • One pre-dose sample was collected prior to taking IP (30 minutes or less before dosing). This sample was to be collected on any one of the following: Visit 4, 6 or 8. It was recommended that the dose associated with this sample be administered in the clinic. • A single PK sample was collected in the time interval of 0.5 to 2 hours post-dose. It was recommended that the dose associated with this sample be administered in the clinic. This sample was to be collected on any one of the following: Visit 4, 6 or 8. • A single PK sample was collected in the time interval of 3 to 6 hours post-dose. This sample was to be collected on any one of the following: Visit 4, 6 or 8. • Two PK samples were collected in the time interval of 6 to 22 hours post-dose. These 2 samples were to be collected on any of the following: Visit 4, 6 or 8. PK Assessments SRT2104 PK parameters were computed for each subject. AUC of SRT2104 for a steadystate dosing interval (0 to 24 hours) was computed using population PK modeling; Cmax was based on the highest observed plasma concentration. A summary of the population PK modeling is contained in Appendix 17.7. 37 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Clinical Study Report SRT-2104-013 31-MAY-2012

9.5.5 Health Outcomes Exploratory clinical activity endpoints included assessments of the subject’s sense of wellbeing, described in the following sections. 9.5.5.1

Patient Health Questionnaire (PHQ-9) and Hospital Anxiety and Depression Scale (HADS) Assessment the effects of SRT2104 on sense of depression and anxiety in subjects with moderate to severe plaque-type psoriasis was an exploratory objective of the study. The PHQ-9, is a 9-item scale used to assesses the DSM-IV depression symptom criteria for frequency of occurrence during the previous 2 weeks. The total score ranges from 0 (no depressive symptoms) to 27 (all symptoms occurring daily). The HADS scale is a 14-item, validated self-rating instrument of symptoms of anxiety and depression. The PHQ-9 and HADS were collected at Visits 2 (Baseline/Day 1), 4 (Day 28), 6 (Day 56), and 8 (Day 84). 9.5.5.2 Psoriasis Quality of Life Questionnaire (PQOL-12) Assessment of the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis was an exploratory objective of the study. Subjects completed Part 1 of the PQOL-12, a validated measure of the quality of life at Visits 2 (Baseline/Day 1) and 8 (Day 84). 9.6 Data Quality Assurance The Sponsor, or its designated representative, conducted a clinical site visit to verify the qualifications of the investigator, inspect clinical site facilities, and inform the Investigator of responsibilities and procedures for ensuring adequate and correct study documentation. The investigator was required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. All information recorded on the electronic CRFs (eCRFs) for this study had to be consistent with the subject’s source documentation. All study data recorded on source documents were entered into the eCRFs. The study was monitored by independent clinical monitors. During the course of the study, the study monitor conducted clinical site visits to review protocol compliance, compare the eCRFs with individual subject’s medical records (source documents), assess drug accountability, and ensure that the study was being conducted according to pertinent regulatory requirements. The review of medical records was performed in a manner to ensure that subject confidentiality was maintained. A compact disc (CD) containing the eCRF entries was provided to the study sites and the Sponsor. Instances of missing or uninterpretable data were to be discussed with the investigator. Study data were entered into a secure, validated data processing system and a backup maintained. Any changes to study data were documented. 9.6.1 Audits Regulatory authorities, the IRB, and/or the Sponsor’s clinical quality assurance group could request access to all source documents, eCRFs, and other study documentation for on-site 38 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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audit or inspection. Direct access to these documents had to be guaranteed by the investigator, who was to provide support at all times for these activities. As of the date of this report, no on-site audits have been conducted for the SRT2104-013 study. 9.7

Statistical Methods Planned in the Protocol and Determination of Sample Size

9.7.1 Statistical and Analytical Plans The following analyses are those planned in the protocol (Appendix 16.1.1) and detailed in the Reporting and Analysis Plan (RAP) (Appendix 16.1.9). 9.7.1.1

Planned Analyses

9.7.1.1.1

Interim Analyses

An ISRC was utilized during the conduct of this study to assess safety and to advise on dose escalation. The membership of the ISRC and the plan for the safety data review are described in detail in the ISRC charter (see Appendix 16.1.13) Dose escalation was dependent upon the review of un-blinded safety data by an ISRC. Safety data generated for all subjects in every cohort completing at least 28 days of dosing were reviewed by the ISRC, including: demography, study termination, ECG values, vital signs, physical examination, AEs and clinical laboratory values. In the event of clinically significant AEs deemed to be of sufficient severity to pause dosing, a full analysis of all safety data would be conducted before continuing with a given dose or with dose escalation. All planned dose escalations occurred. When the last subject in a cohort completed 28 days of dosing, the data for each subject was manually entered into an electronic data capture system. The laboratory data was transferred electronically into the database. The required data for the safety review was transferred from the CRO, Eliassen (Table 6.0-2), to an independent unblinded data analysis team to prepare the data displays for the ISRC. The safety data displays were then sent to the ISRC for review. If the safety data were acceptable, any subjects still active in the current cohort continued dosing, and the ISRC authorized the initiation of dosing to the next cohort of subjects at the higher dose level.

9.7.1.1.2

Full Analyses

The final planned analyses were performed after all subjects completed the study and after database lock/unblinding occurred. 9.7.1.2

Analyses Populations

9.7.1.2.1

Randomized Set (RS)

All subjects randomized were included in the Randomized Set (RS). This is compatible with an ITT population.

9.7.1.2.2

Safety Analysis Set (SAF)

The population for all safety analyses was the Safety Analysis Set (SAF). It included all subjects who received at least one dose of IP.

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9.7.1.2.3

Clinical Study Report SRT-2104-013 31-MAY-2012

Efficacy Analysis Set (EAS)

The Efficacy Analysis Set (EAS) included all randomized subjects who received at least one dose of IP, had at least one activity measurement at baseline, and at least one post-baseline study visit.

9.7.1.2.4

Per-Protocol Analysis Set (PPS)

The Per-Protocol Analysis Population (PPS) was to include all subjects from the EAS who completed the study and were deemed to be protocol compliant. To be protocol compliant, a subject could not have any major protocol deviations which impacted the clinical activity endpoints during the study period. Protocol deviations were identified prior to unblinding and database lock.

9.7.1.2.5

PK Population

The PK population included all subjects who received at least one dose of SRT2104 for whom a pharmacokinetic sample was obtained and analyzed. 9.7.1.3 Hypothesis and Treatment Comparisons The primary objective of the SRT-2104-013 study was to assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity, based on the Krueger criteria, relative to a historical placebo response rate of 5% in subjects with moderate to severe plaque type psoriasis. This analysis was supported by an analysis of clinical activity based on actual treatment arm (actual Placebo response rate). Since previous studies indicated that the PK exposure is relatively variable, the primary objective was accomplished based on an exposure-response analysis. Using the Efficacy Analysis Set population, the treatments were combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs were natural log transformed prior to selecting the mid-point. Point estimates and 90% exact confidence intervals (CIs) based on Blyth-Still-Casella method were constructed for the proportion of responses, defined as “good” or “excellent” Krueger improvements score for each of the exposure groups and all SRT2104-treated, along with a p-value for the comparison to a historical null placebo response of 5% using a one-sided, one sample binomial test. Point estimates and 90% exact CIs were constructed for the differences between the proportion of responses, defined as “good” or “excellent” Krueger improvements score, for each of the exposure groups and all SRT2104-treated relative to the actual placebo group. The exact CI on the difference of two binomial proportions is based on the standardized statistics and inverting a 2-sided test. Point estimates and 90% exact CIs were also constructed for the secondary endpoints of clinical activity (PASI-25, PASI-50, PASI-75, and PGA of “minimal” or “not clear”) for the difference between the proportion of responders for each of the exposure groups, all SRT2104-treated and the actual Placebo response. The clinical activity endpoints were also summarized by treatment group, as a secondary analysis. 40 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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PASI scores at each time point were assessed using an estimation approach to estimate the effect of SRT2104 active treatments relative to placebo. Point estimates and corresponding 90% CIs were constructed as appropriate for comparisons (difference between the mean of each active treatment and the mean of the placebo treatment). For other subject reported outcome endpoints and safety and tolerability endpoints, descriptive statistics by treatment group were presented. No formal hypotheses were tested for these endpoints. 9.7.1.4 Premature Withdrawal and Missing Data All subjects who withdrew prematurely from the study/study drug were documented and the reason for their withdrawal recorded in this Clinical Study Report (CSR). All available data from subjects who withdrew are listed and all available planned data are included in the summaries according to the populations defined in Section 9.7.1.2. 9.7.1.5 Randomization and Stratification On entry into each of the three cohorts, the study subjects were randomized to active SRT2104, 250mg, 500 mg, or 1000 mg (depending upon the cohort) or placebo in a 4:1 ratio favoring SRT2104 using a predetermined randomization schedule. 9.7.1.6 Imputation Strategy For the clinical activity binomial endpoints, if the subject withdrew from the study due to treatment failure (coded as “Disease Progression”) any missing assessments since the date of withdraw were imputed as a non-responder with a value of zero. If the subject withdrew from the study due to reasons other than treatment failure they were excluded from the analysis with the value for the binomial response set to missing. No subjects discontinued due to “disease progression” so this imputation strategy was not utlizied. Missing values were imputed using last-observation-carried forward (LOCF) for the primary analysis of the clinical activity based on PASI-25, PASI-50, PASI-75, and PGA. 9.7.1.7

Statistical Methods

9.7.1.7.1

Study Population Analyses

Summaries of study population data used the RS analysis population; the data was presented by treatment. Disposition of Subjects The total number of subjects randomized and the total number of subjects in each of the analysis populations were summarized by treatment group and overall. The number and percentage of subjects who completed the study as well as subjects who withdrew from the study were summarized by subject status and reason for withdrawal. The reason for withdrawal was listed for subjects who prematurely discontinued the study. If a subject’s treatment blind was broken during study, the date and reason for unblinding was listed. Protocol Deviations Subjects who did not meet all inclusion and exclusion criteria were listed along with the corresponding violated criteria. Protocol exemptions were listed. 41 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Demographic and Baseline Characteristics Demographic and racial characteristics were listed and summarized, including: age, sex, race, ethnicity, height, weight and body mass index (BMI). Medical and surgical history was collected at Screening, was listed and summarized. Concomitant medications were summarized by the Anatomical Therapeutic Chemical (ATC) Level 2 classification; a subject listing was provided. The verbatim text from the medications were coded using the World Health Organization Drug Dictionary (WHO Oslo 2011) version December 08 B2.

9.7.1.7.2

Efficacy/Pharmacodynamic Analyses

Clinical Activity Analyses Analyses of clinical activity were performed on the Efficacy Analysis Set population. The primary analysis was summarized by both the low vs. high exposure groups and by the Actual treatment groups. In addition, SRT2104 dose cohorts were merged to serve as an additional group of treated subjects for all activity comparisons. Histological Assessments of Skin Biopsies of Psoriatic Lesions The primary clinical activity endpoint was the the Day 84 skin biopsy Improvement Score according to the criteria as defined in Section 9.5.3.1.1. This criteria was modified based on the histology score discussed by Zaba, etal [Zaba 2007]. Estimation of the Improvement Score Based on the Krueger Criteria A binomial response was defined for each subject according to whether the subject had an improvement score of “good or excellent improvement” (response=1) or not (response=0). Point estimates and 90% CIs were constructed for the differences between the proportion of responder, defined as “good” or “excellent” Krueger improvement score, for each of the exposure group and all SRT2104-treated relative to placebo. No formal hypothesis testing was performed. The proportion of subjects with improvement of good or excellent in each exposure group and for all SRT2104-treated were compared against a null placebo response rate of 5% using one-sided, one sample binomial tests. Psoriasis Area and Severity Index (PASI) The PASI score was assessed to quantify the extent of psoriasis and the degree of plaque erythema, scaling and thickness on the four body areas: head, trunk, upper limbs, and lower limb. (See Section 9.5.3.1.2 and Appendix 17.1). The following proportions were derived for each time point: • PASI-25: defined as the proportion of subjects who achieve a ≥ 25% reduction in PASI score from baseline • PASI-50: defined as the proportion of subjects who achieve a ≥ 50% reduction in PASI score from baseline • PASI-75: defined as the proportion of subjects who achieve a ≥ 75% reduction in PASI score from baseline 42 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Statistical Analyses of PASI Scores Estimation of Improvement based on PASI-25, PASI-50, and PASI-75 Proportions The PASI-25 (PASI-50/PASI-75) proportion was defined as the proportion of subjects who have a greater than or equal to 25% (50%/75%) reduction from baseline in the PASI score. A binomial response was defined for each subject at each visit in which PASI was collected according to whether the subject achieved a ≥ 25% (50%/75%) reduction from baseline at week 12 in the PASI score (response=1) or not (response=0). Point estimates and 90% CIs were constructed for the differences each of the exposure groups and placebo, for PASI-25, PASI-50, and PASI-75. Repeated Measures Analyses of PASI Scores A repeated measures analysis of the PASI score was performed using a mixed effects model with baseline PASI score, treatment group and time as fixed effects and subject as a random effect. Time was the repeated measures term. Point estimates and their associated 90% CIs were constructed for the differences between each active treatment and placebo at each time point. An appropriate variance–covariance structure was identified for the mixed model. Distributional assumptions underlying the analysis were assessed by examining residual plots. Normality was examined by normal probability plots and variance homogeneity was assessed by plotting the studentized residuals against the predicted values from the model. Physicians Global Assessment (PGA) Two versions of the PGA were distributed to the sites: a 6-point grading scale (see Appendix 17.2) and an older version based on a seven-point grading scale. Only the PGA from the 6point grading scaled was databased and summarized. The PGA data was listed by treatment and assessment time and indicated if the subject improved in PGA by one or more levels Three binomial response variables were defined: 1. for each subject for each visit that PGA was collected according to whether the subject achieved a PGA score of “minimal” or “clear” (response=1) or not (response=0), 2. for post baseline assessment of PGA according to whether the subject achieved an improvement of one or more levels of the PGA (response=1) or not (response=0), 3. if either #1 or # 2 were achieved (response=1) or not (response =0) Point estimates and 90% CIs were constructed for the difference between the proportion of responders for each of the exposure groups and all SRT2104-treated relative to placebo. A binomial response was defined for each subject at week 12 according to whether the subject achieved improvement in the PGA score by one or more levels (response=1) or not (response=0). Biomarkers: hsCRP and FGF21 Biomarkers assessed could include, but not limited to, hsCRP and FGF21; results were listed and summarized. Weight changes An analysis of covariance of changes from baseline in weight was performed for Day 56 and 84, with baseline weight and treatment group included in the model. 43 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Least squares means and their associated 95% CIs were constructed for the differences between each active treatment and placebo at each time point. Lipid changes An analysis of covariance of changes from baseline in lipids (cholesterol, HDL,LDL, HDL/LDL ratio, triglycerides) was performed for Day 42 and 84, with baseline weight and treatment group included in the model. Least squares means and their associated 95% CIs were constructed for the differences between each active treatment and placebo at each time point.

9.7.1.7.3

Safety Analyses

Extent of Exposure The Listing of Drug Administration included the date and time of first dose, the kit and lot numbers. The Listing of Dosing Compliance included whether the subject missed any doses while on study, number of capsules missed, and when the doses were missed. Exposure to SRT2104 was tabulated by treatment group. The table presented number of days on study, defined as number of days from date of first dose to date of last dose taken. For number of days, calculation was last dose – first dose +1. Adverse Events All AEs were coded and classified according to System Organ Class (SOC) and preferred term using MedDRA version12.0. A summary by treatment of the number and percentage of subjects reporting AEs was displayed. AEs were sorted by MedDRA SOCs, in descending order from the SOC with the highest total incidence (i.e., summed across all treatment groups) for any AE within the class to the SOC with the lowest total incidence. In the same manner, AEs were grouped by the MedDRA hierarchy level, Preferred Term (PT). A summary of AEs by severity and highest relationship was summarized. The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text was displayed for AEs. Stop date was not imputed, but the partial or complete missing start dates for AEs were imputed as follows: • Month and year known and study medication start during that month then set start equal to study medication start date • Month and year known and study medication started prior to or after that month then set start date equal to the 1st day of the month • If only year is known, and it is the same as first dose date year, assume it is the first dose date. If it is different from the first dose year, assume it is the first day of the year. • Complete AE start date (i.e., day, month and year are missing) is unknown impute start dates as the study medication start date. Any AEs leading to discontinuation of IP and/or withdrawal from the study, deaths or SAEs that occurred were listed and summarized separately. Death was defined as a subject having an AE outcome of “fatal”. Clinical Laboratory Assessments 44 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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All hematology, coagulation, and clinical chemistry values were listed for each subject who had any values of potential clinical importance (PCI) and flagged relative to the normal range and relative to the PCI value shown in Table 9.7.1.7.3-1, where applicable. For laboratory tests, that did not have criteria for PCI, a listing of values flagged relative to the normal range was produced. Table 9.7.1.7.3-1

Laboratory Values of PCI Range

Hematology Analyte White Blood Cell Count (WBC) Neutrophil Count Hemoglobin Hematocrit Platelet Count Lymphocytes Chemistry Analyte Albumin Calcium Creatinine Glucose Magnesium Phosphorus Potassium Sodium Bicarbonate (CO 2 )

Table 9.7.1.7.3-1 Liver Function Test Analyte ALT/SGPT AST/SGOT Alkaline Phosphatase T Bilirubin T. Bilirubin + ALT

Effect Low High Low High – Male High – Female High – Male High – Female Low High Low Effect Low Low High High High Low High Low High Low High Low High Low High Low High

Values of PCI Range <0.67 x LLN >1.82 x ULN <0.83 x LLN >1.03 x ULN >1.13 x ULN >1.02 x ULN >1.17 x ULN <0.67 x LLN >1.57 x ULN <0.81 x LLN Values of PCI Range <0.86 x LLN <0.91 x LLN >1.06 x ULN >1.3 x ULN >44.2 change from baseline <0.71 x LLN >1.41 x ULN <0.63 x LLN >1.03 x ULN <0.80 x LLN >1.14 x ULN <0.86 x LLN >1.10 x ULN <0.96 x LLN >1.03 x ULN <0.86 x LLN >1.14 x ULN

Unit x109/ L x109/ L x109/ L g/L g/L Ratio of 1 Ratio of 1 x109/ L x109/ L x109/ L Unit g/L mmol/L mmol/L µmol/L µmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L

Laboratory Values of PCI Range (continued) Effect High High High High High

Values of PCI Range ≥2x ULN ≥2x ULN ≥2x ULN ≥1.5xULN ≥1.5xULN T. Bilirubin + ≥2x ULN ALT

Unit U/L U/L U/L µmol/L µmol/L + U/L

All laboratory data were summarized by System International (SI) units for the analysis. Parameter values and change from baseline were summarized separately. A listing of the reference ranges for the clinical laboratory tests was provided. Urinalysis data (dipstick test results) was listed and summarized and listed along with any additional test results (e.g., blood, protein). 45 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Physical Examination Results of physical examinations (PE) conducted at each visit were listed and summarized based on PE status of normal, abnormal and not done. Vital Signs Vital signs data were listed for each subject that had values of PCI and flagged (as High or Low) relative to the normal range and relative to the PCI value shown in Table 9.7.1.7.3-2. Interval data including change from baseline were summarized. The subdivisions used to summarize the increase from baseline vital signs data by category are shown in Table 9.7.1.7.3-3. Table 9.7.1.7.3-2

Vital Signs Values of PCI Range

Table 9.7.1.7.3-3

Vital Signs Change from Baseline Values of PCI Range

Vital Signs Parameter Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP) Heart Rate

Vital Signs Parameter Systolic Blood Pressure (Change from Baseline) Diastolic Blood Pressure (Change from Baseline) Heart Rate (Change from Baseline)

Values of PCI Range <85 and >160 <45 and >100 <40 and >110

Values of PCI Range Increase ≥20 and ≥40 Decrease ≥20 and ≥40 Increase ≥10 and ≥20 Decrease ≥10 and ≥20 Increase ≥15 and ≥30 Decrease ≥ 15and ≥30

Unit mmHg mmHg bpm

Unit mmHg mmHg bpm

12-lead ECG ECG overall impressions (Normal; Abnormal – not clinically significant; Abnormal – clinically significant) were summarized. ECG parameters (heart rate, PR, QRS, QT and QTc) were summarized by treatment and visit, where QTc was expressed as QTcB or QTcF. If a site used another method for calculating QTc, such as NF, the QTc value was used to evaluate PCI values but it was not included in the Summary of ECG values. ECG values were listed for each subject with values of PCI and flagged relative to the PCI value shown in Table 9.7.1.7.3-4. When replicate assessments were performed, they were averaged prior to summarization and prior to evaluation with the PCI criteria. The subdivisions used to summarize the absolute and increase from baseline QTc interval data by category are shown in Table 9.7.1.7.3-5 Table 9.7.1.7.3-4

ECG Values of PCI Range

ECG Parameter Absolute QTc interval Increase from baseline QTc PR interval QRS interval

Values of PCI Range >450 >60 <110 and >220 <75 and >110

Unit msec msec msec msec

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Table 9.7.1.7.3-5

ECG Change from Baseline Values of PCI Range

ECG Parameter Absolute QTc interval Absolute QTc interval Absolute QTc interval Increase from baseline QTc Increase from baseline QTc

9.7.1.7.4

Clinical Study Report SRT-2104-013 31-MAY-2012

Values of PCI Range >450 to ≤480 >480 to ≤500 >500 >30 to ≤60 >60

Unit msec msec msec msec msec

Health Outcomes Analyses

Patient Health Questionnaire (PHQ-9) and Hospital Anxiety and Depression Scale (HADS) The PHQ-9 results were listed, and the change from baseline in the PHQ-9 were summarized by visit. Summary statistics for PHQ-9 scores were summarized by treatment and visit/week, including the total score for part 1 and part 2. The HADS results and the total score were listed by treatment and time. The HADS total score and change from baseline in total score were summarized by treatment and time. Psoriasis Quality of Life Questionnaire (PQOL-12) The PQOL-12 results were listed, and the change from baseline in the PQOL-12 were summarized by visit. Summary statistics for PQOL-12 scores were summarized by treatment and visit.

9.7.1.7.5

Pharmacokinetics Analyses

The estimated AUCs, using a Population PK approach were performed by, or under the direct auspices of, Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline; the details are described in Appendix 17.7. Since previous studies have indicated that the PK exposure of SRT2104 is relatively variable, the imputed AUCs from the active treatment were combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs were natural log transformed prior to selecting the mid-point. AUC and Cmax were summarized by treatment and exposure group.

9.7.1.7.6

Pharmacogenetic, Viral Genotyping and Phenotyping Analyses

Gene expression data and change from baseline for available parameters were summarized by treatment group. Additional exploratory analyses performed to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity were ongoing at the time of this report. 9.7.2 Determination of Sample Size Sample size was based on feasibility. A sample size of 8 evaluable subjects per active treatment group and 6 evaluable placebo subjects in a merged placebo group were planned to be assessed. Subjects who withdrew from the study prior to 8 weeks of treatment could be replaced by another subject at the discretion of the Investigator, Medical Monitor, and Sponsor. 47 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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The information in Table 9.7.2 is provided to estimate the precision of the estimates, assuming SRT2104 histology success rate (an improvement score of “good or excellent” based on the Krueger criteria [Section 9.5.3.1.1] of 0.33%) and the exposure data is dichotomized at the midpoint (n=12 for each exposure group). Table 9.7.2

True Krueger response rate 0.33 0.33

Sample Size Sensitivity Modelling Null placebo response rate 0.05

Power 0.8124

Cut-off value for rejecting Ho 3

0.10

0.5973

4

a. 90% CI is based on exact methods

9.8

Difference between true and null response rate 0.28 0.20 0.23 0.15

90% CI for the differencea (0.1229,0.6084) (0.0719, 0.5272) (0.1230,0.6090) (0.0720, 0.5272)

Changes in the Conduct of the Study or Planned Analyses

9.8.1 Changes in the Conduct of the Study The Original Version 2.0, dated 19-MAR-2010 was amended one time on 22-OCT-2010; the major changes made were: • Added TB test to Screening Visit in the Schedule of Events. • Changed sample size from 10 to 8 evaluable subjects per active treatment group. • Inclusion criteria: added that baseline PASI criteria must have been met for enrollment. • Inclusion criteria: added definition for female of childbearing potential. • Clarified that safety review occurred for 250mg & 500mg dosing cohorts prior to escalation to next dose. • Defined specific visit windows. •

Planned for exposure-response comparisons (low and high exposure groups) for the clinical activity endpoints.

•

Histology response was defined as an improvement of “good” or “excellent” on the Krueger criteria , instead of only “excellent”.

•

Added stipulation that PPS would only be defined if the difference in the number of subjects between FAS population and PPS population was greater than 10%

•

Modified the EAS population to include the presence of keratinocyte K16 expression on baseline biopsies

•

Removed ‘Clinically Significant?’ question from the e-CRF and used GSK standard values of Potential Clinical Importance (PCI) to summarize laboratory abnormalities

•

Discontinued collection of protocol deviations on the e-CRF and replaced this with collection of these in an excel spreadsheet

The original protocol and the amendment are in Appendix 16.1.1

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9.8.2 •

Clinical Study Report SRT-2104-013 31-MAY-2012

Changes in the Planned Analyses Prior to treatment unblinding, the EAS population was modified to no longer require the presence of keratinocyte K16 expression.

•

Ad-hoc graphical displays were produced for the clinical activity endpoints.

•

Ad-hoc statistical analyses of change from baseline in weight and lipids (cholesterol, HDL,LDL, HDL/LDL ratio, triglycerides) were provided.

•

Listings of supportive SAS output from the statistical analyses were provided.

•

PASI-25 was included in the summary and statistical analysis of PASI.

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10

STUDY SUBJECTS

10.1

Disposition of Subjects

The disposition of all randomized subjects, including reasons for withdrawal from the study is summarized in Table 10.1-1. Information regarding the subjects prematurely withdrawn from the study is provided by treatment in Table 10.1-2 and listed in Listing 16.2.1. A total of 40 subjects were randomized into the study as follows: • Seven subjects (18%) received at least one dose of placebo • Nine subjects (23%) received at least one dose of 250 mg SRT2104 • Twelve subjects (30%) received at least one dose of 500 mg SRT2104 • Eleven subjects (28%) received at least one dose of 1000 mg SRT2104 • One subject (3%) received no treatment (See Table 10.1-2) Table 10.1-1 Summary of Subject Disposition (Randomized Set Population, N=40) Parameter, n (%) Completion Status Completed Prematurely withdrawn Primary Reason for Study Withdrawal Adverse event (AE) Lost to follow-up Subject withdrawal or refusal Source: Table 14.1.1

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11)

Placebo (N=7)

250 mg (N=9)

7 (100) 0

5 (56) 4 (44)

9 (75) 3 (25)

0 0 0

2 (22) 1 (11) 1 (11)

1 (8) 0 2 (17)

No Treatment (N=1)

Total (N=40)

9 (82) 2 (18)

0 1 (100)

30 (75) 10 (25)

1 (9) 1 (9) 0

0 0 1 (100)

4 (10) 2 (5) 4 (10)

Table 10.1-2 Reasons for Withdrawal by Subject (Randomized Set Population, N=40)

a. See Section 12.3.3 for details regarding AEs led to withdrawal from IP and from the study.

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Clinical Study Report SRT-2104-013 31-MAY-2012

10.2 Protocol Deviations: Inclusion/Exclusion Criteria No subjects were withdrawn from the study due to protocol deviations. Six subjects (15%) did not meet all inclusion/exclusion criteria listed in Sections 9.3.1 and 9.3.2; these subjects are listed in Table 10.2-1. Table 10.2-1

Subjects with Inclusion/Exclusion Criteria Deviations (Randomized Set Population, N=40)

Source: Listing 16.2.2.1

10.3

Unblinding See Appendix 16.2.1 for details.

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11

Clinical Study Report SRT-2104-013 31-MAY-2012

EFFICACY, PHARMACODYNAMIC, PHARMACOKINETIC, AND HEALTH OUTCOMES EVALUATION

11.1 Data Sets Analyzed The following analysis sets were analyzed: • Randomized Set (RS): all subjects randomized were included in the Randomized Set. This was compatible with an ITT population. • Safety Analysis Set (SAF): the population for all safety analyses was the Safety Analysis Set (SAF). It included all subjects who received at least one dose of IP. • Efficacy Analysis Set (EAS): The EAS included all randomized subjects who received at least one dose of IP, had at least one activity measurement at baseline, and at least one post-baseline study visit. • PK Population: The PK population included all subjects who received at least one dose of SRT2104 for whom a pharmacokinetic sample was obtained and analyzed. A total of 40 subjects were randomized into the study as follows: • Seven subjects (18%) received at least one dose of placebo • Nine subjects (23%) received at least one dose of 250 mg SRT2104 • Twelve subjects (30%) received at least one dose of 500 mg SRT2104 • Eleven subjects (28%) received at least one dose of 1000 mg SRT2104 • One subject (3%) received no treatment (See Table 10.1-2) The numbers of subjects included in each analysis set is summarized in Table 11.1-1. Table 11.1-1 Summary of Analysis Populations (Randomized Set Population, N=40) Population, n (%) Randomized Set (RS) Safety Analysis Set (SAF) Pharmacokinetics Analysis Set (PKS) Efficacy Analysis Set (EAS) Source: Table 14.1.2

11.2

Placebo (N=7) 7 (100) 7 (100) 0 7 (100)

250 mg (N=9) 9 (100) 9 (100) 9 (100) 9 (100)

SRT2104 Dose 500 mg (N=12) 12 (100) 12 (100) 11 (92) 12 (100)

1000 mg (N=11) 11 (100) 11 (100) 11 (100) 11 (100)

No Treatment (N=1) 1 (100) 0 0 0

Total (N=40) 40 (100) 39 (98 31 (78) 39 (98

Demographic and Other Baseline Characteristics

11.2.1 Demographic Characteristics Demographic characteristics and race are summarized for all randomized subjects in Table 14.1.3 and presented in Table 11.2.1-1. Demographic data for individual subjects are provided in Listing 16.2.4.1. The demographics of the study population were predominantly white (85%) males (75%), with notable differences in gender in the treatment groups, except for the SRT2104 1000 mg dose group (45% females and 55% males). The BMI was higher in the SRT2104 250 mg dose group (33.4 kg/m2) compared to the 500 mg and 1000 mg dose groups (27.4 kg/m2 and 28.6 kg/m2, respectively). The highest mean age population was in the SRT2104 500 mg dose group at 49.3 years. 52 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Table 11.2.1-1

Clinical Study Report SRT-2104-013 31-MAY-2012

Summary of Demographic Characteristics (Randomized Set Population, N=40) SRT2104 Dose

Parameter Age (Years) n Mean (SD) Median (Min, Max) Sex, n (%) n Female: Male: Race, n (%) n White Black Asian Other Ethnicity, n (%) n Hispanic or Latino Not Hispanic or Latino Height (cm) n Mean (SD) Median (Min, Max) Weight (kg) n Mean (SD) Median (Min, Max) BMI (kg/m2) n Mean (SD) Median (Min, Max) Source: Table 14.1.3

Placebo (N=7)

250 mg (N=9)

500 mg (N=12)

1000 mg (N=11)

No Treatment (N=1)

7 51.4 (14.9) 50 (27, 72)

9 40.6 (16.1) 45 (19, 60)

12 49.3 (14.4) 52 (26, 68)

11 44.6 (13.6) 43 (26, 65)

0 ---

39 46.4 (14.6) 50 (19, 72)

7 1 (14) 6 (86)

9 3 (33) 6 (67)

12 0 12 (100)

11 5 (45) 6 (55)

1 1 (100) 0

40 10 (25) 30 (75)

7 6 (86) 1 (14) 0 0

9 7 (78) 2 (22) 0 0

12 10 (83) 0 1 (8) 1 (8)

11 10 (91) 1 (9) 0 0

1 1 (100) 0 0 0

40 34 (85) 4 (10) 1 (3) 1 (3)

7 0 7 (100)

9 0 9 (100)

12 3 (25) 9 (75)

11 2 (18) 9 (82)

1 0 1 (100)

40 5 (13) 35 (88)

7 172 (7.99) 175 (155, 178)

9 176 (6.86) 178 (165, 185)

10 177 (7.81) 177 (160, 185)

11 173 (7.72) 175 (160, 188)

1 170

38 174 (7.54) 175 (155, 188)

7 92.7 (11.2) 91.9 (77, 104)

9 105 (24.5) 105 (74, 156)

12 88.1 (15.6) 81.1 (70, 116)

11 84.9 (27.8) 81.6 (62, 158)

1 62.2

7 31.5 (3.81) 32.9 (24, 36)

9 33.4 (5.57) 33.4 (26, 45)

10 27.4 (4.40) 25.9 (23, 35)

11 28.6 (9.63) 25.8 (20, 55)

1 21.5

170

62.2

21.5

Total (N=40)

40 91.2 (22.1) 86.4 (62, 158) 38 29.7 (6.81) 30.1 (20, 55)

11.2.2 Medical and Surgery History Medical and surgical histories, obtained from each subject at the Screening Visit, are summarized in Table 14.1.4 and listed for individual subjects in Listing 16.2.4.2. Of the 40 subjects randomized into the study, 39 (98%) reported medical/surgery histories at baseline. Information by treatment group is presented below: 53 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Placebo: 7 subjects (100%) reported medical/surgery histories at baseline. Those of note included: headache in 2 subjects (29%); hypertension in 2 subjects (29%); heart rate irregular in 1 subject (14%);T2DM in 1 subject (14%); cardiac disorders in 2 subjects (29%), where 1 subject had both arrhythmia and coronary heart disease and 1 subject had right bundle branch block;. 250 mg SRT2104 dose group: 8 subjects (89%) reported medical/surgery histories at baseline. Those of note included: hypertension in 4 subjects (44%); T2DM/diabetes mellitus in 3 subjects (33%). 500 mg SRT2104 dose group: 12 subjects (100%) reported medical/surgery histories at baseline. Those of note included: headache in 1 subject (8%); hypertension in 5 subjects (42%); T2DM in 1 subject (8%); myocardial infarction in 1 subject (8%). 1000 mg SRT2104 dose group: 11 subjects (100%) reported medical/surgery histories at baseline. Those of note included: headache in 1 subject (9%); hypertension in 3 subjects (27%); T2DM in 1 subject (9%); pericarditis in 1 subject (9%). 11.2.3 Concomitant Medications The majority of subjects (95%) received on-therapy concomitant medications (Table 14.1.5). The on-therapy concomitant medications received by >1 subjects across treatment groups are summarized in Table 11.2.3-1 by ACT Level 2 classification. No subjects used rescue medications outside of the protocol defined parameters (Table 14.2.6). See Sections 9.4.7 and 9.5.3.1.4 for details regarding rescue medications.

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Table 11.2.3-1 Summary of Concomitant Medications by ACT Level 2 Classification Received by >1 Subjects Across Treatment Groups (Randomized Set Population, N=40) ATC Level 2 Classification, n (%) Any Medication Anesthetics Agents acting on the ReninAngiotensin System Analgesics Anti-inflammatory and Anti-rheumatic Products Lipid Modifying Agents Antibiotics and Chemotherapy for Dermatological Use Anti-thrombotic Agents Beta Blocking Agents Drugs used in Diabetes Vitamins Antibacterials for Systemic Use Diuretics Corticosteroids, Dermatological Preparations Psychoanaleptics Blood Substitutes and Perfusion Solutions Cough and Cold Preparations Emollients and Protectives Psycholeptics Sex Hormones and Modulators of the Genital System Thyroid Therapy

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 12 (100) 11 (100) 7 (58) 10 (91)

No Treatment (N=1) 1 (100) 0

Total (N=40) 38 (95) 24 (60)

2 (18)

0

10 (25)

3 (25)

1 (9)

0

10 (25)

0

3 (25)

5 (45)

0

10 (25)

1 (14)

2 (22)

5 (42)

2 (18)

0

10 (25)

1 (14)

0

0

6 (55)

0

7 (18)

2 (29) 3 (43) 1 (14) 0 1 (14) 1 (14)

0 0 3 (33) 1 (11) 1 (11) 0

4 (33) 2 (17) 1 (8) 1 (8) 2 (17) 1 (8)

1 (9) 1 (9) 1 (9) 4 (36) 1 (9) 2 (18)

0 0 0 0 0 0

7 (18) 6 (15) 6 (15) 6 (15) 5 (13) 4 (10)

1 (14)

0

1 (8)

1 (9)

0

3 (8)

1 (14)

0

0

2 (18)

0

3 (8)

0

2 (22)

0

0

0

2 (5)

1 (14) 1 (14) 2 (29)

0 1 (11) 0

0 0 0

1 (9) 0 0

0 0 0

2 (5) 2 (5) 2 (5)

0

1 (11)

0

0

1 (100)

2 (5)

0

1 (11)

0

1 (9)

0

2 (5)

Placebo (N=7) 6 (86) 3 (43)

250 mg (N=9) 8 (89) 4 (44)

2 (29)

3 (33)

3 (25)

2 (29)

4 (44)

2 (29)

Source: Table 14.1.5 a. Medications that started and stopped prior to dosing were excluded from the summary table.

11.3 Measurements of Treatment Compliance Compliance of an individual subject was assessed by study personnel based upon the amount of IP dispensed to the subject and the amount returned by the subject when they came to the outpatient clinic. No subjects were withdrawn due to noncompliance in taking the required doses of IP. See Section 12.1 for information regarding IP exposure.

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11.4 Efficacy Results and Tabulations of Individual Subject Data The primary clinical efficacy/PD analyses of clinical activity are presented for the EAS population as follows: • Histological assessments of skin biopsies of psoriatic lesions is summarized in Tables 14.2.4.1 – 14.2.4.6. • Estimation of the improvement score based on the Krueger criteria is summarized in Tables 14.2.1.2 – 14.2.1.4. • Improvement scores according to the Krueger criteria and skin biopsy data are listed for individual subjects in Listings 16.2.6.1 – 16.2.6.1 and 16.2.6.19. The secondary efficacy PD and PK analyses are presented for the EAS population as follows: • PASI scores are summarized in Tables 14.2.2.4 and 14.2.2.5, Figures 14.2.2.1 – 14.2.2.4, Figures 14.2.2.12 – 14.2.2.16, and listed for individual subjects in Listings 16.2.6.4 and 16.2.6.5. • Statistical analyses of PASI scores are summarized in Tables 14.2.2.6 – 14.2.2.11 and Figure 14.2.2.15, and listed for individual subjects in Listings 16.2.6.13 – 16.2.6.15. • PGA scores are summarized in Table 14.2.3.1 and listed for individual subjects in Listing 16.2.6.6 and Listings 16.2.6.16 – 16.2.6.18. • Estimation of improvement based on PGA scores are summarized in Tables 14.2.3.2 – 14.2.3.8. • SRT2104 PK parameters (AUC and Cmax) are summarized in Table 14.2.10. • FGF21 and hsCRP biomarkers are summarized in Tables 14.2.5.1 and 14.2.5.2 and listed by individual subjects in Listing 16.2.6.7. The exploratory analyses are presented for the EAS population as follows: • Gene expression is summarized in Tables 14.4.1.1 and 14.4.1.2. • The HADS is summarized in Tables 14.2.7.1 and 14.2.7.2 and listed for individual subjects in Listings 16.2.6.9 and 16.2.6.10. • The PHQ-9 is summarized in Tables 14.2.8.1 and 14.2.8.2 and listed for individual subjects in Listing 16.2.6.11. • The PQOL-12 is summarized in Tables 14.2.9.1 and 14.2.9.2 and listed for individual subjects in Listing 16.2.6.12. 11.4.1 Clinical Activity Results Analyses of clinical activity were performed on the EAS population. The primary analysis was summarized by both the low vs. high exposure groups and by the actual treatment groups. In addition, all of the SRT2104 dose cohorts were combined to serve as an additional group of treated subjects for all activity comparisons. 11.4.1.1 Results of Primary Analyses The primary clinical activity endpoint is change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks as measured by an Improvement Score according to the Krueger criteria (Table 9.5.3.1.1-1). See Section 9.7.1.7.2 for details regarding the 56 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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clinical activity analyses performed. Supportive SAS output for these statistical analyses are provided in Listings 16.2.6.2 and 16.2.6.3. The improvement score based on the Krueger Criteria with comparison to historical 5% placebo rate on Day 84 for the EAS is summarized in Table 14.2.1.4 and presented in Table 11.4.1.1-1. The difference (90% CI) in proportion of histological improvement between exposure groups or SRT2104 dose groups and placebo on Day 84 for the EAS is summarized in Table 14.2.1.3 and presented in Table 11.4.1.1-2 and Figure 11.4.1.1-1. The overall skin score response rate for all active treatment groups combined was 35% (9 of 32 subjects), with a p-value of <0.0001 when compared to the pre-specified historical placebo response rate of 5% (Table 11.4.1.1-1). A higher proportion of subjects with Good or Excellent Imporvement Scores were observed in the SRT2104 250 mg (3; 50%) and 500 mg (4;44.4%) dose groups.as compared to placebo (1; 14.3%) and the SRT2104 1000 mg (2; 18.2%) group. A higher proportion of subjects in the low exposure group had positive responses (50%) as compared to the high exposure group (21.4%) (Table 11.4.1.1-1 and Table 11.4.1.1-2). Table 11.4.1.1-1

Summary of the Improvement Score based on the Krueger Criteria with Comparison to Historical 5% Placebo Rate Actual Visita: Day 84 (Efficacy Analysis Set Population)

Comparison to 5% Historical Placebo Response Placebo (N=7) SRT2104 250 mg (N=9) SRT2104 500 mg (N=12) SRT2104 1000 mg (N=11) All Actived (N=32) Low Exposuree (N=15f) High Exposuree (N=16)

n 7 6 9 11 26 12 14

Good or Excellent Improvement Scoreb, n (%) 1 (14.3) 3 (50) 4 (44.4) 2 (18.2) 9 (34.6) 5 (41.7) 4 (28.6)

(90%CI) (Blythe-Still-Casella) (0.73, 55.4) (15.3, 84.7) (16.9, 74.9) (3.33, 50.0) (18.0, 54.2) (18.10, 70.60) (10.40, 58.10)

p-valuec -0.0022 0.0006 0.1019 <0.0001 0.0002 0.0042

Source: Table 14.2.1.4 a. Actual visit was based on assessment windows using relative study day. b. Good improvement=Defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but keratinocytes still express K16. Excellent improvement=Defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16. c. No adjustments of the p-value for multiplicity. d. All Active = all SRT2104 dose groups combined. e. Exposure was based on AUC (Section 11.4.2) f. Note: Missing data was not imputed.

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Table 11.4.1.1-2

Clinical Study Report SRT-2104-013 31-MAY-2012

Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo – Actual Visita: Day 84 (Efficacy Analysis Set Population)

Comparison vs Placebo SRT2104 250 mg (N=9) SRT2104 500 mg (N=12) SRT2104 1000 mg (N=11) All Activeb (N=32) Low Exposurec (N=15d) High Exposurec (N=16)

Proportion of Subjects with Good or Excellent Improvement Treatment, n (%) Placebo, n (%) 3 (50) 1 (14.3) 4 (44.4) 1 (14.3) 2 (18.2) 1 (14.3) 9 (34.6) 1 (14.3) 5 (41.7) 1 (14.3) 4 (28.6) 1 (14.3)

Source: Table 14.2.1.3 a. Actual visit was based on assessment windows using relative study day. b. All Active = all SRT2104 dose groups combined. c. Exposure was based on AUC (Section 11.4.2). d. Note: Missing data was not imputed.

Difference (90%CI) 35.7% (24.6, 43.6) 30.2% (20.8, 36.9) 3.9% (-7.93, 10.2) 20.3% (6.91, 24.5) 27.4% (19.9, 31.6) 14.3% (3.96, 21.9)

Figure 11.4.1.1-1 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo - Day 84 (Efficacy Analysis Set Population)

Source: Figure 14.2.1.1 Note: Histological improvement was based on the Krueger Criteria (Table 9.5.3.1.1-1).

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11.4.1.2 Psoriasis Area and Severity Index (PASI) A secondary objective of the study was to assess the effects of SRT2104 on the PASI in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. The PASI score served to quantify the extent of psoriasis and the degree of plaque erythema, scaling and thickness on the four body areas: head, trunk, upper limbs and lower limbs, with possible scores ranging from 0 (no disease) to 72 (maximal disease). See Section 9.7.1.7.2 for details regarding the statistical analyses performed for the PASI. Supportive SAS output for these analyses are provided in Listings 16.2.6.5, 16.2.6.13, 16.2.6.14 and 16.2.6.15. The percent change from baseline for PASI Scores for the EAS is summarized in Table 14.2.25 and presented in Table 11.4.1.2-1 and Figure 11.4.1.2-1. The proportion of subjects with clinical activity in the PASI score (≥PASI 25, ≥PASI 50, ≥PASI 75) for the EAS is summarized in Table 14.2.2.9 and is presented in Table 11.4.1.2-2. The results of repeated measures analysis of PASI score for the EAS is summarized in Table 14.2.2.11 and presented in Table 11.4.1.2-3; a plot of PASI least square mean difference (90%CI) between the SRT2104 treatment groups and placebo are presented by visit in Figure 11.4.1.2-2. An apparent dose-effect was observed (Table 11.4.1.2-1), as improvements in PASI scores were seen across the treatment groups over time. In the 250 mg dose group, mean percent changes in PASI scores were marginally improved on Days 56 and 84 compared to placebo (-20.31 and -30.31 vs. -16.14 and -21.77, respectively), which was not sustained at follow-up. In the 500 mg dose group, mean percent changes in PASI scores were moderately improved on Days 56 and 84 compared to placebo (-30.07 and -36.44 vs. -16.14 and -21.77); this improvement remained at follow-up. In the 1000 mg dose group, mean percent changes in PASI scores showed more improvement on Day 28 (-26.12) vs. placebo (-16.66) and vs the lower dose groups (-5.40 in the 250 mg dose group and -8.68 in the 500 mg dose group); better improvement was also observed in the 1000 mg dose group on Days 56 and 84 (-35.43 and -39.66, respectively), which was sustained at follow-up. While there were improvements in the PASI score observed in both exposure groups, a greater proportion of subjects in the high exposure group had improvement in their PASI scores (Day 84: -42.53 vs -29.22).

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Table 11.4.1.2-1 Summary of Percent Change from Baseline for PASI Scores (Total Score) (Efficacy Analysis Set Population) Treatment Placebo (N=7)

SRT2104 250 mg (N=9) SRT2104 500 mg (N=12) SRT2104 1000 mg (N=11))

All Activeb (N=32)

Low Exposurec (N=15d) High Exposurec (N=16)

n 7 7 7 7 7 9 9 7 6 6 12 12 11 9 10 11 11 11 11 10 32 32 29 26 26 15 15 13 12 12 16 16 16 14 14

Actual Visita Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up Day 1 (Baseline) Day 28 Day 56 Day 84 Follow-up

Mean SD 23.30 (11.13) -16.66 (13.78) -16.14 (22.57) -21.77 (39.20) -18.87 (35.93) 17.13 (4.66) -5.40 (13.14) -20.31 (32.86) -30.31 (44.81) -12.85 (40.15) 18.08 (3.14) -8.68 (30.05) -30.07 (33.18) -36.44 (37.00) -36.89 (36.05) 20.35 (7.99) -26.16 (20.09) -35.43 (26.52) -39.66 (30.23) -34.45 (27.65) 18.59 (5.61) -13.77 (24.08) -29.75 (30.18) -36.39 (34.91) -30.40 (34.10) 18.09 (3.98) -11.26 (16.49) -28.78 (33.39) -29.22 (37.37) -16.18 (34.71) 19.19 (7.026) -18.24 (29.00) -30.53 (28.40) -42.53 (32.78) -42.60 (29.49)

Source: Table 14.2.2.4 and Table 14.2.2.5 a. Actual visit was based on assessment windows using relative study day. b. All Active = all SRT2104 dose groups combined. c. Exposure was based on AUC (Section 11.4.2) d. Note: Missing data was not imputed.

Median (Min, Max) 21.90 (12.0, 36.9) -15.45 (-33.82, 0.00) -10.29 (-57.45, 6.78) -7.44 (-79.17, 20.59) -14.05 (-82.50, 15.38) 16.00 (10.2, 23.7) 0.00 (-28.00, 13.73) -0.44 (-76.00, 0.78) -3.35 (-92.00, 0.78) 4.17 (-92.00, 12.50) 19.00 (13.9, 23.1) -11.05 (-57.55, 64.07) -21.13 (-83.84, 17.61) -33.67 (-90.91, 17.61) -37.90 (-90.91, 17.61) 16.40 (12.2, 40.0) -33.79 (-47.14, 6.12) -31.03 (-69.16, 13.47) -39.63 (-88.68, 20.82) -41.22 (-69.26, 19.50) 17.30 (10.2, 40.0) -11.05 (-57.55, 64.07) -27.87 (-83.84, 17.61) -32.70 (-92.00, 20.82) -32.92 (-92.00, 19.50) 18.20 (10.2, 23.7) -6.25 (-47.14, 13.73) -21.13 (-76.00, 17.61) -9.95 (-92.00, 17.61) -3.66 (-92.00, 19.50) 17.50 (12.2, 40.0) -24.58 (-57.55, 64.07) -29.52 (-83.84, 13.47) -36.65 (-90.91, 20.82) -43.47 (-90.91, 10.16)

90% CI (15, 31) (-26.78, -6.55) (-32.72, 0.43) (-50.56, 7.02) (-45.26, 7.52) (14, 20) (-13.55, 2.74) (-44.44, 3.82) (-67.18, 6.55) (45.88, 20.18) (16, 20) (-24.26, 6.90) (-48.20, -11.94) (-59.38, -13.51) -57.78, -15.99) (16, 25) (-37.14, -15.18) (-49.92, -20.93) (-56.18, -23.14) (-50.48, -18.42) (17, 20) (-20.99, -6.55) (-39.28, -20.21) (-48.09, -24.70) (-41.83, -18.98) (16, 20) (-18.76, -3.76) (-45.29, -12.28) (-48.60, -9.85) (-34.17, 1.82) (16, 22) (-30.95, -5.53) (-42.97, -18.08) (-58.05, -27.02) (-56.56, -28.64)

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Figure 11.4.1.2-1 Plot of Mean ( +/- SE) Percent Change from Baseline in PASI Total Score vs. Time (Efficacy Analysis Set Population)

Source: Figure 14.2.2.12

Table 11.4.1.2-2

Actual Visit Daya PASI Assessment, n (%) Day 28, n 25% Improvement 50% Improvement 75% Improvement Day 56, n 25% Improvement 50% Improvement 75% Improvement Day 84, n 25% Improvement 50% Improvement 75% Improvement

Proportion of Subjects with Clinical Activity in the PASI score(≥PASI 25, ≥PASI 50, ≥PASI 75) (Efficacy Analysis Set Population) Placebo (N=7) 7 2 (29) 0 0 7 2 (29) 1 (14) 0 7 2 (29) 2 (29) 1 (14)

250 mg (N=9) 9 1 (11) 0 0 7 2 (29) 2 (29) 1 (14) 6 2 (33) 2 (33) 2 (33)

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 12 11 3 (25) 7 (64) 1 (8) 0 0 0 11 11 5 (45) 8 (73) 4 (36) 4 (36) 2 (18) 0 9 11 6 (67) 8 (73) 3 (33) 4 (36) 2 (22) 1 (9)

Source: Table 14.2.2.9 a. Actual visit was based on assessment windows using relative study day. b. All Active = all SRT2104 dose groups combined. c. Exposure was based on AUC (Section 11.4.2). d. Note: Missing data was not imputed.

All Activeb (N=32) 32 11 (34) 1 (3) 0 29 15 (52) 10 (34) 3 (10) 26 16 (62) 9 (35) 5 (19)

Low Exposurec (N=15d) 15 3 (20) 0 0 13 5 (38) 5 (38) 2 (15) 12 5 (42) 4 (33) 2 (17)

High Exposurec (N=16) 16 8 (50) 1 (6) 0 16 10 (63) 5 (31) 1 (6) 14 11 (79) 5 (36) 3 (21)

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Table 11.4.1.2-3 Comparison vs Placebo SRT2104 250 mg (N=9) SRT2104 500 mg (N=12) SRT2104 1000 mg (N=11) All Activea (N=32) Low Exposureb (N=15c) High Exposureb (N=16)

Clinical Study Report SRT-2104-013 31-MAY-2012

Summary of Results of Repeated Measures Analysis of PASI Score (Efficacy Analysis Set Population) Actual Visit Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84

Daya

Least Squares (LS) Means Treatment Placebo 17.92 17.55 15.92 16.77 14.41 15.65 18.10 17.55 13.82 16.77 13.32 15.65 14.48 17.55 12.30 16.77 11.43 15.65 16.77 17.66 13.81 16.87 12.87 15.76 17.04 17.64 14.00 16.85 14.24 15.74 16.25 17.64 13.45 16.85 11.59 15.74

Source: Table 14.2.2.11 a. All Active = all SRT2104 dose groups combined. b. Exposure was based on AUC (Section 11.4.2). c. Note: Model includes terms for baseline value, treatment group, day, and treatment*day interaction.

Estimated Difference (90%CI) 0.367 (-5.06, 5.79) -0.853 (-6.41, 4.71) -1.249 (-7.00, 4.51) 0.544 (-4.55, 5.63) -2.950 (-8.08, 2.18) -2.336 (-7.58, 2.91) -3.079 (-8.16, 2.00) -4.466 (-9.55, 0.61) -4.225 (-9.30, 0.85) -0.893 (-5.33, 3.54) -3.068 (-7.52, 1.38) -2.888 (-7.37, 1.59) -0.599 (-5.52, 4.33) -2.849 (-7.82, 2.12) -1.501 (-6.53, 3.53) -1.387 (-6.21, 3.44) -3.401 (-8.23, 1.43) -4.151 (-9.02, 0.72)

Figure 11.4.1.2-2 Plot PASI LS Mean Difference (90% CI) between SRT2104 Treatment Groups and Placebo by Visit (Efficacy Analysis Set Population)

Source: Figure 14.2.2.15

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11.4.1.3

Clinical Study Report SRT-2104-013 31-MAY-2012

Physicians Global Assessment (PGA)

A secondary objective of this study was to assess the effects of SRT2104 on the PGA score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. See Section 9.7.1.7.2 for details regarding the statistical analyses performed for the PGA. Note that subjects in cohort 2 (250 mg) inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6 point grading scale. Supportive SAS output for these analyses are provided in Listings 16.2.6.16, 16.2.6.17, and 16.2.6.18. The PGA overall scores in all treatment/exposure groups are summarized for the EAS in Table 14.2.3.1 and presented in Table 11.4.1.4-1. The proportion of subjects with clinical activity in PGA score are summarized for the EAS in Tables 14.2.3.2, 14.2.3.3, 14.2.3.4, and 14.2.3.5 and presented in Table 11.4.1.4-1. PGA scores improved on Day 56 and Day 84 in the 500 mg, 1000 mg and All Active treatment groups, and this improvement was also observed in the low and high exposure groups (Table 11.4.1.3-1). The PGA improvements were greater for subjects receiving SRT2104 compared to those receiving placebo. On Day 84, no subjects in the placebo group achieved scores of minimal or clear, whereas two subjects (22%) in the SRT2104 500 mg group and three subjects (27%) in the SRT 1000 mg group achieved scores of minimal or clear.

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Table 11.4.1.3-1 Actual Visita Category Day 1, n Very Severe Severe Moderate Mild Minimal Clear Day 28, n Very Severe Severe Moderate Mild Minimal Clear Day 56, n Very Severe Severe Moderate Mild Minimal Clear Day 84, n Very Severe Severe Moderate Mild Minimal Clear

Clinical Study Report SRT-2104-013 31-MAY-2012

Summary of Physician Global Assessment (Overall Score) (Efficacy Analysis Set Population) Placebo (N=7) 5 1 (20) 1 (20) 3 (60) 0 0 0 5 1 (20) 1 (20) 2 (40) 1 (20) 0 0 5 1 (20) 1 (20) 2 (40) 1 (20) 0 0 5 1 (20) 1 (20) 2 (40) 1 (20) 0 0

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 12 11 0 1 (9) 2 (17) 1 (9) 10 (83) 9 (82) 0 0 0 0 0 0 N/A 12 11 0 0 2 (17) 1 (9) 9 (75) 4 (36) 1 (8) 6 (55) 0 0 0 0 N/A 11 11 0 0 1 (9) 0 6 (55) 3 (27) 3 (27) 7 (64) 1 (9) 1 (9) 0 0 N/A 9 11 0 0 2 (22) 0 2 (22) 5 (45) 3 (33) 3 (27) 2 (22) 3 (27) 0 0

250 mg (N=9 N/A

All Activeb (N=32) 23 1 (4) 3 (13) 19 (83) 0 0 0 23 0 3 (13) 13 (57) 7 (30) 0 0 22 0 1 (5) 9 (41) 10 (45) 2 (9) 0 20 0 2 (10) 7 (35) 6 (30) 5 (25) 0

Low Exposurec (N=15d) 7 0 1 (14) 6 (86) 0 0 0 7 0 0 6 (86) 1 (14) 0 0 7 0 1 (14) 2 (29) 4 (57) 0 0 7 0 2 (29) 2 (29) 3 (43) 0 0

High Exposurec (N=16) 15 1 (7) 1 (7) 13 (87) 0 0 0 15 0 2 (13) 7 (47) 6 (40) 0 0 15 0 0 7 (47) 6 (40) 2 (13) 0 13 0 0 5 (38) 3 (23) 5 (38) 0

Source: Table 14.2.3.1 a. Actual visit was based on assessment windows using relative study day. b. All Active = all SRT2104 available dose groups combined (250 mg dose group excluded) c. Exposure was based on AUC (Section 11.4.2). d. Note: Subjects in cohort 1 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available for the SRT2104 250 mg dose group using the 6-point grading scale.

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Table 11.4.1.3-2

Clinical Study Report SRT-2104-013 31-MAY-2012

Proportion of Subjects with Clinical Activity in PGA Score (Efficacy Analysis Set Population)

SRT2104 Dose Placebob 250 mgb 500 mg 1000 mg All Activeb,c a Actual Visit (N=7) (N=9) (N=12) (N=11) (N=32) Improved PGA Score by one or more levels n n (%) n n (%) n n (%) n n (%) Day 28 5 1 (20) N/A 12 2 (17) 11 8 (73) 23 10 (43) Day 56 5 2 (40) N/A 11 5 (45) 11 9 (82) 22 14 (64) Day 84 5 2 (40) N/A 9 5 (56) 11 7 (64) 20 12 (60) PGA Score of Clear or Minimal n n (%) n n (%) n n (%) n n (%) Day 28 5 0 N/A 12 0 11 1 (9) 23 0 5 0 N/A 11 1 (9) 11 1 (9) 22 2 (9) Day 56 Day 84 5 0 N/A 9 2 (22) 11 3 (27) 20 5 (25) PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels n n (%) n n (%) n n (%) n n (%) Day 28 5 1 (20) N/A 12 2 (17) 11 8 (73) 23 10 (43) Day 56 5 2 (40) N/A 11 5 (45) 11 9 (82) 22 14 (64) Day 84 5 2 (40) N/A 9 5 (56) 11 7 (64) 20 12 (60) PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels – using LOCF n n (%) n n (%) n n (%) n n (%) Day 28 5 1 (20) N/A 12 2 (17) 11 8 (73) 23 10 (43) Day 56 5 2 (40) N/A 12 5 (42) 11 9 (82) 23 14 (61) Day 84 5 2 (40) N/A 12 6 (50) 11 7 (64) 23 13 (57)

Low Exposured (N=15e)

High Exposured (N=16)

n 7 7 7

n (%) 2 (29) 4 (57) 3 (43)

n 15 15 13

n (%) 8 (53) 10 (67) 9 (69)

n 7 7 7

n (%) 0 0 0

n 15 15 13

n (%) 0 2 (13) 5 (38)

n 7 7 7

n (%) 2 (29) 4 (57) 3 (43)

n 15 15 13

n (%) 8 (53) 10 (67) 9 (69)

n 7 7 7

n (%) 2 (29) 4 (57) 3 (43)

n 15 15 15

n (%) 8 (53) 10 (67) 10 (67)

Source Data: Table 14.2.3.2, Table 14.2.3.3, Table 14.2.3.4, Table 14.2.3.5 a. Actual visit was based on assessment windows using relative study day. b. Subjects in cohort 1 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available for the SRT2104 250 mg dose group using the 6-point grading scale. c. All Active = all available SRT2104 dose groups combined (250 mg dose group excluded). d. Exposure was based on AUC (Section 11.4.2). e. Note: Missing data was not imputed.

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Clinical Study Report SRT-2104-013 31-MAY-2012

11.4.1.4 Use of Rescue Medications No subjects used rescue medications outside of the protocol defined parameters (Table 14.2.6) (see Sections 9.4.7 and 9.5.3.1.4 for details regarding rescue medications). 11.4.1.5 Biomarkers: hsCRP and FGF21 A secondary objective of the study was to assess the PD effects of SRT2104 as measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation (hsCRP and FGF21) in blood samples collected on Days 1, 28, 56 and 84. The change from baseline values for FGF21 and hsCRP are summarized for the EAS in Table 14.2.5.2 and presented in Table 11.4.1.6-1. No conclusions could be drawn with regard to FGF21. Although the hsCRP mean values tended to decrease with SRT2104 treatment compared to placebo, the small sample size and significant variability made it difficult to drawn firm conclusions with regard to this laboratory parameter. Table 11.4.1.6-1 Summary of FGF21 and hsCRP Change from Baseline (Efficacy Analysis Set Population) Treatment Placebo (N=7) SRT2104 250 mg (N=9) SRT2104 500 mg (N=12) SRT2104 1000 mg (N=11))

Actual Visita Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84 Day 28 Day 56 Day 84

n 6 5 5 6 5 4 11 9 9 9 9 9

FGF21 Mean SD Median (Min, Max) -61.67 (269) 15.7 (-583, 141) -67.04 (277) -1.20 (-541, 180) -86.12 (300) -24.6 (593, 188) -94.53 (154) -48.0 (-348, 40.6) -72.72 (367) -54.0 (-621, 325) -190 (364) -83.7 (-684, 92.6) 56.9 (177) 18.0 (-86.0, 521) 149 (306) 33.6 (-68.4, 919) 58.3 (223) 57.8 (-252, 412) 330 (930) 25.2 (-178, 2789) 268 (961) -13.8 (-440, 2779) -673 (1591) -189 (-4890, 99.0)

Source: Table 14.2.5.2 a. Actual visit was based on assessment windows using relative study day.

n 7 7 7 8 6 5 10 7 8 10 10 10

hsCRP Mean SD Median (Min, Max) 0.11 (2.33) 0.20 (-4.4, 3.5) 0.59 (3.55) 0.10 (-4.4, 7.6) 0.66 (3.90) -0.10 (-4.9, 8.1) -0.14 (1.15) 0.10 (-1.6, 1.7) -0.18 (1.90) -0.50 (-2.4, 2.6) -0.16 (1.06) -0.10 (-1.8, 0.9) 1.18 (1.95) 0.50 (-0.6, 4.4) -1.31 (3.26) -0.20 (-8.6, 0.8) -0.75 (3.16) -0.10 (-8.3, 1.5) -0.96 (2.21) -0.20 (-6.3, 2.0) -0.48 (2.64) -0.30 (-5.8, 5.1) 0.27 (1.35) 0.00 (-1.8, 2.5)

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11.4.2

Clinical Study Report SRT-2104-013 31-MAY-2012

Drug Dose, Drug Concentration, and Relationships to Response

Samples for PK evaluation were collected on Days 28, 56 and 84. The PK parameters of AUC and Cmax are summarized by SRT2104 treatment and exposure for the PK population in Table 14.2.10 and presented in Table 11.4.2-1. See Section 9.7.1.3 for information regarding the use of the PK exposure data in defining the low and high drug exposure groups used in the EAS population. While between patient variability in SRT2104 exposure (AUC and Cmax) was high, average exposure increased in a dose-dependant manner following escalating doses of SRT2104. When categorized by the observed exposure, there was a marked difference in AUC and Cmax values in the low exposure group vs the high exposure group. Table 11.4.2-1 Summary of SRT2104 Pharmacokinetic Parameters by Treatment (PK Population) Treatment SRT2104 250 mg (N=9) SRT2104 500 mg (N=11) SRT2104 1000 mg (N=11) All Activea (N=31) Low Exposureb (N=15c) High Exposureb (N=16)

n 9 11 11 31 15 16

Mean (SD) 2148 (1247) 4189 (2143) 8358 (7467) 5076 (5229) 2064 (1052) 7900 (6006)

Source: Table 14.2.10 a. All Active = all SRT2104 dose groups combined. b. Exposure was based on AUC (Section 11.4.2). c.

AUC

Median (Min, Max) 2114 (144.3, 4497) 3892 (1387, 8870) 6097 (367, 27355) 3892 (144.3, 27355) 2072 (144.3, 3563) 5856 (3892, 27355)

n 9 11 11 31 15 16

Cmax Mean Median (SD) (Min, Max) 262 (134) 285 (6.0, 434) 407 (238) 452 (64.2, 720) 1006 (813) 626 (23.5, 2442) 577 (593) 442 (6.0, 2442) 224 (144) 192 (6.0, 447) 908 (665) 629 (401, 2442)

11.4.3 By-Subject Displays The PK parameters of AUC and Cmax are provided by individual subjects for the SRT2104 treatment groups and the exposure groups in Listing 16.2.10.

11.4.4 • •

•

Efficacy, Pharmacodynamic, and Pharmacokinetic Conclusions

SRT2104 appears to have positive activity in patients with moderate to severe plaque type psoriasis Across all dose groups, approximately 35% of patients treated with SRT2104 achieved good to excellent improvement on skin biopsies at Day 84, based on the Krueger scoring; skin biopsy outcomes did not show positive correlation with dose group or drug exposure levels There appeared to be a dose-dependent improvement in PASI scores and PGA scores for patients treated with SRT2104 compared to placebo; mean PASI improvements approached 40% at Day 84 in the higher SRT2104 dose groups; approximately 25% of 67 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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• •

Clinical Study Report SRT-2104-013 31-MAY-2012

patients achieved minimal to clear PGA scores at Day 84 in the higher SRT2104 dose groups No meaningful conclusions could be drawn with regard to the biomarkers FGF21 or hsCRP Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104; distinct differences in Cmax and AUC were observed between the low exposure group and high exposure group

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11.5

Clinical Study Report SRT-2104-013 31-MAY-2012

Health Outcomes

Exploratory objectives of the study were to: • Assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire 9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS). For examples of the PHQ-9 and HADS, see Appendix 17.3 and 17.4, respectively. • Assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Menter Psoriasis Instrument, PQOL-12. For an example of the PQOL-12, see Appendix 17.5. See Section 9.5.5 for or details regarding the statistical analyses performed for the PHQ-9, HADS, and PQOL-12. 11.5.1

Patient Health Questionnaire (PHQ-9)

The summary statistics of the change from baseline for the PHQ-9 total score are summarized in Table 11.5.1-1. The PHQ-9 is a subset of questions from the self-administered PHQ that specifically address depression. The scores range from 0-3 for each question, for a maximum score of 27. A total score of 0-4 indicates no depression. Scores of >= 5, 10, 15, 20 are used to categorize depression symptoms as mild, moderate, moderately severe and severe, respectively [Kroenke 2001]. Each treatment group had at least one subject with mild or moderate depression. At baseline, the 250 mg group had slightly higher number of subjects with a median PHQ-9 of 7 and a range from 0 to 12 compared to the other treatment groups,. Change over time fluctuated in the range of +2 to -2 across treatment groups. Although not tested statistically, these results do not demonstrate a clinically meaningful impact of STR2104 treatment on depression in subjects that are not depressed at baseline. Table 11.5.1-1

Summary Statistics of PHQ-9 Total Score Change from Baseline (Efficacy Analysis Set Population)

Visit PHQ-9 Total Score Day 1 (Baseline), n Mean (SD) Median (min, max) Day 28, n Mean (SD) Median (min, max) Day 56, n Mean (SD) Median (min, max) Day 84, n Mean (SD) Median (min, max)

Source: Table 14.2.8.1 and Table 14.2.8.2

Placebo (N=7) 7 4.4 (4.96) 2.0 (0, 14) 7 -1.6 (4.24) 0 (-11, 1) 7 -2.1 (4.22) 0 (-11, 1) 7 -0.9 (5.84) 0 (-12, 8)

250 mg (N=9) 9 5.9 (4.08) 7.0 (0, 12) 9 -0.9 (2.93) 0 (-7, 2) 6 -2.3 (4.03) -1.0 (-9, 2) 8 1.4 (4.07) 1.0 (-4, 9)

SRT2104 Dose 500 mg (N=12) 12 2.8 (3.13) 1.5 (0. 7) 12 2.2 (3.76) 1.0 (-4, 8) 9 0 (3.08) 0 (-5, 6) 12 0.2 (3.04) 0.5 (-5, 7)

1000 mg (N=11) 11 3.9 (4.74) 2.0 (0, 14) 11 0.4 (4.20) 0 (-7, 8) 11 0.4 (3.67) 0 (-7, 6) 11 2.0 (7.18) 0 (-7, 16)

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11.5.2

Clinical Study Report SRT-2104-013 31-MAY-2012

Hospital Anxiety and Depression Scale (HADS)

The summary statistics of the change from baseline for the HADS depression and anxiety scores are summarized in Table 11.5.2-1 and Table 11.5.2-2, respectively. The HADS questionnaire consist of two severity subscales, one for depression and one to measure anxiety. Each subscale score is the sum of 7-questions that are scored from 0-3 for a maximum score of 21. For both subscales, a score of 7 or less is considered to be a ‘noncase’; a score of >=11 is considered a case (of depression or anxiety). Depression: The average depression scores at baseline did not indicate clinically significant cases and were comparable between treatment groups, with the 250 mg group having the highest baseline score (5.6). The greatest mean decrease occurred across active treatment arms at the Day 28 visit, and was greatest in the 250 mg group (-2.2) and was greater than placebo in all 3 active arms. Although not tested statistically, these results do not demonstrate a clinically meaningful impact of STR2104 treatment on depression in subjects that are not depressed at baseline. Anxiety: The average anxiety scores at baseline did not indicate clinically significant cases and were comparable between treatment groups, with the 250 mg group having the highest baseline score (6.9). The greatest mean decrease occurred in the 250 mg group at the Day 28 visit (-2.6). Change in scores fluctuated between +2 to -2 across visits and treatment groups and did not demonstrate a consistent pattern of change. Although not tested statistically, these results do not demonstrate a clinically meaningful impact of STR2104 treatment on anxiety in subjects that are not anxious at baseline.

Table 11.5.2-1 Summary Statistics of HADS Depression Score - Change from Baseline (Efficacy Analysis Set Population) Visit Depression Score Day 1 (Baseline), n Mean (SD) Median (min, max) Day 28, n Mean (SD) Median (min, max) Day 56, n Mean (SD) Median (min, max) Day 84, n Mean (SD) Median (min, max)

Source: Table 14.2.7.1 and Table 14.2.7.2

Placebo (N=7) 7 3.3 (2.87) 2.0 (0, 8) 7 0 (1.73) 0 (-2, 2) 7 -0.4 (3.31) 0 (-5, 4) 7 -0.3 (2.98) -1.0 (-4, 5)

250 mg (N=9) 9 5.6 (4.00) 6.0 (0, 10) 9 -2.2 (2.99) -1.0 (-9, 0) 6 -1.7 (1.63) -1.5 (-4, 0) 8 -0.5 (4.11) -0.5 (-6, 8)

SRT2104 Dose 500 mg (N=12) 12 5.2 (3.90) 4.5 (0, 11) 12 -1.3 (4.29) -1.5 (-7, 6) 9 -2.2 (3.70) -3.0 (-9, 2) 12 -1.7 (3.50) -1.5 (-9, 3)

1000 mg (N=11) 11 3.9 (4.23) 2.0 (0, 12) 11 -0.2 (2.36) 0 (-5, 3) 11 -0.1 (4.11) 0 (-6, 7) 11 -0.7 (4.86) -1.0 (-8, 9)

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Clinical Study Report SRT-2104-013 31-MAY-2012

Table 11.5.2-2 Summary Statistics of HADS Anxiety Score - Change from Baseline (Efficacy Analysis Set Population) Visit Anxiety Score Day 1 (Baseline), n Mean (SD) Median (min, max) Day 28, n Mean (SD) Median (min, max) Day 56, n Mean (SD) Median (min, max) Day 84, n Mean (SD) Median (min, max)

Placebo (N=7) 7 3.4 (3.64) 2.0 (0, 9) 7 0.6 (4.58) 0 (-4, 10) 7 0.9 (4.71) 1.0 (-4, 10) 7 0.1 (5.52) -2.0 (-4, 12)

250 mg (N=9) 9 6.9 (3.76) 9.0 (0, 11) 9 -2.6 (3.84) -2.0 (-8, 4) 6 -2.3 (3.61) -2.5 (-8, 2) 8 -1.9 (4.29) -1.5 (-10, 4)

Source: Table 14.2.7.1 and Table 14.2.7.2

11.5.3

SRT2104 Dose 500 mg (N=12) 12 4.0 (2.66) 4.0 (0, 9) 12 1.3 (3.08) 1.5 (-3, 6) 9 1.6 (4.75) 0 (-3, 10) 12 1.8 (3.96) 1.0 (-3, 10)

1000 mg (N=11) 11 4.9 (4.23) 3.0 (0, 14) 11 -0.2 (2.09) 0 (-3, 3) 11 0 (3.35) 0 (-8, 4) 11 -0.9 (1.92) -1.0 (-4, 3)

Psoriasis Quality of Life Questionnaire (PQOL-12)

The summary statistics of the change from baseline for the PQOL-12 total score are summarized in Table 11.5.1-3. The PQOL-12 is a psoriasis specific self-administered questionnaire comprised of 12 questions each scored from 0-10 (lower being better) for a total possible score of 120. Changes of 18 points have been identified as clinically meaningful [Feldman 2005].. Treatment groups were comparable at baseline, with placebo having the lowest baseline mean score (64.9) and the 1000 mg group (78.7) having the highest. Reductions in PQOL-12 scores were higher in all active treatment arms as compared to placebo. Clinically meaningful change was observed in greater than 50% of subjects in the 500 mg group (median:-21.5) and a maximum change of -87 was recorded in this arm.

Table 11.5.3

Summary Statistics of the PQOL-12 Total Score Change from Baseline on Visit Day 84 (Efficacy Analysis Set Population)

PQOL-12 Total Score Day 1 (Baseline), n Mean (SD) Median (min, max) Day 84, n Mean (SD) Median (min, max)

Placebo (N=7) 7 64.9 (34.18) 55.0 (31, 115) 7 -4.3 (16.99) -4.0 (-31, 22)

Source: Table 14.2.9.1 and Table 14.2.9.2

250 mg (N=9) 9 75.6 (32.14) 77.0 (25, 115) 8 -13.3 (26.64) -10.0 (-69, 20)

SRT2104 Dose 500 mg (N=12) 12 72.2 (19.90) 79.0 (34, 92) 12 -23.8 (38.55) -21.5 (-87, 34)

1000 mg (N=11) 11 78.7 (31.86) 77.0 (12, 116) 11 -8.5 (15.18) -12.0 (-28, 23)

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11.5.4

Clinical Study Report SRT-2104-013 31-MAY-2012

Health Outcomes Conclusions

• Most subjects were not clinically depressed or suffering from anxiety at baseline, therefore interpretation of any changes in the depression and anxiety scale scores is of limited value • Psoriasis-Specific Quality of Life scores improved in all SRT2104 treatment groups; the improvements were of greater magnitude in all active treatment groups compared to placebo • More than 50% of the 500 mg group experienced clinically meaningful improvement in their PQOL-12 score.

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11.6

Clinical Study Report SRT-2104-013 31-MAY-2012

Gene Expression Data

An exploratory objective of this study was to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and/or sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. Twenty one individual genes were selected for analysis. Gene expression patterns in the skin biopsy tissues were quantitated via PCR at baseline and at Day 84. Quality of RNA was sometimes suboptimal; therefore not all tissues were usable for gene expression analyses. Mean changes from baseline were calculated for all active dose groups and placebo. The following genes showed reductions from baseline for all active treatment groups compared to the placebo group, which had an increase or no change: CCL20, IL-6, and TNFα. The p65 gene expression also seemed to be reduced at Day 84 after treatment with SRT2104, compared to placebo, which showed an increase in expression of p65. Changes in other genes were inconsistent or did not appear to be differentiated between the active treatment groups and placebo. See Section 9.7.1.7.6 for or details regarding the statistical analyses performed for the gene expression data. Additional analyses were ongoing at the time of this report. Table 11.6-1

Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 1 of 3)

Gene Name Placebo Visit (N=7) CCL20 n Mean (SD) Day 1 7 13.9 (15.05) Day 84 7 28.4 (43.21) CFB 7 14.4 (49.89) CCL20 repeat n Mean (SD) Day 1 7 17.5 (8.75) Day 84 7 11.1 (7.92) CFB 7 -6.3 (10.83) CXCL1 n Mean (SD) Day 1 7 71.4 (60.22) Day 84 7 28.0 (26.37) Change 7 -43.4 (53.49) DEFB4A n Mean (SD) Day 1 7 5132 (2915) Day 84 7 2420 (1782) CFB 7 -2712 (3270) IFNg n Mean (SD) Day 1 7 0.8 (0.56) Day 84 7 0.5 (0.31) CFB 7 -0.3 (0.65) CFB = change from baseline

n 9 9 9 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6

250 mg (N=9) Mean (SD) 7.9 (12.46) 6.1 (9.57) -1.8 (12.60) Mean (SD) 16.1 (8.45) 12.6 (11.17) -3.9 (11.21) Mean (SD) 80.7 (77.35) 25.8 (28.54) -12.5 (39.11) Mean (SD) 6100 (4252) 2892 (3410) -1323 3803) Mean (SD) 4.4 (9.18) 0.9 (0.32) -5.2 (11.27)

n 11 11 11 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) Mean (SD) n Mean (SD) 20.8 (32.30) 11 20.7 (50.42) 6.9 (17.15) 6 11.6 (18.16) -13.9 (26.43) 6 -26.2 (71.78) Mean (SD) n Mean (SD) 16.5 (14.86) 11 15.7(22.38) 14.6 (25.26) 10 17.5 (15.77) -3.4 (21.80) 10 1.7 (12.14) Mean (SD) n Mean (SD) 58.8 (57.73) 11 67.3 (75.72) 28.2 (19.78) 10 82.8 (109.9) -33.0 (53.31) 10 14.0 (90.15) Mean (SD) n Mean (SD) 7222 (5018) 11 7257 (4147) 5010 (5427) 10 8382 (4452) -1514 (7465) 10 1693 (5564) Mean (SD) n Mean (SD) 0.8 (0.56) 11 0.8 (0.56) 0.8 (0.67) 10 0.9 (0.53) -0.1 (0.82) 10 0.3 (0.56)

n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33

Overall (N=39) Mean (SD) 16.4 (32.70) 12.1 (24.37) -6.8 (41.51) Mean (SD) 16.4 (14.94) 14.4 (16.93) -2.5 (15.04) Mean (SD) 68.8 (66.32) 44.3 (66.58) -17.2 (67.49) Mean (SD) 6581 (4177) 5097 (4704) -761.6 (5621) Mean (SD) 1.7 (4.57) 0.8 (0.52) -1.0 (4.94) continued

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Clinical Study Report SRT-2104-013 31-MAY-2012

Table 11.6-1 Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 2 of 3) Placebo Gene Name Visit (N=7) IFNg custom n Mean (SD) Day 1 7 222 (65.59) Day 84 7 179 (45.30) CFB 7 -43.3 (42.90) IL12B n Mean (SD) Day 1 7 0.8 (0.59) Day 84 7 0.6 (0.39) CFB 7 -0.2 (0.46) IL13 n Mean (SD) Day 1 7 0 Day 84 7 0 CFB 7 0 IL17A n Mean (SD) Day 1 7 2.9 (2.58) Day 84 7 1.4 (0.96) CFB 7 -1.5 (2.18) IL1B n Mean (SD) Day 1 7 91.5 (59.84) Day 84 7 36.9 (34.10) CFB 7 -54.6 (53.69) IL1B repeat n Mean (SD) Day 1 7 25.1 (21.11) Day 84 7 14.2 (10.87) CFB 7 -10.9 (24.19) IL22 n Mean (SD) Day 1 7 0.5 (0.39) Day 84 7 0.2 (0.16) CFB 7 -0.3 (0.42) IL23A n Mean (SD) Day 1 7 1.6 (1.00) Day 84 7 1.3 (0.85) CFB 7 -0.4 (1.11) IL6 n Mean (SD) Day 1 7 0.8 (0.38) Day 84 7 0.9 (0.58) CFB 7 0 (0.64) IL8 n Mean (SD) Day 1 7 244 (439) Day 84 7 111 (134) CFB 7 -133 (458) CFB = change from baseline

n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6

250 mg (N=9) Mean (SD) 234 (77.69) 192 (38.78) -41.5 (95.52) Mean (SD) 1.6 (0.95) 0.6 (0.56) -0.8 (1.06) Mean (SD) 0.5 (1.45) 0 -0.7 (1.78) Mean (SD) 2.5 (1.69) 1.5 (1.24) -0.4 (1.12) Mean (SD) 99.5 (92.09) 29.9 (30.94) -18.8 (42.64) Mean (SD) 35.2 (29.14) 10.5 (9.20) -9.4 (16.05) Mean (SD) 6.7 (18.50) 0.2 (0.23) -9.4 (22.62) Mean (SD) 3.1 (1.48) 1.6 (1.04) -1.3 (2.29) Mean (SD) 1.3 (0.97) 0.7 (0.30) -0.6 (1.05) Mean (SD) 133 (165) 25.8 (26.81) -21.2 (65.74)

n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) Mean (SD) n Mean (SD) 222 (40.94) 11 236 (93.71) 233 (113) 10 202 (53.31) 13.8 (103) 10 -30.7 (113.2) Mean (SD) n Mean (SD) 1.3 (0.97) 11 1.1 (0.79) 1.1 (1.34) 10 1.4 (1.79) -0.2 (1.50) 10 0.4 (2.10) Mean (SD) n Mean (SD) 0 11 0.1 (0.11) 0 10 0.1 (0.30) 0 10 0 (0.23) Mean (SD) n Mean (SD) 3.4 (2.77) 11 2.8 (2.08) 3.2 (3.69) 10 2.3 (1.14) -.04 (3.55) 10 -0.3 (2.17) Mean (SD) n Mean (SD) 72.2 (62.64) 11 75.9 (84.47) 38.3 (28.05) 10 88.0 (94.99) -36.9 (68.31) 10 10.6 (80.73) Mean (SD) n Mean (SD) 20.8 (17.03) 11 18.2 (17.54) 13.6 (17.09) 10 19.7 (17.59) -8.8 (16.21) 10 1.5 (18.85) Mean (SD) n Mean (SD) 0.4 (0.36) 11 1.1 (2.27) 0.3 (0.48) 10 0.4 (0.39) -0.1 (0.41) 10 -0.8 (2.43) Mean (SD) n Mean (SD) 1.7 (1.25) 11 1.6 (0.94) 1.9 (2.58) 10 2.2 (1.30) 0.1 (2.54) 10 0.7 (1.25) Mean (SD) n Mean (SD) 1.6 (1.67) 11 2.4 (5.31) 0.9 (0.57) 10 1.1 (0.57) -0.9 (1.86) 10 -1.5 (5.82) Mean (SD) n Mean (SD) 80.5 (100) 11 69.5 (81.62) 55.9 (88.52) 10 68.1 (77.21) -31.7 (75.78) 10 -5.8 (103)

n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33

Overall (N=39) Mean (SD) 229 (69.81) 205 (73.81) -21.9 (94.74) Mean (SD) 1.2 (0.87) 1.0 (1.27) -0.1 (1.50) Mean (SD) 0.1 (0.71) 0 (0.17) -0.1 (0.77) Mean (SD) 2.9 (2.25) 2.2 (2.27) -0.6 (2.49) Mean (SD) 83.3 (74.38) 51.6 (61.09) -23.0 (67.85) Mean (SD) 24.2 (21.48) 15.0 (14.70) -6.2 (18.74) Mean (SD) 2.1 (9.06) 0.3 (0.36) -2.0 (9.70) Mean (SD) 2.0 (1.31) 1.8 (1.66) -0.1 (1.95) Mean (SD) 1.6 (2.99) 0.9 (0.52) -0.8 (3.33) Mean (SD) 120 (214) 65.8 (90.16) -43.4 (217) continued

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Table 11.6-1 Summary of Baseline (Day 1) and Change from Baseline (Day 84) Gene Expression Data (Efficacy Analysis Set Population) (Page 3 of 3) Gene Name Visit K16 Day 1 Day 84 CFB LCN2 Day 1 Day 84 CFB P50 Day 1 Day 84 CFB S100A7

n 7 7 7 n 7 7 7 n 7 7 7 n

Day 1

7

Day 84

7

CFB

7

TNFα Day 1 Day 84 CFB p65 Day 1 Day 84 CFB

n 7 7 7 n 7 7 7

Placebo (N=7) Mean (SD) 4512 (3886) 3207 (1727) -1305 (2347) Mean (SD) 2462 (1267) 1573 (1092) -890 (1084) Mean (SD) 29.5 (10.79) 27.1 (4.88) -2.4 (14.13) Mean (SD) 19482 (5000) 15137 (9943) -4345 (10228) Mean (SD) 3.2 (1.49) 3.4 (1.46) 0.2 (2.02) Mean (SD) 400 (156) 526 (236) 127 (146)

n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6 n 9 6 6

Source: Table 14.4.1.1 and Table 14.4.1.2 CFB=Change from Baseline

250 mg (N=9) Mean (SD) 7079 (5527) 2969 (3113) -2672 (6129) Mean (SD) 2656 (1666) 1613 (1415) -475 (1845) Mean (SD) 45.0 (12.21) 31.9 (14.03) -15.1 (25.95) Mean (SD) 26373 (12600) 17678 (15050) -4985 (16027) Mean (SD) 4.9 (2.93) 3.3 (1.72) -2.4 (2.72) Mean (SD) 619 (192) 537 (56.51) -154 (201)

n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10 n 11 10 10

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) Mean (SD) n Mean (SD) 6512 (3902) 11 8374 (4087) 5087 (4603) 10 8850 (7984) -540 (4600) 10 898.5 (7775) Mean (SD) n Mean (SD) 2991 (1666) 11 2099 (1304) 1958 (1462) 10 2511 (1621) -904 (1834) 10 592 (1691) Mean (SD) n Mean (SD) 34.0 (11.49) 11 33.8 (9.40) 35.4 (11.43) 10 32.1 (6.81) 0.1 (10.21) 10 -0.9 (10.82) Mean (SD) n Mean (SD) 23696 18312 11 (10387) (7801) 15113 25933 10 (11335) (10842) -9469 8531 10 (13091) (9429) Mean (SD) n Mean (SD) 4.5 (2.53) 11 4.1 (2.03) 3.8 (1.54) 10 3.1 (0.94) -0.8 (2.28) 10 -0.8 (2.07) Mean (SD) n Mean (SD) 636 (86.92) 11 642 (237) 718 (370) 10 581 (196) 78.4 (343) 10 -51.1 (261)

n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33 n 38 33 33

Overall (N=39) Mean (SD) 6817 (4411) 5443 (5645) -653.7 (5610) Mean (SD) 2556 (1481) 1981 (1424) -370 (1715) Mean (SD) 35.7 (11.88) 32.0 (9.69) -3.5 (15.38) Mean (SD) 21995 (9733) 18863 (12101) -2112 (13708) Mean (SD) 4.2 (2.32) 3.4 (1.36) -0.9 (2.30) Mean (SD) 590 (194) 258 (528) 7.2 (270)

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12

Clinical Study Report SRT-2104-013 31-MAY-2012

SAFETY EVALUATION

12.1 Extent of Exposure Exposure to SRT2104 is summarized in Table 14.3 and presented in Table 12.2-1. Exposure data for individual subjects is provided in Listing 16.2.5.3. Thirty-nine subjects received study medication, with 7 subject receiving placebo, and 32 subjects receiving SRT2104; mean duration of dosing was 78.6 days (Table 12.1-1).

Table 12.1-1 Summary of SRT2104 Exposure (Safety Analysis Set Population) Parameter Total Cumulative Dose (grams) n Mean (SD) Median (min, max) Duration (days) n Mean (SD) Median (min, max) Source: Table 14.3

12.2

Placebo (N=7)

250 mg (N=9)

SRT2104 Dose 500 mg (N=12)

1000 mg (N=11)

Total (N=39)

7 0 0

9 16.8 (4.76) 20.0 (9, 21)

12 37.8 (8.81) 42.0 (21, 44)

11 83.4 (3.67) 84.0 (75, 89)

39 39.0 (31.6) 41.5 (0, 89)

7 85.6 (1.51) 85.0 (85, 89)

9 69.4 (20.1) 84.0 (36, 85)

12 76.2 (17.8) 85.0 (42, 89)

11 84.5 (3.62) 85.0 (75, 89)

39 78.6 (14.9) 85.0 (36, 89)

Adverse Events (AEs)

12.2.1 Brief Summary of Adverse Events Across all treatment groups, a total of 27 subjects (69%) experienced at least one treatment emergent AE. The incidence of treatment emergent AEs by treatment group was: 3 subjects (43%) in the placebo group; 4 subjects (44%) in the SRT2104 250 mg dose group; 9 subjects (75%) in the SRT2104 500 mg dose group; 11 subjects (100%) in the SRT2104 1000 mg dose group. SAEs were reported for 3 subjects (8%): 2 subjects (22%) in the SRT2104 250 mg and 1 subject (9%) in the SRT2104 1000 mg dose group. All SAEs were considered either likely related or related to IP. An overall summary of the AEs and SAEs that occurred in the study is presented in Table 12.2.1-1.

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Table 12.2.1-1

Overall Summary of AEs (Safety Analysis Set Population)

Subjects with AEs, n (%) Any AE AEs by Maximum Intensity Mild Moderate Severe Life-threatening Death AEs by Highest Relationship to IP Not related Unlikely related Possibly related Related All SAEs All AEs Leading to Discontinuation from Treatment AEs Leading to Death

Source: Table 14.3.1.3, 14.3.1.4, 14.3.2.1, 14.3.2.3

12.2.2

Clinical Study Report SRT-2104-013 31-MAY-2012

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 9 (75) 11 (100)

Placebo (N=7) 3 (43)

250 mg (N=9) 4 (44)

Total (N=39) 27 (69)

2 (29) 1 (14) 0 0 0

2 (22) 1 (11) 1 (11) 0 0

3 (25) 6 (50) 0 0 0

5 (45) 5 (45) 1 (9) 0 0

12 (31) 13 (33) 2 (5) 0 0

1 (14) 1 (14) 1 (14) 0 0

2 (22) 0 2 (22) 0 2 (22)

6 (50) 1 (8) 2 (17) 0 0

4 (36) 3 (27) 3 (27) 1 (9) 1 (9)

13 (33) 5 (13) 8 (21) 1 (3) 3 (8)

0

2 (22)

1 (8)

1 (9)

4 (10)

0

0

0

0

0

Display of Adverse Events

The relationship between all AE SOCs, preferred terms, and verbatim terms provided in Table 14.3.1.1. A summary of all treatment emergent AEs is presented in Table 14.3.1.2, by maximum intensity in Table 14.3.1.3, and by highest relationship to study medication in Table 14.3.1.4. SAEs are summarized in Table 14.3.2.1 and listed in Table 14.3.2.2. AEs leading to discontinuation from treatment are summarized in Table 14.3.2.3 and listed in Table 14.3.2.4. An overall summary of AEs reported during the study is summarized in Table 12.2.1-1. 12.2.3 Analysis of AEs Adverse Events Regardless of Relationship to Treatment The AEs occurring in more than 1 subject across all treatment groups is summarized in Table 12.2.3-1. The most common AEs occurring in at least 3 subjects receiving SRT2104 were: psoriatic arthropathy (1 subject in the 500 mg dose group and 2 subjects in the 1000 mg dose group), dizziness (3 subjects in the 1000 mg dose group), and headache (2 subjects in the 500 mg dose group and 1 subject in the 1000 mg dose group).

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Clinical Study Report SRT-2104-013 31-MAY-2012

Table 12.2.3-1 Summary of AEs Regardless of Relationship to Treatment in >1 Subject (Preferred Term) Across Treatment Groups (Safety Analysis Set Population) System Organ Class (any event), n (%) Preferred Term, n (%)a Subjects with Any Event (Total), n (%) Infections and Infestations Upper respiratory tract infection Gastrointestinal disorders Nausea Vomiting Musculoskeletal and connective tissue disorders Psoriatic arthropathy Pain in extremity Nervous system disorders Dizziness Headache Investigations Alanine aminotransferase increased (ALT) Aspartate aminotransferase increased (AST) Hepatic enzyme increased Skin and subcutaneaous tissue disorders Pruritus General disorders and administrative site conditions Fatigue Pyrexia Source: Table 14.3.1.2 a. MedDRA v12.0

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 9 (75) 11 (100) 5 (42) 4 (36) 1 (8) 1 (9) 2 (17) 3 (27) 0 1 (9) 0 1 (9) 1 (8) 4 (36) 1 (8) 2 (18) 1 (8) 1 (9) 2 (17) 4 (36) 0 3 (27) 2 (17) 1 (9) 1 (8) 4 (36) 0 2 (18) 0 2 (18) 1 (8) 1 (9) 0 2 (18) 0 1 (9)

Placebo (N=7) 3 (43) 2 (29) 1 (14) 1 (14) 0 0 1 (4) 0 0 0 0 0 0 0 0 0 3 (43) 1 (14)

250 mg (N=9) 4 (44) 0 0 3 (33) 1 (11) 1 (11) 0 0 0 0 0 0 0 0 0 0 0 0

Total (N=39) 27 (69) 11 (28) 3 (8) 9 (23) 2 (5) 2 (5) 6 (15) 3 (8) 2 (5) 6 (15) 3 (8) 3 (8) 5 (13) 2 (5) 2 (5) 2 (5) 5 (13) 2 (5)

1 (14)

0

1 (8)

2 (18)

4 (10)

0 1 (14)

0 0

0 0

2 (18) 1 (9)

2 (5) 2 (5)

AEs by Maximum Intensity AEs by maximum intensity are summarized in Table 14.3.1.3. No life-threatening AEs or deaths occurred in the study. The maximum intensity of treatment emergent AEs by treatment group was as follows: • Placebo: mild: 2 subjects; moderate: 1 subject; severe: none • 250 mg SRT2104: mild: 2 subjects; moderate: 1 subject; severe: 1 subject (pancreatitis) • 500 mg SRT2104: mild: 3 subjects; moderate: 6 subjects; severe: none • 1000 mg SRT2104: mild: 5 subjects; moderate: 5 subjects; severe: 1 subject (myalgia) Note: the severe event of pancreatitis was an SAE, see Section 12.3.2. Treatment-Related Adverse Events AEs by the highest relationship to study medication (assigned by the investigator) are summarized in Table 14.3.1.4; the AEs considered by the investigator to be possibly related and/or related to study medication are presented in Table 12.2.4-1. Across all treatment groups, a total of 9 subject (23%) experienced at least one treatment emergent AE that was considered by the investigator to be possibly related and/or related to treatment. The incidence of treatment-related AEs by treatment group was: 1 subject (14%) in the placebo group; 2 subjects (22%) in the SRT2104 250 mg dose group; 2 subjects (17%) in the 78 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Clinical Study Report SRT-2104-013 31-MAY-2012

SRT2104 500 mg dose group; 4 subjects (36%) in the SRT2104 1000 mg dose group. The treatment-related AEs occurring in more than one subject across all treatment groups were: psoriatic arthropathy (1 subject in the 500 mg dose group and 1 subject in the 1000 mg dose group), headache (1 subject in the 500 mg dose group and 1 subject in the 1000 mg dose group), increased ALT (2 subjects in the 1000 mg dose group), increased AST (2 subjects in the 1000 mg dose group), and fatigue (2 subjects in the 1000 mg dose group). Three subjects receiving SRT2104 (all in the 1000 mg dose group) experienced abnormal laboratory values related to the liver that were reported as treatment-related AEs, with values for one subject also reported as an SAE. See Section 12.3.2 (SAEs) Section 12.4.2 (Clinical Chemistry) for details regarding these events. Table 12.2.4-1

Summary of Treatment-Related (Possibly Related and/or Related AEs (Safety Analysis Set Population)

System Organ Class (any event), n (%) Preferred Term, n (%) Subjects with Any Event (Total), n (%) Infections and Infestations Upper respiratory tract infection Gastrointestinal disorders Nausea Pancreatitisa Dyspepsia Musculoskeletal and connective tissue disorders Psoriatic arthropathy Pain in extremity Myalgiab Osteoarthritis Nervous system disorders Headache Dizziness Disturbance in attention Investigations Alanine aminotransferase increased (ALT)c Aspartate aminotransferase increased (AST)c Hepatic enzyme increasedc Blood bilirubin increasedc General disorders and administrative site conditions Fatigue Pyrexia Oedema peripheral Respiratory, thoracic and mediastinal disorders Pneumonitis

SRT2104 Dose 500 mg 1000 mg (N=12) (N=11) 2 (17) 4 (36) 1 (8) 0 1 (8) 0 1 (8) 1 (9) 0 1 (9) 0 0 1 (8) 0 1 (8) 1 (9) 1 (8) 1 (9) 1 (8) 0 0 1 (9) 0 1 (9) 1 (8) 1 (9) 1 (8) 1 (9) 0 1 (9) 0 1 (9) 0 3 (27) 0 2 (18) 0 2 (18) 0 1 (9) 0 1 (9)

Placebo (N=7) 1 (14) 1 (14) 1 (14) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

250 mg (N=9) 2 (22) 0 0 1 (11) 0 1 (11) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Total (N=39) 9 (23) 2 (5) 2 (5 ) 3 (8) 1 (3) 1 (3) 1 (3) 2 (5) 2 (5) 1 (3) 1 (3) 1 (3) 2 (5) 2 (5) 1 (3) 1 (3) 3 (8) 2 (5) 2 (5) 1 (3) 1 (3)

0

0

1 (8)

2 (18)

3 (8)

0 0 0 0 0

0 0 0 1 (11) 1 (11)

0 0 1 (8) 0 0

2 (18) 1 (9) 0 0 0

2 (5) 1 (3) 1 (3) 1 (3) 1 (3)

Source: Table 14.3.1.4 a. the event of pancreatitis was severe in intensity (Table 14.3.1.3) and was reported as an SAE (Section 12.3.2). b. the event of myalgia was severe in intensity (Table 14.3.1.3). c. the event of increase ALT, increase AST, increased hepatic enzyme, and increased bilirubin were reported as SAEs (Section 12.3.2).

12.2.4 Listing of Adverse Events by Subject A listing of all adverse events occurring during the study is provided by individual subject in Listing 16.2.7.1. 79 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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12.3

Clinical Study Report SRT-2104-013 31-MAY-2012

Deaths, Other Serious Adverse Events, and Other Significant Adverse Events

12.3.1 Deaths No deaths occurred during the study 12.3.2 Other Serious Adverse Events Serious adverse events that occurred in the study are summarized in Tables 14.3.2.1 and 14.3.2.2. SAEs were reported for 3 subjects (8%): 2 subjects (22%) in the SRT2104 250 mg and 1 subject (9%) in the SRT2104 1000 mg dose group. All SAEs were considered either likely related or related to IP. Information on individual subjects experiencing SAEs is presented in Table 12.3.2-1. The Narratives for each subject with an SAE are located in Section 14.3.3. Table 12.3.2-1 Subjects with SAEs Reported for Study SRT-2104-013 (Safety Analysis Set Population)

Source: Table 14.3.2.2

12.3.3 Other Significant Adverse Events AEs leading to permanent discontinuation of IP occurred in 4 subjects (10%), and are summarized in Tables 14.3.2.3 and 14.2.3.4. Information on individual subjects is presented in Table 12.3.3-1. Table 12.3.3-1 Subject with AEs Leading to Permanent Discontinuation of IP (Safety Analysis Set Population)

a. These events were SAEs (see Section 12.3.2)

12.3.4 Pregnancies No pregnancies were reported during the study.

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12.4

Clinical Study Report SRT-2104-013 31-MAY-2012

Clinical Laboratory Evaluations

12.4.1

Listing of Individual Laboratory Measurements by Subject and Each Abnormal Laboratory Value Reference ranges for clinical laboratory tests are provided in Table 14.3.3.1. Abnormalities of potential clinical importance (PCI) for hematology and coagulation are provided in Tables 14.3.3.4 and 14.3.3.5, and for clinical chemistry in Tables 14.3.3.8 and 14.3.3.9. 12.4.2

Evaluation of Each Laboratory Parameter

12.4.2.1 Laboratory Values over Time Hematology and Coagulation Mean and mean changes from baseline in hematology and coagulation values are summarized in Table 14.3.3.2 and Table 14.3.3.3, respectively. No apparent dose-related trends and no clinically relevant changes in hematology or coagulation values were observed. Clinical Chemistry Mean and mean changes from baseline in clinical chemistry values are summarized in Table 14.3.3.6 and Table 14.3.3.7, respectively. While individual subject changes occurred in clinical chemistry values during the study, (Section 12.4.2.2) overall, clinically relevant trends were not noted. Eight subjects had glucose values of PCI, Table 14.3.3.8. Five of these 8 subjects have a history of diabetes mellitus. Increases in indirect bilirubin (µmol/L) without concomitant increases in transaminases were observed in some subjects treated with placebo and SRT2104. The highest mean (maximum increase) elevations during the treatment period were 0.9 (8), 3.0 (14), 2.2 (16), and 3.6 (22) in the placebo, 250 mg, 500 mg and 100 mg dose groups, respectively. These increases appeared to be self-limiting and were not considered clinically relevant. Increases in creatinine (µmol/L) were observed in some subjects treated with SRT2104. The highest mean (maximum increase) elevations during the treatment period were 0.0 (17), 6.3 (18), 7.5 (27), and 7.2 (18) in the placebo, 250 mg, 500 mg and 100 mg dose groups, respectively. These increases appeared to be self-limiting and were not considered clinically relevant. 12.4.2.2 Individual Subject Changes Five subjects (1 in the SRT2104 500 mg SRT dose group and 4 in the SRT2104 1000 mg dose group had a clinical laboratory value reported as an AE. The information for these subjects in provided in Table 12.4.2-1.

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Table 12.4.2-1

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Summary of Subjects with Clinical Chemistry Values Reported as AEs (Safety Analysis Set Population)

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12.5

Clinical Study Report SRT-2104-013 31-MAY-2012

Vital Signs, Physical Findings and Other Observations Related to Safety

12.5.1 Vital Signs The vital signs values of PCI are defined in Table 9.7.1.7.3-2. In the Safety Population, no values of PCI in vital signs occurred in the placebo group, or the SRT2104 250 mg and 500 mg dose groups. Of the 11 subjects in the SRT2104 1000 mg dose group, two subjects (18%) had high systolic blood pressure values of PCI (Table 14.3.4.3.

No action was needed/taken for either of these subjects, and both completed the study. Overall, no apparent dose related trends in vital signs values were seen during the study. 12.5.2 Electrocardiograms A summary of ECG overall impressions is presented in Table 14.3.6.1. None of the abnormal findings were considered by the investigator to be clinically significant. The 12lead ECG values of PCI are defined in Table 9.7.1.7.3-4. During the study, a total of 14 subjects had ECG values of PCI (Table 14.3.6.4): 3 subjects in the placebo group, 1 subject in the SRT2104 250 mg dose group, 4 subjects in the SRT2104 500 mg dose group, and 6 subjects in the 1000 mg dose group. None of these values were considered clinically significant. Overall, no apparent dose related trends in ECG values were seen during the study. 12.6 Safety Conclusions • Daily doses of 250 mg, 500 mg, and 1000 mg doses of SRT2104 were generally safe and well tolerated in subjects with moderate to severe plaque psoriasis. • Across all treatment groups, a total of 27 subjects (69%) experienced at least one treatment emergent AE; as the dose of SRT2104 increased, both the rate and severity of treatment-emergent AEs increased. • AEs leading to permanent discontinuation of IP occurred in 4 subjects (10%) in the SRT2104 treatment arms: 2 subjects (22%) in the 250 mg dose group, 1 subject (8%) in the 500 mg dose group, and 1 subject (9%) in the 1000 mg dose group. • Serious adverse events were reported for 3 subjects (8%): 2 subjects (22%) in the SRT2104 250 mg dose group (pneumonitis and pancreatitis) and 1 subject (9%) in the SRT2104 1000 mg dose group (increased bilirubin and AST). All SAEs were considered either likely related or related to IP. • No deaths occurred in the study. • There were some individual laboratory changes noted for indirect bilirubin and creatinine that were typically mild and self-limiting and of unclear clinical relevance. • There were several patients on SRT 2104 that experienced elevations in LFTs leading to study drug discontinuation. LFTs resolved after study drug discontinuation. The relevance of these changes is unclear. 83 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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•

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No clinically relevant changes in vital signs or ECG parameters were observed.

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Clinical Study Report SRT-2104-013 31-MAY-2012

DISCUSSION AND OVERALL CONCLUSIONS

The aims of the SRT-2104-013 study were to determine the effect of escalating doses of oral SRT2104 on clinical activity and safety in subjects with moderate to severe plaque-type psoriasis. SRT2104 is a potent selective small molecule activator of SIRT1 being developed to treat a number of inflammatory conditions, including psoriasis. The study was a multicenter, randomized, double-blind, placebo-controlled, Phase IIa, conducted in the United States. Efficacy SRT2104 appears to have efficacy in patients with moderate to severe plaque type psoriasis based on improvements in skin biopsies, PASI scores and PGA scores compared to the placebo control. High level outcomes are summarized below. • Across all dose groups, approximately 35% of patients treated with SRT2104 achieved good to excellent improvement on skin biopsies at Day 84, based on the Krueger scoring; skin biopsy outcomes did not show positive correlation with dose group or drug exposure levels • There appeared to be a dose-dependent improvement in PASI scores and PGA scores for patients treated with SRT2104 compared to placebo; mean PASI improvements approached 40% at Day 84 in the higher SRT2104 dose groups; approximately 25% of patients achieved minimal to clear PGA scores at Day 84 in the higher SRT2104 dose groups • No meaningful conclusions could be drawn with regard to the biomarkers FGF21 or hsCRP • Patients treated with SRT2104 showed improvements in the PQOL compared to placebo treated subjects • SRT2104 reduced expression of certain genes in the skin at Day 84 compared to placebo including CCL20, IL-6, TNFα, and p65. • Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104; distinct differences in Cmax and AUC were observed between the low exposure group and high exposure group Safety Safety results confirmed previous study findings indicating that escalating doses of SRT2104 are generally safe and well tolerated; no dose-limiting toxicities were observed in this study. Across all treatment groups, a total of 27 subjects (69%) experienced at least one treatment emergent AE; of those 9 subjects (23%) were considered by the investigator to be treatment related. Across all treatment groups, the majority of AEs reported were either mild (31%) or moderate (33%) in intensity. The highest number of subjects reporting an individual AE across all treatment groups was small (3 subjects [8%]). Three subjects (8%) experienced SAEs: pneumonitis and pancreatitis for 2 subjects (22%) in the SRT2104 250 mg dose group; one subject (9%) in the SRT2104 1000 mg dose group experienced increased bilirubin and AST. All SAEs were considered either likely related or related to IP. No deaths occurred during the study. No consistent trends with the SRT2104 escalating doses used in this study were seen for laboratory abnormalities or vital sign changes and no 85 THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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clinically significant changes in ECGs were observed. Some laboratory changes were noted in indirect bilirubin and creatinine but were not considered to be clinically relevant. Some subjects treated with SRT2104 experienced increases in LFTs leading to study drug discontinuation. LFTs returned to normal after study drug discontinuation. The relevance of these observations is unclear. Careful LFT monitoring should be conducted in future studies.

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14

TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT

14.1

Demographic Data

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14.2

Efficacy Data

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14.3

Safety Data

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14.3.1

Displays of Adverse Events

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14.3.2

Listings of Deaths, Other Serious and Significant Adverse Events

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This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient’s privacy. For further information please see the Patient Level Data section of

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15

REFERENCE LIST

Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004;73:417-35. Brakenhielm E, Cao R, Cao Y. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. Faseb J. 2001 Aug, 15:1798-1800. Breen DM, Sanli T, Giacca A, Tsiani E. Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK. Biochem Biophys Res Commun. 2008Sep12;374(1):117. Cohen H, Miller C, Bitterman K, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul;305(5682):390-2. Feldman SR, Koo JY, Menter A, et al. Decision points for the initiation of systemic treatment for psoriasis. J Am Acad Dermatol. 2005; 53:101 Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Experimental Gastroenterology. 2009; 44:41-45. Freyssenet D. Energy sensing and regulation of gene expression in skeletal muscle. J Appl Physiol. 2007 Feb;102(2):529-40. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep; 78:361-369. Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006; 5:97-108. Koo J, Kozma CM, Reinke K. The Development of a Disease-Specific Questionnaire to Assess Quality of Life for Psoriasis Patients: An Analysis of the Reliability, Validity, and Responsiveness of the Psoriasis Quality of Life Questionnaire. Dermatol. Psychosom. 2002;3:171–179. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a Brief Depression Severity Measure. J Gen Intern Med. 2001;16(9): 606–613. Krueger JG, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. NEJM. 2007; 356:580. Lavu S, Boss O, Elliott P, Lambert P. Sirtuins — novel therapeutic targets to treat age associated diseases. Nature. 2008;7Oct:841-853. Michan S. Sinclair D. Sirtuins in mammals: insights into their biological function Biochem J. 2007;404:l-13. Rapp SR, Feldman SR, Exum ML, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41:401-7. Roth, G. S., Ingram, D. K. & Lane, M. A. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001; 928:305-315. Schon MP, Boehncke WH. Psoriasis. NEJM. 2005; 352:1899. THIS DOCUMENT CONTAINS CONFIDENTIAL & PROPRIETARY INFORMATION OF SIRTRIS PHARMACEUTICALS, INC. DO NOT COPY OR DISTRIBUTE WITHOUT WRITTEN PERMISSION.

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Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Systems Biology. 2009; 3:31. Weindruch R, Keenan KP, Carney JM, et al. Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci. 2001 Mar; 56 Spec No 1:20-33. WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment, 2012. Oslo, 2011. Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. JEM 2007; 204:3183-3194

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16

APPENDICES

16.1

Study Information

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16.1.1

Protocol and Protocol Amendments

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16.1.2

Sample Case Report Form

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16.1.3

List of IECs or IRBs

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16.1.4

List and Description of Investigators and Other Important Participants in the Study

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16.1.5

Signatures of Principal or Coordinating Investigator(s)

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PRINCIPAL OR COORDINATING INVESTIGATOR(S) SIGNATURE(S)

OR SPONSOR’S RESPONSIBLE MEDICAL OFFICER

STUDY TITLE:

_______________________________________________ _______________________________________________

STUDY AUTHOR(S):

_______________________________________________

I have read this report and confirm that to the best of my knowledge it accurately describes the conduct and results of the study

INVESTIGATOR(S) OR SPONSOR’S RESPONSIBLE MEDICAL OFFICER: _______________________________________ SIGNATURE(S):

___________________________________

AFFILIATION:

______________________ ______________________ ______________________

DATE:

______________________

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16.1.6

Listing of Patients Receiving Test Drug(s)

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16.1.7

Randomization Scheme and Codes

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16.1.8

Audit Certificates

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16.1.9 Documentation of Statistical Methods As of the date of this report, no on-site audits have been conducted for the SRT2104-013 study.

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16.1.10

Documentation of Inter-laboratory Standardization Methods and Quality Assurance Procedures

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16.1.11

Publications Based on the Study

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16.1.12

Important Publications Referenced in the Report

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16.1.13

Charter for the Internal Safety Review Committee (ISRC)

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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.

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16.2.2

Protocol Deviations

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16.2.3

Patients Excluded from the Efficacy Analysis

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16.2.4

Demographic Data

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16.2.5

Compliance and/or Drug Concentration Data

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16.2.6

Individual Efficacy Response Data

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16.2.7

Adverse Event Listings

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16.2.8

Listing of Individual Laboratory Measurements by Patient

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16.3

Case Report Forms

16.3.1

CRFs for Deaths, Other Serious Adverse Events and Withdrawals for AE

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16.3.2

Other CRFs Submitted

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16.3.3

Individual Patient Data Listings

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17

STUDY RELATED INDICIES

17.1

Psoriasis Area and Severity Index (PASI)

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17.2

Physician’s Global Assessment (PGA)

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(continued on next page)

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17.3

Patient Health Questionnaire (PHQ-9) – Sample Questionnaire

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17.4

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Hospital Anxiety and Depression Scale (HADS)

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17.5

Psoriasis Quality of Life Questionnaire (PQOL-12) This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

(continued on next page)

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17.6

Recommendations for Meals

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17.7

Population PK Modeling

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SRT2104 Sirtris Pharmaceuticals, Inc

Clinical Study Report SRT-2104-013 31-MAY-2012

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Clinical Study Report SRT-2104-013 31-MAY-2012

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Table of Contents

14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT ........ 3 Table 14.1.1 Summary of Subject Disposition .................................................................................................. 3 Table 14.1.2 Summary of Analysis Populations ............................................................................................... 4 Table 14.1.3 Summary of Demographic Characteristics .................................................................................. 5 Table 14.1.4 Summary of Medical and Surgical History ................................................................................... 7 Table 14.1.5 Summary of Concomitant Medications ...................................................................................... 14 Table 14.2.1.2 Summary of Histological Improvement on Day 84 ................................................................. 22 Table 14.2.1.3 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groupsor SRT2104 Treatment Groups and Placebo - Day 84........................................................................ 23 Table 14.2.1.4 Summary of the Improvement Score based on the Krueger Criteria with Comparisonto Historical 5% Placebo Rate............................................................................................................................. 24 Table 14.2.2.4 Summary of Psoriasis Area Severity Index Scores (Total Score) .......................................... 25 Table 14.2.2.5 Summary of Percent Change from Baseline for Psoriasis Area SeverityIndex Scores (Total Score).............................................................................................................................................................. 27 Table 14.2.2.6 Difference (90% CI) in Proportion of Improvement based on >=PASI 25 betweenExposure Groups or Treatment Groups and Placebo..................................................................................................... 29 Table 14.2.2.7 Difference (90% CI) in Proportion of Improvement based on >=PASI 50 betweenExposure Groups or Treatment Groups and Placebo..................................................................................................... 32 Table 14.2.2.8 Difference (90% CI) in Proportion of Improvement based on >=PASI 75 betweenExposure Groups or Treatment Groups and Placebo..................................................................................................... 35 Table 14.2.2.9 Proportion of Subjects with Clinical Activity in the PASI Score .............................................. 38 Table 14.2.2.10 Proportion of Subjects with Clinical Activity in the PASI score using LOCF ......................... 41 Table 14.2.2.11 Summary of Results of Repeated Measures Analysis of Psoriasis Area Severity Index Score............................................................................................................................................................... 44 Table 14.2.3.1 Summary of Physician Global Assessment (Overall Score) ................................................... 47 Table 14.2.3.2 Proportion of Subjects with Clinical Activity in PGA Score ..................................................... 49 Table 14.2.3.3 Proportion of Subjects with Clinical Activity in PGA Score ..................................................... 52 Table 14.2.3.4 Proportion of Subjects with Clinical Activity in PGA Score(PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels)....................................................................................... 55 Table 14.2.3.5 Proportion of Subjects with Clinical Activity in PGA Score(PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels)- using LOCF................................................................. 58 Table 14.2.3.6 Difference (90% CI) in Proportion of improvement based on PGA Score(Score of Clear or Minimal or an Improved PGA Score by One or More Levels)......................................................................... 61 Table 14.2.3.7 Difference (90% CI) in Proportion of improvement based on PGA Score(PGA Score of Clear or Minimal)between Exposure Groups or SRT2104 Treatment Groups and Placebo........................... 64 Table 14.2.3.8 Difference (90% CI) in Proportion of improvement based on PGA Score(Improved PGA Score by One or More Levels)......................................................................................................................... 67 Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts ................................................................ 70 Table 14.2.4.2 Summary of Dermal and Epidermal PBMC Counts - Change from Baseline ......................... 77 Table 14.2.4.4 Proportion of Subjects Expressing Abnormal Cellular Proteins by Visit ................................. 81

Table 14.2.4.5 Shift Table of Proportion of Subjects Expressing Abnormal Cellular Proteins ....................... 82 Table 14.2.5.1 Summary of FGF21 and hsCRP ............................................................................................. 83 Table 14.2.5.2 Summary of FGF21 and hsCRP Change from Baseline ........................................................ 85 Table 14.2.6 Proportion of Subjects Using Rescue Medications .................................................................... 87 Table 14.2.7.1 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) ................................ 88 SRT-2104-013Table 14.2.7.2 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) ......... 90 Table 14.2.8.1 Summary Statistics of the Patient Health Questionnaire by Visit ........................................... 92 Table 14.2.8.2 Summary Statistics of the Patient Health Questionnaire - Change from Baseline ................. 94 Table 14.2.9.1 Summary Statistics of Psoriasis Quality of Life-12 Instrument (PQOL-12 .............................. 95 Table 14.2.9.2 Summary Statistics of Psoriasis Quality of Life-12 Instrument (PQOL-12) - .......................... 96 Table 14.2.10 Summary of SRT2104 Pharmacokinetic Parameters by Treatment ........................................ 97 Table 14.3 Summary of SRT2104 Exposure .................................................................................................. 98 Table 14.4.1.1 Summary of Gene Expression Data ..................................................................................... 902 Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data ................................................ 913

16. APPENDICES ......................................................................................................................... 1615 16.1 Study Information ................................................................................................................................. 920 16.2 Patient Data Listings ........................................................................................................................... 1615

17. STUDY RELATED INDICIES .................................................................................................. 1615 17.1 Psoriasis and Severity Index (PASI) ................................................................................................... 3064 17.2 Physician's Global Assessment (PGA) ............................................................................................... 3065 17.3 Patien Health Questionnaire 9 (PHQ-9) ............................................................................................. 3067 17.4 Hospital Anxiety and Depression Scale (HADS) ................................................................................ 3068 17.5 Psoriasis Quality of Life Questionnaire (PQOL-12) ............................................................................ 3069 17.6 Recommendations for Meals .............................................................................................................. 3070 17.7 Population PK Modelling .................................................................................................................... 3071

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013 Table 14.1.1 Summary of Subject Disposition Randomized Set Population

SRT2104 SRT2104 SRT2104 No Placebo 0.25 g 0.5 g 1.0 g Treatment Total (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) ----------------------------------------------------------------------------------------------------------Completion Status Completed 7 (100%) 5 (56%) 9 (75%) 9 (82%) 0 30 (75%) Prematurely Withdrawn 0 4 (44%) 3 (25%) 2 (18%) 1 (100%) 10 (25%) Primary Reason for Study Withdrawal Adverse Event Lost to Follow-up Subject withdrawal or refusal

0 0 0

2 1 1

(22%) (11%) (11%)

1 0 2

(8%) (17%)

1 1 0

(9%) (9%)

0 0 1 (100%)

4 2 4

(10%) (5%) (10%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013 Table 14.1.2 Summary of Analysis Populations Randomized Set Population

SRT2104 SRT2104 SRT2104 Placebo 0.25 g 0.5 g 1.0 g No Treatment Total Population (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) ------------------------------------------------------------------------------------------------------Randomized Set (RS) Yes 7 (100%) 9 (100%) 12 (100%) 11 (100%) 1 (100%) 40 (100%) No 0 0 0 0 0 0 Safety Analysis Set (SAF) Yes No

7 (100%) 0

9 (100%) 0

12 (100%) 0

11 (100%) 0

0 1 (100%)

39 1

(98%) (3%)

Pharmacokinetics Analysis Set (PKS) Yes No

0 7 (100%)

9 (100%) 0

11 1

(92%) (8%)

11 (100%) 0

0 1 (100%)

31 9

(78%) (23%)

Efficacy Analysis Set (EAS) Yes No

7 (100%) 0

9 (100%) 0

12 (100%) 0

11 (100%) 0

0 1 (100%)

39 1

(98%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.1.3 Summary of Demographic Characteristics Randomized Set Population SRT2104 SRT2104 SRT2104 No Placebo 0.25 g 0.5 g 1.0 g Treatment Total (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) ----------------------------------------------------------------------------------------------Age (Yrs) n 7 9 12 11 0 39 Mean 51.4 40.6 49.3 44.6 46.4 SD 14.88 16.05 14.41 13.58 14.63 Median 50.0 45.0 52.0 43.0 50.0 Min. 27 19 26 26 19 Max. 72 60 68 65 72 Sex

Race

Ethnicity

n Female Male

7 1 6

n American Indian or Alaska Native Asian Black Native Hawaiian or Other Pacific Islander White Other

7 0

n Hispanic or Latino Not Hispanic or Latino

7 0

9 0

7 (100%)

9 (100%)

(14%) (86%)

9 3 6

(33%) (67%)

9 0

12 0 12 (100%)

11 5 (45%) 6 (55%)

1 1 (100%) 0

40 10 (25%) 30 (75%)

12 0

11 0

1 0

40 0

0 1 0

0 2 0

(22%)

1 0 0

(8%)

(14%)

0 1 0

6 0

(86%)

7 0

(78%)

10 1

(83%) (8%)

10 (91%) 0

1 (100%) 0

34 (85%) 1 (3%)

12 3

(25%)

11 2 (18%)

1 0

40 5 (13%)

9

(75%)

9 (82%)

1 (100%)

35 (88%)

(9%)

0 0 0

1 (3%) 4 (10%) 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.1.3 Summary of Demographic Characteristics Randomized Set Population SRT2104 SRT2104 SRT2104 No Placebo 0.25 g 0.5 g 1.0 g Treatment Total (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) ----------------------------------------------------------------------------------------------Height (cm) n 7 9 10 11 1 38 Mean 171.71 176.42 176.80 172.62 170.00 174.38 SD 7.992 6.855 7.809 7.724 7.540 Median 175.00 177.80 176.55 175.30 170.00 175.30 Min. 154.9 165.1 160.0 160.0 170.0 154.9 Max. 177.8 185.4 185.4 188.0 170.0 188.0 Weight (kg) n Mean SD Median Min. Max. Body Mass Index (kg/m^2)

n Mean SD Median Min. Max.

7 92.71 11.173 91.90 76.7 104.3 7 31.51 3.811 32.90 24.3 36.0

9 104.90 24.484 105.60 73.7 156.2 9 33.36 5.574 33.40 26.4 45.4

12 88.11 15.626 81.10 70.3 115.6

11 84.93 27.787 81.60 62.1 158.3

10

11

27.35 4.404 25.95 22.9 35.1

28.59 9.625 25.80 20.2 54.6

1 62.20 62.20 62.2 62.2 1 21.50 21.50 21.5 21.5

40 91.17 22.098 86.40 62.1 158.3 38 29.74 6.810 30.10 20.2 54.6

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Any condition 7 (100%) 8 (89%) 12 (100%) 11 (100%) 1 (100%) 39 (98%) Skin and subcutaneous tissue disorders Any Condition Psoriasis Scar Dermatitis contact Eczema Pruritus

7 (100%) 7 (100%) 1 (14%) 0 0 0

8 8 0 1 1 1

(89%) (89%)

Vascular disorders Any Condition Hypertension

2 2

(29%) (29%)

Metabolism and nutrition disorders Any Condition Hyperlipidaemia Type 2 diabetes mellitus Hypercholesterolaemia Diabetes mellitus Hypertriglyceridaemia Obesity

2 0 1 1 0 0 0

(29%) (14%) (14%)

(67%) (67%)

10 10 1 0 0 0

(91%) (91%) (9%)

(11%) (11%) (11%)

8 8 0 0 0 0

1 (100%) 1 (100%) 0 0 0 0

34 34 2 1 1 1

(85%) (85%) (5%) (3%) (3%) (3%)

4 4

(44%) (44%)

5 5

(42%) (42%)

3 3

(27%) (27%)

0 0

14 14

(35%) (35%)

3 2 2 0 1 0 1

(33%) (22%) (22%)

5 3 1 1 0 0 0

(42%) (25%) (8%) (8%)

3 0 1 2 0 1 0

(27%)

0 0 0 0 0 0 0

13 5 5 4 1 1 1

(33%) (13%) (13%) (10%) (3%) (3%) (3%)

(11%) (11%)

(9%) (18%) (9%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Condition 3 (43%) 3 (33%) 2 (17%) 5 (45%) 0 13 (33%) Psoriatic arthropathy 0 1 (11%) 1 (8%) 3 (27%) 0 5 (13%) Arthralgia 1 (14%) 2 (22%) 0 0 0 3 (8%) Osteoarthritis 1 (14%) 0 0 2 (18%) 0 3 (8%) Myalgia 0 0 0 2 (18%) 0 2 (5%) Arthritis 1 (14%) 0 0 0 0 1 (3%) Back pain 1 (14%) 0 0 0 0 1 (3%) Fibromyalgia 1 (14%) 0 0 0 0 1 (3%) Intervertebral disc 0 0 1 (8%) 0 0 1 (3%) protrusion Muscle spasms 0 1 (11%) 0 0 0 1 (3%) Infections and infestations Any Condition Sinusitis Herpes simplex Urinary tract infection Acne pustular Genital herpes Oral herpes Post procedural sepsis Tuberculosis Upper respiratory tract infection

2 1 0 1 0 0 0 0 0 1

(29%) (14%) (14%)

(14%)

2 1 1 0 0 0 0 0 0 0

(22%) (11%) (11%)

3 1 0 1 0 0 0 0 1 0

(25%) (8%) (8%)

(8%)

5 0 1 0 1 1 1 1 0 0

(45%) (9%) (9%) (9%) (9%) (9%)

0 0 0 0 0 0 0 0 0 0

12 3 2 2 1 1 1 1 1 1

(30%) (8%) (5%) (5%) (3%) (3%) (3%) (3%) (3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Eye disorders Any Condition 4 (57%) 3 (33%) 1 (8%) 2 (18%) 0 10 (25%) Hypermetropia 2 (29%) 3 (33%) 1 (8%) 0 0 6 (15%) Myopia 2 (29%) 0 0 1 (9%) 0 3 (8%) Astigmatism 0 1 (11%) 0 1 (9%) 0 2 (5%) Dry eye 1 (14%) 0 0 0 0 1 (3%) Surgical and medical procedures Any Condition Appendicectomy Tonsillectomy Hysterectomy Vasectomy Cardiac ablation Female sterilisation Gallbladder operation Meniscus operation Prostatectomy Sinus operation Skin neoplasm excision Stent placement Umbilical hernia repair

2 1 1 1 1 1 0 0 0 1 0 0 0 0

(29%) (14%) (14%) (14%) (14%) (14%)

(14%)

1 0 1 0 0 0 0 1 0 0 0 0 0 0

(11%) (11%)

(11%)

2 0 0 0 0 0 0 0 1 0 1 0 1 0

(17%)

(8%) (8%) (8%)

5 2 1 1 1 0 1 0 0 0 0 1 0 1

(45%) (18%) (9%) (9%) (9%) (9%)

(9%) (9%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0

10 3 3 2 2 1 1 1 1 1 1 1 1 1

(25%) (8%) (8%) (5%) (5%) (3%) (3%) (3%) (3%) (3%) (3%) (3%) (3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Immune system disorders Any Condition 3 (43%) 2 (22%) 0 3 (27%) 0 8 (20%) Drug hypersensitivity 2 (29%) 1 (11%) 0 1 (9%) 0 4 (10%) Seasonal allergy 0 0 0 2 (18%) 0 2 (5%) Food allergy 1 (14%) 0 0 0 0 1 (3%) House dust allergy 0 1 (11%) 0 0 0 1 (3%) Hypersensitivity 0 1 (11%) 0 0 0 1 (3%) Injury, poisoning and procedural complications Any Condition Meniscus lesion Ankle fracture Foot fracture Hand fracture Lower limb fracture Subdural haematoma Traumatic haematoma Wrist fracture

2 1 0 0 0 0 1 1 0

(29%) (14%)

Nervous system disorders Any Condition Headache Essential tremor Syncope

4 2 1 1

(57%) (29%) (14%) (14%)

(14%) (14%)

1 1 0 0 0 0 0 0 0 0 0 0 0

(11%) (11%)

4 1 1 1 1 1 0 0 1

(33%) (8%) (8%) (8%) (8%) (8%)

1 1 0 0

(8%) (8%)

(8%)

0 0 0 0 0 0 0 0 0 1 1 0 0

(9%) (9%)

0 0 0 0 0 0 0 0 0

7 3 1 1 1 1 1 1 1

(18%) (8%) (3%) (3%) (3%) (3%) (3%) (3%) (3%)

0 0 0 0

6 4 1 1

(15%) (10%) (3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Psychiatric disorders Any Condition 3 (43%) 0 0 3 (27%) 0 6 (15%) Anxiety 1 (14%) 0 0 1 (9%) 0 2 (5%) Depression 1 (14%) 0 0 1 (9%) 0 2 (5%) Insomnia 2 (29%) 0 0 0 0 2 (5%) Attention 0 0 0 1 (9%) 0 1 (3%) deficit/hyperactivity disorder Social circumstances Any Condition Tobacco user Denture wearer Edentulous Menopause Postmenopause

3 1 1 1 0 0

(43%) (14%) (14%) (14%)

Cardiac disorders Any Condition Arrhythmia Bundle branch block right Coronary artery disease Myocardial infarction Pericarditis

2 1 1 1 0 0

(29%) (14%) (14%) (14%)

1 1 0 0 1 0 0 0 0 0 0 0

(11%) (11%) (11%)

1 1 0 0 0 0

(8%) (8%)

1 0 0 0 1 0

(8%)

(8%)

1 0 0 0 0 1

(9%)

1 0 0 0 0 1

(9%)

(9%)

(9%)

0 0 0 0 0 0

6 3 1 1 1 1

(15%) (8%) (3%) (3%) (3%) (3%)

0 0 0 0 0 0

4 1 1 1 1 1

(10%) (3%) (3%) (3%) (3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Respiratory, thoracic and mediastinal disorders Any Condition 1 (14%) 2 (22%) 0 1 (9%) 0 4 (10%) Asthma 0 1 (11%) 0 1 (9%) 0 2 (5%) Nasal congestion 0 1 (11%) 0 0 0 1 (3%) Nasal septum deviation 1 (14%) 0 0 0 0 1 (3%) Sleep apnoea syndrome 1 (14%) 0 0 0 0 1 (3%) Ear and labyrinth disorders Any Condition Cerumen impaction Deafness unilateral Tinnitus Vertigo Gastrointestinal disorders Any Condition Gastrooesophageal reflux disease Gingival disorder Irritable bowel syndrome Tooth impacted General disorders and administration site conditions Any Condition Oedema peripheral Cyst

2 1 1 1 0

(29%) (14%) (14%) (14%)

1 0

(14%)

2 1

0 1 0

(14%)

1 0 1

1 0 1

(14%) (14%)

0 0 0 0 0

0 0 0

0 0 0 0 0

1 0 0 0 1

(22%) (11%)

0 0

(11%) (11%)

(9%)

0 0 0 0 0

3 1 1 1 1

(8%) (3%) (3%) (3%) (3%)

0 0

0 0

3 1

(8%) (3%)

0 0 0

0 0 0

0 0 0

1 1 1

(3%) (3%) (3%)

0 0 0

2 2 0

0 0 0

3 2 1

(8%) (5%) (3%)

(9%)

(18%) (18%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 7 Clinical Study Report SRT-2104-013

Table 14.1.4 Summary of Medical and Surgical History Randomized Set Population SRT2104 SRT2104 SRT2104 No System Organ Class Placebo 0.25 g 0.5 g 1.0 g Treatment Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) -----------------------------------------------------------------------------------------------------Neoplasms benign, malignant and unspecified (incl cysts and polyps) Any Condition 1 (14%) 0 0 2 (18%) 0 3 (8%) Basal cell carcinoma 0 0 0 1 (9%) 0 1 (3%) Benign neoplasm of skin 0 0 0 1 (9%) 0 1 (3%) Pituitary tumour 0 0 0 1 (9%) 0 1 (3%) Prostate cancer 1 (14%) 0 0 0 0 1 (3%) Endocrine disorders Any Condition Hypothyroidism

0 0

Investigations Any Condition Heart rate irregular

1 1

1 1 (14%) (14%)

0 0

(11%) (11%)

0 0

1 1

0 0

0 0

(9%) (9%)

0 0

2 2

(5%) (5%)

0 0

1 1

(3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------Any medication 6 (86%) 8 (89%) 12 (100%) 11 (100%) 1 (100%) 38 (95%) ANESTHETICS Any medication LIDOCAINE LIDOCAINE W/EPINEPHRINE /00056401/

3 1 2

(43%) (14%) (29%)

4 2 2

(44%) (22%) (22%)

7 7 0

(58%) (58%)

10 6 4

(91%) (55%) (36%)

0 0 0

24 16 8

(60%) (40%) (20%)

AGENTS ACTING ON THE RENIN-ANGIOTENSIN SYSTEM Any medication LISINOPRIL BENICAR HCT DIOVAN /01319601/ LOSARTAN MICARDIS MICARDIS PLUS VASOTEC /00574902/

2 0 1 0 0 0 0 1

(29%)

3 3 0 0 0 0 0 0

(33%) (33%)

3 2 0 0 1 1 1 0

(25%) (17%)

2 1 0 1 0 0 0 0

(18%) (9%)

0 0 0 0 0 0 0 0

10 6 1 1 1 1 1 1

(25%) (15%) (3%) (3%) (3%) (3%) (3%) (3%)

ANALGESICS Any medication EXCEDRIN /00509701/ VICODIN ACETAMINOPHEN ASPIRIN MORPHINE NYQUIL OXYCODONE PERCOCET /00446701/

2 0 0 1 1 0 0 0 0

(29%)

4 0 2 0 0 1 0 1 0

(44%)

3 1 0 0 0 0 1 0 1

(25%) (8%)

1 1 0 0 0 0 0 0 0

(9%) (9%)

0 0 0 0 0 0 0 0 0

10 2 2 1 1 1 1 1 1

(25%) (5%) (5%) (3%) (3%) (3%) (3%) (3%) (3%)

(14%)

(14%)

(14%) (14%)

(22%) (11%) (11%)

(8%) (8%) (8%)

(8%) (8%)

(9%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS Any medication 2 (29%) 0 3 (25%) 5 (45%) 0 10 (25%) IBUPROFEN 0 0 1 (8%) 2 (18%) 0 3 (8%) MOTRIN 0 0 1 (8%) 1 (9%) 0 2 (5%) ADVIL /00044201/ 0 0 1 (8%) 0 0 1 (3%) ADVIL /00109201/ 0 0 0 1 (9%) 0 1 (3%) CELEBREX 1 (14%) 0 0 0 0 1 (3%) DICLOFENAC 1 (14%) 0 0 0 0 1 (3%) MOBIC 0 0 0 1 (9%) 0 1 (3%) NAPROSYN /00256201/ 0 0 1 (8%) 0 0 1 (3%) LIPID MODIFYING AGENTS Any medication CRESTOR /01588601/ LIPITOR SIMVASTATIN CADUET NIACIN OMEGA 3 FISH OIL VYTORIN

1 1 0 0 0 0 0 0

(14%) (14%)

ANTIBIOTICS AND CHEMOTHER. FOR DERMATOLOGICAL USE Any medication BACITRACIN

1 1

(14%) (14%)

2 1 0 1 0 0 0 0

0 0

(22%) (11%) (11%)

5 0 0 1 1 1 1 1

0 0

(42%) (8%) (8%) (8%) (8%) (8%)

2 0 2 0 0 0 0 0

(18%)

6 6

(55%) (55%)

(18%)

0 0 0 0 0 0 0 0

10 2 2 2 1 1 1 1

(25%) (5%) (5%) (5%) (3%) (3%) (3%) (3%)

0 0

7 7

(18%) (18%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------ANTITHROMBOTIC AGENTS Any medication 2 (29%) 0 4 (33%) 1 (9%) 0 7 (18%) ASPIRIN 2 (29%) 0 3 (25%) 1 (9%) 0 6 (15%) ASA 0 0 1 (8%) 0 0 1 (3%) BETA BLOCKING AGENTS Any medication METOPROLOL ATENOLOL METOPROLOL TARTRATE PROPRANOLOL SOTALOL HYDROCHLORIDE TOPROL XL

3 0 0 0 1 1 1

(43%)

DRUGS USED IN DIABETES Any medication GLIMEPIRIDE GLIPIZIDE METFORMIN ACTOS /01460201/ AVANDIA /01445801/ GLUCOPHAGE /00082701/ GLYBURIDE INSULIN LANTUS

1 0 1 0 0 0 0 0 0

(14%)

(14%) (14%) (14%)

(14%)

0 0 0 0 0 0 0 3 2 1 1 1 0 1 0 1

(33%) (22%) (11%) (11%) (11%) (11%) (11%)

2 1 1 1 0 0 0

(17%) (8%) (8%) (8%)

1 1 0 0 0 0 0

(9%) (9%)

0 0 0 0 0 0 0

6 2 1 1 1 1 1

(15%) (5%) (3%) (3%) (3%) (3%) (3%)

1 0 0 1 0 0 0 1 0

(8%)

1 0 0 0 0 1 0 0 0

(9%)

0 0 0 0 0 0 0 0 0

6 2 2 2 1 1 1 1 1

(15%) (5%) (5%) (5%) (3%) (3%) (3%) (3%) (3%)

(8%)

(8%)

(9%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------VITAMINS Any medication 0 1 (11%) 1 (8%) 4 (36%) 0 6 (15%) MULTIVITAMIN /00097801/ 0 0 1 (8%) 2 (18%) 0 3 (8%) VITAMIN D /00107901/ 0 0 0 3 (27%) 0 3 (8%) BIOTIN 0 0 0 1 (9%) 0 1 (3%) ONE A DAY /02262701/ 0 1 (11%) 0 0 0 1 (3%) ANTIBACTERIALS FOR SYSTEMIC USE Any medication AVELOX /01453202/ AZITHROMYCIN BACTRIM DS CEFTIN CEFTRIAXONE CIPROFLOXACIN MOXIFLOXACIN

1 0 0 0 0 0 0 1

(14%)

DIURETICS Any medication HYDROCHLOROTHIAZIDE FUROSEMIDE SPIRONOLACTONE

1 1 0 0

(14%) (14%)

(14%)

1 0 1 0 1 1 0 0 0 0 0 0

(11%) (11%) (11%) (11%)

2 1 0 0 0 0 1 0

(17%) (8%)

1 1 0 0

(8%) (8%)

(8%)

1 0 0 1 0 0 0 0

(9%)

2 0 1 1

(18%)

(9%)

(9%) (9%)

0 0 0 0 0 0 0 0

5 1 1 1 1 1 1 1

(13%) (3%) (3%) (3%) (3%) (3%) (3%) (3%)

0 0 0 0

4 2 1 1

(10%) (5%) (3%) (3%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------CORTICOSTEROIDS, DERMATOLOGICAL PREPARATIONS Any medication 1 (14%) 0 1 (8%) 1 (9%) 0 3 (8%) CLOBEX /00337102/ 0 0 0 1 (9%) 0 1 (3%) HYDROCORTISONE 0 0 0 1 (9%) 0 1 (3%) HYDROCORTISONE BUTYRATE 1 (14%) 0 0 0 0 1 (3%) KENALOG 0 0 0 1 (9%) 0 1 (3%) TRIAMCINOLONE /00031902/ 0 0 1 (8%) 0 0 1 (3%) PSYCHOANALEPTICS Any medication CYMBALTA ADDERALL AMITRIPTYLINE

1 1 0 1

BLOOD SUBSTITUTES AND PERFUSION SOLUTIONS Any medication NORMAL SALINE POTASSIUM CHLORIDE

0 0 0

COUGH AND COLD PREPARATIONS Any medication MUCINEX ROBITUSSIN /00048001/

1 1 0

(14%) (14%) (14%)

0 0 0 0

2 1 1 (14%) (14%)

0 0 0

(22%) (11%) (11%)

0 0 0 0

2 1 1 0

0 0 0

0 0 0

0 0 0

1 0 1

(18%) (9%) (9%)

(9%) (9%)

0 0 0 0

3 2 1 1

(8%) (5%) (3%) (3%)

0 0 0

2 1 1

(5%) (3%) (3%)

0 0 0

2 1 1

(5%) (3%) (3%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------EMOLLIENTS AND PROTECTIVES Any medication 1 (14%) 1 (11%) 0 0 0 2 (5%) EUCERIN /00021201/ 1 (14%) 0 0 0 0 1 (3%) MOISTURIZER 0 1 (11%) 0 0 0 1 (3%) PSYCHOLEPTICS Any medication BENADRYL /00000402/ LUNESTA ZOLPIDEM

2 1 1 1

SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM Any medication DEPO-PROVERA MONONESSA

0 0 0

1 0 1

(11%)

THYROID THERAPY Any medication L-THYROXINE /00068001/ LEVOTHYROXINE

0 0 0

1 0 1

(11%)

ANTI-ACNE PREPARATIONS Any medication ICHTHAMMOL

0 0

ANTIANEMIC PREPARATIONS Any medication VITAMIN B12 /00056201/

1 1

(29%) (14%) (14%) (14%)

(14%) (14%)

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

2 1 1 1

(5%) (3%) (3%) (3%)

0 0 0

0 0 0

1 (100%) 1 (100%) 0

2 1 1

(5%) (3%) (3%)

0 0 0

1 1 0

(9%) (9%)

0 0 0

2 1 1

(5%) (3%) (3%)

0 0

0 0

1 1

(9%) (9%)

0 0

1 1

(3%) (3%)

0 0

0 0

0 0

0 0

1 1

(3%) (3%)

(11%)

(11%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------ANTIDIARR.,INTEST. ANTIINFL./ANTIINFECT. AGENTS Any medication 0 0 0 1 (9%) 0 1 (3%) PROBIOTICA 0 0 0 1 (9%) 0 1 (3%) ANTIEMETICS AND ANTINAUSEANTS Any medication ZOFRAN /00955301/

0 0

1 1

ANTIHISTAMINES FOR SYSTEMIC USE Any medication CLARITIN /00917501/

0 0

ANTIPRURITICS,INCL ANTIHIST,ANESTHET,ETC. Any medication CALAMINE

0 0

0 0

0 0

0 0

1 1

0 0

0 0

0 0

1 1

DRUGS FOR ACID RELATED DISORDERS Any medication PRILOSEC /00661201/

0 0

1 1

0 0

DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS Any medication DICYCLOMINE /00068601/

1 1

0 0

(14%) (14%)

0 0

(11%) (11%)

(11%) (11%)

0 0

1 1

(3%) (3%)

(9%) (9%)

0 0

1 1

(3%) (3%)

(9%) (9%)

0 0

1 1

(3%) (3%)

0 0

0 0

1 1

(3%) (3%)

0 0

0 0

1 1

(3%) (3%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 8 Clinical Study Report SRT-2104-013 Table 14.1.5 Summary of Concomitant Medications Randomized Set Population

SRT2104 SRT2104 SRT2104 No ATC Level 2 Placebo 0.25 g 0.5 g 1.0 g Treatment Total Ingredient (N=7) (N=9) (N=12) (N=11) (N=1) (N=40) --------------------------------------------------------------------------------------------------------DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES Any medication 0 1 (11%) 0 0 0 1 (3%) ALBUTEROL /00139502/ 0 1 (11%) 0 0 0 1 (3%) MINERAL SUPPLEMENTS Any medication MAGNESIUM

1 1

(14%) (14%)

0 0

0 0

0 0

0 0

1 1

(3%) (3%)

MUSCLE RELAXANTS Any medication CYCLOBENZAPRINE

1 1

(14%) (14%)

0 0

0 0

0 0

0 0

1 1

(3%) (3%)

NASAL PREPARATIONS Any medication SALINE /00075401/

1 1

(14%) (14%)

0 0

0 0

0 0

0 0

1 1

(3%) (3%)

OPHTHALMOLOGICALS Any medication SYSTANE

1 1

(14%) (14%)

0 0

0 0

0 0

0 0

1 1

(3%) (3%)

Note: Medications that started and stopped prior to dosing were excluded from the summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.1.2 Summary of Histological Improvement on Day 84 Efficacy Analysis Set Population All Low High Actual SRT2104 SRT2104 SRT2104 Active Exposure Exposure Visit Placebo 0.25g 0.5g 1.0g [3] [4] [4] [1] Krueger Assessment[2] (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) ---------------------------------------------------------------------------------------------------------Day 84

n No improvement Good improvement Excellent improvement

7 6 (86%) 0 1 (14%)

6 3 (50%) 0 3 (50%)

9 5 (56%) 3 (33%) 1 (11%)

11 9 (82%) 1 (9%) 1 (9%)

26 17 (65%) 4 (15%) 5 (19%)

12 6 (50%) 2 (17%) 4 (33%)

14 11 (79%) 2 (14%) 1 (7%)

[1] Actual visit is based on assessment windows using relative study day. [2] No improvement=Defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes. Good improvement=Defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but keratinocytes still express K16. Excellent improvement=Defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16. [3] All Active = all SRT2104 dose groups combine [4] Exposure is based on AUC NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.1.3 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo - Day 84 Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with Good or Good or Excellent Excellent Improvement Improvement 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.25 g SRT2104 - Placebo

3

(50.0%)

1

(14.3%)

35.7%

(

24.55,

43.61)

0.2417

0.5 g SRT2104 - Placebo

4

(44.4%)

1

(14.3%)

30.2%

(

20.82,

36.93)

0.2693

1.0 g SRT2104 - Placebo

2

(18.2%)

1

(14.3%)

3.9%

(

-7.93,

10.19)

0.9198

All Active - Placebo [2]

9

(34.6%)

1

(14.3%)

20.3%

(

6.91,

24.45)

0.3648

Low Exposure - Placebo [3]

6

(50.0%)

1

(14.3%)

35.7%

(

31.44,

39.86)

0.1575

High Exposure - Placebo [3]

3

(21.4%)

1

(14.3%)

7.1%

(

-2.99,

11.87)

0.7846

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.1.4 Summary of the Improvement Score based on the Krueger Criteria with Comparison to Historical 5% Placebo Rate Efficacy Analysis Set Population p-value of Actual Good or Excellent Comparison to 5% Visit Improvement Score[2] 90% Confidence Interval Historical Placebo Treatment N [1] n N (%) (Blyth-Still-Casella) Response [3] -----------------------------------------------------------------------------------------------------------Placebo 7 Day 84 7 1 (14.29) ( 0.73, 55.42) SRT2104 0.25 g

9

Day 84

6

3 (50.00)

( 15.32, 84.68)

0.0022

SRT2104 0.5 g

12

Day 84

9

4 (44.44)

( 16.88, 74.86)

0.0006

SRT2104 1.0 g

11

Day 84

11

2 (18.18)

(

0.1019

All Active[4]

32

Day 84

26

9 (34.62)

( 17.98, 54.21)

<0.0001

Low Exposure[5]

15

Day 84

12

6 (50.00)

( 23.55, 76.45)

<0.0001

High Exposure[5]

16

Day 84

14

3 (21.43)

(

0.0301

3.33, 50.00)

6.11, 50.00)

[1] Actual visit is based on assessment windows using relative study day. [2] Good improvement=Defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but keratinocytes still express K16. Excellent improvement=Defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16. [3] No adjustments of the p-value for multiplicity. [4] All Active = all SRT2104 dose groups combined. [5] Exposure is based on AUC. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.2.4 Summary of Psoriasis Area Severity Index Scores (Total Score) Efficacy Analysis Set Population Treatment N Actual Visit [3] n Mean SD Median Min. Max. 90% CI ----------------------------------------------------------------------------------------Placebo 7 Day 1 7 23.30 11.128 21.90 12.0 36.9 (15,31) Day 28 7 20.07 11.304 16.80 8.1 35.4 (12,28) Day 56 7 19.29 11.103 15.70 8.1 37.8 (11,27) Day 84 7 18.17 12.622 16.40 2.5 39.0 (9,27) Follow-up 7 19.86 13.375 15.50 2.1 39.0 (10,30) SRT2104 0.25 g

9

Day 1 Day 28 Day 56 Day 84 Follow-up

9 9 7 6 6

17.13 16.03 14.94 12.23 14.70

4.659 4.427 7.329 8.403 7.913

16.00 15.00 14.80 13.95 16.05

10.2 10.8 3.6 1.2 1.2

23.7 23.6 23.8 22.7 24.7

(14,20) (13,19) (10,20) (5,19) (8,21)

SRT2104 0.5 g

12

Day 1 Day 28 Day 56 Day 84 Follow-up

12 12 11 9 10

18.08 16.88 12.45 11.73 11.46

3.137 7.709 5.995 6.440 6.057

19.00 16.40 13.20 13.00 12.75

13.9 5.9 3.2 1.8 1.8

23.1 37.9 22.7 19.0 19.0

(16,20) (13,21) (9,16) (8,16) (8,15)

SRT2104 1.0 g

11

Day 1 Day 28 Day 56 Day 84 Follow-up

11 11 11 11 10

20.35 14.88 12.71 11.84 12.55

7.987 6.845 6.439 6.933 5.840

16.40 12.00 10.80 9.90 11.40

12.2 8.5 5.4 1.8 5.7

40.0 29.2 27.8 29.6 23.3

(16,25) (11,19) (9,16) (8,16) (9,16)

All Active[1]

32

Day 1 Day 28 Day 56 Day 84 Follow-up

32 32 29 26 26

18.59 15.96 13.15 11.89 12.63

5.611 6.481 6.343 6.831 6.292

17.30 15.00 13.00 12.70 12.75

10.2 5.9 3.2 1.2 1.2

40.0 37.9 27.8 29.6 24.7

(17,20) (14,18) (11,15) (10,14) (11,15)

[1] All Active = all SRT2104 dose groups combined [2] Exposure is based on AUC [3] Actual visit is based on assessment windows using relative study day. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.2.4 Summary of Psoriasis Area Severity Index Scores (Total Score) Efficacy Analysis Set Population Treatment N Actual Visit [3] n Mean SD Median Min. Max. 90% CI ----------------------------------------------------------------------------------------Low Exposure[2] 15 Day 1 15 18.25 3.845 18.20 10.2 23.7 (17,20) Day 28 15 16.05 3.958 16.30 10.2 23.6 (14,18) Day 56 13 13.54 6.480 14.80 3.6 23.8 (10,17) Day 84 12 12.53 6.641 13.20 1.2 22.7 (9,16) Follow-up 12 15.20 6.220 17.20 1.2 24.7 (12,18) High Exposure[2]

16

Day 1 Day 28 Day 56 Day 84 Follow-up

16 16 16 14 14

19.04 15.64 12.84 11.35 10.42

7.114 8.435 6.423 7.193 5.660

17.25 13.20 12.95 11.90 9.70

[1] All Active = all SRT2104 dose groups combined [2] Exposure is based on AUC [3] Actual visit is based on assessment windows using relative study day. NOTE: Missing data is not imputed.

12.2 5.9 3.2 1.8 1.8

40.0 37.9 27.8 29.6 23.3

(16,22) (12,19) (10,16) (8,15) (8,13)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.2.5 Summary of Percent Change from Baseline for Psoriasis Area Severity Index Scores (Total Score) Efficacy Analysis Set Population Treatment N Actual Visit [3] n Mean SD Median Min. Max. 90% CI -----------------------------------------------------------------------------------------------------------Placebo 7 Day 28 7 -16.6643 13.77683 -15.4500 -33.820 0.000 (-26.78,-6.55) Day 56 7 -16.1443 22.56979 -10.2900 -57.450 6.780 (-32.72,0.43) Day 84 7 -21.7743 39.19975 -7.4400 -79.170 20.590 (-50.56,7.02) Follow-up 7 -18.8700 35.93228 -14.0500 -82.500 15.380 (-45.26,7.52) SRT2104 0.25 g

9

Day 28 Day 56 Day 84 Follow-up

9 7 6 6

-5.4011 -20.3100 -30.3117 -12.8483

13.14194 32.85747 44.81152 40.15209

0.0000 -0.4400 -3.3450 4.1650

-28.000 -76.000 -92.000 -92.000

13.730 0.780 0.780 12.500

(-13.55,2.74) (-44.44,3.82) (-67.18,6.55) (-45.88,20.18)

SRT2104 0.5 g

12

Day 28 Day 56 Day 84 Follow-up

12 11 9 10

-8.6825 -30.0691 -36.4444 -36.8860

30.04988 33.17908 37.00257 36.04784

-11.0450 -21.1300 -33.6700 -37.9000

-57.550 -83.840 -90.910 -90.910

64.070 17.610 17.610 17.610

(-24.26,6.90) (-48.20,-11.94) (-59.38,-13.51) (-57.78,-15.99)

SRT2104 1.0 g

11

Day 28 Day 56 Day 84 Follow-up

11 11 11 10

-26.1573 -35.4264 -39.6636 -34.4510

20.09275 26.51983 30.22836 27.64982

-33.7900 -31.0300 -39.6300 -41.2200

-47.140 -69.160 -88.680 -69.260

6.120 13.470 20.820 19.500

(-37.14,-15.18) (-49.92,-20.93) (-56.18,-23.14) (-50.48,-18.42)

All Active[1]

32

Day 28 Day 56 Day 84 Follow-up

32 29 26 26

-13.7666 -29.7455 -36.3912 -30.4023

24.08362 30.17719 34.91189 34.09970

-11.0450 -27.8700 -32.6950 -32.9150

-57.550 -83.840 -92.000 -92.000

64.070 17.610 20.820 19.500

(-20.99,-6.55) (-39.28,-20.21) (-48.09,-24.70) (-41.83,-18.98)

Low Exposure[2]

15

Day 28 Day 56 Day 84

15 13 12

-10.9707 -28.4546 -32.5858

16.65474 33.67463 36.22851

-6.2500 -21.1300 -26.1050

-47.140 -76.000 -92.000

13.730 17.610 17.610

(-18.54,-3.40) (-45.10,-11.81) (-51.37,-13.80)

[1] All Active = all SRT2104 dose groups combined [2] Exposure based on AUC [3] Actual visit is based on assessment windows using relative study day. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.2.5 Summary of Percent Change from Baseline for Psoriasis Area Severity Index Scores (Total Score) Efficacy Analysis Set Population Treatment N Actual Visit [3] n Mean SD Median Min. Max. 90% CI -----------------------------------------------------------------------------------------------------------Low Exposure[2] 15 Follow-up 12 -16.1767 34.70807 -3.6600 -92.000 19.500 (-34.17,1.82) High Exposure[2]

16

Day 28 Day 56 Day 84 Follow-up

16 16 14 14

-18.5056 -30.7944 -39.6529 -42.5957

28.83566 28.10875 34.76376 29.49401

-24.5800 -29.5150 -32.6950 -43.4650

[1] All Active = all SRT2104 dose groups combined [2] Exposure based on AUC [3] Actual visit is based on assessment windows using relative study day. NOTE: Missing data is not imputed.

-57.550 -83.840 -90.910 -90.910

64.070 13.470 20.820 10.160

(-31.14,-5.87) (-43.11,-18.48) (-56.11,-23.20) (-56.56,-28.64)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.6 Difference (90% CI) in Proportion of Improvement based on >=PASI 25 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-25 PASI-25 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.25 g SRT2104 - Placebo

1

(11.1%)

2

(28.6%)

-17.5%

( -23.79,

-5.25)

0.5573

0.5 g SRT2104 - Placebo

3

(25.0%)

2

(28.6%)

-3.6%

( -12.68,

5.46)

0.9194

1.0 g SRT2104 - Placebo

7

(63.6%)

2

(28.6%)

35.1%

(

30.21,

41.37)

0.1811

All Active - Placebo [2]

11

(34.4%)

2

(28.6%)

5.8%

(

-7.63,

11.09)

0.8848

Low Exposure - Placebo [3]

3

(20.0%)

2

(28.6%)

-8.6%

( -12.40,

2.19)

0.7484

High Exposure - Placebo [3]

8

(50.0%)

2

(28.6%)

21.4%

(

25.51)

0.3972

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

6.24,

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.6 Difference (90% CI) in Proportion of Improvement based on >=PASI 25 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-25 PASI-25 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.25 g SRT2104 - Placebo

2

(28.6%)

2

(28.6%)

0.0%

(

-9.75,

9.77)

1.0000

0.5 g SRT2104 - Placebo

5

(45.5%)

2

(28.6%)

16.9%

(

3.06,

23.73)

0.5626

1.0 g SRT2104 - Placebo

8

(72.7%)

2

(28.6%)

44.2%

(

35.49,

51.02)

0.0822

All Active - Placebo [2]

15

(51.7%)

2

(28.6%)

23.2%

(

18.02,

27.08)

0.3195

Low Exposure - Placebo [3]

5

(38.5%)

2

(28.6%)

9.9%

(

-3.06,

13.83)

0.7873

High Exposure - Placebo [3]

10

(62.5%)

2

(28.6%)

33.9%

(

28.06,

38.79)

0.1620

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.6 Difference (90% CI) in Proportion of Improvement based on >=PASI 25 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-25 PASI-25 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.25 g SRT2104 - Placebo

2

(33.3%)

2

(28.6%)

4.8%

(

-9.77,

12.66)

0.9895

0.5 g SRT2104 - Placebo

6

(66.7%)

2

(28.6%)

38.1%

(

32.49,

43.76)

0.1646

1.0 g SRT2104 - Placebo

8

(72.7%)

2

(28.6%)

44.2%

(

35.49,

51.02)

0.0822

All Active - Placebo [2]

16

(61.5%)

2

(28.6%)

33.0%

(

28.78,

38.00)

0.1349

Low Exposure - Placebo [3]

6

(50.0%)

2

(28.6%)

21.4%

(

5.94,

25.66)

0.4224

High Exposure - Placebo [3]

10

(71.4%)

2

(28.6%)

42.9%

(

35.05,

50.36)

0.0891

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.7 Difference (90% CI) in Proportion of Improvement based on >=PASI 50 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-50 PASI-50 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.25 g SRT2104 - Placebo

0

0.5 g SRT2104 - Placebo

1

1.0 g SRT2104 - Placebo

0

All Active - Placebo [2]

1

Low Exposure - Placebo [3]

0

High Exposure - Placebo [3]

1

(8.3%)

(3.1%)

(6.3%)

0

0.0%

(

-7.14,

4.90)

1.0000

0

8.3%

(

3.05,

12.65)

0.5659

0

0.0%

(

-7.14,

3.67)

1.0000

0

3.1%

(

0.57,

4.54)

0.8234

0

0.0%

(

-7.14,

2.24)

1.0000

0

6.3%

(

1.91,

9.51)

0.5939

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.7 Difference (90% CI) in Proportion of Improvement based on >=PASI 50 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-50 PASI-50 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.25 g SRT2104 - Placebo

2

(28.6%)

1

(14.3%)

14.3%

(

3.43,

22.62)

0.6691

0.5 g SRT2104 - Placebo

4

(36.4%)

1

(14.3%)

22.1%

(

6.91,

26.49)

0.4250

1.0 g SRT2104 - Placebo

4

(36.4%)

1

(14.3%)

22.1%

(

6.91,

26.49)

0.4250

All Active - Placebo [2]

10

(34.5%)

1

(14.3%)

20.2%

(

6.91,

24.35)

0.3725

Low Exposure - Placebo [3]

5

(38.5%)

1

(14.3%)

24.2%

(

18.51,

28.21)

0.3174

High Exposure - Placebo [3]

5

(31.3%)

1

(14.3%)

17.0%

(

5.13,

23.10)

0.4887

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.7 Difference (90% CI) in Proportion of Improvement based on >=PASI 50 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-50 PASI-50 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.25 g SRT2104 - Placebo

2

(33.3%)

2

(28.6%)

4.8%

(

-9.77,

12.66)

0.9895

0.5 g SRT2104 - Placebo

3

(33.3%)

2

(28.6%)

4.8%

(

-8.42,

11.13)

0.9122

1.0 g SRT2104 - Placebo

4

(36.4%)

2

(28.6%)

7.8%

(

-7.60,

14.85)

0.7979

All Active - Placebo [2]

9

(34.6%)

2

(28.6%)

6.0%

(

-7.63,

11.15)

0.8413

Low Exposure - Placebo [3]

4

(33.3%)

2

(28.6%)

4.8%

(

-8.26,

12.97)

0.8749

High Exposure - Placebo [3]

5

(35.7%)

2

(28.6%)

7.1%

(

-7.62,

12.34)

0.8367

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.8 Difference (90% CI) in Proportion of Improvement based on >=PASI 75 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-75 PASI-75 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.25 g SRT2104 - Placebo

0

0

0.0%

(

-7.14,

4.90)

1.0000

0.5 g SRT2104 - Placebo

0

0

0.0%

(

-7.14,

3.12)

1.0000

1.0 g SRT2104 - Placebo

0

0

0.0%

(

-7.14,

3.67)

1.0000

All Active - Placebo [2]

0

0

0.0%

(

-7.14,

0.64)

1.0000

Low Exposure - Placebo [3]

0

0

0.0%

(

-7.14,

2.24)

1.0000

High Exposure - Placebo [3]

0

0

0.0%

(

-7.14,

1.92)

1.0000

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.8 Difference (90% CI) in Proportion of Improvement based on >=PASI 75 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-75 PASI-75 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.25 g SRT2104 - Placebo

1

(14.3%)

0

14.3%

(

6.90,

21.59)

0.5199

0.5 g SRT2104 - Placebo

2

(18.2%)

0

18.2%

(

13.64,

22.93)

0.3231

1.0 g SRT2104 - Placebo

0

0

0.0%

(

-7.14,

3.67)

1.0000

All Active - Placebo [2]

3

(10.3%)

0

10.3%

(

8.62,

12.07)

0.4901

Low Exposure - Placebo [3]

2

(15.4%)

0

15.4%

(

11.54,

19.36)

0.3941

High Exposure - Placebo [3]

1

(6.3%)

0

6.3%

(

1.91,

9.51)

0.5939

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.8 Difference (90% CI) in Proportion of Improvement based on >=PASI 75 between Exposure Groups or Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Proportion of Subjects with Subjects with PASI-75 PASI-75 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] --------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.25 g SRT2104 - Placebo

2

(33.3%)

1

(14.3%)

19.0%

(

4.95,

27.11)

0.5778

0.5 g SRT2104 - Placebo

2

(22.2%)

1

(14.3%)

7.9%

(

1.27,

13.39)

0.7020

1.0 g SRT2104 - Placebo

1

(9.1%)

1

(14.3%)

-5.2%

( -10.58,

3.93)

0.7979

All Active - Placebo [2]

5

(19.2%)

1

(14.3%)

4.9%

(

-7.42,

10.19)

0.8413

Low Exposure - Placebo [3]

2

(16.7%)

1

(14.3%)

2.4%

(

-8.28,

9.62)

0.9810

High Exposure - Placebo [3]

3

(21.4%)

1

(14.3%)

7.1%

(

-2.99,

11.87)

0.7846

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.9 Proportion of Subjects with Clinical Activity in the PASI Score (>=PASI 75, >=PASI 50, >=PASI 25) Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 n 7 9 12 11 32 15 16 25% Improvement

2 (29%)

1 (11%)

3 (25%)

7 (64%)

50% Improvement

0

0

1

0

1

75% Improvement

0

0

0

0

0

(8%)

11 (34%)

[1] Actual visit is based on assessment windows using relative study day [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data is not imputed.

(3%)

3 (20%)

8 (50%)

0

1

0

0

(6%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.9 Proportion of Subjects with Clinical Activity in the PASI Score (>=PASI 75, >=PASI 50, >=PASI 25) Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 n 7 7 11 11 29 13 16 25% Improvement

2 (29%)

2 (29%)

5 (45%)

8 (73%)

15 (52%)

5 (38%)

10 (63%)

50% Improvement

1 (14%)

2 (29%)

4 (36%)

4 (36%)

10 (34%)

5 (38%)

5 (31%)

75% Improvement

0

1 (14%)

2 (18%)

0

3 (10%)

2 (15%)

1

[1] Actual visit is based on assessment windows using relative study day [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data is not imputed.

(6%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.9 Proportion of Subjects with Clinical Activity in the PASI Score (>=PASI 75, >=PASI 50, >=PASI 25) Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 n 7 6 9 11 26 12 14 25% Improvement

2 (29%)

2 (33%)

6 (67%)

8 (73%)

16 (62%)

6 (50%)

10 (71%)

50% Improvement

2 (29%)

2 (33%)

3 (33%)

4 (36%)

9 (35%)

4 (33%)

5 (36%)

75% Improvement

1 (14%)

2 (33%)

2 (22%)

1

5 (19%)

2 (17%)

3 (21%)

(9%)

[1] Actual visit is based on assessment windows using relative study day [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.10 Proportion of Subjects with Clinical Activity in the PASI score (>=PASI 75, >=PASI 50, >=PASI25) - using LOCF Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 n 7 9 12 11 32 15 16 25% Improvement

2 (29%)

1 (11%)

3 (25%)

7 (64%)

50% Improvement

0

0

1

0

1

75% Improvement

0

0

0

0

0

(8%)

11 (34%) (3%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data was imputed using last observation carried forward imputation.

3 (20%)

8 (50%)

0

1

0

0

(6%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.10 Proportion of Subjects with Clinical Activity in the PASI score (>=PASI 75, >=PASI 50, >=PASI25) - using LOCF Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 n 7 9 12 11 32 15 16 25% Improvement

2 (29%)

2 (22%)

5 (42%)

8 (73%)

15 (47%)

5 (33%)

10 (63%)

50% Improvement

1 (14%)

2 (22%)

4 (33%)

4 (36%)

10 (31%)

5 (33%)

5 (31%)

75% Improvement

0

1 (11%)

2 (17%)

0

2 (13%)

1

3

(9%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data was imputed using last observation carried forward imputation.

(6%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.10 Proportion of Subjects with Clinical Activity in the PASI score (>=PASI 75, >=PASI 50, >=PASI25) - using LOCF Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure PASI Placebo 0.25g 0.5g 1.0g [2] [3] [3] Assessment (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) -------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 n 7 9 12 11 32 15 16 25% Improvement

2 (29%)

2 (22%)

6 (50%)

8 (73%)

16 (50%)

6 (40%)

10 (63%)

50% Improvement

2 (29%)

2 (22%)

3 (25%)

4 (36%)

9 (28%)

4 (27%)

5 (31%)

75% Improvement

1 (14%)

2 (22%)

2 (17%)

1

5 (16%)

2 (13%)

3 (19%)

(9%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC Note: Missing data was imputed using last observation carried forward imputation.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.11 Summary of Results of Repeated Measures Analysis of Psoriasis Area Severity Index Score Efficacy Analysis Set Population Least Squares Least Squares 90% CI Means for Means for Estimated for Difference Parameter Day Comparison Treatment Placebo Difference (Lower,Upper) ---------------------------------------------------------------------------------------------------------Total Score 28 0.25g SRT2104 - Placebo 17.92 17.55 0.367 ( -5.06, 5.79) 0.5g SRT2104 - Placebo

18.10

17.55

0.544

(

-4.55,

5.63)

1.0g SRT2104 - Placebo

14.48

17.55

-3.079

(

-8.16,

2.00)

All Active - Placebo[1]

16.77

17.66

-0.893

(

-5.33,

3.54)

Low Exposure - Placebo[2]

17.12

17.65

-0.526

(

-5.46,

4.41)

High Exposure - Placebo[2]

16.17

17.65

-1.483

(

-6.33,

3.36)

Note: Model includes terms for baseline value, treatment group, day, and treatment*day interaction. [1] All Active = all SRT2104 dose groups combined [2] Exposure based on AUC

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.11 Summary of Results of Repeated Measures Analysis of Psoriasis Area Severity Index Score Efficacy Analysis Set Population Least Squares Least Squares 90% CI Means for Means for Estimated for Difference Parameter Day Comparison Treatment Placebo Difference (Lower,Upper) ---------------------------------------------------------------------------------------------------------Total Score 56 0.25g SRT2104 - Placebo 15.92 16.77 -0.853 ( -6.41, 4.71) 0.5g SRT2104 - Placebo

13.82

16.77

-2.950

(

-8.08,

2.18)

1.0g SRT2104 - Placebo

12.30

16.77

-4.466

(

-9.55,

0.61)

All Active - Placebo[1]

13.81

16.87

-3.068

(

-7.52,

1.38)

Low Exposure - Placebo[2]

14.09

16.86

-2.772

(

-7.75,

2.20)

High Exposure - Placebo[2]

13.37

16.86

-3.497

(

-8.35,

1.35)

Note: Model includes terms for baseline value, treatment group, day, and treatment*day interaction. [1] All Active = all SRT2104 dose groups combined [2] Exposure based on AUC

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.2.11 Summary of Results of Repeated Measures Analysis of Psoriasis Area Severity Index Score Efficacy Analysis Set Population Least Squares Least Squares 90% CI Means for Means for Estimated for Difference Parameter Day Comparison Treatment Placebo Difference (Lower,Upper) ---------------------------------------------------------------------------------------------------------Total Score 84 0.25g SRT2104 - Placebo 14.41 15.65 -1.249 ( -7.00, 4.51) 0.5g SRT2104 - Placebo

13.32

15.65

-2.336

(

-7.58,

2.91)

1.0g SRT2104 - Placebo

11.43

15.65

-4.225

(

-9.30,

0.85)

All Active - Placebo[1]

12.87

15.76

-2.888

(

-7.37,

1.59)

Low Exposure - Placebo[2]

13.73

15.75

-2.020

(

-7.05,

3.02)

High Exposure - Placebo[2]

12.01

15.75

-3.737

(

-8.63,

1.16)

Note: Model includes terms for baseline value, treatment group, day, and treatment*day interaction. [1] All Active = all SRT2104 dose groups combined [2] Exposure based on AUC

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.3.1 Summary of Physician Global Assessment (Overall Score) Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure Placebo 0.25g 0.5g 1.0g [2] [3] [3] Actual Visit[1] Result (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) --------------------------------------------------------------------------------------------------------Day 1

Day 28

Day 56

n Very Severe Severe Moderate Mild Minimal Clear

5 1 (20%) 1 (20%) 3 (60%) 0 0 0

n Very Severe Severe Moderate Mild Minimal Clear

1 1 2 1 0 0

n Very Severe Severe Moderate Mild Minimal Clear

1 1 2 1 0 0

5 (20%) (20%) (40%) (20%)

5 (20%) (20%) (40%) (20%)

0

12 0 2 (17%) 10 (83%) 0 0 0

11 1 (9%) 1 (9%) 9 (82%) 0 0 0

23 1 (4%) 3 (13%) 19 (83%) 0 0 0

7 0 1 (14%) 6 (86%) 0 0 0

15 1 (7%) 1 (7%) 13 (87%) 0 0 0

0

12 0 2 (17%) 9 (75%) 1 (8%) 0 0

11 0 1 (9%) 4 (36%) 6 (55%) 0 0

23 0 3 (13%) 13 (57%) 7 (30%) 0 0

7 0 0 6 (86%) 1 (14%) 0 0

15 0 2 (13%) 7 (47%) 6 (40%) 0 0

0

11 0 1 (9%) 6 (55%) 3 (27%) 1 (9%) 0

11 0 0 3 (27%) 7 (64%) 1 (9%) 0

22 0 1 (5%) 9 (41%) 10 (45%) 2 (9%) 0

7 0 1 (14%) 1 (14%) 5 (71%) 0 0

15 0 0 8 (53%) 5 (33%) 2 (13%) 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC NOTE: Subjects in cohort 1 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.3.1 Summary of Physician Global Assessment (Overall Score) Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure Placebo 0.25g 0.5g 1.0g [2] [3] [3] Actual Visit[1] Result (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) --------------------------------------------------------------------------------------------------------Day 84

n Very Severe Severe Moderate Mild Minimal Clear

1 1 2 1 0 0

5 (20%) (20%) (40%) (20%)

0 0 0 0 0 0 0

9 0 2 2 3 2 0

(22%) (22%) (33%) (22%)

11 0 0 5 (45%) 3 (27%) 3 (27%) 0

20 0 2 7 6 5 0

(10%) (35%) (30%) (25%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC NOTE: Subjects in cohort 1 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale.

7 0 2 1 3 1 0

(29%) (14%) (43%) (14%)

13 0 0 6 (46%) 3 (23%) 4 (31%) 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.2 Proportion of Subjects with Clinical Activity in PGA Score (Improved PGA Score by one or more levels) Efficacy Analysis Set Population Improved PGA Score by Actual Visit[1] Trt. N n one or more levels [4] --------------------------------------------------------------------------------------------------Day 28 Placebo 7 5 1 (20%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

2 (17%)

SRT2104 1.0 g

11

11

8 (73%)

All Active[2]

32

23

10 (43%)

Low Exposure[3]

15

7

2 (29%)

High Exposure[3]

16

15

8 (53%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.2 Proportion of Subjects with Clinical Activity in PGA Score (Improved PGA Score by one or more levels) Efficacy Analysis Set Population Improved PGA Score by Actual Visit[1] Trt. N n one or more levels [4] --------------------------------------------------------------------------------------------------Day 56 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

11

5 (45%)

SRT2104 1.0 g

11

11

9 (82%)

All Active[2]

32

22

14 (64%)

Low Exposure[3]

15

7

5 (71%)

High Exposure[3]

16

15

9 (60%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.2 Proportion of Subjects with Clinical Activity in PGA Score (Improved PGA Score by one or more levels) Efficacy Analysis Set Population Improved PGA Score by Actual Visit[1] Trt. N n one or more levels [4] --------------------------------------------------------------------------------------------------Day 84 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

9

5 (56%)

SRT2104 1.0 g

11

11

7 (64%)

All Active[2]

32

20

12 (60%)

Low Exposure[3]

15

7

4 (57%)

High Exposure[3]

16

13

8 (62%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.3 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal) Efficacy Analysis Set Population PGA Score of Actual Visit[1] Trt. N n Clear or Minimal [4] --------------------------------------------------------------------------------------------------Day 28 Placebo 7 5 0 SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

0

SRT2104 1.0 g

11

11

0

All Active[2]

32

23

0

Low Exposure[3]

15

7

0

High Exposure[3]

16

15

0

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.3 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal) Efficacy Analysis Set Population PGA Score of Actual Visit[1] Trt. N n Clear or Minimal [4] --------------------------------------------------------------------------------------------------Day 56 Placebo 7 5 0 SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

11

1

(9%)

SRT2104 1.0 g

11

11

1

(9%)

All Active[2]

32

22

2

(9%)

Low Exposure[3]

15

7

0

High Exposure[3]

16

15

2 (13%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.3 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal) Efficacy Analysis Set Population PGA Score of Actual Visit[1] Trt. N n Clear or Minimal [4] --------------------------------------------------------------------------------------------------Day 84 Placebo 7 5 0 SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

9

2 (22%)

SRT2104 1.0 g

11

11

3 (27%)

All Active[2]

32

20

5 (25%)

Low Exposure[3]

15

7

1 (14%)

High Exposure[3]

16

13

4 (31%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.4 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 28 Placebo 7 5 1 (20%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

2 (17%)

SRT2104 1.0 g

11

11

8 (73%)

All Active[2]

32

23

10 (43%)

Low Exposure[3]

15

7

2 (29%)

High Exposure[3]

16

15

8 (53%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.4 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 56 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

11

5 (45%)

SRT2104 1.0 g

11

11

9 (82%)

All Active[2]

32

22

14 (64%)

Low Exposure[3]

15

7

5 (71%)

High Exposure[3]

16

15

9 (60%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.4 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 84 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

9

5 (56%)

SRT2104 1.0 g

11

11

7 (64%)

All Active[2]

32

20

12 (60%)

Low Exposure[3]

15

7

4 (57%)

High Exposure[3]

16

13

8 (62%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.5 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) - using LOCF Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 28 Placebo 7 5 1 (20%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

2 (17%)

SRT2104 1.0 g

11

11

8 (73%)

All Active[2]

32

23

10 (43%)

Low Exposure[3]

15

7

2 (29%)

High Exposure[3]

16

15

8 (53%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data was imputed using last observation carried forward imputation.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.5 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) - using LOCF Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 56 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

5 (42%)

SRT2104 1.0 g

11

11

9 (82%)

All Active[2]

32

23

14 (61%)

Low Exposure[3]

15

7

5 (71%)

High Exposure[3]

16

15

9 (60%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data was imputed using last observation carried forward imputation.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.5 Proportion of Subjects with Clinical Activity in PGA Score (PGA Score of Clear or Minimal or an Improved PGA Score by One or More Levels) - using LOCF Efficacy Analysis Set Population PGA Score of Clear or Minimal or an Improved PGA Score by Actual Visit[1] Trt. N n One or More Levels[4] --------------------------------------------------------------------------------------------------Day 84 Placebo 7 5 2 (40%) SRT2104 0.25 g

9

0

0

SRT2104 0.5 g

12

12

6 (50%)

SRT2104 1.0 g

11

11

7 (64%)

All Active[2]

32

23

13 (57%)

Low Exposure[3]

15

7

4 (57%)

High Exposure[3]

16

15

9 (60%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure based on AUC [4] Subjects in cohort 2 inadvertently used an incorrect version of the PGA scale and thus do not have PGA data available using the 6-point grading scale. Note: Missing data was imputed using last observation carried forward imputation.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.6 Difference (90% CI) in Proportion of improvement based on PGA Score (Score of Clear or Minimal or an Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.5 g SRT2104 - Placebo

2

(16.7%)

1

(20.0%)

-3.3%

( -13.29,

1.0 g SRT2104 - Placebo

8

(72.7%)

1

(20.0%)

52.7%

(

All Active - Placebo [2]

10

(43.5%)

1

(20.0%)

23.5%

(

Low Exposure - Placebo [3]

2

(28.6%)

1

(20.0%)

8.6%

High Exposure - Placebo [3]

8

(53.3%)

1

(20.0%)

33.3%

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

4.85)

0.9685

46.18,

59.18)

0.0706

8.05,

31.43)

0.4096

( -10.23,

15.60)

0.8200

(

37.58)

0.2524

26.10,

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.6 Difference (90% CI) in Proportion of improvement based on PGA Score (Score of Clear or Minimal or an Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.5 g SRT2104 - Placebo

5

(45.5%)

2

(40.0%)

5.5%

( -11.22,

14.52)

0.8909

1.0 g SRT2104 - Placebo

9

(81.8%)

2

(40.0%)

41.8%

(

29.70,

51.34)

0.1081

All Active - Placebo [2]

14

(63.6%)

2

(40.0%)

23.6%

(

19.05,

29.80)

0.4095

Low Exposure - Placebo [3]

5

(71.4%)

2

(40.0%)

31.4%

(

20.24,

38.77)

0.3638

High Exposure - Placebo [3]

9

(60.0%)

2

(40.0%)

20.0%

(

5.76,

30.98)

0.5739

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.6 Difference (90% CI) in Proportion of improvement based on PGA Score (Score of Clear or Minimal or an Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.5 g SRT2104 - Placebo

5

(55.6%)

2

(40.0%)

15.6%

(

2.41,

21.18)

0.6648

1.0 g SRT2104 - Placebo

7

(63.6%)

2

(40.0%)

23.6%

(

7.08,

32.76)

0.4810

All Active - Placebo [2]

12

(60.0%)

2

(40.0%)

20.0%

(

5.96,

30.75)

0.4949

Low Exposure - Placebo [3]

4

(57.1%)

2

(40.0%)

17.1%

(

3.16,

30.44)

0.6577

High Exposure - Placebo [3]

8

(61.5%)

2

(40.0%)

21.5%

(

6.31,

31.64)

0.4727

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.7 Difference (90% CI) in Proportion of improvement based on PGA Score (PGA Score of Clear or Minimal) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.5 g SRT2104 - Placebo

0

0

0.0%

( -10.00,

2.50)

1.0000

1.0 g SRT2104 - Placebo

0

0

0.0%

( -10.00,

2.86)

1.0000

All Active - Placebo [2]

0

0

0.0%

( -10.00,

0.93)

1.0000

Low Exposure - Placebo [3]

0

0

0.0%

( -10.00,

6.01)

1.0000

High Exposure - Placebo [3]

0

0

0.0%

( -10.00,

1.83)

1.0000

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.7 Difference (90% CI) in Proportion of improvement based on PGA Score (PGA Score of Clear or Minimal) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.5 g SRT2104 - Placebo

1

(9.1%)

0

9.1%

(

2.85,

13.67)

0.5880

1.0 g SRT2104 - Placebo

1

(9.1%)

0

9.1%

(

2.85,

13.67)

0.5880

All Active - Placebo [2]

2

(9.1%)

0

9.1%

(

4.51,

12.77)

0.6897

Low Exposure - Placebo [3]

0

0

0.0%

( -10.00,

6.01)

1.0000

High Exposure - Placebo [3]

2

0

13.3%

16.75)

0.5686

(13.3%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

(

6.56,

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.7 Difference (90% CI) in Proportion of improvement based on PGA Score (PGA Score of Clear or Minimal) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.5 g SRT2104 - Placebo

2

(22.2%)

0

22.2%

(

16.67,

28.89)

0.3837

1.0 g SRT2104 - Placebo

3

(27.3%)

0

27.3%

(

22.73,

32.49)

0.2653

All Active - Placebo [2]

5

(25.0%)

0

25.0%

(

22.50,

30.08)

0.2858

Low Exposure - Placebo [3]

1

(14.3%)

0

14.3%

(

5.84,

21.43)

0.5573

High Exposure - Placebo [3]

4

(30.8%)

0

30.8%

(

26.65,

34.64)

0.2106

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.8 Difference (90% CI) in Proportion of improvement based on PGA Score (Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 28 0.5 g SRT2104 - Placebo

2

(16.7%)

1

(20.0%)

-3.3%

( -13.29,

1.0 g SRT2104 - Placebo

8

(72.7%)

1

(20.0%)

52.7%

(

All Active - Placebo [2]

10

(43.5%)

1

(20.0%)

23.5%

(

Low Exposure - Placebo [3]

2

(28.6%)

1

(20.0%)

8.6%

High Exposure - Placebo [3]

8

(53.3%)

1

(20.0%)

33.3%

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

4.85)

0.9685

46.18,

59.18)

0.0706

8.05,

31.43)

0.4096

( -10.23,

15.60)

0.8200

(

37.58)

0.2524

26.10,

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.8 Difference (90% CI) in Proportion of improvement based on PGA Score (Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 56 0.5 g SRT2104 - Placebo

5

(45.5%)

2

(40.0%)

5.5%

( -11.22,

14.52)

0.8909

1.0 g SRT2104 - Placebo

9

(81.8%)

2

(40.0%)

41.8%

(

29.70,

51.34)

0.1081

All Active - Placebo [2]

14

(63.6%)

2

(40.0%)

23.6%

(

19.05,

29.80)

0.4095

Low Exposure - Placebo [3]

5

(71.4%)

2

(40.0%)

31.4%

(

20.24,

38.77)

0.3638

High Exposure - Placebo [3]

9

(60.0%)

2

(40.0%)

20.0%

(

5.76,

30.98)

0.5739

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 3 Clinical Study Report SRT-2104-013

Table 14.2.3.8 Difference (90% CI) in Proportion of improvement based on PGA Score (Improved PGA Score by One or More Levels) between Exposure Groups or SRT2104 Treatment Groups and Placebo Efficacy Analysis Set Population Proportion of Subjects with PGA Score of Clear or Minimal or Improved PGA Score by One or More Levels ______________________________________ 90% Confidence for Treatment for Placebo Interval for p-value Comparison n (%) n (%) Difference Difference [4] ----------------------------------------------------------------------------------------------------------Actual Visit[1] : Day 84 0.5 g SRT2104 - Placebo

5

(55.6%)

2

(40.0%)

15.6%

(

2.41,

21.18)

0.6648

1.0 g SRT2104 - Placebo

7

(63.6%)

2

(40.0%)

23.6%

(

7.08,

32.76)

0.4810

All Active - Placebo [2]

12

(60.0%)

2

(40.0%)

20.0%

(

5.96,

30.75)

0.4949

Low Exposure - Placebo [3]

4

(57.1%)

2

(40.0%)

17.1%

(

3.16,

30.44)

0.6577

High Exposure - Placebo [3]

8

(61.5%)

2

(40.0%)

21.5%

(

6.31,

31.64)

0.4727

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined [3] Exposure based on AUC [4] No adjustments of the p-value for multiplicity. NOTE: Missing data is not imputed.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Placebo 7 CD11c+ dendritic dermis Day 1 7 351.86 212.399 459.00 64.0 585.0 Day 84 7 307.14 147.766 297.00 70.0 531.0 CD11c+ dendritic epidermis

Day 1 Day 84

7 7

72.00 65.71

71.412 85.712

54.00 33.00

0.0 0.0

184.0 220.0

CD3+ T-cells dermis

Day 1 Day 84

7 7

179.00 291.86

123.801 285.225

173.00 149.00

23.0 3.0

364.0 820.0

CD3+ T-cells epidermis

Day 1 Day 84

7 7

76.43 89.71

78.494 91.518

27.00 68.00

7.0 0.0

195.0 236.0

Epidermal Thickness

Day 1 Day 84

7 7

307.41 251.79

141.206 125.725

291.40 226.80

138.8 100.1

473.5 435.7

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------SRT2104 0.25 g 9 CD11c+ dendritic dermis Day 1 9 437.33 438.580 268.00 58.0 1525.0 Day 84 6 211.00 150.470 225.50 38.0 427.0 CD11c+ dendritic epidermis

Day 1 Day 84

9 6

73.11 40.83

92.383 43.531

38.00 35.50

3.0 0.0

285.0 91.0

CD3+ T-cells dermis

Day 1 Day 84

9 6

351.00 167.67

200.182 146.597

332.00 140.00

105.0 20.0

729.0 438.0

CD3+ T-cells epidermis

Day 1 Day 84

9 6

255.00 82.17

428.367 79.615

126.00 62.00

20.0 11.0

1386.0 215.0

Epidermal Thickness

Day 1 Day 84

9 6

354.03 306.47

101.885 191.971

359.10 294.45

193.1 90.4

476.2 598.5

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------SRT2104 0.5 g 12 CD11c+ dendritic dermis Day 1 12 497.08 477.991 287.00 81.0 1798.0 Day 84 9 347.44 296.189 276.00 43.0 855.0 CD11c+ dendritic epidermis

Day 1 Day 84

12 9

76.75 51.33

74.574 59.900

46.50 35.00

19.0 0.0

286.0 152.0

CD3+ T-cells dermis

Day 1 Day 84

12 9

230.67 172.89

199.539 147.300

215.00 107.00

23.0 57.0

793.0 461.0

CD3+ T-cells epidermis

Day 1 Day 84

12 9

102.67 53.44

78.999 43.087

86.50 46.00

14.0 10.0

258.0 110.0

Epidermal Thickness

Day 1 Day 84

12 9

384.06 294.22

157.309 124.317

362.15 251.10

210.5 173.4

800.5 486.5

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------SRT2104 1.0 g 11 CD11c+ dendritic dermis Day 1 11 498.64 246.680 540.00 66.0 796.0 Day 84 11 425.82 212.510 443.00 144.0 716.0 CD11c+ dendritic epidermis

Day 1 Day 84

11 11

64.45 69.45

47.243 42.463

75.00 58.00

0.0 2.0

158.0 130.0

CD3+ T-cells dermis

Day 1 Day 84

11 11

264.27 323.00

176.705 199.134

187.00 292.00

49.0 58.0

551.0 663.0

CD3+ T-cells epidermis

Day 1 Day 84

11 11

92.00 95.27

77.728 50.321

60.00 102.00

22.0 7.0

263.0 170.0

Epidermal Thickness

Day 1 Day 84

11 11

413.91 361.44

185.574 137.011

352.90 361.10

129.9 166.1

801.2 633.4

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------All Active[2] 32 CD11c+ dendritic dermis Day 1 32 480.81 388.722 420.00 58.0 1798.0 Day 84 26 349.12 240.486 289.50 38.0 855.0 CD11c+ dendritic epidermis

Day 1 Day 84

32 26

71.50 56.58

70.177 48.895

50.50 47.00

0.0 0.0

286.0 152.0

CD3+ T-cells dermis

Day 1 Day 84

32 26

276.06 235.19

192.404 181.624

223.00 161.50

23.0 20.0

793.0 663.0

CD3+ T-cells epidermis

Day 1 Day 84

32 26

141.84 77.77

238.141 56.808

86.00 84.50

14.0 7.0

1386.0 215.0

Epidermal Thickness

Day 1 Day 84

32 26

385.87 325.48

152.129 144.334

358.60 275.00

129.9 90.4

801.2 633.4

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Low 15 CD11c+ dendritic dermis Day 1 15 588.40 495.828 421.00 58.0 1798.0 Exposure[3] Day 84 12 313.17 273.258 237.00 38.0 855.0 CD11c+ dendritic epidermis

Day 1 Day 84

15 12

84.53 52.08

91.093 55.403

51.00 44.00

3.0 0.0

286.0 152.0

CD3+ T-cells dermis

Day 1 Day 84

15 12

333.33 192.33

226.136 153.336

332.00 161.50

23.0 20.0

793.0 545.0

CD3+ T-cells epidermis

Day 1 Day 84

15 12

196.13 68.92

339.367 62.314

93.00 59.50

14.0 10.0

1386.0 215.0

Epidermal Thickness

Day 1 Day 84

15 12

355.51 299.59

100.300 157.185

359.10 253.05

193.1 90.4

492.8 598.5

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 7 Clinical Study Report SRT-2104-013

Table 14.2.4.1 Summary of Dermal and Epidermal PBMC Counts Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------High 16 CD11c+ dendritic dermis Day 1 16 392.38 245.509 389.00 66.0 761.0 Exposure[3] Day 84 14 379.93 214.056 386.50 87.0 716.0 CD11c+ dendritic epidermis

Day 1 Day 84

16 14

61.31 60.43

45.631 44.336

52.00 52.00

0.0 0.0

158.0 130.0

CD3+ T-cells dermis

Day 1 Day 84

16 14

226.63 271.93

150.275 200.981

208.00 219.50

49.0 57.0

551.0 663.0

CD3+ T-cells epidermis

Day 1 Day 84

16 14

93.94 85.36

64.517 52.783

69.50 101.00

22.0 7.0

242.0 170.0

Epidermal Thickness

Day 1 Day 84

16 14

419.69 347.68

189.234 134.189

362.15 361.45

129.9 166.1

801.2 633.4

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 4 Clinical Study Report SRT-2104-013

Table 14.2.4.2 Summary of Dermal and Epidermal PBMC Counts - Change from Baseline Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------Placebo 7 CD11c+ dendritic dermis Day 84 7 -44.71 240.954 -49.00 -487.0 233.0

SRT2104 0.25 g

9

CD11c+ dendritic epidermis

Day 84

7

-6.29

63.358

-7.00

-88.0

108.0

CD3+ T-cells dermis

Day 84

7

112.86

264.833

91.00

-171.0

463.0

CD3+ T-cells epidermis

Day 84

7

13.29

38.793

14.00

-48.0

55.0

Epidermal Thickness

Day 84

7

-55.63

99.050

-62.20

-191.3

88.0

CD11c+ dendritic dermis

Day 84

6

-289.33

484.932

-105.50

-1222.0

63.0

CD11c+ dendritic epidermis

Day 84

6

-34.67

130.370

-16.50

-283.0

78.0

CD3+ T-cells dermis

Day 84

6

-230.67

294.888

-188.00

-572.0

90.0

CD3+ T-cells epidermis

Day 84

6

-232.67

559.729

-32.00

-1364.0

122.0

Epidermal Thickness

Day 84

6

-61.48

131.201

-95.70

-183.2

125.3

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 4 Clinical Study Report SRT-2104-013

Table 14.2.4.2 Summary of Dermal and Epidermal PBMC Counts - Change from Baseline Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------SRT2104 0.5 g 12 CD11c+ dendritic dermis Day 84 9 -180.89 482.534 -100.00 -943.0 411.0

SRT2104 1.0 g

11

CD11c+ dendritic epidermis

Day 84

9

-28.33

74.973

-34.00

-141.0

125.0

CD3+ T-cells dermis

Day 84

9

-78.22

266.927

-14.00

-640.0

256.0

CD3+ T-cells epidermis

Day 84

9

-40.78

67.401

-24.00

-148.0

61.0

Epidermal Thickness

Day 84

9

-66.34

91.565

-91.90

-181.1

113.4

CD11c+ dendritic dermis

Day 84

11

-72.82

309.904

-93.00

-568.0

551.0

CD11c+ dendritic epidermis

Day 84

11

5.00

49.047

7.00

-52.0

109.0

CD3+ T-cells dermis

Day 84

11

58.73

217.121

19.00

-307.0

436.0

CD3+ T-cells epidermis

Day 84

11

3.27

92.206

4.00

-193.0

127.0

Epidermal Thickness

Day 84

11

-52.47

138.671

-58.60

-240.4

200.6

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 4 Clinical Study Report SRT-2104-013

Table 14.2.4.2 Summary of Dermal and Epidermal PBMC Counts - Change from Baseline Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------All Active[2] 32 CD11c+ dendritic dermis Day 84 26 -160.19 409.234 -96.50 -1222.0 551.0

Low Exposure[3]

15

CD11c+ dendritic epidermis

Day 84

26

-15.69

80.576

-19.50

-283.0

125.0

CD3+ T-cells dermis

Day 84

26

-55.46

268.960

-8.00

-640.0

436.0

CD3+ T-cells epidermis

Day 84

26

-66.42

276.624

-15.00

-1364.0

127.0

Epidermal Thickness

Day 84

26

-59.35

117.716

-85.55

-240.4

200.6

CD11c+ dendritic dermis

Day 84

12

-344.50

458.987

-255.50

-1222.0

411.0

CD11c+ dendritic epidermis

Day 84

12

-36.50

105.710

-36.00

-283.0

125.0

CD3+ T-cells dermis

Day 84

12

-160.25

287.391

-14.00

-640.0

121.0

CD3+ T-cells epidermis

Day 84

12

-142.42

394.557

-27.50

-1364.0

122.0

Epidermal Thickness

Day 84

12

-63.24

113.867

-57.70

-240.4

125.3

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 4 Clinical Study Report SRT-2104-013

Table 14.2.4.2 Summary of Dermal and Epidermal PBMC Counts - Change from Baseline Efficacy Analysis Set Population Actual Visit Treatment N Assessment [1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------High 16 CD11c+ dendritic dermis Day 84 14 -2.21 292.524 -49.00 -445.0 551.0 Exposure[3] CD11c+ dendritic epidermis

Day 84

14

2.14

47.833

5.00

-81.0

109.0

CD3+ T-cells dermis

Day 84

14

34.36

224.507

2.50

-307.0

436.0

CD3+ T-cells epidermis

Day 84

14

-1.29

74.366

-8.50

-113.0

127.0

Epidermal Thickness

Day 84

14

-56.02

125.105

-103.70

-192.7

200.6

Note: PBMC stands for peripheral blood mononuclear cell. [1] Actual visit is based on assessment windows using relative study day. [2] All Active = all STR2104 dose groups combined. [3] Exposure based on AUC.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.4.4 Proportion of Subjects Expressing Abnormal Cellular Proteins by Visit Efficacy Analysis Set Population All Low High SRT2104 SRT2104 SRT2104 Active Exposure Exposure Actual Placebo 0.25g 0.5g 1.0g [2] [3] [3] Test Name Visit[1] Result (N=7) (N=9) (N=12) (N=11) (N=32) (N=15) (N=16) ----------------------------------------------------------------------------------------------------------K-16 epidermis

Day 1

Day 84

n

7

9

NEG NEG/POS POS

1 6

0 (14%) (86%)

1 8

0 (11%) (89%)

n NEG NEG/POS POS

1

7 (14%) 0 (86%)

3

6 (50%) 0 (50%)

6

3

12

11

0 0 12 (100%)

1 1 9

9 (22%) (22%) (56%)

1 1 9

2 2 5

(9%) (9%) (82%)

32

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC

0

16

1 2 29

(3%) (6%) (91%)

1 14

(7%) (93%)

1 1 14

6 3 17

26 (23%) (12%) (65%)

5 1 6

12 (42%) (8%) (50%)

1 2 11

11 (9%) (9%) (82%)

15

(6%) (6%) (88%) 14 (7%) (14%) (79%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.4.5 Shift Table of Proportion of Subjects Expressing Abnormal Cellular Proteins Efficacy Analysis Set Population Day 84 Value[1] Baseline -----------------------------------------Assessment Treatment n Value NEG NEG/POS POS ------------------------------------------------------------------------------------------------------K-16 epidermis Placebo 7 NEG 0 0 0 NEG/POS 0 0 1 (14.3%) POS 1 (14.3%) 0 5 (71.4%) SRT2104 0.25 g

SRT2104 0.5 g

SRT2104 1.0 g

All Active[2]

Low Exposure[3]

High Exposure[3]

6

9

11

26

12

14

NEG NEG/POS POS

0 0 3

NEG NEG/POS POS

0 0 2

NEG NEG/POS POS

0 0 1

NEG NEG/POS POS

0 0 6

NEG NEG/POS POS

0 0 5

NEG NEG/POS POS

0 0 1

(50.0%)

0 0 0

0 0 3

(50.0%)

(22.2%)

0 0 2

(22.2%)

0 0 5

(55.6%)

(9.1%)

0 0 1

(9.1%)

1 1 7

(9.1%) (9.1%) (63.6%)

(23.1%)

0 0 3

(11.5%)

1 1 15

(3.8%) (3.8%) (57.7%)

(41.7%)

0 0 1

(8.3%)

0 0 6

(50.0%)

(7.1%)

0 0 2

(14.3%)

1 1 9

(7.1%) (7.1%) (64.3%)

[1] Actual visit is based on assessment windows using relative study day. [2] All Active = all SRT2104 dose groups combined [3] Exposure is based on AUC

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013 Table 14.2.5.1 Summary of FGF21 and hsCRP Efficacy Analysis Set Population

Test Name Actual (Unit) Treatment N Visit[1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------FGF-21 (pg/ml) Placebo 7 Day 1 6 332.50 308.923 193.00 107.4 904.8 Day 28 7 281.06 155.647 248.40 82.4 570.8 Day 56 6 319.60 191.946 325.90 104.0 643.6 Day 84 6 293.00 204.221 301.20 63.0 651.4 SRT2104 0.25 g

9

Day Day Day Day

1 28 56 84

8 7 6 5

371.88 271.20 388.50 269.56

307.526 200.466 210.286 145.787

363.20 203.60 329.40 251.20

30.0 60.4 126.8 91.4

959.4 611.4 743.4 496.6

SRT2104 0.5 g

12

Day Day Day Day

1 28 56 84

11 12 9 9

269.73 322.02 414.93 324.31

204.362 317.989 390.876 221.555

240.00 235.70 200.20 392.80

30.0 30.0 30.0 30.0

670.4 1191.0 1158.6 593.6

SRT2104 1.0 g

11

Day Day Day Day

1 28 56 84

9 11 11 10

1126.21 1254.57 1276.98 590.60

1970.584 2625.450 2623.692 582.755

532.80 455.80 451.40 344.90

147.8 123.8 144.4 131.6

6344.5 9133.5 9123.0 1830.0

[1] Actual visit is based on assessment windows using relative study day.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013 Table 14.2.5.1 Summary of FGF21 and hsCRP Efficacy Analysis Set Population

Test Name Actual (Unit) Treatment N Visit[1] n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------hsCRP (mg/l) Placebo 7 Day 1 7 4.31 4.595 3.70 0.2 11.1 Day 28 7 4.43 3.734 4.00 0.4 11.5 Day 56 7 4.90 6.412 3.50 0.2 18.7 Day 84 7 4.97 6.730 3.20 0.2 19.2 SRT2104 0.25 g

9

Day Day Day Day

1 28 56 84

9 8 6 5

3.73 4.03 3.55 2.70

2.647 2.507 2.790 2.125

2.70 3.90 2.75 2.30

0.3 1.2 0.2 0.2

8.1 8.4 7.4 5.7

SRT2104 0.5 g

12

Day Day Day Day

1 28 56 84

11 11 8 9

5.06 6.02 2.53 2.59

7.817 8.516 2.543 2.655

2.00 2.60 1.75 1.50

0.2 0.4 0.9 0.4

23.8 27.8 8.6 8.9

SRT2104 1.0 g

11

Day Day Day Day

1 28 56 84

11 10 10 10

2.75 2.00 2.48 3.21

2.935 2.039 2.948 3.188

2.20 1.15 1.35 2.10

0.4 0.3 0.3 0.3

9.0 6.7 8.3 8.8

[1] Actual visit is based on assessment windows using relative study day.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.5.2 Summary of FGF21 and hsCRP Change from Baseline Efficacy Analysis Set Population Test Name Actual (Unit) Treatment N Visit[1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------FGF-21 (pg/ml) Placebo 7 Day 28 6 -61.67 269.031 15.70 -582.8 141.0 Day 56 5 -67.04 276.937 -1.20 -541.2 179.8 Day 84 5 -86.12 300.144 -24.60 -593.2 187.6 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

6 5 4

-94.53 -72.72 -189.60

154.104 366.774 364.475

-48.00 -54.00 -83.70

-348.0 -621.2 -683.6

40.6 325.0 92.6

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

11 9 9

56.93 148.93 58.31

177.244 305.634 223.237

18.00 33.60 57.80

-86.0 -68.4 -252.6

520.6 918.6 412.2

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

9 9 9

329.82 268.39 -673.32

930.329 961.010 1590.594

25.20 -13.80 -189.20

-178.2 -439.6 -4890.1

2789.0 2778.5 99.0

[3] Actual visit is based on assessment windows using relative study day.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.5.2 Summary of FGF21 and hsCRP Change from Baseline Efficacy Analysis Set Population Test Name Actual (Unit) Treatment N Visit[1] n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------hsCRP (mg/l) Placebo 7 Day 28 7 0.11 2.330 0.20 -4.4 3.5 Day 56 7 0.59 3.552 0.10 -4.4 7.6 Day 84 7 0.66 3.895 -0.10 -4.9 8.1 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

8 6 5

-0.14 -0.18 -0.16

1.148 1.897 1.055

0.10 -0.50 -0.10

-1.6 -2.4 -1.8

1.7 2.6 0.9

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

10 7 8

1.18 -1.31 -0.75

1.954 3.261 3.159

0.50 -0.20 -0.10

-0.6 -8.6 -8.3

4.4 0.8 1.5

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

10 10 10

-0.96 -0.48 0.27

2.211 2.640 1.351

-0.20 -0.30 0.00

-6.3 -5.8 -1.8

2.0 5.1 2.5

[3] Actual visit is based on assessment windows using relative study day.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.6 Proportion of Subjects Using Rescue Medications Efficacy Analysis Set Population

No data to report

It was used it within the limits set in the protocol, and details are in Listing 16.2.6.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.7.1 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score by Visit Efficacy Analysis Set Population Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------------------Day 1 Depression n 7 9 12 11 Mean 3.3 5.6 5.2 3.9 SD 2.87 4.00 3.90 4.23 Median 2.0 6.0 4.5 2.0 Min. 0 0 0 0 Max. 8 10 11 12

Day 28

Anxiety

n Mean SD Median Min. Max.

7 3.4 3.64 2.0 0 9

9 6.9 3.76 9.0 0 11

12 4.0 2.66 4.0 0 9

11 4.9 4.23 3.0 0 14

Depression

n Mean SD Median Min. Max.

7 3.3 2.87 2.0 0 8

9 3.3 3.24 2.0 0 8

12 3.8 2.89 3.0 0 10

11 3.7 3.64 3.0 0 8

Anxiety

n Mean SD Median Min. Max.

7 4.0 4.20 2.0 0 12

9 4.3 3.28 4.0 0 11

12 5.3 2.81 5.0 1 11

11 4.7 3.98 4.0 0 12

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.7.1 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score by Visit Efficacy Analysis Set Population Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------------------Day 56 Depression n 7 6 9 11 Mean 2.9 4.2 3.4 3.8 SD 3.48 3.31 3.47 3.19 Median 2.0 4.5 2.0 3.0 Min. 0 0 0 0 Max. 9 8 10 9

Day 84

Anxiety

n Mean SD Median Min. Max.

7 4.3 3.95 3.0 0 12

6 4.7 4.63 2.5 0 11

9 5.1 4.23 4.0 0 11

11 4.9 3.39 4.0 1 13

Depression

n Mean SD Median Min. Max.

7 3.0 3.96 2.0 0 11

8 5.8 5.20 7.0 0 15

12 3.5 3.75 2.5 0 12

11 3.2 4.05 1.0 0 10

Anxiety

n Mean SD Median Min. Max.

7 3.6 5.13 1.0 0 14

8 5.9 5.06 6.5 0 13

12 5.8 4.00 5.5 1 13

11 4.0 4.92 2.0 0 14

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.7.2 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score - Change from Baseline Efficacy Analysis Set Population Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------------------Day 28 Depression n 7 9 12 11 Mean 0.0 -2.2 -1.3 -0.2 SD 1.73 2.99 4.29 2.36 Median 0.0 -1.0 -1.5 0.0 Min. -2 -9 -7 -5 Max. 2 0 6 3

Day 56

Anxiety

n Mean SD Median Min. Max.

7 0.6 4.58 0.0 -4 10

9 -2.6 3.84 -2.0 -8 4

12 1.3 3.08 1.5 -3 6

11 -0.2 2.09 0.0 -3 3

Depression

n Mean SD Median Min. Max.

7 -0.4 3.31 0.0 -5 4

6 -1.7 1.63 -1.5 -4 0

9 -2.2 3.70 -3.0 -9 2

11 -0.1 4.11 0.0 -6 7

Anxiety

n Mean SD Median Min. Max.

7 0.9 4.71 1.0 -4 10

6 -2.3 3.61 -2.5 -8 2

9 1.6 4.75 0.0 -3 10

11 0.0 3.35 0.0 -8 4

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.7.2 Summary Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score - Change from Baseline Efficacy Analysis Set Population Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------------------Day 84 Depression n 7 8 12 11 Mean -0.3 -0.5 -1.7 -0.7 SD 2.98 4.11 3.50 4.86 Median -1.0 -0.5 -1.5 -1.0 Min. -4 -6 -9 -8 Max. 5 8 3 9 Anxiety

n Mean SD Median Min. Max.

7 0.1 5.52 -2.0 -4 12

8 -1.9 4.29 -1.5 -10 4

12 1.8 3.96 1.0 -3 10

11 -0.9 1.92 -1.0 -4 3

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.2.8.1 Summary Statistics of the Patient Health Questionnaire by Visit Efficacy Analysis Set Population Total Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit Score (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------Day 1 n 7 9 12 11 Mean 4.4 5.9 2.8 3.9 SD 4.96 4.08 3.13 4.74 Median 2.0 7.0 1.5 2.0 Min. 0 0 0 0 Max. 14 12 7 14

Day 28

n Mean SD Median Min. Max.

7 2.9 2.79 2.0 0 8

9 5.0 4.21 3.0 0 12

12 5.0 4.55 4.5 0 13

11 4.3 4.86 2.0 0 14

Day 56

n Mean SD Median Min. Max.

7 2.3 1.80 2.0 0 5

6 3.0 3.58 1.5 0 8

9 3.8 3.19 4.0 0 10

11 4.3 4.73 2.0 0 12

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Table 14.2.8.1 Summary Statistics of the Patient Health Questionnaire by Visit Efficacy Analysis Set Population Total Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit Score (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------Day 84 n 7 8 12 11 Mean 3.6 7.8 3.0 5.9 SD 4.61 5.85 2.13 7.38 Median 2.0 5.5 2.5 2.0 Min. 0 0 0 0 Max. 12 16 7 17

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.8.2 Summary Statistics of the Patient Health Questionnaire - Change from Baseline Efficacy Analysis Set Population Total Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit Score (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------Day 28 n 7 9 12 11 Mean -1.6 -0.9 2.2 0.4 SD 4.24 2.93 3.76 4.20 Median 0.0 0.0 1.0 0.0 Min. -11 -7 -4 -7 Max. 1 2 8 8

Day 56

n Mean SD Median Min. Max.

7 -2.1 4.22 0.0 -11 1

6 -2.3 4.03 -1.0 -9 2

9 0.0 3.08 0.0 -5 6

11 0.4 3.67 0.0 -7 6

Day 84

n Mean SD Median Min. Max.

7 -0.9 5.84 0.0 -12 8

8 1.4 4.07 1.0 -4 9

12 0.2 3.04 0.5 -5 7

11 2.0 7.18 0.0 -7 16

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.9.1 Summary Statistics of Psoriasis Quality of Life-12 Instrument (PQOL-12) by Visit Efficacy Analysis Set Population Total Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit Score (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------Day 1 n 7 9 12 11 Mean 64.9 75.6 72.2 78.7 SD 34.18 32.14 19.90 31.86 Median 55.0 77.0 79.0 77.0 Min. 31 25 34 12 Max. 115 115 92 116

Day 84

n Mean SD Median Min. Max.

7 60.6 43.14 77.0 10 114

8 67.0 38.59 76.0 16 110

12 48.3 27.80 56.0 5 94

11 70.2 38.24 60.0 0 117

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.9.2 Summary Statistics of Psoriasis Quality of Life-12 Instrument (PQOL-12) Change from Baseline Efficacy Analysis Set Population Total Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Visit Score (N=7) (N=9) (N=12) (N=11) -------------------------------------------------------------------------------Day 84 n 7 8 12 11 Mean -4.3 -13.3 -23.8 -8.5 SD 16.99 26.64 38.55 15.18 Median -4.0 -10.0 -21.5 -12.0 Min. -31 -69 -87 -28 Max. 22 20 34 23

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.2.10 Summary of SRT2104 Pharmacokinetic Parameters by Treatment PK Parameters Treatment N n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------AUC SRT2104 0.25 g 9 9 2579.21 1563.000 2602.57 99.4 5519.6 SRT2104 0.5 g 11 11 4501.46 2258.042 4674.61 1266.3 8819.9 SRT2104 1.0 g 11 11 9842.22 8719.677 7341.41 367.2 29627.4 All Active[1] 31 31 5838.50 6116.800 4190.20 99.4 29627.4 Low Exposure[2] 15 15 2229.78 1154.888 2303.38 99.4 4150.6 High Exposure[2] 16 16 9221.67 6953.692 6422.39 4190.2 29627.4 Cmax

SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g All Active[1] Low Exposure[2] High Exposure[2]

9 11 11 31 15 16

9 11 11 31 15 16

[1] All Active = all SRT2104 dose groups combined [2] Exposure is based on AUC

261.64 406.67 1005.89 577.19 254.77 879.47

134.403 237.787 813.346 593.378 223.145 675.501

285.07 451.70 626.15 441.62 192.00 607.39

6.0 64.2 23.5 6.0 6.0 401.4

433.7 720.0 2441.6 2441.6 907.4 2441.6

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013 Table 14.3 Summary of SRT2104 Exposure Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 Placebo 0.25 g 0.5 g 1.0 g Total (N=7) (N=9) (N=12) (N=11) (N=39) -------------------------------------------------------------------------------------------------Total Cumulative n 7 9 12 11 39 Dose (g) Mean 0.0 16.8 37.8 83.4 39.0 SD 0.00 4.76 8.81 3.67 31.58 Median 0.0 20.0 42.0 84.0 41.5 Min. 0 9 21 75 0 Max. 0 21 44 89 89 Duration (days)

n Mean SD Median Min. Max.

7 85.6 1.51 85.0 85 89

9 69.4 20.11 84.0 36 85

12 76.2 17.75 85.0 42 89

11 84.5 3.62 85.0 75 89

39 78.6 14.86 85.0 36 89

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 4 Clinical Study Report SRT-2104-013

Table 14.3.1.1 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text Safety Analysis Set Population System Organ Class Preferred Term Verbatim Text ------------------------------------------------------------------------------------------------Cardiac disorders Conduction disorder BORDERLINE INTRAVENTRICULAR CONDUCTION DEFECT Eye disorders

Eye pain

LEFT LATERAL EYE PAIN

Gastrointestinal disorders

Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Nausea

STOMACH ACHE CONSTIPATION DIARRHEA HEARTBURN-INTERMITTENT DAILY GASSINESS (FLATUS) FOOD POISONING MILD NAUSEA NAUSEA PANCREATITIS, IDIOPATHIC TOOTH ACHE NAUSEA / VOMITING VOMITING

Pancreatitis Toothache Vomiting General disorders and administration site conditions

Fatigue Malaise Oedema peripheral Pyrexia

Infections and infestations

Furuncle Influenza Nasal abscess Pharyngitis

FATIGUE GENERAL FATIGUE GENERAL MALAISE LEFT HAND EDEMA LEFT LOWER EXTREMITY EDEMA FEVER OCCASIONAL FEVERS FURUNCLE (CYST) OF LEFT LABIA MAJORA FLU NASAL ABSCESS PHARYNGITIS

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 4 Clinical Study Report SRT-2104-013

Table 14.3.1.1 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text Safety Analysis Set Population System Organ Class Preferred Term Verbatim Text ------------------------------------------------------------------------------------------------Infections and infestations Sinusitis SINUS INFECTION Skin infection SKIN INFECTION Upper respiratory tract UPPER RESPIRATORY INFECTION infection URI Urinary tract infection URINARY TRACT INFECTION Viral infection VIRAL INFECTION Injury, poisoning and procedural complications

Contusion Injury Joint sprain

Investigations

Alanine aminotransferase increased Aspartate aminotransferase increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased Hepatic enzyme increased

Metabolism and nutrition disorders

Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

CONTUSION OF THIRD TOE ON RIGHT FOOT ABDOMINAL CONTUSION SECONDARY TO BLUNT TRAUMA SPRAINED RIGHT WRIST ELEVATED (BUMP) IN ALT LAB VALUE ELEVATED ALAT GROSSLY ELEVATED ALT ELEVATED ASAT GROSSLY ELEVATED AST ELEVATED TOTAL BILIRUBIN DECREASED PHOSPHOROUS ELEVATED POTASSIUM ELEVATED LIVER ENZYMES LIVER EVENT, ELEVATED ENZYMES DEHYDRATION WORSENING OF DIABETES MELLITUS II HYPOKALEMIA HYPONATREMIA

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 4 Clinical Study Report SRT-2104-013

Table 14.3.1.1 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text Safety Analysis Set Population System Organ Class Preferred Term Verbatim Text ------------------------------------------------------------------------------------------------Musculoskeletal and connective Arthralgia KNEE PAIN(RIGHT) tissue disorders Back pain BACKACHE Flank pain RIGHT FLANK PAIN Myalgia GENERAL MUSCLE ACHES RIGHT LOWER QUADRANT ABDOMINAL MUSCLE PAIN Osteoarthritis WORSENING OF OSTEOARTHRITIS Pain in extremity LEFT ARM SORENESS LEFT HAND PAIN Psoriatic arthropathy PSORIATIC ARTHRITIS WORSENING OF PSORIATIC ARTHRITIS WORSENING OF PSORIATIC ARTHRITIS (OF LOWER BACK). Nervous system disorders

Disturbance in attention Dizziness

Paraesthesia

DIFFICULTY CONCENTRATING DIZZINESS DIZZY SPELLS DIZZYNESS HEADACHE HEADACHE-INTERMITTENT DAILY INCREASED FREQUENCY OF HEADACHES POUNDING HEADACHE LEFT ARM "TINGLING"

Psychiatric disorders

Depression

DEPRESSION

Respiratory, thoracic and mediastinal disorders

Pneumonitis

PNEUMONITIS

Wheezing

OCCASIONAL WHEEZES ON R LOBE

Headache

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 4 Clinical Study Report SRT-2104-013

Table 14.3.1.1 Relationship of Adverse Event System Organ Class, Preferred Term, and Verbatim Text Safety Analysis Set Population System Organ Class Preferred Term Verbatim Text ------------------------------------------------------------------------------------------------Skin and subcutaneous tissue Actinic keratosis ACTINIC KERATOSIS-HELIX AND disorders ANTI HELIX OF R EAR Erythema annulare ERYTHEMA ANNULARE CENTRIFUGUM Ingrowing nail ONYCHOCRYPTOSIS LEFT GREAT TOE Pruritus GENERAL PRURITIS, WORSE AT NIGHT PRURITIS OF BILATERAL WRIST PSORIATIC PLAQUES PRURITIS OF LEGS

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 4 Clinical Study Report SRT-2104-013 Table 14.3.1.2 Summary of All Adverse Events Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------ANY EVENT 3 (43%) 4 (44%) 9 (75%) 11 (100%) 27 (69%)

NOTE:

Infections and infestations Any event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection

2 1 0 0 0 1 0 0 0 0

(29%) (14%)

Gastrointestinal disorders Any event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

1 0 0 0 1 0 0 0 0 0 0

(14%)

(14%)

(14%)

0 0 0 0 0 0 0 0 0 0 3 1 1 0 0 0 0 0 0 1 1

(33%) (11%) (11%)

(11%) (11%)

Only treatment emergent adverse events are summarized.

5 1 0 1 0 0 1 1 0 1

(42%) (8%)

2 0 0 1 0 0 1 0 0 0 0

(17%)

(8%) (8%) (8%) (8%)

(8%) (8%)

4 1 1 0 1 0 0 0 1 0

(36%) (9%) (9%)

3 1 1 0 0 1 0 1 1 0 0

(27%) (9%) (9%)

(9%)

(9%)

(9%) (9%) (9%)

11 3 1 1 1 1 1 1 1 1

(28%) (8%) (3%) (3%) (3%) (3%) (3%) (3%) (3%) (3%)

9 2 2 1 1 1 1 1 1 1 1

(23%) (5%) (5%) (3%) (3%) (3%) (3%) (3%) (3%) (3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 4 Clinical Study Report SRT-2104-013 Table 14.3.1.2 Summary of All Adverse Events Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any event 1 (14%) 0 1 (8%) 4 (36%) 6 (15%) Psoriatic arthropathy 0 0 1 (8%) 2 (18%) 3 (8%) Pain in extremity 0 0 1 (8%) 1 (9%) 2 (5%) Arthralgia 0 0 0 1 (9%) 1 (3%) Back pain 0 0 0 1 (9%) 1 (3%) Flank pain 1 (14%) 0 0 0 1 (3%) Myalgia 0 0 0 1 (9%) 1 (3%) Osteoarthritis 0 0 0 1 (9%) 1 (3%) Nervous system disorders Any event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

0 0 0 0 0

0 0 0 0 0

2 0 2 0 0

(17%)

0 0

0 0

1 0

0

0

0

0 0 0 0

0 0 0 0

1 0 0 0

Only treatment emergent adverse events are summarized.

(17%)

4 3 1 1 1

(36%) (27%) (9%) (9%) (9%)

6 3 3 1 1

(15%) (8%) (8%) (3%) (3%)

(8%)

4 2

(36%) (18%)

5 2

(13%) (5%)

2

(18%)

2

(5%)

1 1 1 1

(9%) (9%) (9%) (9%)

2 1 1 1

(5%) (3%) (3%) (3%)

(8%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 4 Clinical Study Report SRT-2104-013 Table 14.3.1.2 Summary of All Adverse Events Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any event 3 (43%) 0 0 2 (18%) 5 (13%) Pruritus 1 (14%) 0 0 1 (9%) 2 (5%) Actinic keratosis 0 0 0 1 (9%) 1 (3%) Erythema annulare 1 (14%) 0 0 0 1 (3%) Ingrowing nail 1 (14%) 0 0 0 1 (3%)

NOTE:

General disorders and administration site conditions Any event Fatigue Pyrexia Malaise Oedema peripheral

1 0 1 0 0

Injury, poisoning and procedural complications Any event Contusion Injury Joint sprain Metabolism and nutrition disorders Any event Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

(14%)

0 0 0 0 0

1 0 0 0 1

(8%)

0 0 0 0

0 0 0 0

1 0 0 1

(8%)

0 0 0 0 0

2 1 1 1 1

(14%)

(22%) (11%) (11%) (11%) (11%)

Only treatment emergent adverse events are summarized.

0 0 0 0 0

(8%)

(8%)

2 2 1 1 0

(18%) (18%) (9%) (9%)

4 2 2 1 1

(10%) (5%) (5%) (3%) (3%)

2 1 1 0

(18%) (9%) (9%)

3 1 1 1

(8%) (3%) (3%) (3%)

2 1 1 1 1

(5%) (3%) (3%) (3%) (3%)

0 0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 4 Clinical Study Report SRT-2104-013 Table 14.3.1.2 Summary of All Adverse Events Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------Eye disorders Any event 0 0 0 1 (9%) 1 (3%) Eye pain 0 0 0 1 (9%) 1 (3%)

NOTE:

Psychiatric disorders Any event Depression

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any event Pneumonitis

0 0

1 1

(11%) (11%)

Only treatment emergent adverse events are summarized.

0 0

1 1

0 0

0 0

(9%) (9%)

1 1

(3%) (3%)

1 1

(3%) (3%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ____________________________Placebo (N=7)____________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------ANY EVENT 2 (29%) 1 (14%) 0 0 0 Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

NOTE:

1 (14%) 0

1 (14%) 1 (14%)

0 0

0 0

0 0

0 0 0 1 (14%) 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

1 (14%) 0 0 0 1 (14%) 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.25 g (N=9)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------ANY EVENT 2 (22%) 1 (11%) 1 (11%) 0 0 Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

NOTE:

0 0

0 0

0 0

0 0

0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

1 (11%) 1 (11%) 0 0 0 0 0 0 0 0 1 (11%)

1 (11%) 0 1 (11%) 0 0 0 0 0 0 0 0

1 (11%) 0 0 0 0 0 0 0 0 1 (11%) 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.5 g (N=12)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------ANY EVENT 3 (25%) 6 (50%) 0 0 0 Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

NOTE:

2 (17%) 0

3 (25%) 1 (8%)

0 0

0 0

0 0

0 1 0 0 0 0 0 1

(8%)

0 0 0 0 1 1 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

2 (17%) 0 0 1 (8%) 0 0 1 (8%) 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

(8%)

(8%) (8%)

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 1.0 g (N=11)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------ANY EVENT 5 (45%) 5 (45%) 1 (9%) 0 0 Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

NOTE:

1 0 0 0 0 0 0 0 1 0 1 1 0 0 0 0 0 1 0 0 0

(9%)

(9%)

(9%) (9%)

(9%)

3 (27%) 1 (9%)

0 0

0 0

0 0

1 0 1 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

(9%) (9%)

2 (18%) 0 1 (9%) 0 0 1 (9%) 0 0 1 (9%) 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ____________________________Placebo (N=7)____________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 1 (14%) 0 0 0 Psoriatic arthropathy 0 0 0 0 0 Pain in extremity 0 0 0 0 0 Arthralgia 0 0 0 0 0 Back pain 0 0 0 0 0 Flank pain 0 1 (14%) 0 0 0 Myalgia 0 0 0 0 0 Osteoarthritis 0 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0

0 0

0 0

0 0

0 0

0

0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.25 g (N=9)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 0 0 0 0 Psoriatic arthropathy 0 0 0 0 0 Pain in extremity 0 0 0 0 0 Arthralgia 0 0 0 0 0 Back pain 0 0 0 0 0 Flank pain 0 0 0 0 0 Myalgia 0 0 0 0 0 Osteoarthritis 0 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0

0 0

0 0

0 0

0 0

0

0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.5 g (N=12)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 1 (8%) 0 0 0 Psoriatic arthropathy 0 1 (8%) 0 0 0 Pain in extremity 1 (8%) 0 0 0 0 Arthralgia 0 0 0 0 0 Back pain 0 0 0 0 0 Flank pain 0 0 0 0 0 Myalgia 0 0 0 0 0 Osteoarthritis 0 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

2 (17%) 0 2 (17%) 0 0

0 0 0 0 0

0 0

1 0

0

0

0 0 0 0

1 0 0 0

(8%)

(8%)

Only treatment emergent adverse events are summarized.

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0

0 0

0 0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 1.0 g (N=11)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 1 (9%) 2 (18%) 1 (9%) 0 0 Psoriatic arthropathy 0 2 (18%) 0 0 0 Pain in extremity 1 (9%) 0 0 0 0 Arthralgia 1 (9%) 0 0 0 0 Back pain 0 1 (9%) 0 0 0 Flank pain 0 0 0 0 0 Myalgia 0 0 1 (9%) 0 0 Osteoarthritis 0 1 (9%) 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

3 (27%) 3 (27%) 0 1 (9%) 1 (9%)

1 0 1 0 0

(9%) (9%)

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

3 (27%) 1 (9%)

1 1

(9%) (9%)

0 0

0 0

0 0

1

(9%)

1

(9%)

0

0

0

1 0 1 1

(9%)

0 1 0 0

(9%)

0 0 0 0

0 0 0 0

0 0 0 0

(9%) (9%)

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ____________________________Placebo (N=7)____________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 2 (29%) 1 (14%) 0 0 0 Pruritus 0 1 (14%) 0 0 0 Actinic keratosis 0 0 0 0 0 Erythema annulare 1 (14%) 0 0 0 0 Ingrowing nail 1 (14%) 0 0 0 0 General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

1 (14%) 0 1 (14%) 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

NOTE:

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.25 g (N=9)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 0 0 0 0 0 Pruritus 0 0 0 0 0 Actinic keratosis 0 0 0 0 0 Erythema annulare 0 0 0 0 0 Ingrowing nail 0 0 0 0 0 General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

NOTE:

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.5 g (N=12)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 0 0 0 0 0 Pruritus 0 0 0 0 0 Actinic keratosis 0 0 0 0 0 Erythema annulare 0 0 0 0 0 Ingrowing nail 0 0 0 0 0 General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 0 0

1 0 0 0 1

(8%)

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

0 0 0 0

1 0 0 1

(8%)

NOTE:

(8%)

(8%)

Only treatment emergent adverse events are summarized.

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 1.0 g (N=11)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 1 (9%) 1 (9%) 0 0 0 Pruritus 0 1 (9%) 0 0 0 Actinic keratosis 1 (9%) 0 0 0 0 Erythema annulare 0 0 0 0 0 Ingrowing nail 0 0 0 0 0 General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

1 (9%) 2 (18%) 1 (9%) 0 0

1 0 0 1 0

(9%)

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

1 0 1 0

1 1 0 0

(9%) (9%)

NOTE:

(9%) (9%)

(9%)

Only treatment emergent adverse events are summarized.

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ____________________________Placebo (N=7)____________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Metabolism and nutrition disorders Any Event 0 0 0 0 0 Dehydration 0 0 0 0 0 Diabetes mellitus 0 0 0 0 0 Hypokalaemia 0 0 0 0 0 Hyponatraemia 0 0 0 0 0 Eye disorders Any Event Eye pain

0 0

0 0

0 0

0 0

0 0

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

0 0

0 0

0 0

NOTE:

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.25 g (N=9)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Metabolism and nutrition disorders Any Event 2 (22%) 0 0 0 0 Dehydration 1 (11%) 0 0 0 0 Diabetes mellitus 1 (11%) 0 0 0 0 Hypokalaemia 1 (11%) 0 0 0 0 Hyponatraemia 1 (11%) 0 0 0 0 Eye disorders Any Event Eye pain

0 0

0 0

0 0

0 0

0 0

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

1 (11%) 1 (11%)

0 0

0 0

0 0

NOTE:

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 0.5 g (N=12)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Metabolism and nutrition disorders Any Event 0 0 0 0 0 Dehydration 0 0 0 0 0 Diabetes mellitus 0 0 0 0 0 Hypokalaemia 0 0 0 0 0 Hyponatraemia 0 0 0 0 0 Eye disorders Any Event Eye pain

0 0

0 0

0 0

0 0

0 0

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

0 0

0 0

0 0

NOTE:

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.3 Summary of Adverse Events by the Maximum Intensity Safety Analysis Set Population ________________________SRT2104 1.0 g (N=11)_________________________ System Organ Class Life Preferred Term Mild Moderate Severe Threatening Death ---------------------------------------------------------------------------------------------------Metabolism and nutrition disorders Any Event 0 0 0 0 0 Dehydration 0 0 0 0 0 Diabetes mellitus 0 0 0 0 0 Hypokalaemia 0 0 0 0 0 Hyponatraemia 0 0 0 0 0 Eye disorders Any Event Eye pain

0 0

0 0

Psychiatric disorders Any Event Depression

0 0

1 1

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

NOTE:

1 1 (9%) (9%)

Only treatment emergent adverse events are summarized.

(9%) (9%)

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ______________________Placebo (N=7)_______________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------ANY EVENT 1 (14%) 1 (14%) 1 (14%) 0

NOTE:

Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection

0 0 0 0 0 0 0 0 0 0

1 (14%) 0 0 0 0 1 (14%) 0 0 0 0

1 (14%) 1 (14%) 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

0 0 0 0 0 0 0 0 0 0 0

1 (14%) 0 0 0 1 (14%) 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.25 g (N=9)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------ANY EVENT 2 (22%) 0 2 (22%) 0

NOTE:

Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection

0 0 0 0 0 0 0 0 0 0

Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

2 1 1 0 0 0 0 0 0 0 1

(22%) (11%) (11%)

(11%)

0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

1 (11%) 0 0 0 0 0 0 0 0 1 (11%) 0

0 0 0 0 0 0 0 0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.5 g (N=12)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------ANY EVENT 6 (50%) 1 (8%) 2 (17%) 0

NOTE:

Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection

3 (25%) 0 0 1 (8%) 0 0 0 1 (8%) 0 1 (8%)

1 0 0 0 0 0 1 0 0 0

Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

1 0 0 1 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

(8%) (8%)

Only treatment emergent adverse events are summarized.

(8%)

(8%)

1 1 0 0 0 0 0 0 0 0

(8%) (8%)

0 0 0 0 0 0 0 0 0 0

1 0 0 0 0 0 1 0 0 0 0

(8%)

0 0 0 0 0 0 0 0 0 0 0

(8%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 1.0 g (N=11)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------ANY EVENT 4 (36%) 3 (27%) 3 (27%) 1 (9%)

NOTE:

Infections and infestations Any Event Upper respiratory tract infection Furuncle Influenza Nasal abscess Pharyngitis Sinusitis Skin infection Urinary tract infection Viral infection

1 1 0 0 0 0 0 0 0 0

Gastrointestinal disorders Any Event Nausea Vomiting Abdominal pain upper Constipation Diarrhoea Dyspepsia Flatulence Food poisoning Pancreatitis Toothache

2 (18%) 0 1 (9%) 0 0 1 (9%) 0 1 (9%) 1 (9%) 0 0

(9%) (9%)

3 (27%) 0 1 (9%) 0 1 (9%) 0 0 0 1 (9%) 0

0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

1 1 0 0 0 0 0 0 0 0 0

Only treatment emergent adverse events are summarized.

0 0 0 0 0 0 0 0 0 0 (9%) (9%)

0 0 0 0 0 0 0 0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ______________________Placebo (N=7)_______________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 1 (14%) 0 0 Psoriatic arthropathy 0 0 0 0 Pain in extremity 0 0 0 0 Arthralgia 0 0 0 0 Back pain 0 0 0 0 Flank pain 0 1 (14%) 0 0 Myalgia 0 0 0 0 Osteoarthritis 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0

0 0

0 0

0 0

0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.25 g (N=9)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 0 0 0 Psoriatic arthropathy 0 0 0 0 Pain in extremity 0 0 0 0 Arthralgia 0 0 0 0 Back pain 0 0 0 0 Flank pain 0 0 0 0 Myalgia 0 0 0 0 Osteoarthritis 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0

0 0

0 0

0 0

0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.5 g (N=12)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 0 0 1 (8%) 0 Psoriatic arthropathy 0 0 1 (8%) 0 Pain in extremity 0 0 1 (8%) 0 Arthralgia 0 0 0 0 Back pain 0 0 0 0 Flank pain 0 0 0 0 Myalgia 0 0 0 0 Osteoarthritis 0 0 0 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

1 0 1 0 0

(8%) (8%)

0 0 0 0 0

1 0 1 0 0

1 0

(8%)

0 0

0 0

0 0

0

0

0

0 0 0 0

0 0 0 0

0 0 0 0

0 1 0 0 0

(8%)

Only treatment emergent adverse events are summarized.

(8%) (8%)

0 0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 1.0 g (N=11)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Musculoskeletal and connective tissue disorders Any Event 2 (18%) 1 (9%) 1 (9%) 0 Psoriatic arthropathy 0 1 (9%) 1 (9%) 0 Pain in extremity 0 1 (9%) 0 0 Arthralgia 1 (9%) 0 0 0 Back pain 1 (9%) 0 0 0 Flank pain 0 0 0 0 Myalgia 0 0 1 (9%) 0 Osteoarthritis 0 0 1 (9%) 0 Nervous system disorders Any Event Dizziness Headache Disturbance in attention Paraesthesia Investigations Any Event Alanine aminotransferase increased Aspartate aminotransferase increased Hepatic enzyme increased Blood bilirubin increased Blood phosphorus decreased Blood potassium increased

NOTE:

1 1 0 0 0

(9%) (9%)

2 (18%) 1 (9%) 0 0 1 (9%)

1 1 1 1 0

(9%) (9%) (9%) (9%)

0 0 0 0 0

1 0

(9%)

0 0

2 (18%) 1 (9%)

1 1

(9%) (9%)

0

0

1

(9%)

1

(9%)

0 0 1 1

0 0 0 0

1 0 0 0

(9%)

0 1 0 0

(9%)

(9%) (9%)

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ______________________Placebo (N=7)_______________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 3 (43%) 0 0 0 Pruritus 1 (14%) 0 0 0 Actinic keratosis 0 0 0 0 Erythema annulare 1 (14%) 0 0 0 Ingrowing nail 1 (14%) 0 0 0

NOTE:

General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 0 0

1 (14%) 0 1 (14%) 0 0

0 0 0 0 0

0 0 0 0 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Metabolism and nutrition disorders Any Event Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.25 g (N=9)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 0 0 0 0 Pruritus 0 0 0 0 Actinic keratosis 0 0 0 0 Erythema annulare 0 0 0 0 Ingrowing nail 0 0 0 0

NOTE:

General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

Metabolism and nutrition disorders Any Event Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

2 1 1 1 1

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

(22%) (11%) (11%) (11%) (11%)

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.5 g (N=12)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 0 0 0 0 Pruritus 0 0 0 0 Actinic keratosis 0 0 0 0 Erythema annulare 0 0 0 0 Ingrowing nail 0 0 0 0

NOTE:

General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 0 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain

1 0 0 1

Metabolism and nutrition disorders Any Event Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

0 0 0 0 0

(8%) (8%)

0 0 0 0 0

1 0 0 0 1

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

Only treatment emergent adverse events are summarized.

(8%)

(8%)

0 0 0 0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 1.0 g (N=11)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Skin and subcutaneous tissue disorders Any Event 1 (9%) 1 (9%) 0 0 Pruritus 0 1 (9%) 0 0 Actinic keratosis 1 (9%) 0 0 0 Erythema annulare 0 0 0 0 Ingrowing nail 0 0 0 0

NOTE:

General disorders and administration site conditions Any Event Fatigue Pyrexia Malaise Oedema peripheral

0 0 0 1 0

Injury, poisoning and procedural complications Any Event Contusion Injury Joint sprain Metabolism and nutrition disorders Any Event Dehydration Diabetes mellitus Hypokalaemia Hyponatraemia

0 0 0 0 0

2 (18%) 2 (18%) 1 (9%) 0 0

0 0 0 0 0

2 (18%) 1 (9%) 1 (9%) 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 0 0

(9%)

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ______________________Placebo (N=7)_______________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Eye disorders Any Event 0 0 0 0 Eye pain 0 0 0 0

NOTE:

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

0 0

0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.25 g (N=9)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Eye disorders Any Event 0 0 0 0 Eye pain 0 0 0 0

NOTE:

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

1 (11%) 1 (11%)

0 0

Only treatment emergent adverse events are summarized.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 0.5 g (N=12)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Eye disorders Any Event 0 0 0 0 Eye pain 0 0 0 0

NOTE:

Psychiatric disorders Any Event Depression

0 0

0 0

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

0 0

0 0

Only treatment emergent adverse events are summarized.

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Page 16 of 16 Clinical Study Report SRT-2104-013

Table 14.3.1.4 Summary of Adverse Events by the Highest Relationship to Study Medication Safety Analysis Set Population ___________________SRT2104 1.0 g (N=11)___________________ System Organ Class Unlikely Possibly Preferred Term Not Related Related Related Related ----------------------------------------------------------------------------------------------Eye disorders Any Event 0 1 (9%) 0 0 Eye pain 0 1 (9%) 0 0

NOTE:

Psychiatric disorders Any Event Depression

0 0

1 1

Respiratory, thoracic and mediastinal disorders Any Event Pneumonitis

0 0

0 0

Only treatment emergent adverse events are summarized.

(9%) (9%)

0 0

0 0

0 0

0 0

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Page 1 of 1 Clinical Study Report SRT-2104-013 Table 14.3.2.1 Summary of Serious Adverse Events Safety Analysis Set Population

SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------ANY EVENT 0 2 (22%) 0 1 (9%) 3 (8%) Gastrointestinal disorders Any event Pancreatitis

0 0

1 (11%) 1 (11%)

0 0

0 0

Investigations Any event Alanine aminotransferase increased Blood bilirubin increased

0 0

0 0

0 0

1 1

0

0

0

1

0 0

1 (11%) 1 (11%)

0 0

0 0

Respiratory, thoracic and mediastinal disorders Any event Pneumonitis

NOTE:

Only treatment emergent adverse events are summarized.

1 1

(3%) (3%)

(9%) (9%)

1 1

(3%) (3%)

(9%)

1

(3%)

1 1

(3%) (3%)

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Page 1 of 2 Clinical Study Report SRT-2104-013 Table 14.3.2.2 Listing of Serious Adverse Events Safety Analysis Set Population

Treatment: SRT2104 0.25 g Age(y)/ Outcome/ Conmed Sex/ Onset Date/ Time Since Frequency/ or Race/ System Organ Class/ Time/ 1st Dose/ Action Taken/ Other Weight Preferred Term/ Date of Resolution/ Time Since Intensity/ Relation to Trt. Subj. (kg) Verbatim Text Duration (days) Last Dose Serious Study Drug Given This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.3.2.3 Summary of Adverse Events Leading to Permanent Discontinuation from Treatment Safety Analysis Set Population SRT2104 SRT2104 SRT2104 System Organ Class Placebo 0.25 g 0.5 g 1.0 g Total Preferred Term (N=7) (N=9) (N=12) (N=11) (N=39) ----------------------------------------------------------------------------------------------ANY EVENT 0 2 (22%) 1 (8%) 1 (9%) 4 (10%) Investigations Any event Alanine aminotransferase increased Aspartate aminotransferase increased Blood bilirubin increased Hepatic enzyme increased

NOTE:

0 0

0 0

1 0

0

0

0

0 0

0 0

0 1

Gastrointestinal disorders Any event Pancreatitis

0 0

1 (11%) 1 (11%)

0 0

Respiratory, thoracic and mediastinal disorders Any event Pneumonitis

0 0

1 (11%) 1 (11%)

0 0

Only treatment emergent adverse events are summarized.

(8%)

(8%)

1 1

(9%) (9%)

2 1

(5%) (3%)

1

(9%)

1

(3%)

1 0

(9%)

1 1

(3%) (3%)

0 0

1 1

(3%) (3%)

0 0

1 1

(3%) (3%)

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Page 1 of 3 Clinical Study Report SRT-2104-013

Table 14.3.2.4 Listing of Adverse Events Leading to Permanent Discontinuation from Treatment Safety Analysis Set Population Treatment: SRT2104 0.25 g Age(y)/ Sex/ Race/ System Organ Class/ Weight Preferred Term/ Subj. (kg) Verbatim Text

Outcome/ Onset Date/ Time/ Date of Resolution/ Duration (days)

Time Since 1st Dose/ Time Since Intensity/ Last Dose Serious

Frequency/ Action Taken/ Relation to Study Drug

Conmed or Other Trt. Given

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.3.2.5 Listing of Adverse Events Leading to Deaths Safety Analysis Set Population

No data to report

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Hematology BASOPHILS DNN % Female 30 - 72 0 2 Male 19 - 68 0 2 BASOPHILS ABSOLUTE AB4 GI/L Female 30 - 72 0 0.2 Male 19 - 68 0 0.2 EOSINOPHILS DLN % Female 30 - 72 0 7 Male 19 - 68 0 7 EOSINOPHILS ABSOLUTE AB3 GI/L Female 30 - 72 0.05 0.55 Male 19 - 68 0.05 0.55 HEMATOCRIT HCT 1 Female 30 - 64 0.35 0.46 65 - 72 0.33 0.46 Male 19 - 64 0.41 0.5 65 - 68 0.36 0.49 HEMOGLOBIN HG9 G/L Female 30 - 64 120 156 65 - 72 111 155 Male 19 - 64 138 172 65 - 68 118 168 LYMPHOCYTES DDN % Female 30 - 72 16 46 Male 19 - 68 16 46 LYMPHOCYTES ABSOLUTE AB1 GI/L Female 30 - 72 0.85 4.1 Male 19 - 68 0.85 4.1 MCH MCH PG Female 30 - 64 27 33 65 - 72 27 35 Male 19 - 64 27 33 65 - 68 27 35 MCHC CHC G/L Female 30 - 72 320 360 Male 19 - 68 320 360 MCV MCV FL Female 30 - 64 80 100 65 - 72 82 103 Male 19 - 64 80 100 65 - 68 82 103 Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

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Page 2 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Hematology MONOCYTES DJN % Female 30 - 72 0 12 Male 19 - 68 0 12 MONOCYTES ABSOLUTE AB2 GI/L Female 30 - 72 0.2 1.1 Male 19 - 68 0.2 1.1 NEUTROPHIL, SEGS DBN % Female 30 - 72 40 75 Male 19 - 68 40 75 NEUTROPHILS ABSOLUTE AB0 GI/L Female 30 - 72 1.8 8 Male 19 - 68 1.8 8 PLATELET COUNT PLT GI/L Female 30 - 72 130 400 Male 19 - 68 130 400 RDW RDW % Female 30 - 72 9 15 Male 19 - 68 9 15 RED CELL COUNT RBC TI/L Female 30 - 64 3.9 5.2 65 - 72 3.6 5.1 Male 19 - 64 4.4 5.8 65 - 68 3.7 5.5 TOTAL NEUTROPHILS DCM % Female 30 - 72 40 75 Male 19 - 68 40 75 TOTAL NEUTROPHILS AB 2DM GI/L Female 30 - 72 1.8 8 Male 19 - 68 1.8 8 WHITE CELL COUNT WBC GI/L Female 30 - 72 3.8 10.8 Male 19 - 68 3.8 10.8

Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

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Page 3 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Chemistry ALAT (SGPT) XGP U/L Female 30 - 72 0 48 Male 19 - 68 0 48 ALBUMIN XAL G/L Female 30 - 72 32 50 Male 19 - 68 32 50 ALKALINE PHOSPHATASE XLK U/L Female 30 - 72 20 125 Male 19 - 19 30 225 23 - 68 20 125 AMYLASE, SERUM AMYC U/L Female 30 - 72 29 103 Male 19 - 68 29 103 ASAT (SGOT) XGO U/L Female 30 - 64 0 42 65 - 72 0 55 Male 19 - 64 0 42 65 - 68 0 55 BILIRUBIN, DIRECT XDB UMOL/L Female 30 - 72 0 6 Male 19 - 68 0 6 BILIRUBIN, INDIRECT XIB UMOL/L Female 30 - 72 0 22 Male 19 - 68 0 22 BILIRUBIN, TOTAL XBT UMOL/L Female 30 - 72 0 22 Male 19 - 68 0 22 CALCIUM XAB MMOL/L Female 30 - 72 2.12 2.56 Male 19 - 68 2.12 2.56 CHLORIDE DCL MMOL/L Female 30 - 72 95 108 Male 19 - 68 95 108 CHOLESTEROL, TOTAL XCH MMOL/L Female 30 - 72 0 5.15 Male 19 - 19 0 4.35 23 - 68 0 5.15 CO2 CONTENT XO2 MMOL/L Female 30 - 72 20 32 Male 19 - 68 20 32 CPK, TOTAL CK0 U/L Female 30 - 72 0 190 Male 19 - 68 0 235 Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Chemistry CREATININE PD9 UMOL/L Female 30 - 72 44 124 Male 19 - 68 44 124 CRP HIGH SENSITIVITY CRPH MG/L Female 30 - 72 3 Male 19 - 68 3 GGT XGT U/L Female 30 - 64 0 45 65 - 72 0 75 Male 19 - 64 0 65 65 - 68 0 75 GLUCOSE, PLASMA 5GL MMOL/L Female 30 - 72 3.9 6.1 Male 19 - 68 3.9 6.1 HCV RNA, PCR, QUANT HQ2 LOGIU/ML Female 64 - 64 1.69999 Male 26 - 26 1.69999 HR1 IU/ML Female 64 - 64 49.9999 Male 26 - 26 49.9999 HDL CHOL DIRECT XZH MMOL/L Female 30 - 72 0.9 99.99 Male 19 - 68 0.9 99.99 LACTIC DEHYDROGENASE XDH U/L Female 30 - 64 0 250 65 - 72 0 270 Male 19 - 64 0 250 65 - 68 0 270 LDL-CHOL CALCULATION XLC MMOL/L Female 30 - 72 0 3.35 Male 19 - 19 0 2.85 23 - 68 0 3.35 MAGNESIUM DGO MMOL/L Female 30 - 72 0.6 1 Male 19 - 68 0.6 1 NEFA NEA MMOL/L Female 30 - 72 0.8999 Male 19 - 68 0.8999 PHOSPHORUS INORGANIC XP4 MMOL/L Female 30 - 64 0.8 1.45 65 - 72 0.7 1.4 Male 19 - 64 0.8 1.45 Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

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Page 5 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Chemistry PHOSPHORUS INORGANIC XP4 MMOL/L Male 65 - 68 0.7 1.4 POTASSIUM XKB MMOL/L Female 30 - 72 3.5 5.3 Male 19 - 68 3.5 5.3 SODIUM XNA MMOL/L Female 30 - 72 135 146 Male 19 - 68 135 146 TRIGLYCERIDES XRI MMOL/L Female 30 - 72 0 2.24 Male 19 - 68 0 2.24 UREA NITROGEN XUN MMOL/L Female 30 - 64 2.5 9 65 - 72 2.5 10.5 Male 19 - 64 2.5 9 65 - 68 2.5 10.5 URIC ACID XUA UMOL/L Female 30 - 72 150 450 Male 19 - 68 240 510

Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

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Page 6 of 6 Clinical Study Report SRT-2104-013

Table 14.3.3.1 Listing of Reference Ranges for Clinical Laboratory Tests Safety Analysis Set Population Normal Range Test Standard Age ---------------------Lab Test Code Units Sex Range Lower Upper ----------------------------------------------------------------------------------------------------Antibody ACTIN ANTIBODY IGG AAIG UNITS Female 64 - 64 19.9999 ANA, TITER ANEI TITER Female 64 - 64 0 39 ANEI1 TITER Female 64 - 64 0 39 ANEI2 TITER Female 64 - 64 0 39 ANEI3 TITER Female 64 - 64 0 39 CMV IGM ANTIBODY CMIMA INDEX Female 64 - 64 0.8999 Male 26 - 26 0.8999 LKM-1 ANTIBODY IGG LKM UNITS Female 64 - 64 20 STRENGTH OF SIGNAL: QSS1 ISR Female 64 - 64 0.9 Male 26 - 26 0.9 Coagulation

Urinalysis

APTT

PTTG

INR

INRG

PROTHROMBIN TIME

PTGL

RBC/HPF

UARBC

REACTION PH

UEN

SPECIFIC GRAVITY

UCN

WBC/HPF

UAWBC

SECONDS

SECONDS

Female Male Female Male Female Male

30 19 30 19 30 19

-

72 68 72 68 72 68

22 22 0.9 0.9 9 9

34 34 1.1 1.1 11.5 11.5

Female Male Female Male Female Male Female Male

30 23 30 19 30 19 30 23

-

72 66 72 68 72 68 72 66

0 0 4.6 4.6 1.001 1.001 0 0

3 3 8 8 1.035 1.035 10 5

Note: Age ranges are derived from the existing age values in the lab data specific to the currenty study.

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Page 1 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------APTT (SECONDS) Placebo 7 Screening 6 32.3 2.42 32.0 29 36 Day 1 7 32.6 3.87 32.0 28 39 Day 42 7 34.1 6.49 33.0 29 48 Day 84 7 33.0 2.38 33.0 30 36 SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

29.6 30.6 30.0 30.8

1.51 2.13 2.65 3.11

29.0 31.0 29.0 30.0

28 26 27 28

33 34 33 36

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 12 11 9

31.8 30.8 31.4 32.0

3.74 2.86 4.43 3.81

31.0 30.5 30.0 32.0

27 27 28 27

39 38 41 38

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

10 10 10 9

30.8 32.8 31.7 31.6

3.55 2.78 4.85 2.19

30.5 32.5 30.0 32.0

25 28 27 29

37 37 44 36

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Page 2 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------BASOPHILS (%) Placebo 7 Screening 7 0.31 0.135 0.30 0.1 0.5 Day 1 7 0.30 0.115 0.30 0.2 0.5 Day 14 7 0.40 0.115 0.40 0.2 0.5 Day 28 7 0.37 0.111 0.40 0.2 0.5 Day 42 7 0.44 0.151 0.40 0.2 0.7 Day 56 7 0.23 0.221 0.20 0.0 0.6 Day 70 7 0.36 0.162 0.30 0.1 0.6 Day 84 7 0.44 0.140 0.50 0.3 0.6 Follow-up 7 0.40 0.191 0.40 0.1 0.7 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

0.36 0.34 0.39 0.30 0.26 0.37 0.48 0.32 0.28

0.113 0.159 0.169 0.166 0.140 0.163 0.164 0.148 0.098

0.40 0.30 0.40 0.30 0.30 0.40 0.40 0.30 0.30

0.2 0.1 0.1 0.1 0.0 0.1 0.3 0.1 0.1

0.5 0.6 0.6 0.6 0.4 0.6 0.7 0.5 0.4

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

0.26 0.40 0.31 0.38 0.37 0.37 0.33 0.33 0.37

0.156 0.113 0.100 0.133 0.253 0.187 0.150 0.200 0.206

0.20 0.40 0.30 0.40 0.30 0.30 0.30 0.40 0.40

0.0 0.2 0.2 0.2 0.1 0.2 0.1 0.0 0.1

0.5 0.6 0.5 0.6 0.9 0.8 0.5 0.6 0.8

SRT2104 1.0 g

11

Screening Day 1

11 11

0.33 0.49

0.110 0.255

0.30 0.50

0.1 0.1

0.5 0.9

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Page 3 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------BASOPHILS (%) SRT2104 1.0 g 11 Day 14 11 0.40 0.249 0.40 0.0 0.7 Day 28 11 0.50 0.286 0.50 0.2 1.1 Day 42 11 0.45 0.151 0.50 0.2 0.6 Day 56 11 0.45 0.093 0.50 0.3 0.6 Day 70 10 0.44 0.151 0.40 0.3 0.7 Day 84 10 0.48 0.225 0.45 0.2 0.9 Follow-up 10 0.43 0.340 0.30 0.2 1.2

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------BASOPHILS Placebo 7 Screening 7 0.021 0.0121 0.020 0.00 0.04 ABSOLUTE (GI/L) Day 1 7 0.020 0.0058 0.020 0.01 0.03 Day 14 7 0.030 0.0115 0.030 0.01 0.04 Day 28 7 0.027 0.0125 0.020 0.01 0.04 Day 42 7 0.031 0.0107 0.030 0.02 0.05 Day 56 7 0.014 0.0140 0.010 0.00 0.04 Day 70 7 0.026 0.0162 0.020 0.00 0.05 Day 84 7 0.030 0.0163 0.030 0.01 0.06 Follow-up 7 0.030 0.0163 0.040 0.01 0.05 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

0.027 0.022 0.029 0.023 0.020 0.030 0.042 0.024 0.022

0.0122 0.0067 0.0117 0.0112 0.0129 0.0126 0.0192 0.0089 0.0117

0.030 0.020 0.030 0.020 0.020 0.035 0.040 0.030 0.020

0.01 0.01 0.01 0.01 0.00 0.01 0.02 0.01 0.01

0.04 0.03 0.05 0.04 0.04 0.04 0.07 0.03 0.04

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

0.017 0.024 0.020 0.023 0.021 0.026 0.023 0.018 0.023

0.0098 0.0079 0.0095 0.0142 0.0114 0.0133 0.0206 0.0120 0.0158

0.015 0.020 0.020 0.020 0.020 0.030 0.010 0.020 0.020

0.00 0.01 0.01 0.01 0.01 0.01 0.01 0.00 0.00

0.03 0.04 0.04 0.06 0.04 0.05 0.07 0.03 0.05

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Page 5 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------BASOPHILS SRT2104 1.0 g 11 Screening 11 0.025 0.0093 0.030 0.01 0.04 ABSOLUTE (GI/L) Day 1 11 0.035 0.0211 0.030 0.01 0.08 Day 14 11 0.028 0.0214 0.020 0.00 0.07 Day 28 11 0.032 0.0172 0.030 0.01 0.06 Day 42 11 0.032 0.0133 0.030 0.02 0.06 Day 56 11 0.033 0.0119 0.030 0.02 0.05 Day 70 10 0.029 0.0120 0.030 0.01 0.05 Day 84 10 0.032 0.0199 0.025 0.01 0.07 Follow-up 10 0.035 0.0381 0.025 0.01 0.13

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Page 6 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------EOSINOPHILS Placebo 7 Screening 7 2.29 1.672 2.00 0.2 5.0 (%) Day 1 7 2.77 1.024 2.10 1.9 4.3 Day 14 7 2.61 1.514 2.20 0.7 4.7 Day 28 7 2.36 1.267 2.40 0.7 4.1 Day 42 7 2.34 1.730 1.70 0.5 5.0 Day 56 7 2.27 1.516 2.00 0.6 4.2 Day 70 7 2.04 1.166 1.70 0.9 3.7 Day 84 7 3.20 2.717 2.30 0.4 8.2 Follow-up 7 2.64 1.552 2.20 1.0 5.4 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

2.22 1.73 1.71 2.14 2.57 2.67 2.16 2.26 2.02

1.750 0.828 0.947 1.350 1.734 1.288 1.126 0.456 0.886

1.90 1.70 1.80 1.90 2.50 3.25 2.00 2.30 2.10

0.3 0.3 0.4 0.5 0.6 0.7 0.8 1.8 0.5

6.3 3.1 2.9 4.8 5.7 3.7 3.8 2.8 3.1

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

2.80 3.52 3.51 3.85 3.25 2.93 3.60 3.43 3.33

1.373 2.355 1.814 2.411 2.155 2.618 3.365 2.405 2.411

2.50 3.15 3.10 3.70 2.60 2.00 3.00 2.90 2.90

1.0 1.2 1.3 1.2 1.2 1.1 1.0 1.2 1.1

5.2 9.7 7.8 9.6 7.3 9.6 12.2 9.3 8.7

SRT2104 1.0 g

11

Screening

11

2.82

2.695

1.90

0.2

7.8

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Page 7 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------EOSINOPHILS SRT2104 1.0 g 11 Day 1 11 2.72 2.267 1.90 0.1 7.3 (%) Day 14 11 3.08 2.915 1.80 0.1 8.7 Day 28 11 3.41 2.587 2.80 0.2 9.4 Day 42 11 2.68 2.322 1.90 0.0 7.7 Day 56 11 2.55 2.692 1.70 0.1 9.2 Day 70 10 1.88 1.381 1.35 0.2 4.5 Day 84 10 2.61 2.586 1.35 0.2 8.4 Follow-up 10 2.47 2.214 1.50 0.3 7.3

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Page 8 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------EOSINOPHILS Placebo 7 Screening 7 0.140 0.0927 0.140 0.01 0.29 ABSOLUTE (GI/L) Day 1 7 0.169 0.0308 0.160 0.13 0.21 Day 14 7 0.166 0.0798 0.150 0.07 0.32 Day 28 7 0.160 0.0695 0.180 0.06 0.24 Day 42 7 0.141 0.0815 0.120 0.05 0.26 Day 56 7 0.134 0.0785 0.150 0.05 0.25 Day 70 7 0.136 0.0702 0.120 0.06 0.26 Day 84 7 0.179 0.1549 0.120 0.04 0.51 Follow-up 7 0.177 0.0871 0.170 0.07 0.35 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

0.189 0.133 0.122 0.161 0.213 0.213 0.190 0.208 0.182

0.1913 0.1037 0.0815 0.1276 0.1704 0.1143 0.1313 0.0792 0.1065

0.100 0.100 0.120 0.130 0.170 0.250 0.130 0.190 0.185

0.02 0.02 0.02 0.03 0.04 0.04 0.07 0.10 0.02

0.64 0.36 0.26 0.41 0.54 0.33 0.36 0.30 0.33

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

0.152 0.185 0.215 0.230 0.184 0.172 0.218 0.228 0.221

0.0541 0.0766 0.1017 0.1309 0.1035 0.1127 0.1337 0.1912 0.1933

0.165 0.195 0.190 0.240 0.150 0.130 0.170 0.140 0.160

0.07 0.08 0.08 0.06 0.06 0.06 0.06 0.09 0.07

0.22 0.36 0.41 0.41 0.33 0.41 0.51 0.69 0.69

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------EOSINOPHILS SRT2104 1.0 g 11 Screening 11 0.207 0.1924 0.140 0.02 0.59 ABSOLUTE (GI/L) Day 1 11 0.195 0.1715 0.130 0.01 0.47 Day 14 11 0.201 0.2010 0.120 0.01 0.64 Day 28 11 0.223 0.1727 0.150 0.02 0.51 Day 42 11 0.180 0.1515 0.120 0.00 0.50 Day 56 11 0.169 0.1650 0.120 0.01 0.53 Day 70 10 0.129 0.1013 0.080 0.02 0.35 Day 84 10 0.189 0.1885 0.085 0.01 0.56 Follow-up 10 0.181 0.1508 0.140 0.02 0.44

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------HEMATOCRIT (1) Placebo 7 Screening 7 0.4456 0.02070 0.4550 0.407 0.467 Day 1 7 0.4403 0.03581 0.4320 0.384 0.494 Day 14 7 0.4321 0.02857 0.4360 0.385 0.462 Day 28 7 0.4400 0.03793 0.4400 0.364 0.482 Day 42 7 0.4383 0.03086 0.4400 0.382 0.470 Day 56 7 0.4377 0.03454 0.4470 0.392 0.480 Day 70 7 0.4416 0.03367 0.4410 0.395 0.480 Day 84 7 0.4356 0.03656 0.4270 0.371 0.477 Follow-up 7 0.4376 0.03702 0.4370 0.385 0.497 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

0.4340 0.4322 0.4312 0.4336 0.4326 0.4325 0.4562 0.4520 0.4463

0.03209 0.02993 0.03609 0.03595 0.03379 0.04644 0.03921 0.03646 0.03837

0.4240 0.4290 0.4320 0.4470 0.4530 0.4465 0.4670 0.4600 0.4585

0.392 0.385 0.375 0.370 0.382 0.359 0.388 0.393 0.392

0.472 0.476 0.470 0.468 0.468 0.483 0.489 0.488 0.484

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

0.4444 0.4481 0.4302 0.4335 0.4285 0.4394 0.4426 0.4348 0.4337

0.02513 0.02532 0.01875 0.03443 0.02716 0.03920 0.03426 0.03274 0.03570

0.4385 0.4475 0.4315 0.4320 0.4170 0.4380 0.4370 0.4310 0.4310

0.402 0.405 0.397 0.397 0.394 0.373 0.395 0.384 0.377

0.498 0.493 0.463 0.484 0.468 0.516 0.506 0.497 0.497

SRT2104 1.0 g

11

Screening Day 1

11 11

0.4605 0.4499

0.03635 0.03783

0.4670 0.4530

0.388 0.383

0.516 0.494

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------HEMATOCRIT (1) SRT2104 1.0 g 11 Day 14 11 0.4385 0.04017 0.4550 0.372 0.501 Day 28 11 0.4429 0.04297 0.4530 0.379 0.512 Day 42 11 0.4401 0.03814 0.4400 0.386 0.511 Day 56 11 0.4523 0.04734 0.4450 0.383 0.533 Day 70 10 0.4405 0.04322 0.4405 0.388 0.529 Day 84 10 0.4441 0.04249 0.4475 0.366 0.519 Follow-up 10 0.4403 0.04161 0.4455 0.362 0.492

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------HEMOGLOBIN Placebo 7 Screening 7 146.3 7.25 148.0 135 154 (G/L) Day 1 7 144.1 12.60 139.0 127 165 Day 14 7 141.4 11.69 148.0 124 153 Day 28 7 142.9 12.95 143.0 118 160 Day 42 7 143.4 11.01 143.0 126 158 Day 56 7 143.3 11.50 145.0 129 159 Day 70 7 144.1 11.71 143.0 130 159 Day 84 7 140.3 12.20 140.0 118 152 Follow-up 7 143.1 11.26 141.0 130 163 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

143.8 143.1 142.2 143.8 145.0 143.2 150.4 149.2 147.7

13.02 11.19 11.22 12.13 12.96 14.96 12.78 14.55 12.99

141.0 142.0 144.0 150.0 151.0 148.5 156.0 154.0 152.0

124 126 124 122 127 123 128 125 127

160 158 154 155 158 158 159 163 159

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

148.8 149.3 143.0 144.6 142.7 145.4 146.3 144.3 144.4

10.72 7.47 6.99 12.40 7.90 9.71 9.81 9.10 10.42

145.5 148.5 143.5 146.0 142.0 144.0 146.0 142.0 146.0

135 136 133 128 131 127 132 128 128

173 161 154 164 154 159 163 158 160

SRT2104 1.0 g

11

Screening

11

150.7

13.15

150.0

123

166

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------HEMOGLOBIN SRT2104 1.0 g 11 Day 1 11 146.9 13.19 145.0 119 162 (G/L) Day 14 11 144.5 14.10 147.0 119 167 Day 28 11 146.1 14.60 147.0 123 170 Day 42 11 144.0 13.87 143.0 124 168 Day 56 11 148.3 16.26 146.0 122 176 Day 70 10 144.7 13.80 144.0 126 172 Day 84 10 145.9 14.44 149.0 116 166 Follow-up 10 145.5 14.75 147.0 116 164 INR

Placebo

7

Screening Day 1 Day 42 Day 84

6 7 7 7

1.08 1.14 1.36 1.09

0.075 0.113 0.770 0.069

1.10 1.10 1.10 1.10

1.0 1.0 1.0 1.0

1.2 1.3 3.1 1.2

SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

1.04 1.04 1.04 1.06

0.073 0.073 0.079 0.055

1.10 1.10 1.00 1.10

0.9 0.9 1.0 1.0

1.1 1.1 1.2 1.1

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 12 11 9

1.07 1.09 1.09 1.11

0.049 0.067 0.054 0.078

1.10 1.10 1.10 1.10

1.0 1.0 1.0 1.0

1.1 1.2 1.2 1.3

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

10 10 10 9

1.09 1.12 1.14 1.10

0.057 0.042 0.178 0.071

1.10 1.10 1.10 1.10

1.0 1.1 1.0 1.0

1.2 1.2 1.5 1.2

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------LYMPHOCYTES Placebo 7 Screening 7 32.23 14.412 26.80 20.8 63.6 (%) Day 1 7 26.73 7.076 27.60 18.9 39.7 Day 14 7 27.06 3.619 25.80 21.4 31.1 Day 28 7 23.27 2.749 22.20 20.3 28.1 Day 42 7 25.46 3.997 24.70 20.7 33.3 Day 56 7 25.59 2.881 25.20 22.0 29.3 Day 70 7 26.60 5.514 25.00 19.5 34.9 Day 84 7 27.81 4.799 27.80 20.3 33.6 Follow-up 7 27.19 5.299 27.10 20.2 35.8 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

30.19 30.68 29.02 30.82 26.97 33.75 29.60 27.82 29.25

6.658 8.833 8.723 7.542 8.157 8.548 6.749 4.959 7.723

29.30 34.00 24.60 35.20 25.80 34.60 31.70 26.50 27.90

20.6 18.9 20.9 19.0 17.9 22.6 21.9 23.5 21.1

39.3 41.4 41.8 40.6 38.5 44.2 36.2 35.4 40.2

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

28.23 28.84 26.50 27.01 30.35 29.07 27.07 28.91 31.14

8.975 7.874 6.280 6.605 9.102 7.109 8.633 9.657 6.836

28.00 30.20 27.60 27.70 30.60 29.80 27.10 30.30 32.60

10.3 10.5 12.9 14.9 14.2 17.6 12.8 9.0 16.7

42.1 38.3 39.2 35.9 47.0 39.0 37.6 39.7 37.7

SRT2104 1.0 g

11

Screening

11

24.11

7.434

24.40

12.9

36.7

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------LYMPHOCYTES SRT2104 1.0 g 11 Day 1 11 28.05 6.935 26.70 17.5 40.0 (%) Day 14 11 29.07 5.981 28.30 17.3 38.0 Day 28 11 27.82 7.630 27.40 18.2 43.4 Day 42 11 26.80 6.686 26.40 18.4 39.0 Day 56 11 26.35 8.653 24.70 15.7 43.2 Day 70 10 25.96 7.226 25.90 13.6 36.9 Day 84 10 27.58 6.896 28.35 16.8 38.0 Follow-up 10 25.52 8.488 26.00 15.9 40.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------LYMPHOCYTES Placebo 7 Screening 7 2.051 0.8677 1.800 1.33 3.88 ABSOLUTE (GI/L) Day 1 7 1.670 0.2453 1.610 1.38 2.11 Day 14 7 1.830 0.3265 1.750 1.37 2.40 Day 28 7 1.693 0.3449 1.680 1.29 2.32 Day 42 7 1.767 0.3810 1.810 1.33 2.43 Day 56 7 1.676 0.3718 1.490 1.33 2.25 Day 70 7 1.819 0.4102 1.880 1.37 2.48 Day 84 7 1.740 0.4779 1.690 1.14 2.51 Follow-up 7 1.917 0.3706 1.860 1.58 2.61 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

2.262 2.144 2.077 2.136 2.251 2.632 2.588 2.560 2.432

0.9023 0.9979 0.9238 0.8074 1.1501 0.9145 1.1827 0.9875 1.0574

1.890 1.770 1.840 1.830 1.610 2.465 2.980 2.420 2.240

1.44 1.35 1.01 1.34 1.09 1.67 1.23 1.73 1.20

4.43 4.58 4.32 3.69 4.13 4.16 4.08 4.14 3.76

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

1.598 1.643 1.633 1.564 1.745 1.781 1.764 1.708 1.977

0.5154 0.4287 0.4396 0.4161 0.4431 0.3223 0.4403 0.3825 0.5014

1.535 1.540 1.525 1.580 1.630 1.940 1.650 1.750 1.840

0.98 1.11 1.16 0.87 1.26 1.28 1.25 1.12 1.44

2.64 2.57 2.78 2.17 2.87 2.14 2.74 2.13 3.17

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------LYMPHOCYTES SRT2104 1.0 g 11 Screening 11 1.830 0.6272 1.710 1.16 3.38 ABSOLUTE (GI/L) Day 1 11 2.025 0.8049 1.820 0.84 3.88 Day 14 11 1.883 0.3595 1.820 1.28 2.65 Day 28 11 1.765 0.4446 1.720 1.31 2.65 Day 42 11 1.798 0.3621 1.740 1.29 2.66 Day 56 11 1.843 0.5334 1.770 1.19 3.15 Day 70 10 1.778 0.5042 1.855 1.06 2.63 Day 84 10 1.816 0.3576 1.775 1.38 2.62 Follow-up 10 1.858 0.6510 1.695 1.25 3.31

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCH (PG) Placebo 7 Screening 7 30.49 1.849 31.30 27.9 32.6 Day 1 7 30.50 1.587 30.80 28.3 32.3 Day 14 7 30.56 1.793 31.00 28.1 32.6 Day 28 7 30.39 1.704 30.90 28.0 32.5 Day 42 7 30.46 1.981 31.40 27.5 32.6 Day 56 7 30.37 1.834 31.10 27.7 32.2 Day 70 7 30.37 1.680 31.20 27.4 31.8 Day 84 7 29.91 1.799 30.60 27.3 31.8 Follow-up 7 30.21 1.885 30.80 27.0 31.9 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

31.07 30.96 30.97 30.71 30.69 30.63 30.08 29.94 30.15

2.789 2.651 2.265 2.055 2.129 2.032 2.010 1.922 1.629

30.40 30.10 30.30 30.10 30.40 30.45 30.00 30.00 30.20

27.4 28.0 28.0 27.5 27.5 27.4 27.5 27.1 27.6

37.6 37.5 36.3 35.0 34.6 33.6 33.1 32.5 32.7

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

31.81 31.84 31.72 31.62 31.39 31.76 31.71 31.90 31.83

1.803 1.776 1.963 1.841 1.479 1.537 1.537 1.469 1.359

31.95 32.20 32.10 32.00 31.70 32.00 32.20 32.30 32.40

29.3 28.9 28.7 28.9 29.1 28.6 28.5 28.9 28.8

35.7 35.5 35.8 35.5 33.6 33.2 33.0 33.6 33.4

SRT2104 1.0 g

11

Screening Day 1

11 11

31.75 31.70

1.904 1.891

31.00 31.20

29.1 28.8

35.5 35.5

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 19 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCH (PG) SRT2104 1.0 g 11 Day 14 11 31.96 1.739 31.80 29.2 35.4 Day 28 11 31.98 1.703 31.60 29.5 35.3 Day 42 11 31.87 1.822 31.60 29.1 35.4 Day 56 11 31.99 1.701 31.90 29.1 35.1 Day 70 10 32.07 1.553 31.65 30.4 34.9 Day 84 10 31.83 1.755 31.50 28.8 34.8 Follow-up 10 31.56 1.610 31.35 28.3 34.1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 20 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCHC (G/L) Placebo 7 Screening 7 328.0 7.53 328.0 315 338 Day 1 7 326.9 5.46 327.0 320 335 Day 14 7 326.6 8.08 329.0 314 338 Day 28 7 324.6 6.32 324.0 318 334 Day 42 7 327.1 5.49 328.0 320 336 Day 56 7 327.3 7.20 328.0 314 335 Day 70 7 326.1 3.85 324.0 322 332 Day 84 7 322.0 4.40 321.0 317 328 Follow-up 7 327.6 6.43 328.0 321 338 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

331.0 330.8 330.2 331.4 334.6 331.7 329.6 329.8 331.0

9.62 5.61 5.70 4.75 4.93 8.73 4.16 7.01 4.86

330.0 332.0 329.0 332.0 335.0 331.5 330.0 331.0 331.0

317 321 322 324 326 318 325 318 324

342 339 340 339 341 343 335 336 337

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

334.8 333.4 332.1 333.5 333.2 331.4 330.7 332.7 333.2

7.11 6.33 6.92 6.67 6.98 10.60 5.22 7.60 6.80

334.0 333.5 331.5 334.0 336.0 335.0 331.0 333.0 335.0

324 319 324 323 322 308 322 317 322

347 340 347 343 341 342 337 343 340

SRT2104 1.0 g

11

Screening Day 1

11 11

327.3 326.5

8.31 7.98

326.0 326.0

317 311

342 339

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 21 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCHC (G/L) SRT2104 1.0 g 11 Day 14 11 329.6 5.97 331.0 321 338 Day 28 11 329.8 4.02 331.0 324 337 Day 42 11 326.7 6.15 325.0 318 336 Day 56 11 327.7 5.64 328.0 317 337 Day 70 10 328.7 5.31 327.0 322 339 Day 84 10 328.5 7.53 329.5 317 340 Follow-up 10 330.3 6.88 331.5 320 340

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 22 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCV (FL) Placebo 7 Screening 7 92.9 4.22 95.0 86 97 Day 1 7 93.1 3.85 94.0 88 98 Day 14 7 93.6 3.55 94.0 88 98 Day 28 7 93.6 4.50 95.0 86 98 Day 42 7 92.9 4.67 95.0 86 97 Day 56 7 93.0 5.45 95.0 83 98 Day 70 7 93.3 4.57 95.0 85 97 Day 84 7 92.9 5.18 93.0 85 99 Follow-up 7 92.3 4.86 93.0 84 98 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

94.1 93.7 93.8 92.6 91.7 92.3 91.2 90.8 90.8

7.52 7.26 5.76 5.46 6.32 5.32 5.85 4.32 4.17

91.0 94.0 93.0 91.0 89.0 91.5 92.0 90.0 90.5

87 86 85 83 84 86 83 85 85

111 111 107 103 104 102 99 97 98

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

95.2 95.6 95.6 94.8 94.2 95.7 95.9 95.9 95.8

5.18 5.37 5.12 5.64 4.42 4.44 4.62 4.51 4.06

97.0 97.0 96.5 94.0 97.0 97.0 98.0 98.0 97.0

87 89 89 87 89 88 88 87 88

103 107 105 105 99 102 100 100 100

SRT2104 1.0 g

11

Screening Day 1

11 11

97.1 97.1

4.55 4.85

97.0 96.0

91 91

104 105

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 23 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MCV (FL) SRT2104 1.0 g 11 Day 14 11 97.2 5.55 96.0 91 106 Day 28 11 97.0 4.96 95.0 91 106 Day 42 11 97.5 5.22 95.0 91 110 Day 56 11 97.5 4.76 96.0 92 107 Day 70 10 97.6 4.72 96.0 93 107 Day 84 10 96.9 4.84 97.0 91 105 Follow-up 10 95.5 4.67 95.5 88 101

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 24 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MONOCYTES (%) Placebo 7 Screening 7 5.96 1.656 5.20 4.4 9.1 Day 1 7 5.77 2.016 5.90 2.9 8.4 Day 14 7 6.06 1.739 6.80 3.6 8.1 Day 28 7 6.34 2.220 5.40 4.0 8.9 Day 42 7 6.44 1.854 5.50 4.5 9.0 Day 56 7 5.46 2.257 5.10 2.0 8.2 Day 70 7 6.67 2.210 6.50 4.2 10.9 Day 84 7 6.96 1.426 6.70 4.9 8.7 Follow-up 7 7.13 2.178 7.50 4.4 9.7 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

5.01 5.53 6.73 6.33 5.31 5.25 5.96 6.10 5.47

1.853 1.509 2.865 2.144 2.110 1.164 2.201 1.623 1.347

4.60 5.30 6.50 6.60 4.90 5.25 5.60 6.40 5.40

1.6 3.8 3.9 3.1 2.9 3.7 3.4 3.6 3.6

7.4 8.7 12.7 9.1 8.6 6.8 9.3 8.1 7.3

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

6.54 6.73 7.26 6.92 7.19 6.31 6.40 6.43 7.26

2.002 1.966 1.831 1.478 2.173 1.034 1.556 1.639 1.962

6.20 6.40 6.80 6.70 6.50 6.10 6.30 6.70 6.60

2.5 4.3 5.3 5.3 4.9 4.5 3.6 3.3 5.2

10.5 11.9 12.1 10.0 11.5 7.9 9.3 9.0 11.5

SRT2104 1.0 g

11

Screening Day 1

11 11

5.65 6.38

1.892 2.409

5.90 5.30

1.7 3.6

8.6 11.4

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 25 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MONOCYTES (%) SRT2104 1.0 g 11 Day 14 11 6.49 2.247 6.30 2.7 10.4 Day 28 11 6.56 2.081 6.40 3.2 9.1 Day 42 11 6.51 2.338 6.90 2.0 10.9 Day 56 11 5.84 1.719 6.40 2.8 8.9 Day 70 10 5.72 2.184 5.65 2.7 9.5 Day 84 10 6.08 1.821 6.55 1.9 8.1 Follow-up 10 5.84 2.496 4.90 3.1 10.6

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 26 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MONOCYTES Placebo 7 Screening 7 0.383 0.1098 0.390 0.21 0.52 ABSOLUTE (GI/L) Day 1 7 0.376 0.1503 0.370 0.17 0.57 Day 14 7 0.416 0.1197 0.440 0.17 0.55 Day 28 7 0.470 0.1889 0.410 0.20 0.72 Day 42 7 0.451 0.1414 0.520 0.21 0.59 Day 56 7 0.356 0.1559 0.350 0.13 0.58 Day 70 7 0.464 0.1525 0.500 0.20 0.63 Day 84 7 0.437 0.1298 0.460 0.25 0.63 Follow-up 7 0.514 0.1817 0.530 0.26 0.73 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

0.366 0.382 0.461 0.422 0.430 0.403 0.490 0.536 0.435

0.1696 0.1343 0.1860 0.1417 0.2096 0.1041 0.2266 0.1519 0.1228

0.310 0.320 0.370 0.410 0.440 0.400 0.440 0.530 0.455

0.19 0.27 0.30 0.24 0.20 0.26 0.27 0.37 0.23

0.75 0.61 0.85 0.69 0.82 0.55 0.87 0.75 0.59

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

0.400 0.408 0.470 0.424 0.440 0.413 0.447 0.407 0.481

0.1984 0.1864 0.2123 0.1873 0.1863 0.1642 0.1785 0.1526 0.1977

0.380 0.375 0.390 0.370 0.410 0.350 0.450 0.340 0.430

0.13 0.24 0.29 0.23 0.23 0.24 0.26 0.25 0.26

0.88 0.88 0.99 0.87 0.82 0.73 0.87 0.74 0.90

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 27 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------MONOCYTES SRT2104 1.0 g 11 Screening 11 0.428 0.1528 0.400 0.16 0.71 ABSOLUTE (GI/L) Day 1 11 0.425 0.0838 0.390 0.33 0.58 Day 14 11 0.405 0.0804 0.400 0.28 0.53 Day 28 11 0.416 0.1366 0.360 0.25 0.67 Day 42 11 0.441 0.1589 0.410 0.15 0.69 Day 56 11 0.405 0.0855 0.430 0.26 0.50 Day 70 10 0.375 0.0837 0.370 0.23 0.49 Day 84 10 0.400 0.1227 0.410 0.19 0.57 Follow-up 10 0.416 0.1488 0.360 0.28 0.75

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 28 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------NEUTROPHIL, Placebo 7 Screening 7 59.21 13.664 66.00 31.1 70.7 SEGS (%) Day 1 7 64.43 8.117 67.20 51.2 74.5 Day 14 7 63.87 4.838 63.00 58.2 71.6 Day 28 7 67.66 3.100 68.00 63.6 72.9 Day 42 7 65.31 5.165 66.40 56.0 71.8 Day 56 7 66.46 4.320 65.60 62.5 75.0 Day 70 7 64.33 5.997 64.30 56.4 74.8 Day 84 7 61.59 7.584 60.90 49.0 70.7 Follow-up 7 62.64 6.624 60.80 54.2 73.4 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

62.22 61.71 62.14 60.40 64.89 57.97 61.80 63.50 62.98

6.506 9.758 8.661 7.292 9.267 7.223 7.317 4.212 7.183

63.30 60.20 64.90 61.00 62.40 56.00 58.40 62.10 63.25

51.0 49.4 49.2 50.7 54.5 50.4 54.5 58.3 53.6

69.7 74.5 73.2 74.1 77.2 68.9 71.3 68.5 71.3

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

62.17 60.51 62.43 61.85 58.84 61.32 62.60 60.89 57.90

9.758 8.797 5.796 7.237 9.844 7.465 11.142 10.358 7.300

62.30 60.70 62.25 64.00 58.70 58.80 63.10 56.40 57.40

47.7 47.7 53.1 47.2 39.1 52.1 46.1 51.4 47.7

80.6 79.6 73.8 72.2 77.3 73.2 80.6 83.5 72.4

SRT2104 1.0 g

11

Screening

11

67.10

8.440

63.30

58.0

81.1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 29 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------NEUTROPHIL, SRT2104 1.0 g 11 Day 1 11 62.36 6.185 61.50 55.4 73.2 SEGS (%) Day 14 11 60.95 8.373 60.80 48.2 74.1 Day 28 11 61.71 9.116 62.40 43.5 75.3 Day 42 11 63.56 7.722 63.00 50.3 75.1 Day 56 11 64.83 9.919 65.40 47.1 77.0 Day 70 10 66.00 8.755 67.05 52.9 79.1 Day 84 10 63.25 7.670 62.95 54.3 74.9 Follow-up 10 65.74 9.634 68.75 49.0 76.7

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 30 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------NEUTROPHILS Placebo 7 Screening 7 3.921 1.4323 4.520 1.90 5.57 ABSOLUTE (GI/L) Day 1 7 4.310 1.4327 4.150 1.95 6.26 Day 14 7 4.460 1.3206 4.350 2.84 6.40 Day 28 7 4.977 1.0789 5.380 3.12 6.17 Day 42 7 4.737 1.6642 4.520 2.24 7.75 Day 56 7 4.376 0.9616 4.460 2.94 5.85 Day 70 7 4.526 1.2131 4.820 2.45 5.98 Day 84 7 4.014 1.6064 3.290 2.10 6.71 Follow-up 7 4.579 1.3164 4.720 2.38 6.75 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

4.718 4.407 4.490 4.249 5.057 4.537 5.064 5.866 5.343

1.5657 1.5667 1.4036 1.3725 0.6901 1.1364 1.0451 1.8967 2.2079

4.040 4.580 5.220 4.350 5.070 4.710 4.900 6.820 5.265

2.45 2.12 2.16 2.03 3.81 2.87 3.99 3.57 2.30

6.94 6.41 6.00 6.74 5.94 5.81 6.77 7.78 8.56

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

3.780 3.774 4.037 3.744 3.763 4.120 4.779 4.474 4.066

1.7797 1.7484 1.5026 1.3566 1.9527 1.7277 2.9133 3.6141 2.1934

3.425 3.485 3.730 3.600 3.580 3.760 3.930 3.210 3.670

2.10 1.76 2.50 1.89 1.64 2.22 1.94 1.96 1.86

8.95 8.44 8.04 7.00 8.89 6.40 10.56 13.69 9.27

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Page 31 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------NEUTROPHILS SRT2104 1.0 g 11 Screening 11 5.354 1.8017 5.250 2.38 9.33 ABSOLUTE (GI/L) Day 1 11 4.441 1.1079 4.810 2.66 5.78 Day 14 11 4.144 1.4413 4.080 2.43 7.38 Day 28 11 4.117 1.3230 4.560 1.99 5.72 Day 42 11 4.486 1.3413 4.670 2.11 6.68 Day 56 11 4.957 1.9961 5.250 1.84 8.55 Day 70 10 4.747 1.5123 5.695 2.16 6.17 Day 84 10 4.444 1.5321 4.320 2.45 6.98 Follow-up 10 5.051 1.6728 5.530 2.30 7.04

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 32 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------PLATELET COUNT Placebo 7 Screening 7 265.1 44.16 279.0 211 326 (GI/L) Day 1 7 257.4 57.20 253.0 185 341 Day 14 7 257.7 55.74 253.0 196 359 Day 28 7 263.4 49.05 261.0 186 332 Day 42 7 263.7 48.69 282.0 178 327 Day 56 7 254.4 43.51 259.0 202 311 Day 70 7 255.6 45.11 259.0 189 323 Day 84 7 248.6 44.68 270.0 184 300 Follow-up 7 271.9 57.88 290.0 194 352 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

236.8 253.6 252.9 259.0 278.7 267.7 297.8 283.8 267.7

44.88 61.22 63.15 49.97 40.46 46.77 43.42 33.71 65.61

240.0 255.0 253.0 266.0 272.0 256.5 284.0 292.0 281.5

170 158 162 177 226 208 241 226 166

293 328 364 320 355 338 345 312 335

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

220.3 222.2 219.6 229.9 225.5 229.2 222.9 220.4 225.0

63.05 58.68 59.81 67.20 52.43 86.75 52.97 72.70 75.32

194.5 204.0 201.0 205.0 207.0 197.0 218.0 201.0 197.0

150 149 150 167 166 141 150 131 158

343 342 339 373 329 391 341 367 399

SRT2104 1.0 g

11

Screening

11

237.1

58.34

229.0

142

331

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Page 33 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------PLATELET COUNT SRT2104 1.0 g 11 Day 1 11 227.6 50.25 213.0 164 317 (GI/L) Day 14 11 233.5 45.57 232.0 163 315 Day 28 11 219.3 54.23 212.0 141 310 Day 42 11 231.2 52.29 212.0 165 321 Day 56 11 233.8 51.89 236.0 161 315 Day 70 10 232.1 60.64 217.0 162 346 Day 84 10 236.4 61.06 218.0 175 345 Follow-up 10 235.9 60.63 225.5 160 350 PROTHROMBIN TIME (SECONDS)

Placebo

7

Screening

6

10.87

0.550

10.70

10.4

11.9

Day 1 Day 42 Day 84

7 7 7

11.37 13.59 11.00

0.976 7.117 0.563

11.00 11.00 11.00

10.2 10.4 10.3

12.7 29.7 11.9

SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

10.50 10.50 10.59 10.66

0.561 0.587 0.623 0.462

10.60 10.60 10.50 10.60

9.5 9.6 10.0 10.1

11.2 11.4 11.9 11.3

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 12 11 9

10.78 11.00 10.88 11.13

0.484 0.702 0.449 0.775

10.70 10.80 10.80 10.80

10.0 10.0 10.4 10.3

11.5 12.5 12.0 12.9

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

10 10 10 9

10.96 11.26 11.43 10.90

0.513 0.389 1.515 0.552

10.90 11.25 10.95 10.90

10.3 10.7 10.2 10.2

12.1 12.0 14.7 11.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 34 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------RDW (%) Placebo 7 Screening 7 14.57 1.039 14.80 13.5 16.4 Day 1 7 14.91 1.108 14.60 13.5 16.9 Day 14 7 14.87 1.194 14.90 13.2 16.4 Day 28 7 15.10 0.952 15.40 13.5 16.2 Day 42 7 14.93 1.163 15.20 13.2 16.4 Day 56 7 14.93 0.899 15.30 13.6 16.1 Day 70 7 14.79 0.915 15.20 13.4 15.7 Day 84 7 14.87 1.001 14.60 13.6 16.6 Follow-up 7 14.39 0.760 14.60 13.1 15.3 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

14.41 14.44 14.57 14.18 14.20 14.42 14.06 13.86 14.00

1.114 1.057 0.935 1.016 0.971 0.904 0.873 0.619 0.429

14.10 14.20 14.50 14.40 13.70 14.15 13.90 13.60 14.05

13.3 12.8 13.1 12.9 13.2 13.6 13.2 13.2 13.5

16.7 16.2 15.8 16.1 15.8 16.0 15.2 14.7 14.5

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

13.95 14.08 14.10 14.35 14.41 14.53 14.61 14.86 14.68

0.645 0.688 0.720 0.636 0.881 1.028 1.017 1.271 1.318

14.05 14.15 14.05 14.10 14.70 14.20 14.30 14.60 14.60

12.5 12.6 12.5 13.6 12.9 13.3 12.9 13.2 12.6

14.7 15.2 15.3 15.6 16.1 16.1 16.2 17.0 16.4

SRT2104 1.0 g

11

Screening Day 1

11 11

14.68 14.65

1.423 1.223

14.40 14.50

13.2 12.8

18.1 17.3

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Page 35 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------RDW (%) SRT2104 1.0 g 11 Day 14 11 14.89 1.059 15.10 13.5 17.1 Day 28 11 14.84 0.793 14.80 13.9 16.4 Day 42 11 14.98 0.917 14.50 13.8 16.6 Day 56 11 14.85 0.961 14.60 13.5 16.6 Day 70 10 14.57 0.767 14.65 13.6 15.6 Day 84 10 14.84 1.100 14.55 13.5 16.9 Follow-up 10 14.18 1.075 14.05 12.8 16.6

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 36 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------RED CELL COUNT Placebo 7 Screening 7 4.81 0.261 4.90 4.3 5.1 (TI/L) Day 1 7 4.71 0.363 4.80 4.0 5.1 Day 14 7 4.63 0.287 4.70 4.0 4.8 Day 28 7 4.69 0.422 4.80 3.8 5.1 Day 42 7 4.71 0.344 4.80 4.0 5.1 Day 56 7 4.71 0.302 4.80 4.1 5.0 Day 70 7 4.76 0.270 4.80 4.2 5.0 Day 84 7 4.70 0.289 4.80 4.1 4.9 Follow-up 7 4.76 0.346 4.90 4.1 5.1 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

4.66 4.66 4.62 4.70 4.76 4.68 5.00 4.98 4.92

0.520 0.469 0.438 0.424 0.431 0.488 0.300 0.335 0.331

4.60 4.60 4.60 4.70 4.70 4.75 5.00 5.00 4.95

3.8 3.8 4.0 3.9 4.1 3.9 4.7 4.6 4.5

5.3 5.3 5.2 5.2 5.3 5.2 5.3 5.4 5.4

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

4.68 4.71 4.54 4.61 4.56 4.60 4.62 4.56 4.56

0.356 0.318 0.334 0.468 0.347 0.450 0.455 0.425 0.433

4.80 4.70 4.55 4.60 4.60 4.60 4.50 4.50 4.60

4.1 4.2 4.1 4.0 4.0 3.8 4.0 3.9 3.9

5.3 5.3 5.1 5.4 5.2 5.2 5.3 5.1 5.2

SRT2104 1.0 g

11

Screening

11

4.74

0.367

4.70

4.2

5.3

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Page 37 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------RED CELL COUNT SRT2104 1.0 g 11 Day 1 11 4.66 0.398 4.70 4.1 5.3 (TI/L) Day 14 11 4.53 0.434 4.40 3.9 5.2 Day 28 11 4.59 0.461 4.40 4.1 5.4 Day 42 11 4.54 0.443 4.30 4.0 5.4 Day 56 11 4.65 0.489 4.50 4.1 5.5 Day 70 10 4.53 0.495 4.30 4.1 5.5 Day 84 10 4.60 0.403 4.55 4.0 5.3 Follow-up 10 4.62 0.408 4.50 4.1 5.3

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 38 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------TOTAL Placebo 7 Screening 7 3.921 1.4323 4.520 1.90 5.57 NEUTROPHILS AB (GI/L) Day 1 7 4.310 1.4327 4.150 1.95 6.26 Day 14 7 4.460 1.3206 4.350 2.84 6.40 Day 28 7 4.977 1.0789 5.380 3.12 6.17 Day 42 7 4.737 1.6642 4.520 2.24 7.75 Day 56 7 4.376 0.9616 4.460 2.94 5.85 Day 70 7 4.526 1.2131 4.820 2.45 5.98 Day 84 7 4.014 1.6064 3.290 2.10 6.71 Follow-up 7 4.579 1.3164 4.720 2.38 6.75 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

4.718 4.407 4.490 4.249 5.057 4.537 5.064 5.866 5.343

1.5657 1.5667 1.4036 1.3725 0.6901 1.1364 1.0451 1.8967 2.2079

4.040 4.580 5.220 4.350 5.070 4.710 4.900 6.820 5.265

2.45 2.12 2.16 2.03 3.81 2.87 3.99 3.57 2.30

6.94 6.41 6.00 6.74 5.94 5.81 6.77 7.78 8.56

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

3.780 3.774 4.037 3.744 3.763 4.120 4.779 4.474 4.066

1.7797 1.7484 1.5026 1.3566 1.9527 1.7277 2.9133 3.6141 2.1934

3.425 3.485 3.730 3.600 3.580 3.760 3.930 3.210 3.670

2.10 1.76 2.50 1.89 1.64 2.22 1.94 1.96 1.86

8.95 8.44 8.04 7.00 8.89 6.40 10.56 13.69 9.27

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 39 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------TOTAL SRT2104 1.0 g 11 Screening 11 5.354 1.8017 5.250 2.38 9.33 NEUTROPHILS AB (GI/L) Day 1 11 4.441 1.1079 4.810 2.66 5.78 Day 14 11 4.144 1.4413 4.080 2.43 7.38 Day 28 11 4.117 1.3230 4.560 1.99 5.72 Day 42 11 4.486 1.3413 4.670 2.11 6.68 Day 56 11 4.957 1.9961 5.250 1.84 8.55 Day 70 10 4.747 1.5123 5.695 2.16 6.17 Day 84 10 4.444 1.5321 4.320 2.45 6.98 Follow-up 10 5.051 1.6728 5.530 2.30 7.04

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 40 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------TOTAL Placebo 7 Screening 7 59.21 13.664 66.00 31.1 70.7 NEUTROPHILS (%) Day 1 7 64.43 8.117 67.20 51.2 74.5 Day 14 7 63.87 4.838 63.00 58.2 71.6 Day 28 7 67.66 3.100 68.00 63.6 72.9 Day 42 7 65.31 5.165 66.40 56.0 71.8 Day 56 7 66.46 4.320 65.60 62.5 75.0 Day 70 7 64.33 5.997 64.30 56.4 74.8 Day 84 7 61.59 7.584 60.90 49.0 70.7 Follow-up 7 62.64 6.624 60.80 54.2 73.4 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

62.22 61.71 62.14 60.40 64.89 57.97 61.80 63.50 62.98

6.506 9.758 8.661 7.292 9.267 7.223 7.317 4.212 7.183

63.30 60.20 64.90 61.00 62.40 56.00 58.40 62.10 63.25

51.0 49.4 49.2 50.7 54.5 50.4 54.5 58.3 53.6

69.7 74.5 73.2 74.1 77.2 68.9 71.3 68.5 71.3

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

62.17 60.51 62.43 61.85 58.84 61.32 62.60 60.89 57.90

9.758 8.797 5.796 7.237 9.844 7.465 11.142 10.358 7.300

62.30 60.70 62.25 64.00 58.70 58.80 63.10 56.40 57.40

47.7 47.7 53.1 47.2 39.1 52.1 46.1 51.4 47.7

80.6 79.6 73.8 72.2 77.3 73.2 80.6 83.5 72.4

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 41 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------TOTAL SRT2104 1.0 g 11 Screening 11 67.10 8.440 63.30 58.0 81.1 NEUTROPHILS (%) Day 1 11 62.36 6.185 61.50 55.4 73.2 Day 14 11 60.95 8.373 60.80 48.2 74.1 Day 28 11 61.71 9.116 62.40 43.5 75.3 Day 42 11 63.56 7.722 63.00 50.3 75.1 Day 56 11 64.83 9.919 65.40 47.1 77.0 Day 70 10 66.00 8.755 67.05 52.9 79.1 Day 84 10 63.25 7.670 62.95 54.3 74.9 Follow-up 10 65.74 9.634 68.75 49.0 76.7

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 42 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------WHITE CELL Placebo 7 Screening 7 6.51 1.373 6.40 4.2 8.2 COUNT (GI/L) Day 1 7 6.54 1.539 6.80 3.8 8.4 Day 14 7 6.90 1.594 6.90 4.6 9.3 Day 28 7 7.33 1.444 7.60 4.9 9.0 Day 42 7 7.13 2.034 6.80 4.0 10.8 Day 56 7 6.56 1.263 6.30 4.7 8.5 Day 70 7 6.97 1.471 7.50 4.2 8.2 Day 84 7 6.40 2.009 6.20 3.7 9.8 Follow-up 7 7.21 1.521 7.40 4.4 9.2 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

7.56 7.09 7.18 6.99 7.97 7.82 8.38 9.20 8.42

2.375 2.292 1.991 1.926 1.852 1.770 2.346 2.808 3.191

6.40 7.00 7.70 7.70 7.30 7.75 8.60 10.30 8.75

4.8 4.3 4.4 3.8 6.1 5.7 5.6 5.8 4.3

11.9 11.5 10.4 9.1 10.9 10.4 11.6 11.7 12.0

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 11 9 9 9 9

5.94 6.03 6.38 5.98 6.15 6.51 7.23 6.83 6.77

1.893 1.849 1.803 1.721 2.145 2.045 3.071 3.812 2.708

5.40 6.00 6.15 6.00 6.10 6.40 6.30 5.80 6.40

4.2 3.7 4.2 3.4 4.2 4.0 4.2 3.7 3.9

11.1 10.6 10.9 9.7 11.5 9.3 13.1 16.4 12.8

SRT2104 1.0 g

11

Screening

11

7.85

1.902

8.30

4.0

11.5

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 43 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.2 Summary of Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------WHITE CELL SRT2104 1.0 g 11 Day 1 11 7.12 1.659 7.20 4.8 9.7 COUNT (GI/L) Day 14 11 6.66 1.580 6.40 4.8 10.4 Day 28 11 6.55 1.446 6.70 3.7 8.3 Day 42 11 6.94 1.468 7.00 4.2 9.4 Day 56 11 7.41 2.170 7.50 3.9 11.1 Day 70 10 7.06 1.700 7.75 4.0 9.4 Day 84 10 6.88 1.736 6.85 4.5 10.2 Follow-up 10 7.54 1.971 7.45 4.7 11.1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------APTT (SECONDS) Placebo 7 Day 42 7 1.6 9.50 -1.0 -10 20 Day 84 7 0.4 4.28 2.0 -8 4 SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.4 1.2

2.30 2.77

-1.0 0.0

-4 -2

3 5

SRT2104 0.5 g

12 Day 42 Day 84

11 9

0.5 0.8

4.52 3.49

-1.0 -1.0

-7 -2

8 8

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 9 9

1.0 -0.7 -1.1

5.32 3.92

1.0 -1.0 -1.0

1 -7 -5

1 10 8

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BASOPHILS (%) Placebo 7 Day 14 7 0.10 0.173 0.10 -0.2 0.3 Day 28 7 0.07 0.095 0.10 -0.1 0.2 Day 42 7 0.14 0.127 0.10 0.0 0.3 Day 56 7 -0.07 0.170 -0.10 -0.3 0.2 Day 70 7 0.06 0.162 0.10 -0.2 0.2 Day 84 7 0.14 0.127 0.10 0.0 0.3 Follow-up 7 0.10 0.245 0.20 -0.4 0.3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.04 -0.04 -0.04 0.07 0.18 0.02 -0.05

0.219 0.174 0.288 0.314 0.342 0.228 0.164

0.10 0.00 0.00 0.10 0.10 0.00 0.00

-0.4 -0.4 -0.6 -0.5 -0.3 -0.2 -0.3

0.3 0.1 0.3 0.4 0.6 0.3 0.1

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.09 -0.03 -0.04 -0.02 -0.06 -0.06 -0.02

0.162 0.156 0.242 0.211 0.181 0.174 0.273

0.00 0.00 0.00 -0.10 0.00 0.00 0.00

-0.4 -0.3 -0.3 -0.3 -0.3 -0.4 -0.5

0.1 0.2 0.5 0.4 0.2 0.2 0.4

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

0.10 -0.08 0.02 -0.04 -0.04 -0.05 -0.04

0.392 0.397 0.196 0.250 0.331 0.288

0.10 -0.20 -0.10 0.00 0.00 -0.10 -0.05

0.1 -0.7 -0.4 -0.3 -0.4 -0.6 -0.4

0.1 0.6 1.0 0.2 0.4 0.6 0.6

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BASOPHILS (%) SRT2104 1.0 g 11 Follow-up 10 -0.01 0.354 -0.05 -0.4 0.8

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BASOPHILS ABSOLUTE Placebo 7 Day 14 7 0.010 0.0115 0.010 -0.01 0.02 (GI/L) Day 28 7 0.007 0.0125 0.000 -0.01 0.02 Day 42 7 0.011 0.0107 0.010 0.00 0.03 Day 56 7 -0.006 0.0140 -0.010 -0.02 0.02 Day 70 7 0.006 0.0151 0.000 -0.01 0.03 Day 84 7 0.010 0.0153 0.000 0.00 0.04 Follow-up 7 0.010 0.0173 0.020 -0.02 0.03 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.007 0.001 -0.003 0.007 0.020 0.002 0.000

0.0122 0.0078 0.0189 0.0186 0.0255 0.0164 0.0110

0.010 0.000 -0.010 0.010 0.020 0.010 0.000

-0.01 -0.01 -0.03 -0.02 -0.01 -0.02 -0.01

0.02 0.01 0.03 0.03 0.06 0.02 0.02

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.004 -0.002 -0.004 0.001 -0.001 -0.007 -0.001

0.0079 0.0098 0.0143 0.0105 0.0209 0.0112 0.0145

0.000 0.000 0.000 0.000 0.000 -0.010 0.000

-0.02 -0.01 -0.03 -0.01 -0.03 -0.03 -0.02

0.01 0.02 0.02 0.02 0.04 0.01 0.02

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.000 -0.006 -0.003 -0.003 -0.002 -0.006

0.0277 0.0249 0.0149 0.0204 0.0250

0.000 -0.010 -0.010 0.000 0.000 -0.010

0.00 -0.04 -0.03 -0.03 -0.04 -0.05

0.00 0.04 0.05 0.01 0.03 0.04

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BASOPHILS ABSOLUTE SRT2104 1.0 g 11 Day 84 10 -0.005 0.0217 -0.005 -0.04 0.03 (GI/L) Follow-up 10 0.002 0.0305 0.000 -0.03 0.06

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------EOSINOPHILS (%) Placebo 7 Day 14 7 -0.16 0.844 0.10 -1.2 1.2 Day 28 7 -0.41 0.576 -0.20 -1.2 0.3 Day 42 7 -0.43 0.774 -0.30 -1.4 0.7 Day 56 7 -0.50 0.728 -0.40 -1.3 0.7 Day 70 7 -0.73 0.991 -0.60 -2.7 0.4 Day 84 7 0.43 2.712 -0.70 -1.5 6.2 Follow-up 7 -0.13 0.899 -0.40 -0.9 1.7 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.02 0.41 0.80 0.65 0.24 0.34 0.23

0.761 0.964 1.454 0.985 0.899 0.577 0.547

-0.30 0.20 0.10 0.65 0.20 0.40 0.20

-0.8 -0.6 -0.3 -0.7 -0.5 -0.5 -0.6

1.2 2.7 3.6 2.0 1.7 1.1 0.9

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.01 0.15 -0.43 -0.57 0.10 -0.07 -0.17

1.180 1.639 1.526 1.169 1.329 1.254 1.205

0.15 -0.20 -0.40 -0.10 0.10 0.00 -0.50

-1.9 -3.3 -2.9 -3.1 -1.5 -2.4 -1.7

2.6 2.6 2.1 0.9 2.5 2.0 2.0

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

0.00 0.36 0.69 -0.04 -0.17 -0.58 -0.28

1.108 0.842 1.021 1.053 2.104 0.824

0.00 0.00 0.70 -0.10 0.00 0.05 -0.25

0.0 -1.3 -1.0 -2.3 -1.8 -6.4 -1.5

0.0 2.7 2.1 1.1 1.9 0.9 1.1

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------EOSINOPHILS (%) SRT2104 1.0 g 11 Follow-up 10 -0.28 0.903 -0.25 -1.6 1.6

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------EOSINOPHILS ABSOLUTE Placebo 7 Day 14 7 -0.003 0.0652 0.000 -0.07 0.11 (GI/L) Day 28 7 -0.009 0.0546 0.010 -0.10 0.04 Day 42 7 -0.027 0.0588 -0.030 -0.09 0.05 Day 56 7 -0.034 0.0588 -0.020 -0.11 0.04 Day 70 7 -0.033 0.0680 -0.030 -0.15 0.05 Day 84 7 0.010 0.1519 -0.040 -0.09 0.34 Follow-up 7 0.009 0.0657 0.010 -0.06 0.14 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.011 0.028 0.061 0.040 0.026 0.044 0.037

0.0575 0.0993 0.1526 0.0713 0.1069 0.0688 0.0565

-0.010 0.020 0.020 0.030 -0.010 0.040 0.045

-0.10 -0.11 -0.05 -0.03 -0.06 -0.06 -0.03

0.05 0.26 0.39 0.15 0.21 0.12 0.10

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.030 0.038 -0.007 -0.012 0.033 0.043 0.037

0.0914 0.1097 0.0770 0.0667 0.0735 0.1679 0.1648

0.005 0.020 -0.020 0.000 0.030 0.000 -0.020

-0.05 -0.17 -0.14 -0.10 -0.09 -0.09 -0.06

0.28 0.19 0.12 0.07 0.15 0.46 0.46

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-0.010 0.005 0.027 -0.015 -0.026 -0.040

0.0778 0.0526 0.0719 0.0761 0.1438

-0.010 0.000 0.030 -0.010 -0.010 0.010

-0.01 -0.15 -0.09 -0.21 -0.20 -0.40

-0.01 0.18 0.12 0.05 0.06 0.10

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------EOSINOPHILS ABSOLUTE SRT2104 1.0 g 11 Day 84 10 -0.018 0.0745 -0.025 -0.15 0.11 (GI/L) Follow-up 10 -0.021 0.0818 -0.020 -0.16 0.15

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------HEMATOCRIT (1) Placebo 7 Day 14 7 -0.0081 0.01590 -0.0070 -0.036 0.012 Day 28 7 -0.0003 0.01535 0.0040 -0.020 0.018 Day 42 7 -0.0020 0.02165 -0.0070 -0.024 0.037 Day 56 7 -0.0026 0.01688 -0.0010 -0.031 0.023 Day 70 7 0.0013 0.02498 -0.0060 -0.016 0.054 Day 84 7 -0.0047 0.01928 -0.0050 -0.028 0.033 Follow-up 7 -0.0027 0.00736 -0.0010 -0.014 0.005 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.0010 0.0013 0.0029 0.0027 0.0192 0.0150 0.0113

0.01376 0.01713 0.01493 0.02523 0.02083 0.02751 0.02877

-0.0050 0.0050 -0.0040 0.0025 0.0220 0.0280 0.0105

-0.019 -0.024 -0.012 -0.035 -0.006 -0.030 -0.019

0.025 0.022 0.032 0.032 0.045 0.038 0.057

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.0179 -0.0142 -0.0171 -0.0081 -0.0050 -0.0128 -0.0139

0.01535 0.01938 0.01996 0.02127 0.01578 0.01173 0.01819

-0.0140 -0.0140 -0.0300 -0.0120 -0.0080 -0.0130 -0.0140

-0.047 -0.050 -0.038 -0.037 -0.031 -0.035 -0.045

0.008 0.015 0.020 0.023 0.021 0.004 0.011

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-0.0220 -0.0135 -0.0090 -0.0118 0.0004 -0.0072 -0.0073

0.01444 0.02207 0.02139 0.02060 0.02522 0.02950

-0.0220 -0.0150 -0.0040 -0.0100 0.0050 0.0015 -0.0090

-0.022 -0.032 -0.049 -0.049 -0.043 -0.059 -0.055

-0.022 0.015 0.034 0.017 0.026 0.019 0.042

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------HEMATOCRIT (1) SRT2104 1.0 g 11 Follow-up 10 -0.0143 0.02791 -0.0185 -0.051 0.027

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------HEMOGLOBIN (G/L) Placebo 7 Day 14 7 -2.7 6.90 -3.0 -13 9 Day 28 7 -1.3 7.06 -1.0 -10 8 Day 42 7 -0.7 7.25 -2.0 -8 13 Day 56 7 -0.9 4.30 0.0 -6 6 Day 70 7 0.0 9.63 -3.0 -8 20 Day 84 7 -3.9 8.15 -3.0 -13 11 Follow-up 7 -1.0 3.37 -2.0 -5 3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.9 0.7 2.3 0.2 4.6 3.4 3.3

3.02 4.85 3.86 4.54 6.31 8.88 8.24

-1.0 2.0 1.0 0.0 4.0 8.0 2.5

-5 -7 -2 -6 -2 -10 -8

3 9 9 7 15 12 17

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-6.3 -4.2 -5.7 -3.7 -2.8 -4.8 -4.7

3.98 7.55 5.33 5.24 5.61 3.90 6.87

-7.0 -5.0 -9.0 -5.0 -4.0 -6.0 -2.0

-12 -15 -11 -10 -11 -10 -18

0 9 6 3 6 1 4

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-5.0 -2.9 -1.3 -3.4 0.9 -1.2 -1.7

6.19 7.31 6.39 6.20 7.94 7.51

-5.0 -4.0 -1.0 -2.0 1.0 0.5 -0.5

-5 -11 -16 -15 -10 -15 -16

-5 6 8 5 11 9 8

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------HEMOGLOBIN (G/L) SRT2104 1.0 g 11 Follow-up 10 -2.2 6.60 -1.0 -13 8 INR

Placebo

7 Day 42 Day 84

7 7

0.21 -0.06

0.840 0.113

0.00 0.00

-0.3 -0.2

2.1 0.1

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.01 0.02

0.069 0.045

0.00 0.00

-0.1 0.0

0.1 0.1

SRT2104 0.5 g

12 Day 42 Day 84

11 9

-0.01 0.00

0.070 0.100

0.00 0.00

-0.1 -0.1

0.1 0.2

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 9 9

0.10 0.04 -0.01

0.194 0.078

0.10 0.00 0.00

0.1 -0.2 -0.1

0.1 0.4 0.1

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LYMPHOCYTES (%) Placebo 7 Day 14 7 0.33 5.045 1.70 -9.9 5.7 Day 28 7 -3.46 5.403 -2.70 -11.6 3.2 Day 42 7 -1.27 4.953 -3.00 -6.4 5.8 Day 56 7 -1.14 7.444 -1.10 -10.7 10.4 Day 70 7 -0.13 4.123 0.60 -6.5 4.8 Day 84 7 1.09 7.334 0.10 -9.0 14.7 Follow-up 7 0.46 3.494 -0.50 -3.9 7.1 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-1.66 0.14 -0.97 4.88 -1.26 -3.04 -2.98

4.533 6.227 5.389 8.866 3.245 7.801 5.090

-0.70 0.10 -0.30 4.35 -2.50 -4.40 -3.30

-11.2 -9.1 -8.4 -7.7 -4.6 -10.5 -11.3

3.8 12.9 5.0 18.7 2.2 5.7 3.3

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-2.34 -0.97 1.55 -0.43 -2.43 -0.59 1.64

3.552 4.045 6.554 6.703 3.708 6.882 5.837

-1.10 -1.60 -0.50 -2.00 -1.30 -0.20 0.80

-8.5 -6.3 -6.5 -11.7 -7.5 -11.3 -4.6

2.4 4.4 18.4 10.4 3.6 9.9 15.4

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

11.80 2.10 0.85 -0.17 -0.63 -1.45 0.01

7.793 8.976 7.580 9.784 8.333 9.350

11.80 3.20 -1.00 -2.30 -4.40 -3.45 -1.60

11.8 -14.5 -8.5 -6.7 -8.9 -12.9 -10.7

11.8 17.3 18.0 21.5 25.7 17.2 20.5

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LYMPHOCYTES (%) SRT2104 1.0 g 11 Follow-up 10 -1.49 9.626 -2.90 -10.6 23.3

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LYMPHOCYTES ABSOLUTE Placebo 7 Day 14 7 0.160 0.2301 0.160 -0.14 0.52 (GI/L) Day 28 7 0.023 0.3331 -0.010 -0.42 0.44 Day 42 7 0.097 0.3054 0.020 -0.30 0.55 Day 56 7 0.006 0.4146 0.110 -0.72 0.43 Day 70 7 0.149 0.2776 0.270 -0.24 0.50 Day 84 7 0.070 0.4197 -0.080 -0.42 0.63 Follow-up 7 0.247 0.1943 0.220 0.03 0.51 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.068 -0.009 0.000 0.248 0.054 0.026 0.027

0.2597 0.5961 0.4405 0.5520 0.4826 0.3527 0.5764

-0.150 0.060 -0.190 0.070 -0.120 -0.020 -0.070

-0.34 -0.89 -0.45 -0.42 -0.50 -0.44 -0.82

0.33 1.26 0.89 1.17 0.59 0.38 0.91

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.010 0.005 0.137 0.098 0.081 0.024 0.293

0.3114 0.3085 0.3096 0.4097 0.2893 0.3961 0.3601

0.035 0.050 0.150 0.070 0.160 0.080 0.130

-0.56 -0.44 -0.44 -0.57 -0.45 -0.53 -0.12

0.41 0.47 0.68 0.83 0.51 0.56 0.91

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.600 -0.087 -0.205 -0.172 -0.127 -0.195

0.5606 0.6868 0.5318 0.4992 0.6586

0.600 -0.010 -0.280 -0.190 -0.050 -0.195

0.60 -1.23 -1.37 -1.22 -0.75 -1.58

0.60 0.93 1.19 0.80 0.84 0.55

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LYMPHOCYTES ABSOLUTE SRT2104 1.0 g 11 Day 84 10 -0.185 0.6802 -0.065 -1.83 0.87 (GI/L) Follow-up 10 -0.163 0.6340 -0.290 -1.22 1.08

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCH (PG) Placebo 7 Day 14 7 0.06 0.447 -0.20 -0.4 0.9 Day 28 7 -0.11 0.518 -0.20 -0.8 0.8 Day 42 7 -0.04 0.650 -0.20 -0.8 1.2 Day 56 7 -0.13 0.427 -0.30 -0.6 0.7 Day 70 7 -0.13 0.660 -0.40 -0.9 1.0 Day 84 7 -0.59 1.054 -0.50 -2.5 1.0 Follow-up 7 -0.29 0.722 -0.40 -1.3 0.9 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.01 -0.24 -0.31 -0.38 -0.94 -1.08 -0.72

0.468 0.913 1.196 1.793 1.963 2.242 2.017

0.20 0.00 0.00 0.35 -0.30 0.00 0.15

-1.2 -2.5 -2.9 -3.9 -4.4 -5.0 -4.8

0.3 0.6 0.7 0.8 0.3 0.3 0.3

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.13 -0.12 -0.12 -0.01 -0.06 0.13 0.07

0.273 0.194 0.343 0.448 0.224 0.480 0.439

-0.20 -0.10 -0.20 0.00 0.00 0.10 -0.10

-0.6 -0.6 -0.6 -0.9 -0.4 -0.8 -0.5

0.4 0.1 0.6 0.6 0.3 0.9 0.7

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

0.20 0.28 0.30 0.19 0.31 0.47 0.19

0.414 0.293 0.375 0.522 0.890 0.515

0.20 0.30 0.30 0.20 0.50 0.35 0.30

0.2 -0.7 -0.2 -0.6 -0.7 -0.6 -0.7

0.2 0.8 0.7 0.7 0.9 2.5 0.8

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 19 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCH (PG) SRT2104 1.0 g 11 Follow-up 10 0.26 0.474 0.40 -0.5 0.8

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 20 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCHC (G/L) Placebo 7 Day 14 7 -0.3 6.73 -2.0 -7 11 Day 28 7 -2.3 5.88 -3.0 -11 7 Day 42 7 0.3 2.14 1.0 -3 3 Day 56 7 0.4 6.29 -2.0 -6 13 Day 70 7 -0.7 5.09 0.0 -8 5 Day 84 7 -4.9 7.17 -2.0 -17 1 Follow-up 7 0.7 5.09 1.0 -7 8 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.6 0.7 2.7 -0.8 -3.8 -3.6 -0.3

6.31 6.30 4.15 9.99 6.94 2.97 8.89

2.0 2.0 4.0 -3.0 -2.0 -3.0 -3.0

-11 -7 -5 -11 -14 -8 -10

6 12 7 15 4 -1 16

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-1.3 0.7 -0.4 -2.1 -2.9 -0.9 -0.3

6.21 8.27 4.76 5.62 4.48 3.59 4.47

-3.5 1.0 1.0 -3.0 -2.0 -2.0 1.0

-9 -12 -10 -11 -10 -5 -8

10 11 5 6 3 5 6

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

4.0 3.5 3.7 0.6 1.6 2.7 1.6

6.59 6.48 9.22 8.13 8.78 6.75

4.0 4.0 4.0 5.0 4.0 3.0 1.5

4 -7 -7 -18 -11 -11 -11

4 12 14 10 11 19 10

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 21 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCHC (G/L) SRT2104 1.0 g 11 Follow-up 10 5.5 7.60 7.0 -11 14

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 22 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCV (FL) Placebo 7 Day 14 7 0.4 1.40 0.0 -2 2 Day 28 7 0.4 1.27 1.0 -2 2 Day 42 7 -0.3 1.80 -1.0 -2 3 Day 56 7 -0.1 2.48 0.0 -5 3 Day 70 7 0.1 1.68 1.0 -3 2 Day 84 7 -0.3 2.69 0.0 -4 3 Follow-up 7 -0.9 2.04 -1.0 -4 2 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.1 -1.1 -1.7 -1.0 -1.8 -2.2 -2.3

2.52 3.41 2.50 4.69 6.38 6.72 5.65

0.0 0.0 -1.0 0.0 -1.0 0.0 0.0

-4 -8 -7 -9 -12 -14 -13

4 3 1 5 4 2 2

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.0 -0.6 -0.4 0.3 0.6 0.6 0.4

1.28 2.01 1.57 1.00 1.51 1.42 2.07

0.0 -1.0 0.0 0.0 0.0 1.0 0.0

-2 -3 -3 -1 -1 -2 -2

2 3 2 2 3 2 3

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-1.0 0.0 -0.2 0.4 0.4 0.6 0.1

1.34 1.47 2.34 1.50 1.35 1.45

-1.0 0.0 0.0 0.0 0.0 1.0 0.0

-1 -2 -2 -2 -2 -2 -2

-1 2 3 5 2 2 2

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 23 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MCV (FL) SRT2104 1.0 g 11 Follow-up 10 -0.9 2.42 -0.5 -5 2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 24 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MONOCYTES (%) Placebo 7 Day 14 7 0.29 1.189 0.60 -1.4 1.5 Day 28 7 0.57 1.929 0.50 -2.8 2.8 Day 42 7 0.67 1.907 0.60 -2.7 3.1 Day 56 7 -0.31 2.687 0.70 -6.2 1.5 Day 70 7 0.90 1.690 0.70 -1.7 3.2 Day 84 7 1.19 1.997 1.80 -1.9 4.3 Follow-up 7 1.36 1.010 1.30 0.3 3.3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

1.20 0.80 -0.01 -0.22 0.16 0.30 -0.35

2.377 1.663 1.144 1.573 1.036 1.851 2.455

0.60 0.60 -0.10 0.00 0.50 1.10 0.50

-0.3 -1.4 -1.9 -2.7 -1.3 -2.2 -5.1

7.4 3.5 1.6 1.7 1.4 2.0 1.3

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.52 0.09 0.33 -0.14 -0.06 -0.02 0.80

0.880 1.215 2.190 1.081 1.037 0.902 1.329

0.65 0.20 -0.40 0.00 0.00 0.10 0.90

-1.2 -1.9 -2.6 -1.9 -1.9 -1.2 -1.2

1.7 1.8 5.4 1.4 1.9 1.5 3.2

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

0.60 0.16 0.24 0.18 -0.49 -0.56 -0.41

1.660 1.635 1.861 2.150 1.888 2.146

0.60 0.20 0.30 0.60 -0.40 -0.20 -0.15

0.6 -2.4 -3.3 -3.4 -4.7 -3.4 -4.8

0.6 2.7 3.1 2.6 2.1 1.9 2.4

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 25 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MONOCYTES (%) SRT2104 1.0 g 11 Follow-up 10 -0.21 1.425 -0.50 -2.5 2.3

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 26 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MONOCYTES ABSOLUTE Placebo 7 Day 14 7 0.040 0.1094 0.040 -0.12 0.20 (GI/L) Day 28 7 0.094 0.1755 0.040 -0.16 0.34 Day 42 7 0.076 0.1699 0.040 -0.20 0.32 Day 56 7 -0.020 0.1932 0.030 -0.44 0.13 Day 70 7 0.089 0.1358 0.140 -0.11 0.30 Day 84 7 0.061 0.1677 0.080 -0.24 0.28 Follow-up 7 0.139 0.0618 0.130 0.06 0.25 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.079 0.040 0.017 -0.030 0.036 0.082 0.012

0.1226 0.1107 0.1216 0.1094 0.1701 0.1522 0.1550

0.040 0.020 -0.040 -0.040 -0.010 0.090 -0.030

-0.04 -0.11 -0.13 -0.16 -0.15 -0.12 -0.18

0.32 0.21 0.21 0.16 0.26 0.29 0.27

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.062 0.013 0.028 0.010 0.043 0.003 0.078

0.0759 0.0721 0.1066 0.1469 0.0919 0.1208 0.1202

0.085 -0.010 0.030 -0.030 0.050 0.010 0.050

-0.07 -0.06 -0.15 -0.15 -0.12 -0.14 -0.05

0.14 0.17 0.21 0.29 0.17 0.24 0.37

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.000 -0.019 -0.008 0.016 -0.019 -0.034

0.0986 0.1258 0.1349 0.1262 0.1182

0.000 -0.030 0.000 0.030 -0.050 -0.045

0.00 -0.17 -0.25 -0.24 -0.26 -0.17

0.00 0.14 0.21 0.19 0.17 0.12

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 27 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MONOCYTES ABSOLUTE SRT2104 1.0 g 11 Day 84 10 -0.030 0.1116 -0.005 -0.25 0.12 (GI/L) Follow-up 10 -0.001 0.1227 -0.020 -0.14 0.18

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 28 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------NEUTROPHIL, SEGS (%) Placebo 7 Day 14 7 -0.56 5.752 -1.50 -7.6 10.6 Day 28 7 3.23 6.591 1.30 -6.2 12.4 Day 42 7 0.89 5.511 3.00 -7.8 7.2 Day 56 7 2.03 9.439 1.50 -9.9 15.7 Day 70 7 -0.10 4.549 -0.80 -6.0 7.1 Day 84 7 -2.84 10.556 1.20 -25.5 5.6 Follow-up 7 -1.79 4.341 -0.70 -11.0 3.0 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.43 -1.31 0.23 -5.38 0.68 2.38 3.15

5.036 5.654 6.208 9.199 4.363 9.262 7.316

-0.20 -1.40 -0.50 -6.25 -0.40 6.20 1.65

-6.3 -11.5 -8.8 -16.8 -3.4 -9.1 -5.5

10.1 7.0 10.0 8.9 6.3 12.2 16.4

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

1.92 0.75 -1.42 1.17 2.44 0.73 -2.26

4.927 6.081 8.183 7.699 4.849 7.741 7.187

0.40 0.70 -0.50 1.60 -0.20 1.20 -0.20

-5.8 -7.6 -21.4 -10.8 -2.7 -10.6 -18.9

11.1 8.7 11.2 14.9 9.7 11.9 7.7

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-12.50 -2.55 -1.79 0.06 1.33 2.64 0.72

7.708 8.588 7.621 9.778 8.755 9.334

-12.50 -3.80 0.10 1.50 3.90 3.00 2.25

-12.5 -16.0 -17.5 -19.4 -22.6 -15.8 -15.3

-12.5 15.6 9.0 10.1 14.7 14.2 13.9

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 29 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------NEUTROPHIL, SEGS (%) SRT2104 1.0 g 11 Follow-up 10 1.99 8.902 3.45 -20.7 11.2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 30 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------NEUTROPHILS ABSOLUTE Placebo 7 Day 14 7 0.150 0.9535 -0.220 -1.05 1.82 (GI/L) Day 28 7 0.667 0.9744 1.130 -0.87 1.61 Day 42 7 0.427 1.3710 0.290 -1.13 3.17 Day 56 7 0.066 1.0692 0.410 -1.80 1.27 Day 70 7 0.216 0.5329 0.260 -0.48 0.87 Day 84 7 -0.296 1.6288 -0.170 -3.22 2.13 Follow-up 7 0.269 0.5727 0.430 -1.00 0.69 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.083 -0.158 0.037 -0.535 0.260 1.062 0.940

1.1861 1.0102 1.4054 1.4486 1.0579 2.2653 2.1875

0.040 -0.010 0.380 -0.600 0.430 0.830 0.215

-1.77 -1.98 -2.24 -2.41 -1.51 -1.95 -1.52

1.95 1.48 1.81 1.97 1.28 3.94 4.72

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.263 -0.045 0.043 0.248 0.907 0.602 0.193

0.8108 0.8075 0.5367 1.4808 1.8308 3.2004 2.0730

0.500 -0.010 0.240 -0.090 0.310 -0.240 -0.180

-1.13 -1.44 -1.08 -2.04 -0.45 -2.78 -3.71

1.52 1.22 0.64 3.27 5.62 8.75 4.33

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-1.390 -0.424 -0.450 -0.081 0.390 0.281

0.9107 0.5922 1.2788 1.7485 1.0209

-1.390 -0.610 -0.280 -0.520 -0.010 0.395

-1.39 -1.52 -1.66 -1.31 -1.51 -1.57

-1.39 2.01 0.24 3.32 4.06 2.07

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 31 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------NEUTROPHILS ABSOLUTE SRT2104 1.0 g 11 Day 84 10 -0.002 1.3195 -0.035 -1.94 2.78 (GI/L) Follow-up 10 0.363 0.8572 0.225 -1.05 1.79

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 32 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------PLATELET COUNT (GI/L) Placebo 7 Day 14 7 0.3 17.92 5.0 -35 18 Day 28 7 6.0 24.51 9.0 -35 38 Day 42 7 6.3 22.31 -7.0 -14 42 Day 56 7 -3.0 19.24 -4.0 -30 19 Day 70 7 -1.9 19.74 -2.0 -33 27 Day 84 7 -8.9 43.62 -7.0 -87 36 Follow-up 7 14.4 25.44 11.0 -26 54 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.7 5.4 -1.6 -17.2 7.8 -6.2 -1.0

23.49 25.19 22.12 33.57 36.75 30.77 27.10

-6.0 13.0 0.0 -8.5 17.0 -16.0 -0.5

-35 -53 -37 -71 -47 -41 -30

36 27 27 16 48 37 45

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-2.6 1.1 1.0 2.1 -4.2 -6.7 -2.1

15.17 29.66 15.87 25.03 34.55 16.04 37.32

-1.0 -2.0 -4.0 -4.0 -5.0 -11.0 3.0

-23 -43 -16 -35 -51 -23 -75

18 68 31 49 61 25 57

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-18.0 4.2 -10.0 1.9 4.5 9.3 5.5

19.83 32.17 15.62 18.56 35.46 27.66

-18.0 -1.0 -7.0 2.0 1.0 0.5 3.0

-18 -36 -91 -30 -23 -26 -34

-18 31 35 31 41 75 71

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 33 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------PLATELET COUNT (GI/L) SRT2104 1.0 g 11 Follow-up 10 2.9 30.65 0.5 -42 76 PROTHROMBIN TIME (SECONDS)

Placebo

7 Day 42

7

2.21

7.698

-0.40

-2.3

19.5

Day 84

7

-0.37

0.936

0.00

-1.7

0.9

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.03 0.22

0.489 0.319

-0.10 0.30

-0.7 -0.2

0.8 0.6

SRT2104 0.5 g

12 Day 42 Day 84

11 9

-0.16 -0.07

0.827 1.001

0.10 -0.10

-1.8 -1.1

1.1 2.2

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 9 9

0.80 0.32 -0.32

1.743 0.608

0.80 -0.10 -0.40

0.8 -1.8 -1.4

0.8 3.6 0.5

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 34 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------RDW (%) Placebo 7 Day 14 7 -0.04 0.621 0.00 -0.9 0.9 Day 28 7 0.19 0.677 0.20 -0.7 1.1 Day 42 7 0.01 0.590 0.10 -0.9 0.9 Day 56 7 0.01 0.828 0.00 -1.4 0.9 Day 70 7 -0.13 0.682 0.10 -1.4 0.6 Day 84 7 -0.04 0.890 -0.20 -1.1 1.1 Follow-up 7 -0.53 0.647 -0.50 -1.6 0.4 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.12 -0.27 -0.34 -0.20 -0.24 -0.44 -0.38

0.719 0.797 0.922 0.899 1.197 0.971 0.711

0.20 -0.10 -0.40 -0.15 0.00 -0.60 -0.60

-1.3 -2.0 -2.1 -1.7 -2.1 -1.8 -1.2

1.4 0.8 0.7 1.0 1.0 0.8 0.7

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.03 0.15 0.35 0.43 0.51 0.76 0.58

0.196 0.375 0.587 0.577 0.544 0.826 0.850

0.00 0.30 0.30 0.50 0.30 0.80 0.70

-0.2 -0.6 -0.4 -0.5 -0.1 -0.5 -0.5

0.4 0.6 1.4 1.2 1.6 2.3 1.9

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-0.20 0.22 0.16 0.31 0.17 -0.18 0.16

0.646 0.537 0.575 0.488 0.811 0.814

-0.20 0.30 0.10 0.40 0.30 0.10 0.20

-0.2 -0.8 -0.9 -0.7 -0.7 -1.7 -1.0

-0.2 1.4 1.1 1.1 0.7 0.8 1.5

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 35 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------RDW (%) SRT2104 1.0 g 11 Follow-up 10 -0.64 0.642 -0.65 -2.1 0.2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 36 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------RED CELL COUNT (TI/L) Placebo 7 Day 14 7 -0.09 0.186 -0.10 -0.4 0.2 Day 28 7 -0.03 0.189 0.00 -0.2 0.3 Day 42 7 0.00 0.191 0.00 -0.2 0.3 Day 56 7 0.00 0.115 0.00 -0.2 0.1 Day 70 7 0.04 0.237 0.00 -0.2 0.5 Day 84 7 -0.01 0.204 0.10 -0.3 0.2 Follow-up 7 0.04 0.079 0.10 -0.1 0.1 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.03 0.04 0.11 0.03 0.26 0.24 0.20

0.132 0.224 0.248 0.314 0.365 0.434 0.482

0.00 0.00 0.00 0.00 0.10 0.20 0.15

-0.2 -0.3 -0.1 -0.3 0.0 -0.3 -0.3

0.2 0.5 0.6 0.6 0.9 0.9 1.1

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

-0.17 -0.10 -0.17 -0.12 -0.10 -0.17 -0.17

0.130 0.249 0.162 0.233 0.218 0.173 0.255

-0.20 -0.10 -0.20 -0.20 -0.20 -0.20 -0.10

-0.4 -0.4 -0.3 -0.4 -0.4 -0.4 -0.6

0.0 0.4 0.2 0.2 0.3 0.1 0.2

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-0.20 -0.15 -0.09 -0.15 -0.04 -0.12 -0.10

0.175 0.247 0.230 0.191 0.230 0.258

-0.20 -0.20 0.00 -0.10 0.00 -0.10 -0.10

-0.2 -0.4 -0.6 -0.5 -0.4 -0.5 -0.5

-0.2 0.1 0.2 0.1 0.2 0.2 0.3

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 37 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------RED CELL COUNT (TI/L) SRT2104 1.0 g 11 Follow-up 10 -0.12 0.239 -0.10 -0.5 0.2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 38 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------TOTAL NEUTROPHILS (%) Placebo 7 Day 14 7 -0.56 5.752 -1.50 -7.6 10.6 Day 28 7 3.23 6.591 1.30 -6.2 12.4 Day 42 7 0.89 5.511 3.00 -7.8 7.2 Day 56 7 2.03 9.439 1.50 -9.9 15.7 Day 70 7 -0.10 4.549 -0.80 -6.0 7.1 Day 84 7 -2.84 10.556 1.20 -25.5 5.6 Follow-up 7 -1.79 4.341 -0.70 -11.0 3.0 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.43 -1.31 0.23 -5.38 0.68 2.38 3.15

5.036 5.654 6.208 9.199 4.363 9.262 7.316

-0.20 -1.40 -0.50 -6.25 -0.40 6.20 1.65

-6.3 -11.5 -8.8 -16.8 -3.4 -9.1 -5.5

10.1 7.0 10.0 8.9 6.3 12.2 16.4

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

1.92 0.75 -1.42 1.17 2.44 0.73 -2.26

4.927 6.081 8.183 7.699 4.849 7.741 7.187

0.40 0.70 -0.50 1.60 -0.20 1.20 -0.20

-5.8 -7.6 -21.4 -10.8 -2.7 -10.6 -18.9

11.1 8.7 11.2 14.9 9.7 11.9 7.7

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-12.50 -2.55 -1.79 0.06 1.33 2.64 0.72

7.708 8.588 7.621 9.778 8.755 9.334

-12.50 -3.80 0.10 1.50 3.90 3.00 2.25

-12.5 -16.0 -17.5 -19.4 -22.6 -15.8 -15.3

-12.5 15.6 9.0 10.1 14.7 14.2 13.9

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 39 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------TOTAL NEUTROPHILS (%) SRT2104 1.0 g 11 Follow-up 10 1.99 8.902 3.45 -20.7 11.2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 40 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------TOTAL NEUTROPHILS AB Placebo 7 Day 14 7 0.150 0.9535 -0.220 -1.05 1.82 (GI/L) Day 28 7 0.667 0.9744 1.130 -0.87 1.61 Day 42 7 0.427 1.3710 0.290 -1.13 3.17 Day 56 7 0.066 1.0692 0.410 -1.80 1.27 Day 70 7 0.216 0.5329 0.260 -0.48 0.87 Day 84 7 -0.296 1.6288 -0.170 -3.22 2.13 Follow-up 7 0.269 0.5727 0.430 -1.00 0.69 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.083 -0.158 0.037 -0.535 0.260 1.062 0.940

1.1861 1.0102 1.4054 1.4486 1.0579 2.2653 2.1875

0.040 -0.010 0.380 -0.600 0.430 0.830 0.215

-1.77 -1.98 -2.24 -2.41 -1.51 -1.95 -1.52

1.95 1.48 1.81 1.97 1.28 3.94 4.72

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.263 -0.045 0.043 0.248 0.907 0.602 0.193

0.8108 0.8075 0.5367 1.4808 1.8308 3.2004 2.0730

0.500 -0.010 0.240 -0.090 0.310 -0.240 -0.180

-1.13 -1.44 -1.08 -2.04 -0.45 -2.78 -3.71

1.52 1.22 0.64 3.27 5.62 8.75 4.33

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-1.390 -0.424 -0.450 -0.081 0.390 0.281

0.9107 0.5922 1.2788 1.7485 1.0209

-1.390 -0.610 -0.280 -0.520 -0.010 0.395

-1.39 -1.52 -1.66 -1.31 -1.51 -1.57

-1.39 2.01 0.24 3.32 4.06 2.07

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 41 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------TOTAL NEUTROPHILS AB SRT2104 1.0 g 11 Day 84 10 -0.002 1.3195 -0.035 -1.94 2.78 (GI/L) Follow-up 10 0.363 0.8572 0.225 -1.05 1.79

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 42 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------WHITE CELL COUNT Placebo 7 Day 14 7 0.36 1.130 -0.20 -0.7 2.5 (GI/L) Day 28 7 0.79 1.185 0.60 -1.0 2.3 Day 42 7 0.59 1.600 0.20 -0.8 4.0 Day 56 7 0.01 1.045 -0.10 -1.5 1.7 Day 70 7 0.43 0.736 0.10 -0.4 1.5 Day 84 7 -0.14 1.697 -0.10 -2.2 3.0 Follow-up 7 0.67 0.457 0.60 -0.2 1.2 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.09 -0.10 0.11 -0.27 0.40 1.22 1.02

1.324 1.430 1.752 1.571 1.525 2.495 2.605

0.10 0.30 0.80 -0.35 0.30 0.50 0.10

-1.9 -2.4 -2.4 -2.3 -1.8 -1.9 -1.6

1.9 1.6 2.5 2.1 2.4 4.6 5.0

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 11 9 9 9 9

0.34 0.01 0.20 0.34 1.07 0.67 0.60

1.100 0.936 0.550 1.671 2.046 3.438 2.338

0.40 0.20 0.30 -0.10 0.60 -0.10 0.00

-1.7 -1.2 -0.4 -1.3 -0.7 -2.4 -2.8

2.2 1.6 0.9 4.0 6.2 9.5 5.9

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-0.80 -0.53 -0.64 -0.25 0.22 0.01

0.782 0.818 1.619 1.904 1.169

-0.80 -0.60 -0.50 -0.60 -0.40 0.20

-0.8 -2.0 -1.9 -2.2 -1.7 -2.3

-0.8 0.7 0.6 3.9 4.3 1.7

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 43 of 43 Clinical Study Report SRT-2104-013

Table 14.3.3.3 Summary of Change from Baseline for Hematology and Coagulation Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------WHITE CELL COUNT SRT2104 1.0 g 11 Day 84 10 -0.24 1.500 -0.25 -2.7 2.7 (GI/L) Follow-up 10 0.18 0.964 -0.15 -0.9 2.0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.3.3.4 Listing of Hematology and Coagulation Abnormalities of Potential Clinical Importance Safety Analysis Set Population Treatment: SRT2104 0.5 g Age(y)/ Sex/ Lab Test Subj. Race (Units)

Planned Visit

Date/ Time

Study Day

Value

Normal Range

Flag[1] PCI BL

NR

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

[1] NR for Normal Range flag, PCI for Potential Clinical Importance flag, BL for Change from Baseline flag. H=Above range, L=Below range.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 50 Clinical Study Report SRT-2104-013

Table 14.3.3.5 Listing of All Hematology and Coagulation Data for Subjects with Abnormalities of Potential Clinical Importance Safety Analysis Set Population Treatment: SRT2104 0.5 g Age(y)/ Sex/ Lab Test Subj. Race (Units)

Planned Visit

Date/ Time

Study Day

Value

Normal Range

Flag[1] PCI BL

NR

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

[1] NR for Normal Range flag, PCI for Potential Clinical Importance flag, BL for Change from Baseline flag. H=Above range, L=Below range.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALAT (SGPT) Placebo 7 Screening 7 27.6 12.07 26.0 13 48 (U/L) Day 1 7 32.7 14.43 28.0 18 58 Day 14 7 27.0 10.39 25.0 17 45 Day 28 7 25.4 7.41 27.0 15 38 Day 42 7 23.9 7.40 21.0 17 37 Day 56 7 24.3 6.70 25.0 14 36 Day 70 7 29.7 12.55 29.0 16 53 Day 84 7 25.0 12.26 22.0 12 48 Follow-up 7 23.4 6.75 25.0 15 35 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

20.2 18.4 18.8 18.7 20.9 22.5 21.8 22.4 21.0

8.44 6.50 6.91 8.31 10.62 6.80 7.76 7.20 7.07

19.0 17.0 18.0 20.0 19.0 21.5 23.5 24.0 18.0

9 9 8 8 8 15 12 13 15

35 30 29 36 36 35 28 29 32

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

24.8 23.7 24.0 30.9 45.0 23.6 33.0 26.0 25.4

11.77 9.75 9.74 34.13 71.54 8.71 20.29 12.88 9.12

24.5 23.0 22.0 22.0 22.5 22.0 24.0 25.0 24.0

10 13 8 16 13 14 14 9 12

51 47 43 133 247 42 76 56 40

SRT2104 1.0 g

11

Screening

11

26.7

15.76

22.0

5

57

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALAT (SGPT) SRT2104 1.0 g 11 Day 1 11 28.0 19.03 22.0 4 70 (U/L) Day 14 11 25.3 12.88 25.0 4 44 Day 28 11 31.5 16.24 38.0 4 58 Day 42 11 36.6 28.48 35.0 4 110 Day 56 11 36.1 22.94 38.0 5 85 Day 70 10 54.0 72.24 29.5 5 250 Day 84 10 37.8 24.05 39.5 7 87 Follow-up 10 35.2 22.94 34.5 6 73

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALBUMIN (G/L) Placebo 7 Screening 7 46.3 2.81 45.0 43 51 Day 1 7 45.3 2.93 47.0 41 49 Day 14 7 44.4 2.88 45.0 42 50 Day 28 7 44.7 2.98 45.0 41 49 Day 42 7 44.7 3.35 45.0 40 50 Day 56 7 44.4 2.37 46.0 41 46 Day 70 7 44.3 2.93 44.0 41 49 Day 84 7 44.1 2.34 45.0 41 47 Follow-up 7 45.1 3.24 44.0 41 50 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

42.7 41.1 41.3 41.7 42.3 41.3 41.5 42.0 43.0

2.29 2.67 2.40 2.18 2.29 2.34 3.32 1.41 1.87

42.0 41.0 40.0 41.0 42.0 41.5 40.5 43.0 44.0

41 38 40 39 40 38 39 40 41

48 46 47 45 47 45 46 43 45

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

44.8 44.5 43.2 43.6 43.1 43.8 44.9 43.9 43.9

1.71 2.38 2.59 3.38 2.28 1.56 1.46 1.69 3.14

45.0 45.0 43.5 44.0 43.5 44.0 45.0 44.0 45.0

41 40 37 35 38 41 43 42 37

47 48 48 49 46 46 47 47 47

SRT2104 1.0 g

11

Screening Day 1

11 11

46.5 44.7

4.46 3.93

47.0 45.0

40 39

55 51

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALBUMIN (G/L) SRT2104 1.0 g 11 Day 14 11 43.5 2.94 43.0 39 49 Day 28 11 44.2 3.12 45.0 37 48 Day 42 11 44.4 2.80 45.0 39 47 Day 56 11 45.6 3.91 46.0 39 52 Day 70 10 44.2 2.94 44.5 40 50 Day 84 10 45.5 4.01 45.5 39 51 Follow-up 10 43.8 3.52 45.0 39 48

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALKALINE Placebo 7 Screening 7 86.6 22.95 78.0 63 116 PHOSPHATASE (U/L) Day 1 7 89.4 23.25 83.0 65 121 Day 14 7 85.9 20.84 82.0 64 112 Day 28 7 88.1 20.51 78.0 68 116 Day 42 7 87.3 21.84 81.0 66 116 Day 56 7 85.9 21.63 78.0 63 112 Day 70 7 87.6 20.37 79.0 66 119 Day 84 7 81.7 20.30 81.0 60 105 Follow-up 7 83.4 20.27 90.0 57 108 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

74.4 70.6 70.1 69.4 69.6 65.7 60.3 65.4 64.4

14.21 14.95 16.69 15.40 13.58 12.63 8.66 13.13 13.03

74.0 73.0 71.0 71.0 68.0 66.0 60.5 67.0 66.0

57 51 50 46 52 48 50 51 51

100 96 96 91 87 83 70 85 83

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

86.5 85.5 85.3 93.5 94.9 79.0 77.0 74.3 75.6

13.93 21.35 23.12 24.09 41.91 18.16 20.44 17.28 16.66

87.5 86.0 79.5 91.0 82.5 80.0 74.0 76.0 79.0

60 58 57 49 56 49 52 45 52

105 129 136 135 201 100 111 107 103

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ALKALINE SRT2104 1.0 g 11 Screening 11 80.1 12.18 80.0 52 97 PHOSPHATASE (U/L) Day 1 11 76.5 11.43 77.0 57 94 Day 14 11 73.5 13.43 74.0 44 94 Day 28 11 74.0 16.79 77.0 46 109 Day 42 11 73.4 16.07 73.0 48 111 Day 56 11 75.5 16.79 78.0 47 109 Day 70 10 73.4 15.24 76.0 47 104 Day 84 10 78.3 23.95 77.0 51 140 Follow-up 10 73.8 11.61 76.0 52 87

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------AMYLASE, SERUM Placebo 7 Screening 7 42.3 15.98 45.0 20 65 (U/L) Day 1 7 44.4 18.37 49.0 22 71 Day 14 7 44.4 14.99 47.0 25 61 Day 28 7 43.1 20.48 38.0 20 75 Day 42 7 44.0 16.52 44.0 22 67 Day 56 7 42.4 16.20 44.0 19 62 Day 70 7 43.0 17.28 51.0 19 62 Day 84 7 41.9 15.87 45.0 22 68 Follow-up 7 43.4 16.66 51.0 21 61 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

46.6 47.4 47.7 47.7 47.7 42.2 47.2 48.4 48.5

17.56 16.86 14.87 16.61 16.49 11.39 22.13 16.47 15.98

41.0 41.0 50.0 47.0 55.0 41.5 36.0 47.0 50.5

28 27 28 26 25 29 29 25 24

78 83 70 74 70 57 80 66 67

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

48.8 47.4 47.3 49.7 49.5 47.3 48.6 48.1 47.4

14.52 19.61 22.72 18.86 25.47 16.34 16.21 17.70 20.37

48.0 42.0 41.5 53.0 42.5 48.0 50.0 43.0 44.0

25 29 29 24 26 27 28 26 28

74 90 111 75 112 80 71 76 81

SRT2104 1.0 g

11

Screening

11

46.6

25.40

41.0

27

120

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------AMYLASE, SERUM SRT2104 1.0 g 11 Day 1 11 44.4 18.41 42.0 25 93 (U/L) Day 14 11 41.7 15.03 40.0 23 73 Day 28 11 37.5 10.41 37.0 24 59 Day 42 11 38.3 9.05 38.0 25 53 Day 56 11 40.7 10.91 45.0 24 57 Day 70 10 41.8 13.97 39.5 23 64 Day 84 10 35.9 10.05 34.5 25 52 Follow-up 10 42.4 10.59 43.0 27 65

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ASAT (SGOT) Placebo 7 Screening 7 26.6 6.85 25.0 19 37 (U/L) Day 1 7 30.7 9.09 27.0 19 46 Day 14 7 32.7 27.49 22.0 17 94 Day 28 7 26.1 5.90 26.0 16 35 Day 42 7 24.0 5.54 24.0 17 31 Day 56 7 26.7 8.14 25.0 16 38 Day 70 7 27.6 7.25 28.0 17 37 Day 84 7 24.6 16.70 19.0 10 60 Follow-up 7 22.6 4.96 22.0 16 31 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

20.2 18.7 18.8 19.0 20.6 23.3 21.3 21.4 21.2

6.69 4.97 5.29 6.02 5.56 5.47 1.26 2.30 5.59

19.0 18.0 18.0 18.0 23.0 22.5 21.0 21.0 19.0

10 9 12 11 10 17 20 19 16

33 26 30 33 27 32 23 25 29

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

25.0 21.9 24.9 27.6 32.9 23.9 28.0 24.9 23.4

8.72 4.53 8.28 17.22 33.23 3.62 9.93 6.83 5.15

25.0 22.0 23.0 22.0 22.0 24.0 27.0 22.0 23.0

14 17 17 19 16 18 20 15 17

45 33 48 79 126 28 49 36 33

SRT2104 1.0 g

11

Screening

11

27.6

15.25

22.0

15

59

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------ASAT (SGOT) SRT2104 1.0 g 11 Day 1 11 25.5 10.93 23.0 14 53 (U/L) Day 14 11 23.3 6.33 21.0 16 36 Day 28 10 31.6 20.41 21.5 15 81 Day 42 11 29.8 18.02 21.0 16 76 Day 56 11 29.8 13.30 24.0 15 56 Day 70 10 37.1 30.73 21.0 15 110 Day 84 10 36.6 25.25 25.0 14 80 Follow-up 10 27.4 19.00 23.0 13 79

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, Placebo 7 Screening 7 2.0 0.00 2.0 2 2 DIRECT (UMOL/L) Day 1 7 2.0 0.00 2.0 2 2 Day 14 7 1.7 0.76 2.0 0 2 Day 28 7 2.0 0.00 2.0 2 2 Day 42 7 2.0 1.15 2.0 0 4 Day 56 7 2.0 0.00 2.0 2 2 Day 70 7 1.7 0.76 2.0 0 2 Day 84 7 2.0 0.00 2.0 2 2 Follow-up 7 1.7 0.76 2.0 0 2 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

1.6 2.2 2.2 2.7 2.3 2.3 2.5 2.8 2.8

1.33 0.67 1.20 1.41 0.76 1.51 1.00 2.28 1.79

2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0

0 2 0 2 2 0 2 0 2

4 4 4 6 4 4 4 6 6

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

2.5 2.5 3.2 2.7 3.2 2.7 2.6 2.7 2.3

0.90 1.29 1.80 1.01 1.69 1.00 0.98 1.00 0.71

2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0

2 2 2 2 2 2 2 2 2

4 6 6 4 6 4 4 4 4

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, SRT2104 1.0 g 11 Screening 11 2.4 1.50 2.0 0 6 DIRECT (UMOL/L) Day 1 11 2.4 0.81 2.0 2 4 Day 14 11 3.1 2.07 2.0 0 6 Day 28 11 3.3 1.62 2.0 2 6 Day 42 11 2.9 1.87 2.0 0 6 Day 56 11 3.1 2.07 2.0 0 6 Day 70 10 3.4 2.12 2.0 2 8 Day 84 10 2.8 1.40 2.0 2 6 Follow-up 10 2.6 0.97 2.0 2 4

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, Placebo 7 Screening 7 4.3 0.76 4.0 4 6 INDIRECT (UMOL/L) Day 1 7 5.4 1.51 6.0 4 8 Day 14 7 4.6 0.98 4.0 4 6 Day 28 7 4.9 1.07 4.0 4 6 Day 42 7 4.9 1.07 4.0 4 6 Day 56 7 6.3 1.80 6.0 4 8 Day 70 7 6.0 1.15 6.0 4 8 Day 84 7 6.3 2.93 6.0 4 12 Follow-up 7 4.9 1.07 4.0 4 6 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

6.2 7.3 7.8 7.6 7.7 7.0 10.5 9.6 9.2

3.07 3.46 6.44 4.10 3.55 3.74 5.97 4.34 5.22

6.0 6.0 6.0 6.0 6.0 6.0 12.0 8.0 8.0

4 4 4 4 4 4 2 6 4

14 14 24 14 12 14 16 16 18

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

6.7 7.5 9.5 7.6 7.8 9.6 7.4 8.7 4.5

3.34 2.54 4.91 3.88 2.74 3.13 1.51 2.24 1.77

6.0 8.0 8.0 6.0 6.0 10.0 8.0 8.0 4.0

4 4 6 4 6 6 4 4 2

16 12 22 14 14 14 8 12 8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, SRT2104 1.0 g 11 Screening 11 9.3 6.08 6.0 4 24 INDIRECT (UMOL/L) Day 1 11 7.1 3.27 8.0 4 12 Day 14 11 10.7 7.55 8.0 4 24 Day 28 11 9.6 5.64 8.0 4 20 Day 42 11 10.7 7.06 8.0 4 26 Day 56 11 10.4 6.38 8.0 4 22 Day 70 10 10.8 10.38 6.0 4 30 Day 84 10 9.2 5.98 7.0 4 24 Follow-up 10 6.8 4.13 5.0 4 16

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, Placebo 7 Screening 7 6.3 0.76 6.0 6 8 TOTAL (UMOL/L) Day 1 7 7.4 1.51 8.0 6 10 Day 14 7 6.3 0.76 6.0 6 8 Day 28 7 6.9 1.07 6.0 6 8 Day 42 7 6.9 1.07 6.0 6 8 Day 56 7 8.3 1.80 8.0 6 10 Day 70 7 7.7 1.38 8.0 6 10 Day 84 7 8.3 2.93 8.0 6 14 Follow-up 7 6.6 0.98 6.0 6 8 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

7.8 9.6 10.0 10.2 10.0 9.3 13.0 12.4 12.0

4.06 3.71 7.21 5.33 4.00 4.84 6.22 6.23 6.93

6.0 8.0 6.0 8.0 8.0 9.0 15.0 10.0 10.0

4 6 6 6 6 4 4 6 6

18 16 28 20 16 18 18 20 24

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

9.2 10.0 12.7 10.4 11.0 12.2 10.0 11.3 6.8

3.46 2.83 5.74 4.54 4.03 3.67 2.00 3.00 1.49

8.0 10.0 11.0 8.0 9.0 12.0 10.0 10.0 6.0

6 6 8 6 8 8 6 6 6

18 14 28 18 18 18 12 16 10

SRT2104 1.0 g

11

Screening

11

11.6

7.37

8.0

6

30

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------BILIRUBIN, SRT2104 1.0 g 11 Day 1 11 9.5 3.70 10.0 6 16 TOTAL (UMOL/L) Day 14 11 13.8 9.44 10.0 6 30 Day 28 11 12.9 7.06 10.0 6 26 Day 42 11 13.6 8.62 12.0 6 32 Day 56 11 13.5 8.15 10.0 6 28 Day 70 10 14.2 12.35 9.0 6 38 Day 84 10 12.0 7.06 10.0 6 30 Follow-up 10 9.4 4.90 7.0 6 20

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CALCIUM Placebo 7 Screening 7 2.386 0.0619 2.400 2.32 2.48 (MMOL/L) Day 1 7 2.386 0.1031 2.400 2.22 2.50 Day 14 7 2.346 0.0877 2.320 2.22 2.44 Day 28 7 2.371 0.0944 2.400 2.18 2.48 Day 42 7 2.337 0.1036 2.320 2.20 2.50 Day 56 7 2.371 0.0527 2.380 2.30 2.44 Day 70 7 2.360 0.0566 2.380 2.28 2.44 Day 84 7 2.331 0.0691 2.340 2.20 2.42 Follow-up 7 2.357 0.0761 2.320 2.28 2.50 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

2.324 2.298 2.313 2.324 2.326 2.320 2.310 2.316 2.336

0.0915 0.0777 0.0686 0.0691 0.0597 0.0716 0.0775 0.0740 0.0297

2.320 2.300 2.340 2.300 2.300 2.320 2.290 2.300 2.340

2.18 2.14 2.22 2.28 2.28 2.20 2.24 2.24 2.30

2.44 2.40 2.42 2.50 2.42 2.40 2.42 2.44 2.38

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

2.385 2.356 2.357 2.349 2.344 2.356 2.354 2.318 2.363

0.0823 0.0731 0.0590 0.0961 0.0815 0.0726 0.0670 0.0821 0.1118

2.400 2.340 2.380 2.320 2.330 2.320 2.380 2.280 2.380

2.24 2.22 2.22 2.22 2.20 2.28 2.28 2.20 2.18

2.50 2.48 2.42 2.50 2.50 2.44 2.44 2.44 2.54

SRT2104 1.0 g

11

Screening

11

2.427

0.1063

2.420

2.20

2.56

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CALCIUM SRT2104 1.0 g 11 Day 1 11 2.384 0.1245 2.400 2.18 2.60 (MMOL/L) Day 14 11 2.335 0.1062 2.340 2.10 2.54 Day 28 10 2.356 0.1091 2.330 2.20 2.52 Day 42 11 2.338 0.1157 2.320 2.14 2.52 Day 56 11 2.404 0.1203 2.400 2.18 2.60 Day 70 10 2.364 0.1169 2.320 2.18 2.60 Day 84 10 2.366 0.1350 2.370 2.12 2.60 Follow-up 10 2.382 0.0835 2.390 2.28 2.56

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 19 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CHLORIDE Placebo 7 Screening 7 102.1 1.57 102.0 100 104 (MMOL/L) Day 1 7 103.0 2.00 103.0 100 106 Day 14 7 104.1 2.04 104.0 101 107 Day 28 7 103.4 2.99 103.0 99 107 Day 42 7 103.1 2.73 104.0 100 106 Day 56 7 103.1 2.27 103.0 100 106 Day 70 7 102.4 2.44 103.0 99 105 Day 84 7 103.1 3.89 102.0 100 111 Follow-up 7 103.0 2.38 103.0 99 106 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

105.0 105.0 104.8 105.1 105.3 103.8 105.0 103.4 104.2

1.50 2.18 2.68 2.26 2.75 1.94 0.82 1.14 1.92

105.0 106.0 104.0 106.0 105.0 103.5 105.0 103.0 104.0

103 101 101 102 103 101 104 102 102

107 108 109 108 111 106 106 105 107

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

102.9 104.2 103.3 103.0 103.0 104.1 103.7 102.9 104.4

2.57 2.86 2.64 2.32 3.06 2.09 2.06 1.27 2.13

103.0 105.0 103.5 103.0 104.0 105.0 104.0 103.0 104.5

98 100 99 98 98 100 100 101 101

106 108 107 106 107 106 106 105 108

SRT2104 1.0 g

11

Screening

11

103.3

2.97

104.0

99

107

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 20 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CHLORIDE SRT2104 1.0 g 11 Day 1 11 103.9 2.55 104.0 100 109 (MMOL/L) Day 14 11 104.8 1.99 105.0 102 109 Day 28 11 105.1 1.97 105.0 103 108 Day 42 11 104.6 2.80 105.0 100 109 Day 56 11 103.1 2.47 103.0 100 107 Day 70 10 104.0 1.83 104.0 101 107 Day 84 10 102.3 3.20 102.0 97 107 Follow-up 10 104.0 2.21 104.0 100 107 CHOLESTEROL, TOTAL (MMOL/L)

Placebo

7

Screening

7

4.836

0.5072

4.550

4.25

5.65

Day 1 Day 42 Day 84

7 7 6

4.964 4.736 4.725

0.9746 1.1006 0.9501

4.800 4.750 4.725

4.15 3.60 3.60

6.95 6.65 6.30

SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

4.178 4.056 3.879 4.360

0.6870 0.5520 0.6473 0.8510

3.900 4.100 4.050 4.250

3.55 3.40 2.75 3.35

5.50 4.95 4.55 5.60

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 11 10 9

4.975 5.059 4.720 4.633

0.7964 0.3448 1.0942 0.5979

4.850 5.150 4.550 4.800

3.55 4.55 3.30 3.80

7.05 5.50 7.30 5.45

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

11 11 11 10

5.673 5.477 4.950 5.305

1.6397 1.2606 1.0684 1.3696

5.600 5.400 4.950 4.950

3.65 4.00 2.95 3.60

9.75 8.35 7.05 7.80

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 21 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CO2 CONTENT Placebo 7 Screening 7 24.6 2.44 25.0 21 28 (MMOL/L) Day 1 7 24.4 3.55 25.0 18 30 Day 14 7 24.1 1.46 24.0 23 27 Day 28 7 25.7 2.43 25.0 22 30 Day 42 7 24.7 2.56 26.0 20 27 Day 56 7 24.7 2.43 24.0 21 28 Day 70 7 24.7 2.50 24.0 22 29 Day 84 7 24.3 3.59 26.0 18 29 Follow-up 7 25.0 1.63 25.0 22 27 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

24.0 23.6 23.1 23.3 23.4 23.7 23.0 23.0 24.0

1.73 1.33 1.45 1.87 1.90 1.37 0.82 2.24 1.41

24.0 24.0 24.0 24.0 23.0 24.0 23.0 23.0 25.0

22 21 21 21 21 22 22 20 22

28 25 25 26 26 25 24 26 25

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

24.1 23.6 23.8 24.0 23.8 23.6 24.0 22.4 24.9

3.00 3.38 3.16 2.83 2.78 2.51 1.53 2.70 1.36

24.0 24.0 24.0 24.0 23.5 23.0 24.0 22.0 25.0

18 19 19 18 20 20 22 19 22

28 28 28 27 28 27 26 26 26

SRT2104 1.0 g

11

Screening

11

22.7

2.28

23.0

19

26

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 22 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CO2 CONTENT SRT2104 1.0 g 11 Day 1 11 22.5 2.73 23.0 18 27 (MMOL/L) Day 14 11 21.7 1.56 22.0 19 24 Day 28 10 22.6 2.17 23.0 19 26 Day 42 11 22.5 1.29 23.0 20 24 Day 56 11 21.1 2.74 22.0 16 25 Day 70 10 23.4 2.88 24.0 17 27 Day 84 10 21.4 2.63 20.5 18 25 Follow-up 10 22.2 2.39 23.0 18 25

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 23 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CPK, TOTAL Placebo 7 Screening 7 209.3 179.37 114.0 60 509 (U/L) Day 1 7 235.0 207.82 132.0 62 631 Day 14 7 609.1 1248.10 111.0 70 3431 Day 28 7 204.4 157.00 116.0 79 442 Day 42 7 175.4 122.06 118.0 57 378 Day 56 7 254.0 249.37 135.0 89 771 Day 70 7 183.4 145.76 111.0 67 432 Day 84 7 365.1 554.18 113.0 67 1579 Follow-up 7 157.7 94.17 129.0 62 342 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

157.0 135.8 162.4 196.4 114.6 277.3 146.0 177.4 125.0

136.05 130.45 207.69 249.03 85.72 311.15 89.40 119.33 139.08

68.0 68.0 77.0 75.0 90.0 147.0 109.0 142.0 79.0

43 34 39 39 52 47 88 67 33

450 375 685 721 290 859 278 367 371

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

206.1 112.4 245.0 132.8 136.3 165.0 155.1 209.0 145.9

271.99 55.11 405.81 99.79 68.95 120.88 62.60 223.85 63.78

133.5 125.0 129.0 98.0 130.0 116.0 157.0 145.0 144.0

33 49 38 41 54 36 41 40 52

1038 229 1512 385 259 444 213 791 256

SRT2104 1.0 g

11

Screening

11

131.0

125.83

97.0

60

506

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 24 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CPK, TOTAL SRT2104 1.0 g 11 Day 1 11 119.7 71.52 95.0 44 302 (U/L) Day 14 11 109.5 100.35 74.0 55 397 Day 28 11 152.4 174.27 81.0 48 541 Day 42 11 115.3 97.06 77.0 63 399 Day 56 11 93.5 44.45 86.0 50 199 Day 70 10 81.2 21.54 81.0 57 125 Day 84 10 107.8 68.29 73.5 46 270 Follow-up 10 93.3 59.14 72.5 51 249

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 25 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CREATININE Placebo 7 Screening 7 79.6 14.29 80.0 53 97 (UMOL/L) Day 1 7 87.1 21.24 88.0 53 115 Day 14 7 85.7 14.91 88.0 62 106 Day 28 7 85.9 13.01 88.0 62 97 Day 42 7 83.4 15.01 80.0 62 106 Day 56 7 84.7 15.83 80.0 62 106 Day 70 7 85.9 14.01 88.0 62 106 Day 84 7 87.1 16.28 97.0 62 106 Follow-up 7 90.9 13.07 88.0 71 106 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

67.9 68.9 69.9 70.8 72.1 68.0 71.0 69.0 72.6

14.68 14.53 12.90 13.84 13.86 10.90 12.73 12.98 13.05

71.0 62.0 71.0 71.0 71.0 66.5 75.5 71.0 71.0

53 53 44 53 53 53 53 53 53

97 97 88 97 97 80 80 88 88

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

79.6 75.5 84.1 83.5 85.9 78.7 74.6 77.7 78.5

12.87 15.85 14.65 17.24 14.86 19.37 13.15 21.02 16.48

80.0 71.0 80.0 88.0 80.0 71.0 71.0 71.0 71.0

62 53 62 62 71 62 62 53 62

97 106 106 106 115 106 97 115 106

SRT2104 1.0 g

11

Screening

11

78.0

18.82

80.0

53

115

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 26 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CREATININE SRT2104 1.0 g 11 Day 1 11 78.1 18.00 71.0 62 124 (UMOL/L) Day 14 11 79.7 13.56 80.0 62 106 Day 28 11 81.3 14.53 80.0 62 106 Day 42 11 81.2 17.05 80.0 53 106 Day 56 11 86.0 17.66 88.0 62 124 Day 70 10 83.3 17.21 80.0 62 124 Day 84 10 78.8 15.74 80.0 53 106 Follow-up 10 77.8 18.95 75.5 44 115

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 27 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------CRP HIGH Placebo 7 Day 1 7 4.31 4.595 3.70 0.2 11.1 SENSITIVITY (MG/L) Day 28 7 4.43 3.734 4.00 0.4 11.5 Day 56 7 4.90 6.412 3.50 0.2 18.7 Day 84 7 4.97 6.730 3.20 0.2 19.2 SRT2104 0.25 g

9

Day Day Day Day

1 28 56 84

9 8 6 5

3.73 4.03 3.55 2.70

2.647 2.507 2.790 2.125

2.70 3.90 2.75 2.30

0.3 1.2 0.2 0.2

8.1 8.4 7.4 5.7

SRT2104 0.5 g

12

Day Day Day Day

1 28 56 84

11 11 8 9

5.06 6.02 2.53 2.59

7.817 8.516 2.543 2.655

2.00 2.60 1.75 1.50

0.2 0.4 0.9 0.4

23.8 27.8 8.6 8.9

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

1 11 10 10 10

8.80 2.75 2.00 2.48 3.21

2.935 2.039 2.948 3.188

8.80 2.20 1.15 1.35 2.10

8.8 0.4 0.3 0.3 0.3

8.8 9.0 6.7 8.3 8.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 28 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------GGT (U/L) Placebo 7 Screening 7 35.9 21.96 31.0 19 83 Day 1 7 36.1 23.69 27.0 18 86 Day 14 7 33.1 20.82 26.0 17 77 Day 28 7 35.3 24.08 27.0 19 88 Day 42 7 33.3 21.84 26.0 17 80 Day 56 7 32.1 18.50 26.0 16 67 Day 70 7 34.9 21.54 32.0 16 81 Day 84 7 32.1 17.66 25.0 18 69 Follow-up 7 33.6 18.08 30.0 18 70 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

33.2 29.8 28.9 30.4 33.1 33.8 30.3 42.6 32.4

17.73 12.23 11.92 19.16 19.27 18.37 11.47 33.62 17.17

28.0 29.0 31.0 26.0 27.0 28.5 32.0 31.0 33.0

17 13 13 12 15 14 15 13 17

76 56 54 78 75 65 42 100 60

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

31.8 31.2 30.5 38.2 38.9 28.3 27.1 29.4 27.8

14.20 16.80 16.90 24.91 29.89 11.83 14.33 12.60 10.01

29.0 26.0 25.0 27.0 26.5 24.0 22.0 26.0 26.0

18 18 15 17 15 16 16 15 15

63 70 73 79 105 51 56 51 47

SRT2104 1.0 g

11

Screening Day 1

11 11

47.2 42.8

45.22 37.96

33.0 31.0

14 13

165 146

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 29 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------GGT (U/L) SRT2104 1.0 g 11 Day 14 11 41.1 32.00 32.0 13 118 Day 28 11 45.5 45.52 30.0 12 169 Day 42 11 47.2 46.94 31.0 11 173 Day 56 11 50.5 44.12 35.0 14 161 Day 70 10 48.9 41.02 41.5 13 142 Day 84 10 43.9 32.26 27.0 15 107 Follow-up 10 35.5 22.74 25.5 14 76

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 30 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------GLUCOSE, Placebo 7 Screening 6 5.32 0.512 5.40 4.7 6.1 PLASMA (MMOL/L) Day 1 7 5.69 0.527 5.80 5.1 6.6 Day 14 6 5.90 0.984 5.40 5.2 7.7 Day 28 7 5.67 0.743 5.80 4.6 6.8 Day 42 7 5.93 0.727 5.70 4.9 7.0 Day 56 7 5.73 0.757 5.60 4.7 7.0 Day 70 7 6.19 1.635 5.70 5.0 9.7 Day 84 7 5.70 0.572 5.80 4.8 6.4 Follow-up 7 5.87 1.745 5.40 4.1 9.5 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 5 5 6

6.46 6.56 6.43 6.49 6.36 6.90 6.08 5.98 6.28

3.064 3.133 2.132 2.040 2.231 2.775 1.747 2.181 1.961

5.10 5.10 5.30 5.30 5.30 5.30 5.50 5.10 5.70

4.4 4.2 4.7 4.8 4.3 4.9 4.7 4.5 4.6

13.4 13.9 9.6 10.3 9.9 11.3 9.0 9.8 10.0

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 12 12 11 10 9 9 9 9

5.41 5.58 6.88 5.65 6.94 6.30 5.81 6.09 6.08

2.359 1.829 2.683 1.371 2.746 3.936 1.433 2.450 1.506

4.85 5.30 5.80 5.20 5.75 5.20 5.30 5.30 5.60

3.4 2.9 4.8 4.6 3.3 4.3 4.7 4.4 3.9

12.6 10.7 14.1 9.1 11.4 16.7 8.4 12.4 8.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 31 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------GLUCOSE, SRT2104 1.0 g 11 Screening 8 5.35 0.411 5.45 4.4 5.7 PLASMA (MMOL/L) Day 1 10 5.11 0.534 5.20 3.9 5.8 Day 14 11 5.90 0.815 5.90 4.1 7.3 Day 28 11 5.26 0.488 5.30 4.3 6.0 Day 42 11 5.72 0.479 5.80 5.1 6.7 Day 56 11 5.37 0.555 5.40 4.5 6.3 Day 70 11 5.82 1.293 5.90 3.3 8.3 Day 84 10 5.54 1.120 5.70 4.1 7.3 Follow-up 10 5.16 0.502 5.30 4.5 6.1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 32 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------HDL CHOL Placebo 7 Screening 7 1.336 0.2462 1.250 1.15 1.85 DIRECT (MMOL/L) Day 1 7 1.336 0.1520 1.250 1.20 1.60 Day 42 7 1.300 0.2533 1.250 1.00 1.80 Day 84 6 1.225 0.2911 1.175 0.90 1.75 SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

1.278 1.278 1.100 1.050

0.3632 0.4063 0.1555 0.1414

1.200 1.200 1.150 1.000

0.90 0.85 0.90 0.90

2.15 2.30 1.30 1.20

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 11 10 9

1.217 1.273 1.080 1.350

0.2987 0.3946 0.2137 0.3631

1.175 1.250 1.100 1.250

0.65 0.80 0.60 0.95

1.90 2.35 1.30 2.05

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

11 11 11 10

1.445 1.355 1.427 1.435

0.7894 0.5841 0.6178 0.7028

1.200 1.150 1.250 1.175

0.60 0.70 0.80 0.85

3.25 2.55 2.90 3.15

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 33 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------LACTIC Placebo 7 Screening 7 171.9 22.53 178.0 125 188 DEHYDROGENASE (U/L) Day 1 7 177.4 16.17 181.0 146 192 Day 14 7 183.7 43.49 172.0 117 259 Day 28 7 181.1 25.91 178.0 145 218 Day 42 7 170.6 29.00 170.0 120 205 Day 56 7 176.7 24.95 186.0 129 198 Day 70 7 167.9 18.43 172.0 132 187 Day 84 7 163.9 20.64 169.0 140 189 Follow-up 7 161.4 20.48 166.0 122 186 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

142.7 135.1 136.7 138.3 148.4 148.8 142.0 145.6 133.8

36.35 27.51 23.33 29.94 19.05 28.33 22.32 28.58 32.08

139.0 140.0 133.0 135.0 149.0 143.5 143.0 151.0 120.0

109 92 102 92 116 117 114 103 103

228 166 180 198 180 201 168 182 182

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

165.7 157.9 166.3 169.5 164.7 159.6 167.0 171.2 164.8

23.52 20.52 43.81 45.07 54.22 19.52 14.64 30.83 18.09

169.5 156.0 156.5 159.0 154.5 162.0 173.0 161.0 165.5

124 133 100 127 111 135 141 137 135

200 205 266 285 309 196 183 225 186

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 34 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------LACTIC SRT2104 1.0 g 11 Screening 11 175.8 34.51 161.0 133 236 DEHYDROGENASE (U/L) Day 1 11 171.9 29.58 169.0 125 222 Day 14 11 163.3 36.07 150.0 113 219 Day 28 10 182.4 42.40 168.0 139 262 Day 42 11 167.8 34.32 150.0 120 216 Day 56 11 170.1 31.61 162.0 121 221 Day 70 10 170.5 51.16 149.5 124 299 Day 84 10 170.0 33.99 171.5 117 234 Follow-up 10 156.9 33.69 149.5 114 223

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 35 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------LDL-CHOL Placebo 7 Screening 7 2.856 0.5708 2.690 2.02 3.71 CALCULATION (MMOL/L) Day 1 7 2.956 0.9207 2.620 1.91 4.78 Day 42 7 2.797 1.0295 2.700 1.78 4.59 Day 84 6 2.705 0.9382 2.780 1.70 4.28 SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

2.032 2.068 1.993 2.342

0.6399 0.6325 0.6562 0.5705

2.190 2.050 2.190 2.260

0.92 0.94 0.58 1.71

2.88 2.94 2.60 3.10

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 11 10 9

2.933 3.078 2.739 2.680

0.8097 0.4504 0.9533 0.5270

2.805 3.230 2.765 2.460

1.97 2.38 1.27 2.16

5.19 3.55 4.65 3.55

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

8 9 11 7

2.878 2.948 2.705 2.490

0.7785 0.7826 0.8406 0.8006

3.015 3.060 2.690 2.710

1.86 1.90 1.24 1.00

3.82 4.09 3.76 3.39

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 36 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------MAGNESIUM Placebo 7 Screening 7 0.834 0.0608 0.860 0.76 0.90 (MMOL/L) Day 1 7 0.857 0.1219 0.860 0.70 1.06 Day 14 7 0.863 0.1230 0.860 0.70 1.06 Day 28 7 0.874 0.1295 0.900 0.70 1.06 Day 42 7 0.849 0.0965 0.800 0.76 1.00 Day 56 7 0.854 0.1170 0.860 0.70 1.00 Day 70 7 0.817 0.1104 0.800 0.70 1.00 Day 84 7 0.826 0.0755 0.800 0.76 0.96 Follow-up 7 0.826 0.0755 0.860 0.70 0.90 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

0.773 0.747 0.744 0.760 0.743 0.747 0.790 0.776 0.812

0.0539 0.0787 0.0477 0.0707 0.0787 0.0745 0.0663 0.0219 0.0522

0.760 0.760 0.760 0.760 0.760 0.730 0.800 0.760 0.800

0.66 0.60 0.66 0.66 0.60 0.66 0.70 0.76 0.76

0.86 0.86 0.80 0.90 0.86 0.86 0.86 0.80 0.90

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

0.860 0.838 0.830 0.849 0.840 0.851 0.851 0.831 0.853

0.0603 0.0642 0.0562 0.0547 0.0699 0.0593 0.0620 0.0633 0.0465

0.860 0.860 0.830 0.860 0.800 0.860 0.860 0.800 0.860

0.76 0.76 0.76 0.80 0.76 0.76 0.76 0.76 0.80

0.96 0.90 0.90 0.96 0.96 0.96 0.96 0.96 0.90

SRT2104 1.0 g

11

Screening

11

0.880

0.0815

0.860

0.70

0.96

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 37 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------MAGNESIUM SRT2104 1.0 g 11 Day 1 11 0.845 0.0795 0.860 0.70 1.00 (MMOL/L) Day 14 11 0.847 0.0553 0.860 0.76 0.96 Day 28 11 0.853 0.0634 0.860 0.76 0.96 Day 42 11 0.845 0.0688 0.860 0.70 0.96 Day 56 11 0.833 0.0859 0.860 0.66 0.96 Day 70 10 0.850 0.0675 0.860 0.76 0.96 Day 84 10 0.842 0.0553 0.830 0.76 0.90 Follow-up 10 0.864 0.0610 0.860 0.80 1.00 NEFA (MMOL/L)

Placebo

7

Screening Day 1 Day 42 Day 84

7 7 6 6

0.479 0.486 0.458 0.585

0.2196 0.2529 0.3226 0.3740

0.440 0.400 0.400 0.400

0.20 0.19 0.17 0.30

0.72 0.84 1.01 1.21

SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

0.333 0.412 0.409 0.490

0.1707 0.1977 0.1570 0.1402

0.300 0.380 0.390 0.470

0.12 0.12 0.22 0.35

0.61 0.77 0.62 0.68

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 9 11 4

0.473 0.341 0.365 0.305

0.2592 0.1765 0.2260 0.0968

0.450 0.350 0.320 0.305

0.09 0.12 0.05 0.20

1.00 0.68 0.78 0.41

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

11 9 9 10

0.605 0.468 0.243 0.650

0.3328 0.1966 0.1412 0.5126

0.480 0.430 0.230 0.440

0.21 0.24 0.08 0.26

1.31 0.93 0.49 1.76

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 38 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------PHOSPHORUS Placebo 7 Screening 7 1.107 0.1239 1.050 0.95 1.25 INORGANIC (MMOL/L) Day 1 7 1.071 0.1524 1.150 0.85 1.20 Day 14 7 1.079 0.1868 1.100 0.75 1.30 Day 28 7 1.086 0.2528 1.200 0.55 1.25 Day 42 7 0.993 0.2405 1.050 0.60 1.30 Day 56 7 1.136 0.1651 1.050 0.90 1.35 Day 70 7 1.121 0.1113 1.150 0.95 1.25 Day 84 7 1.043 0.1813 1.100 0.70 1.25 Follow-up 7 1.214 0.1887 1.200 0.95 1.45 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

1.267 1.139 1.189 1.128 1.229 1.217 1.125 1.220 1.170

0.2305 0.1596 0.1244 0.1003 0.1318 0.1402 0.0500 0.1857 0.1718

1.200 1.150 1.150 1.150 1.250 1.250 1.150 1.150 1.250

1.00 0.90 1.05 0.95 1.05 1.05 1.05 1.10 0.90

1.70 1.30 1.35 1.25 1.45 1.40 1.15 1.55 1.30

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

1.138 1.123 1.150 1.095 1.100 1.094 1.157 1.106 1.225

0.1170 0.1232 0.1595 0.1739 0.1269 0.1044 0.2009 0.1467 0.2550

1.125 1.100 1.150 1.050 1.075 1.150 1.200 1.150 1.300

0.95 0.95 0.80 0.75 0.95 0.95 0.85 0.85 0.85

1.30 1.30 1.35 1.30 1.35 1.25 1.45 1.30 1.60

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 39 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------PHOSPHORUS SRT2104 1.0 g 11 Screening 11 1.091 0.1656 1.100 0.85 1.40 INORGANIC (MMOL/L) Day 1 11 1.145 0.1557 1.150 0.95 1.40 Day 14 11 1.041 0.1772 1.050 0.70 1.35 Day 28 11 1.082 0.1168 1.050 0.90 1.25 Day 42 11 1.027 0.1191 0.950 0.90 1.30 Day 56 11 1.082 0.1585 1.100 0.85 1.40 Day 70 10 1.085 0.2015 1.050 0.80 1.55 Day 84 10 1.075 0.1875 1.050 0.80 1.40 Follow-up 10 1.020 0.1751 1.050 0.60 1.30

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 40 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------POTASSIUM Placebo 7 Screening 7 4.47 0.464 4.60 3.9 5.2 (MMOL/L) Day 1 7 4.43 0.269 4.40 4.0 4.8 Day 14 7 4.56 0.447 4.60 4.0 5.2 Day 28 7 4.83 0.439 4.90 4.3 5.6 Day 42 7 4.74 0.395 4.80 4.0 5.3 Day 56 7 4.64 0.374 4.60 4.2 5.2 Day 70 7 4.44 0.516 4.40 3.6 5.2 Day 84 7 4.40 0.351 4.40 4.0 5.0 Follow-up 7 4.47 0.571 4.40 3.6 5.4 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

4.41 4.49 4.46 4.42 4.53 4.43 4.53 4.54 4.78

0.382 0.382 0.480 0.319 0.368 0.356 0.419 0.329 0.512

4.30 4.40 4.50 4.50 4.40 4.35 4.70 4.70 4.80

3.8 4.1 3.7 3.8 4.2 4.1 3.9 4.1 4.0

5.1 5.3 5.2 4.9 5.2 4.9 4.8 4.9 5.4

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

4.31 4.37 4.37 4.55 4.43 4.44 4.54 4.31 4.59

0.334 0.300 0.429 0.378 0.452 0.433 0.522 0.326 0.461

4.20 4.20 4.30 4.50 4.40 4.60 4.30 4.20 4.45

3.8 4.1 3.9 4.0 3.8 3.8 4.0 3.7 4.0

5.1 4.9 5.0 5.4 5.0 5.0 5.4 4.8 5.3

SRT2104 1.0 g

11

Screening

11

4.22

0.354

4.10

3.7

4.8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 41 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------POTASSIUM SRT2104 1.0 g 11 Day 1 11 4.38 0.279 4.30 4.1 4.9 (MMOL/L) Day 14 11 4.20 0.310 4.30 3.5 4.6 Day 28 10 4.32 0.432 4.30 3.5 5.0 Day 42 11 4.34 0.461 4.10 3.8 5.1 Day 56 11 4.44 0.585 4.30 3.9 6.1 Day 70 10 4.27 0.362 4.30 3.8 4.7 Day 84 10 4.29 0.477 4.20 3.5 5.2 Follow-up 10 4.41 0.722 4.25 3.7 6.3

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 42 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------SODIUM Placebo 7 Screening 7 140.9 2.34 141.0 138 144 (MMOL/L) Day 1 7 141.9 3.44 141.0 138 148 Day 14 7 140.3 2.29 141.0 136 143 Day 28 7 141.1 2.79 141.0 137 146 Day 42 7 140.1 2.54 140.0 137 144 Day 56 7 140.9 2.67 141.0 137 145 Day 70 7 140.0 1.73 141.0 137 142 Day 84 7 139.4 2.64 139.0 137 145 Follow-up 7 140.4 1.72 141.0 138 142 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

140.1 140.2 139.2 140.0 139.9 138.8 140.5 139.0 139.6

1.83 2.11 1.39 1.66 2.34 1.83 0.58 2.55 1.34

140.0 140.0 139.0 140.0 139.0 139.0 140.5 138.0 139.0

137 138 137 137 138 136 140 137 138

143 143 141 142 145 141 141 143 141

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

139.8 141.2 139.8 140.2 140.3 141.2 139.9 139.6 140.9

2.14 1.60 2.29 2.09 2.58 1.86 1.21 1.59 1.25

140.0 141.0 140.0 140.0 141.0 142.0 140.0 140.0 141.0

135 139 136 136 135 138 138 136 139

143 144 144 144 145 144 141 141 142

SRT2104 1.0 g

11

Screening

11

140.5

1.81

141.0

138

144

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 43 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------SODIUM SRT2104 1.0 g 11 Day 1 11 140.1 1.04 140.0 139 142 (MMOL/L) Day 14 11 139.8 1.40 140.0 138 142 Day 28 11 141.7 2.24 141.0 139 147 Day 42 11 140.8 1.94 141.0 137 144 Day 56 11 140.4 2.20 140.0 138 145 Day 70 10 140.6 1.90 140.5 138 144 Day 84 10 139.6 1.78 140.0 137 142 Follow-up 10 140.6 2.12 140.0 138 145 TRIGLYCERIDES (MMOL/L)

Placebo

7

Screening

7

1.403

0.4075

1.280

0.98

2.24

Day 1 Day 42 Day 84

7 7 6

1.469 1.391 1.717

0.4867 0.4398 0.6281

1.400 1.400 1.510

0.92 0.98 1.06

2.26 2.22 2.72

SRT2104 0.25 g

9

Screening Day 1 Day 42 Day 84

9 9 7 5

1.891 1.547 1.714 2.108

1.2768 0.9381 0.8649 1.1167

1.620 1.160 1.680 2.160

0.40 0.36 0.56 0.50

4.42 2.96 2.86 3.48

SRT2104 0.5 g

12

Screening Day 1 Day 42 Day 84

12 11 10 9

1.798 1.542 1.968 1.318

0.8642 0.5330 1.1980 0.3603

1.760 1.480 1.390 1.200

0.60 0.70 0.80 0.86

3.08 2.50 4.00 1.94

SRT2104 1.0 g

11

Screening Day 1 Day 42 Day 84

11 11 11 10

2.645 2.509 1.782 2.424

2.3774 2.0509 1.0472 1.6924

1.860 1.820 1.700 1.810

0.64 0.76 0.56 0.54

7.62 6.28 3.52 5.04

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 44 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------UREA NITROGEN Placebo 7 Screening 7 5.86 1.435 5.50 4.0 8.0 (MMOL/L) Day 1 7 5.79 2.252 5.50 3.0 9.0 Day 14 7 6.79 2.736 7.00 3.0 11.0 Day 28 7 5.21 1.380 5.00 3.5 8.0 Day 42 7 6.14 1.520 6.00 4.5 8.0 Day 56 7 6.07 2.130 6.50 3.5 9.0 Day 70 7 6.07 2.507 6.00 3.0 10.5 Day 84 7 5.29 0.859 5.00 4.5 7.0 Follow-up 7 6.21 1.799 5.50 4.5 9.0 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

5.11 4.61 4.94 4.78 5.36 4.42 3.88 4.30 3.90

1.850 1.516 1.357 1.349 1.464 0.801 0.250 0.758 0.894

4.50 4.50 5.50 4.50 4.50 4.50 4.00 4.50 4.00

3.5 3.0 3.0 3.5 4.5 3.5 3.5 3.0 3.0

9.5 7.0 7.0 8.0 8.5 5.5 4.0 5.0 5.0

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

5.58 5.59 5.46 5.55 6.00 5.44 5.43 5.33 5.44

1.203 1.514 1.437 1.665 1.333 1.862 1.669 1.714 0.729

5.50 5.50 5.75 5.50 6.25 5.00 5.50 5.50 5.50

4.0 3.0 3.0 3.0 3.5 3.5 3.0 3.0 4.5

8.0 8.0 8.0 9.0 8.0 9.0 8.0 8.5 7.0

SRT2104 1.0 g

11

Screening

11

5.36

2.038

5.00

3.0

10.5

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 45 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------UREA NITROGEN SRT2104 1.0 g 11 Day 1 11 5.41 1.562 5.00 4.0 9.5 (MMOL/L) Day 14 11 5.82 1.750 5.50 3.5 10.0 Day 28 11 5.41 1.800 5.00 3.0 10.0 Day 42 11 5.27 2.017 4.50 3.0 10.0 Day 56 11 5.23 1.421 5.50 3.0 8.0 Day 70 10 5.25 2.125 5.25 2.5 10.0 Day 84 10 5.20 2.163 4.75 2.5 10.5 Follow-up 10 5.00 1.667 5.00 2.5 8.0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 46 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------URIC ACID Placebo 7 Screening 7 402.9 78.25 370.0 320 530 (UMOL/L) Day 1 7 418.6 91.37 390.0 310 550 Day 14 7 414.3 69.97 430.0 300 500 Day 28 7 412.9 72.74 420.0 320 490 Day 42 7 428.6 94.24 430.0 290 550 Day 56 7 441.4 80.30 420.0 330 560 Day 70 7 430.0 98.15 450.0 310 570 Day 84 7 405.7 106.12 390.0 260 580 Follow-up 7 427.1 72.04 420.0 330 550 SRT2104 0.25 g

9

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 9 9 7 6 4 5 5

323.3 336.7 331.1 357.8 360.0 371.7 402.5 390.0 354.0

95.00 106.30 120.46 113.33 127.54 130.14 118.15 125.70 77.01

320.0 350.0 280.0 360.0 390.0 375.0 440.0 420.0 380.0

210 200 190 220 210 220 240 210 270

490 500 550 560 540 510 490 520 450

SRT2104 0.5 g

12

Screening Day 1 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 12 11 10 9 7 9 8

380.8 385.5 359.2 379.1 390.0 411.1 402.9 388.9 418.8

63.31 63.78 85.86 85.14 91.65 98.04 70.41 111.41 70.60

375.0 380.0 360.0 360.0 385.0 420.0 420.0 350.0 415.0

310 300 200 240 270 240 300 240 320

500 510 510 540 570 570 490 630 500

SRT2104 1.0 g

11

Screening

11

399.1

116.23

390.0

210

660

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 47 of 47 Clinical Study Report SRT-2104-013 Table 14.3.3.6 Summary of Clinical Chemistry Data Safety Analysis Set Population

Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------URIC ACID SRT2104 1.0 g 11 Day 1 11 402.7 122.24 360.0 230 670 (UMOL/L) Day 14 11 368.2 155.68 320.0 210 710 Day 28 11 370.0 154.98 330.0 170 720 Day 42 11 369.1 148.29 330.0 150 670 Day 56 11 388.2 141.76 400.0 220 710 Day 70 10 372.0 134.56 345.0 160 670 Day 84 10 390.0 124.10 345.0 240 670 Follow-up 10 386.0 117.21 360.0 200 630

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALAT (SGPT) (U/L) Placebo 7 Day 14 7 -5.7 15.48 -1.0 -27 17 Day 28 7 -7.3 8.20 -5.0 -20 2 Day 42 7 -8.9 12.01 -7.0 -27 5 Day 56 7 -8.4 13.02 -2.0 -30 5 Day 70 7 -3.0 10.41 0.0 -21 9 Day 84 7 -7.7 15.21 -12.0 -24 20 Follow-up 7 -9.3 12.09 -3.0 -29 1 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.3 0.2 1.9 1.8 0.5 2.0 3.2

4.53 4.58 6.99 5.00 2.38 3.67 3.96

0.0 1.0 0.0 1.5 0.5 0.0 3.0

-7 -7 -8 -3 -2 -1 -2

9 6 12 7 3 8 8

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

0.0 9.0 18.9 -2.7 4.6 -0.2 -0.5

4.39 33.74 72.21 4.09 11.57 6.55 3.74

0.5 0.0 -2.5 -3.0 0.0 -4.0 -1.5

-6 -8 -14 -10 -5 -6 -7

7 110 224 5 29 12 5

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-8.0 -3.5 2.8 7.9 7.4 26.9 7.9

11.32 15.41 30.89 24.70 75.76 24.21

-8.0 -1.0 0.0 2.0 3.0 0.0 1.5

-8 -34 -32 -33 -32 -41 -22

-8 11 24 93 68 233 65

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALAT (SGPT) (U/L) SRT2104 1.0 g 11 Follow-up 10 5.3 21.60 -0.5 -26 52

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALBUMIN (G/L) Placebo 7 Day 14 7 -0.9 1.35 -1.0 -2 1 Day 28 7 -0.6 1.99 -1.0 -3 2 Day 42 7 -0.6 0.98 -1.0 -2 1 Day 56 7 -0.9 1.57 -1.0 -3 2 Day 70 7 -1.0 1.63 0.0 -3 1 Day 84 7 -1.1 1.68 -2.0 -3 2 Follow-up 7 -0.1 2.91 0.0 -5 3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.2 0.6 1.3 0.0 0.5 0.8 1.8

1.79 2.07 2.21 1.79 0.58 2.17 2.17

1.0 1.0 1.0 -0.5 0.5 2.0 3.0

-2 -3 -2 -2 0 -3 -2

3 4 4 3 1 2 3

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-1.3 -0.9 -0.8 -0.8 0.1 -0.7 -0.6

2.64 2.59 1.75 2.28 1.95 2.83 3.89

-1.0 -1.0 -0.5 -1.0 1.0 -2.0 0.5

-7 -5 -4 -4 -3 -4 -9

2 3 2 4 2 4 3

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-5.0 -1.6 -1.0 -0.8 0.5 -1.2 -0.2

1.96 1.41 1.99 2.25 1.55 1.32

-5.0 -1.0 -1.0 -1.0 0.0 -1.0 0.0

-5 -7 -3 -4 -2 -3 -2

-5 0 1 2 5 1 2

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALBUMIN (G/L) SRT2104 1.0 g 11 Follow-up 10 -1.4 1.58 -1.5 -3 1

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALKALINE PHOSPHATASE Placebo 7 Day 14 7 -3.6 9.73 -2.0 -16 11 (U/L) Day 28 7 -1.3 4.92 -3.0 -8 5 Day 42 7 -2.1 4.63 -2.0 -8 4 Day 56 7 -3.6 11.34 -5.0 -15 17 Day 70 7 -1.9 12.32 0.0 -23 13 Day 84 7 -7.7 9.43 -6.0 -20 5 Follow-up 7 -6.0 14.26 -8.0 -27 13 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.4 -1.1 -1.9 -1.7 -1.8 0.0 -1.4

7.16 4.73 5.11 5.85 4.57 4.64 4.10

-1.0 0.0 -2.0 -2.0 -2.0 0.0 -4.0

-13 -9 -9 -11 -7 -5 -5

14 5 6 5 4 6 4

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.7 5.2 11.8 -1.1 -1.3 -5.8 -6.0

10.29 20.55 40.00 7.32 10.53 13.07 12.82

-2.5 2.0 1.0 -1.0 -6.0 -4.0 -4.5

-17 -15 -17 -14 -12 -22 -23

25 56 122 8 20 16 12

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-6.0 -3.5 -3.0 -3.6 -1.5 -3.6

6.04 10.10 9.81 9.36 6.57

-6.0 -2.0 -4.0 -7.0 3.0 -4.0

-6 -13 -23 -18 -15 -14

-6 4 15 17 15 10

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ALKALINE PHOSPHATASE SRT2104 1.0 g 11 Day 84 10 1.2 16.46 -4.0 -11 46 (U/L) Follow-up 10 -1.5 6.50 -2.0 -11 11

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------AMYLASE, SERUM (U/L) Placebo 7 Day 14 7 0.0 5.16 3.0 -10 4 Day 28 7 -1.3 6.50 -1.0 -13 7 Day 42 7 -0.4 3.78 0.0 -7 3 Day 56 7 -2.0 5.69 -3.0 -9 7 Day 70 7 -1.4 4.20 -1.0 -9 5 Day 84 7 -2.6 3.78 -2.0 -9 1 Follow-up 7 -1.0 4.65 0.0 -11 3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

0.2 0.2 4.0 -1.5 2.2 3.4 4.7

12.03 9.51 14.28 10.99 11.10 3.85 11.84

-1.0 -1.0 1.0 -0.5 2.0 3.0 1.5

-13 -13 -16 -16 -10 -2 -7

22 16 26 16 20 8 26

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.8 -0.2 3.1 -0.9 3.6 -0.1 -0.1

8.24 7.70 7.37 4.08 6.83 9.12 8.43

-3.5 -1.0 1.0 -1.0 1.0 -3.0 -1.0

-7 -15 -3 -10 -3 -14 -9

21 12 22 4 17 18 18

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-27.0 -5.1 -9.3 -8.5 -6.1 -5.7 -10.1

21.59 21.85 19.68 20.93 19.25 21.14

-27.0 -3.0 -2.0 -4.0 -1.0 -3.5 -4.5

-27 -62 -74 -67 -68 -56 -68

-27 31 4 3 6 20 5

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------AMYLASE, SERUM (U/L) SRT2104 1.0 g 11 Follow-up 10 -5.5 24.93 2.0 -75 10

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ASAT (SGOT) (U/L) Placebo 7 Day 14 7 2.0 25.61 -3.0 -19 58 Day 28 7 -4.6 6.08 -3.0 -13 4 Day 42 7 -6.7 7.78 -5.0 -19 3 Day 56 7 -4.0 8.02 0.0 -20 2 Day 70 7 -3.1 5.21 -2.0 -13 3 Day 84 7 -6.1 14.59 -7.0 -19 24 Follow-up 7 -8.1 7.86 -7.0 -20 1 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.1 0.3 1.4 2.5 2.3 1.6 2.8

4.40 4.92 5.29 7.34 1.71 3.21 3.11

1.0 0.0 1.0 2.0 2.5 3.0 2.0

-9 -9 -8 -7 0 -4 -1

7 10 8 15 4 4 6

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

1.1 4.6 7.8 -1.6 1.0 -0.6 -2.4

3.53 19.57 35.87 6.69 11.94 4.69 8.45

1.5 2.0 -0.5 0.0 3.0 -2.0 0.0

-5 -20 -26 -17 -23 -9 -23

7 60 107 5 16 8 3

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 10 11 11 10 10

1.0 -2.1 6.0 4.5 4.5 11.8 10.4

5.96 14.82 9.75 10.09 30.31 17.33

1.0 -1.0 1.0 1.0 3.0 1.0 3.0

1 -17 -7 -5 -8 -7 -9

1 4 45 23 29 93 44

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------ASAT (SGOT) (U/L) SRT2104 1.0 g 11 Follow-up 10 3.1 10.22 -0.5 -6 26

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, DIRECT Placebo 7 Day 14 7 -0.3 0.76 0.0 -2 0 (UMOL/L) Day 28 7 0.0 0.00 0.0 0 0 Day 42 7 0.0 1.15 0.0 -2 2 Day 56 7 0.0 0.00 0.0 0 0 Day 70 7 -0.3 0.76 0.0 -2 0 Day 84 7 0.0 0.00 0.0 0 0 Follow-up 7 -0.3 0.76 0.0 -2 0 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.0 0.4 0.0 0.0 0.0 0.4 0.4

1.00 0.88 0.00 1.26 0.00 1.67 0.89

0.0 0.0 0.0 0.0 0.0 0.0 0.0

-2 0 0 -2 0 -2 0

2 2 0 2 0 2 2

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

0.7 0.2 0.8 0.4 0.3 0.4 0.0

1.56 1.89 1.40 0.88 0.76 1.33 1.07

0.0 0.0 0.0 0.0 0.0 0.0 0.0

0 -4 0 0 0 -2 -2

4 2 4 2 2 2 2

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.0 0.7 0.9 0.5 0.7 1.0

1.62 1.04 1.57 1.62 1.41

0.0 0.0 0.0 0.0 0.0 0.0

0 -2 0 -2 -2 0

0 4 2 4 4 4

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, DIRECT SRT2104 1.0 g 11 Day 84 10 0.6 1.65 0.0 -2 4 (UMOL/L) Follow-up 10 0.2 0.63 0.0 0 2

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, INDIRECT Placebo 7 Day 14 7 -0.9 2.27 -2.0 -4 2 (UMOL/L) Day 28 7 -0.6 1.51 0.0 -2 2 Day 42 7 -0.6 2.23 0.0 -4 2 Day 56 7 0.9 2.27 0.0 -2 4 Day 70 7 0.6 1.90 2.0 -2 2 Day 84 7 0.9 3.24 0.0 -2 8 Follow-up 7 -0.6 2.23 0.0 -4 2 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.4 0.2 -0.3 -1.0 3.0 0.8 0.4

6.31 4.18 3.90 4.34 3.83 5.22 5.18

0.0 2.0 0.0 0.0 4.0 2.0 0.0

-10 -8 -8 -8 -2 -8 -6

14 4 4 4 6 6 8

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

2.2 0.4 0.4 2.2 0.9 1.3 -2.3

5.22 4.63 2.46 3.53 2.54 3.00 3.28

0.0 0.0 1.0 2.0 2.0 2.0 -2.0

-2 -6 -4 -4 -4 -4 -6

16 8 4 8 4 6 4

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.0 3.6 2.5 3.6 3.3 3.4

6.44 5.37 5.57 5.75 8.95

0.0 2.0 0.0 2.0 2.0 0.0

0 -6 -4 -4 -4 -4

0 16 14 14 14 22

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, INDIRECT SRT2104 1.0 g 11 Day 84 10 2.6 6.04 0.0 -4 16 (UMOL/L) Follow-up 10 -0.2 3.19 0.0 -6 4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, TOTAL Placebo 7 Day 14 7 -1.1 1.95 -2.0 -4 2 (UMOL/L) Day 28 7 -0.6 1.51 0.0 -2 2 Day 42 7 -0.6 2.23 0.0 -4 2 Day 56 7 0.9 2.27 0.0 -2 4 Day 70 7 0.3 1.80 0.0 -2 2 Day 84 7 0.9 3.24 0.0 -2 8 Follow-up 7 -0.9 2.27 -2.0 -4 2 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.4 0.7 -0.3 -1.0 3.0 1.2 0.8

6.91 4.69 3.90 4.86 3.83 5.93 5.93

0.0 2.0 0.0 -1.0 4.0 2.0 0.0

-10 -8 -8 -8 -2 -8 -6

16 6 4 6 6 8 10

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

2.8 0.5 1.2 2.7 1.1 1.8 -2.3

6.06 5.73 3.43 4.12 1.95 3.23 3.45

1.0 0.0 2.0 2.0 2.0 2.0 -3.0

-2 -8 -4 -4 -2 -4 -6

20 10 8 10 4 6 4

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.0 4.4 3.5 4.2 4.0 4.4

7.42 6.01 6.48 6.69 10.01

0.0 2.0 2.0 0.0 0.0 0.0

0 -6 -4 -4 -4 -4

0 18 16 16 16 26

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------BILIRUBIN, TOTAL SRT2104 1.0 g 11 Day 84 10 3.2 7.25 0.0 -4 20 (UMOL/L) Follow-up 10 0.0 3.53 0.0 -6 6

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CALCIUM (MMOL/L) Placebo 7 Day 14 7 -0.040 0.1317 -0.060 -0.20 0.16 Day 28 7 -0.014 0.0755 -0.020 -0.10 0.12 Day 42 7 -0.049 0.0807 -0.040 -0.20 0.06 Day 56 7 -0.014 0.1187 -0.020 -0.20 0.16 Day 70 7 -0.026 0.1165 -0.020 -0.20 0.16 Day 84 7 -0.054 0.0971 -0.100 -0.16 0.14 Follow-up 7 -0.029 0.1311 -0.060 -0.22 0.16 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.016 0.027 0.037 0.037 0.045 0.056 0.076

0.1009 0.0943 0.0795 0.0889 0.0806 0.0953 0.0942

0.040 0.000 0.040 0.030 0.040 0.020 0.040

-0.16 -0.08 -0.08 -0.10 -0.04 -0.04 -0.04

0.14 0.16 0.14 0.16 0.14 0.20 0.20

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.005 -0.015 -0.004 -0.013 -0.011 -0.051 -0.012

0.0672 0.0800 0.0729 0.0632 0.0552 0.0889 0.1265

0.000 0.000 -0.020 -0.020 -0.040 -0.040 -0.010

-0.10 -0.18 -0.12 -0.12 -0.06 -0.22 -0.24

0.10 0.08 0.16 0.10 0.10 0.08 0.20

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 10 11 11 10 10

-0.140 -0.062 -0.036 -0.058 0.007 -0.042 -0.042

0.0777 0.0771 0.0982 0.1001 0.0702 0.1125

-0.140 -0.080 -0.050 -0.060 0.000 -0.050 -0.060

-0.14 -0.18 -0.14 -0.18 -0.12 -0.14 -0.26

-0.14 0.10 0.06 0.10 0.16 0.10 0.16

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CALCIUM (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 -0.036 0.0878 -0.030 -0.18 0.12

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 19 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CHLORIDE (MMOL/L) Placebo 7 Day 14 7 1.1 2.12 0.0 -1 5 Day 28 7 0.4 3.21 2.0 -5 4 Day 42 7 0.1 2.04 0.0 -3 3 Day 56 7 0.1 2.48 -1.0 -3 3 Day 70 7 -0.6 1.81 0.0 -3 2 Day 84 7 0.1 2.73 -1.0 -3 5 Follow-up 7 0.0 2.31 -1.0 -2 3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.2 0.1 0.0 -1.7 -0.3 -2.4 -1.8

2.49 1.90 3.16 1.37 1.71 0.89 2.68

0.0 -1.0 -1.0 -2.0 -0.5 -3.0 -3.0

-3 -2 -2 -3 -2 -3 -4

5 4 7 0 2 -1 2

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.7 -1.4 -0.9 0.4 0.3 -0.8 0.9

1.67 2.69 3.00 2.74 2.98 2.28 3.44

-1.0 -1.0 0.0 1.0 0.0 0.0 1.0

-4 -5 -6 -3 -4 -4 -4

2 3 4 5 4 2 7

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

3.0 1.2 1.5 1.0 -0.5 0.3 -1.1

1.47 2.07 1.61 2.77 2.00 2.38

3.0 1.0 1.0 1.0 -2.0 0.5 -1.0

3 -1 -1 -1 -3 -3 -4

3 4 6 4 6 4 2

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 20 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CHLORIDE (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 0.4 2.27 0.0 -2 6 CHOLESTEROL, TOTAL (MMOL/L)

Placebo

7 Day 42

7

-0.229

0.3264

-0.300

-0.70

0.20

Day 84

6

-0.350

0.3391

-0.425

-0.65

0.25

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.186 0.050

0.3497 0.3588

-0.100 -0.050

-0.70 -0.30

0.35 0.65

SRT2104 0.5 g

12 Day 42 Day 84

10 9

-0.170 -0.200

1.0422 0.5006

-0.375 -0.400

-1.25 -0.75

2.45 0.55

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 11 10

-0.150 -0.541 -0.195

0.5272 0.5480

-0.150 -0.550 -0.450

-0.15 -1.30 -0.80

-0.15 0.30 0.60

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 21 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CO2 CONTENT (MMOL/L) Placebo 7 Day 14 7 -0.3 2.69 -1.0 -3 5 Day 28 7 1.3 3.04 1.0 -3 7 Day 42 7 0.3 2.75 1.0 -4 4 Day 56 7 0.3 2.63 -1.0 -3 3 Day 70 7 0.3 2.50 -1.0 -3 4 Day 84 7 -0.1 3.98 1.0 -7 5 Follow-up 7 0.6 2.57 1.0 -4 4 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.4 -0.2 0.1 0.5 -0.5 -0.2 0.8

1.01 1.20 2.34 2.26 2.08 1.79 2.17

-1.0 0.0 1.0 0.5 -0.5 0.0 1.0

-2 -2 -4 -3 -3 -2 -2

1 2 2 4 2 2 4

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

0.1 0.3 -0.3 0.3 0.9 -0.8 2.1

2.75 1.95 1.95 3.04 3.18 1.92 2.85

0.0 0.0 1.0 0.0 -1.0 -1.0 1.5

-4 -3 -4 -5 -3 -3 -1

7 4 1 5 6 3 6

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 10 11 11 10 10

-4.0 -1.2 -0.6 -0.5 -1.8 0.5 -1.4

2.52 3.17 2.25 3.19 3.21 2.95

-4.0 -2.0 -1.0 -1.0 -1.0 0.5 -1.5

-4 -5 -4 -4 -7 -6 -7

-4 2 5 4 1 6 4

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 22 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CO2 CONTENT (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 -1.1 2.18 -1.5 -4 3

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 23 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CPK, TOTAL (U/L) Placebo 7 Day 14 7 374.1 1070.41 -10.0 -111 2800 Day 28 7 -30.6 87.55 -15.0 -220 49 Day 42 7 -59.6 116.14 -14.0 -318 7 Day 56 7 19.0 69.27 25.0 -93 140 Day 70 7 -51.6 112.41 4.0 -278 39 Day 84 7 130.1 365.19 9.0 -91 948 Follow-up 7 -77.3 157.19 -17.0 -418 51 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

26.7 60.7 -1.6 148.8 10.5 34.2 41.4

129.92 136.35 22.84 309.47 43.90 59.72 87.15

1.0 13.0 0.0 36.5 27.5 30.0 3.0

-115 -65 -42 -18 -54 -32 -3

353 389 30 776 41 130 197

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

55.5 -53.1 -81.3 -60.2 -106.0 -16.2 -87.0

138.36 201.51 279.26 212.22 318.65 101.51 305.36

16.0 -2.0 -4.5 -13.0 -8.0 24.0 8.0

-41 -653 -860 -594 -825 -247 -841

474 61 133 149 63 61 66

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

5.0 -9.8 33.1 -4.0 -25.7 -19.8 -10.9

45.24 154.52 50.85 54.09 42.65 55.04

5.0 -15.0 -18.0 0.0 -24.0 -24.5 -8.5

5 -83 -90 -75 -103 -81 -100

5 95 449 97 71 55 57

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 24 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CPK, TOTAL (U/L) SRT2104 1.0 g 11 Follow-up 10 -28.7 42.00 -42.0 -87 37

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 25 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CREATININE (UMOL/L) Placebo 7 Day 14 7 -1.4 11.97 0.0 -18 9 Day 28 7 -1.3 13.85 0.0 -18 17 Day 42 7 -3.7 8.69 0.0 -18 9 Day 56 7 -2.4 9.76 0.0 -17 9 Day 70 7 -1.3 9.62 0.0 -18 9 Day 84 7 0.0 9.00 0.0 -9 9 Follow-up 7 3.7 9.98 0.0 -9 18 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

1.0 1.9 6.3 3.0 2.3 3.4 10.6

8.35 7.39 9.83 7.35 4.50 7.89 14.36

0.0 0.0 9.0 4.5 0.0 8.0 9.0

-9 -9 -9 -9 0 -9 0

18 9 18 9 9 9 35

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

7.5 5.6 7.3 4.0 3.9 3.0 4.5

8.44 7.97 9.10 7.94 7.08 7.79 4.81

9.0 8.0 9.0 0.0 9.0 9.0 4.5

0 -8 -9 -9 -9 -9 0

27 18 18 18 9 9 9

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-8.0 0.9 2.5 2.4 7.2 5.4 -0.8

9.87 10.47 11.32 7.72 4.65 9.62

-8.0 0.0 9.0 0.0 8.0 9.0 0.0

-8 -18 -18 -18 0 0 -18

-8 17 17 18 18 9 9

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 26 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------CREATININE (UMOL/L) SRT2104 1.0 g 11 Follow-up 10 -2.7 7.15 0.0 -18 8 CRP HIGH SENSITIVITY (MG/L)

Placebo

7 Day 28

7

0.11

2.330

0.20

-4.4

3.5

Day 56 Day 84

7 7

0.59 0.66

3.552 3.895

0.10 -0.10

-4.4 -4.9

7.6 8.1

SRT2104 0.25 g

9 Day 28 Day 56 Day 84

8 6 5

-0.14 -0.18 -0.16

1.148 1.897 1.055

0.10 -0.50 -0.10

-1.6 -2.4 -1.8

1.7 2.6 0.9

SRT2104 0.5 g

12 Day 28 Day 56 Day 84

10 7 8

1.18 -1.31 -0.75

1.954 3.261 3.159

0.50 -0.20 -0.10

-0.6 -8.6 -8.3

4.4 0.8 1.5

SRT2104 1.0 g

11 Day 28 Day 56 Day 84

9 9 9

-0.86 -0.34 0.50

2.318 2.763 1.207

-0.10 -0.20 0.20

-6.3 -5.8 -1.1

2.0 5.1 2.5

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 27 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------GGT (U/L) Placebo 7 Day 14 7 -3.0 3.32 -2.0 -9 1 Day 28 7 -0.9 4.45 -3.0 -6 7 Day 42 7 -2.9 2.79 -3.0 -6 2 Day 56 7 -4.0 7.26 -3.0 -19 4 Day 70 7 -1.3 6.85 -3.0 -10 9 Day 84 7 -4.0 6.19 -2.0 -17 2 Follow-up 7 -2.6 6.24 -1.0 -16 3 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.9 0.7 1.9 1.5 3.0 9.6 3.4

3.33 8.51 8.40 5.58 2.94 19.26 1.95

0.0 -1.0 2.0 1.0 2.5 2.0 4.0

-6 -7 -7 -7 0 0 0

4 22 19 9 7 44 5

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.5 9.5 6.9 0.2 -0.3 1.3 -1.5

3.23 20.59 26.76 5.83 4.23 6.82 5.04

-1.5 1.0 -2.0 0.0 -2.0 -1.0 -0.5

-4 -3 -8 -6 -3 -6 -10

5 54 82 12 9 16 7

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-2.0 -1.9 2.5 4.2 7.5 4.4 -0.3

13.66 11.46 10.27 10.97 13.35 16.66

-2.0 -1.0 -1.0 -1.0 1.0 -2.0 0.0

-2 -28 -7 -8 -2 -10 -39

-2 30 27 27 29 28 28

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 28 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------GGT (U/L) SRT2104 1.0 g 11 Follow-up 10 2.8 8.89 0.0 -9 20

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 29 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------GLUCOSE, PLASMA Placebo 7 Day 14 6 0.25 0.554 0.15 -0.5 1.1 (MMOL/L) Day 28 7 -0.01 0.701 0.20 -1.3 0.6 Day 42 7 0.24 0.746 0.20 -1.0 1.2 Day 56 7 0.04 0.655 0.30 -1.2 0.6 Day 70 7 0.50 1.257 0.20 -0.8 3.1 Day 84 7 0.01 0.669 0.30 -1.1 0.7 Follow-up 7 0.19 1.428 -0.10 -1.8 2.9 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 5 5 6

-0.12 -0.07 -0.74 0.93 0.68 0.58 0.93

1.984 2.137 3.988 1.075 0.901 1.057 1.172

0.20 0.50 0.40 0.35 0.30 0.20 0.55

-5.1 -5.6 -9.6 0.1 -0.1 -0.3 -0.4

2.2 1.5 2.5 2.5 1.7 2.4 2.6

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 9 9 9

1.30 0.54 1.28 0.61 0.12 0.40 0.39

1.183 1.166 1.602 2.351 1.506 0.730 1.069

1.25 0.00 0.60 -0.10 0.10 0.20 0.40

-0.1 -0.8 -0.3 -1.5 -2.5 -0.5 -1.9

3.4 2.9 4.3 6.0 2.5 1.7 2.0

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 10 10 10 10 10

-0.90 0.70 0.05 0.53 0.14 0.61

0.787 0.732 0.602 0.667 1.321

-0.90 0.70 -0.05 0.55 -0.05 0.75

-0.9 -0.9 -1.1 -0.7 -0.8 -1.8

-0.9 1.6 1.2 1.3 1.5 2.9

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 30 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------GLUCOSE, PLASMA SRT2104 1.0 g 11 Day 84 10 0.34 1.117 0.40 -1.7 1.8 (MMOL/L) Follow-up 9 0.01 0.708 -0.20 -1.0 0.8 HDL CHOL DIRECT (MMOL/L)

Placebo

7 Day 42

7

-0.036

0.1249

-0.050

-0.20

0.20

Day 84

6

-0.125

0.1573

-0.175

-0.30

0.15

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.036 -0.080

0.1406 0.0908

0.000 -0.100

-0.30 -0.20

0.15 0.05

SRT2104 0.5 g

12 Day 42 Day 84

10 9

-0.110 0.006

0.1776 0.3477

-0.050 0.000

-0.45 -0.55

0.10 0.75

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 11 10

0.200 0.091 0.150

0.1772 0.1841

0.200 0.100 0.100

0.20 -0.25 0.00

0.20 0.35 0.60

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 31 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LACTIC DEHYDROGENASE Placebo 7 Day 14 7 6.3 34.11 -9.0 -29 67 (U/L) Day 28 7 3.7 18.56 -1.0 -22 30 Day 42 7 -6.9 16.65 -9.0 -28 13 Day 56 7 -0.7 11.29 -1.0 -17 17 Day 70 7 -9.6 11.00 -9.0 -27 8 Day 84 7 -13.6 19.59 -5.0 -41 9 Follow-up 7 -16.0 18.48 -16.0 -42 19 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

1.6 3.2 11.4 9.7 10.5 8.4 11.4

12.27 19.09 10.64 16.68 13.53 17.40 7.13

0.0 0.0 14.0 9.5 7.0 1.0 11.0

-16 -30 -6 -14 -1 -9 2

22 32 23 35 29 35 22

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

5.7 9.5 1.9 -6.7 -6.7 5.0 -1.1

36.66 42.13 56.22 18.68 22.66 35.50 31.83

-5.5 -2.0 -13.5 1.0 3.0 -6.0 6.0

-34 -27 -42 -36 -38 -30 -43

75 129 153 16 24 79 33

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 10 11 11 10

12.0 -7.5 7.0 -3.0 -0.7 0.9

17.29 36.18 16.60 20.72 30.96

12.0 -10.0 1.5 -3.0 -1.0 -5.0

12 -34 -45 -42 -33 -40

12 33 80 21 34 77

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 32 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------LACTIC DEHYDROGENASE SRT2104 1.0 g 11 Day 84 10 4.3 29.88 3.0 -50 52 (U/L) Follow-up 10 -12.8 11.99 -11.0 -41 1 LDL-CHOL CALCULATION (MMOL/L)

Placebo

7 Day 42

7

-0.159

0.3596

-0.130

-0.81

0.32

Day 84

6

-0.307

0.3452

-0.365

-0.73

0.25

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.144 -0.062

0.3720 0.2781

-0.100 -0.010

-0.70 -0.36

0.26 0.24

SRT2104 0.5 g

12 Day 42 Day 84

10 9

-0.253 -0.154

0.8981 0.2788

-0.515 -0.160

-1.11 -0.54

2.04 0.31

SRT2104 1.0 g

11 Day 42 Day 84

8 7

-0.315 -0.259

0.3916 0.5431

-0.310 -0.280

-0.89 -0.90

0.41 0.43

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 33 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MAGNESIUM (MMOL/L) Placebo 7 Day 14 7 0.006 0.0526 0.000 -0.10 0.06 Day 28 7 0.017 0.0605 0.040 -0.06 0.10 Day 42 7 -0.009 0.0414 0.000 -0.06 0.06 Day 56 7 -0.003 0.0454 0.000 -0.06 0.06 Day 70 7 -0.040 0.0529 -0.060 -0.10 0.06 Day 84 7 -0.031 0.0540 -0.060 -0.10 0.06 Follow-up 7 -0.031 0.0701 0.000 -0.16 0.06 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.002 0.013 0.006 0.020 0.025 0.024 0.068

0.0418 0.0640 0.0412 0.0310 0.0500 0.0780 0.0769

0.000 0.000 0.000 0.000 0.000 0.060 0.100

-0.06 -0.10 -0.04 0.00 0.00 -0.10 -0.06

0.06 0.10 0.06 0.06 0.10 0.10 0.14

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.018 -0.007 0.002 0.004 -0.006 -0.016 0.008

0.0422 0.0516 0.0643 0.0631 0.0900 0.0564 0.0534

0.000 0.000 0.040 0.000 -0.040 0.000 0.000

-0.10 -0.10 -0.10 -0.10 -0.10 -0.10 -0.06

0.04 0.06 0.06 0.10 0.10 0.06 0.10

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

0.040 0.005 0.011 0.004 -0.009 0.010 0.002

0.0537 0.0589 0.0454 0.0683 0.0464 0.0569

0.040 0.000 0.000 0.000 0.000 0.000 0.000

0.04 -0.10 -0.06 -0.06 -0.10 -0.06 -0.06

0.04 0.06 0.10 0.10 0.10 0.10 0.10

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 34 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------MAGNESIUM (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 0.014 0.0472 0.000 -0.06 0.10 NEFA (MMOL/L)

Placebo

7 Day 42 Day 84

6 6

-0.077 0.083

0.2461 0.1834

-0.180 0.025

-0.30 -0.08

0.28 0.37

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.014 0.096

0.2339 0.1272

-0.010 0.070

-0.41 -0.09

0.30 0.23

SRT2104 0.5 g

12 Day 42 Day 84

11 4

-0.015 -0.155

0.2033 0.1370

-0.070 -0.150

-0.27 -0.32

0.32 0.00

SRT2104 1.0 g

11 Day 42 Day 84

9 10

-0.180 0.217

0.1794 0.5147

-0.220 -0.030

-0.35 -0.19

0.25 1.24

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 35 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------PHOSPHORUS INORGANIC Placebo 7 Day 14 7 0.007 0.1134 0.000 -0.15 0.15 (MMOL/L) Day 28 7 0.014 0.1676 0.100 -0.30 0.20 Day 42 7 -0.079 0.1113 -0.100 -0.25 0.10 Day 56 7 0.064 0.1406 0.100 -0.15 0.20 Day 70 7 0.050 0.1500 0.100 -0.15 0.30 Day 84 7 -0.029 0.1254 -0.050 -0.20 0.15 Follow-up 7 0.143 0.2353 0.050 -0.10 0.60 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.050 -0.011 0.086 0.067 -0.025 0.100 0.120

0.1639 0.1083 0.1520 0.1915 0.2102 0.2958 0.1440

0.050 0.000 0.150 0.075 -0.050 -0.050 0.150

-0.25 -0.15 -0.20 -0.25 -0.25 -0.15 -0.05

0.30 0.15 0.25 0.25 0.25 0.55 0.30

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

0.012 -0.027 -0.065 -0.039 0.029 -0.028 0.094

0.1047 0.1292 0.1156 0.1654 0.1655 0.1954 0.1821

0.025 0.000 -0.050 -0.050 0.000 -0.050 0.100

-0.15 -0.25 -0.20 -0.30 -0.25 -0.30 -0.15

0.15 0.25 0.10 0.25 0.20 0.25 0.30

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

0.000 -0.105 -0.064 -0.118 -0.064 -0.050

0.1604 0.1502 0.2003 0.1762 0.2236

0.000 -0.050 -0.050 -0.150 -0.050 -0.050

0.00 -0.45 -0.35 -0.45 -0.30 -0.35

0.00 0.05 0.20 0.20 0.30 0.40

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 36 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------PHOSPHORUS INORGANIC SRT2104 1.0 g 11 Day 84 10 -0.090 0.2307 -0.075 -0.45 0.25 (MMOL/L) Follow-up 10 -0.130 0.2452 -0.100 -0.55 0.15

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 37 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------POTASSIUM (MMOL/L) Placebo 7 Day 14 7 0.13 0.335 0.00 -0.3 0.6 Day 28 7 0.40 0.294 0.30 0.1 0.9 Day 42 7 0.31 0.212 0.30 0.0 0.6 Day 56 7 0.21 0.186 0.20 -0.1 0.5 Day 70 7 0.01 0.273 -0.10 -0.4 0.4 Day 84 7 -0.03 0.340 0.10 -0.5 0.3 Follow-up 7 0.04 0.351 0.10 -0.4 0.6 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-0.03 -0.07 0.04 -0.07 -0.10 0.02 0.22

0.415 0.316 0.305 0.207 0.383 0.377 0.432

-0.10 0.00 -0.10 0.00 0.00 0.00 0.20

-0.5 -0.5 -0.2 -0.4 -0.6 -0.4 -0.3

0.9 0.4 0.7 0.2 0.2 0.6 0.7

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

0.02 0.18 0.12 0.11 0.27 -0.02 0.23

0.426 0.346 0.405 0.348 0.550 0.277 0.433

-0.05 0.20 -0.10 0.20 0.10 0.00 0.05

-0.6 -0.5 -0.3 -0.4 -0.3 -0.4 -0.2

0.8 0.7 0.8 0.6 1.2 0.4 0.9

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 10 11 11 10 10

0.20 -0.16 -0.04 -0.03 0.07 -0.07 -0.10

0.246 0.320 0.429 0.573 0.333 0.424

0.20 -0.20 -0.10 -0.10 0.00 -0.10 -0.05

0.2 -0.6 -0.6 -0.8 -0.4 -0.6 -0.8

0.2 0.2 0.6 0.7 1.7 0.5 0.8

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 38 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------POTASSIUM (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 0.02 0.716 -0.10 -0.6 1.9

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 39 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------SODIUM (MMOL/L) Placebo 7 Day 14 7 -1.6 3.82 -2.0 -7 5 Day 28 7 -0.7 2.87 -2.0 -3 5 Day 42 7 -1.7 2.29 -1.0 -5 2 Day 56 7 -1.0 2.58 -2.0 -3 4 Day 70 7 -1.9 3.24 -2.0 -7 4 Day 84 7 -2.4 2.44 -2.0 -7 1 Follow-up 7 -1.4 2.70 -2.0 -6 2 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-1.0 -0.2 -0.6 -1.8 0.3 -1.2 -0.2

2.12 2.86 3.46 3.43 2.75 3.27 2.17

-1.0 1.0 -1.0 -0.5 0.5 -1.0 0.0

-5 -6 -4 -7 -3 -6 -3

2 3 6 2 3 3 3

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-1.3 -1.1 -0.7 0.1 -1.4 -1.6 -0.1

2.14 2.59 2.11 1.90 2.44 1.94 2.42

-2.0 -1.0 0.0 0.0 -1.0 -2.0 0.0

-3 -4 -5 -3 -5 -4 -5

3 3 2 3 2 2 3

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

-1.0 -0.4 1.5 0.6 0.2 0.3 -0.4

1.03 2.21 1.57 1.94 1.42 1.51

-1.0 0.0 1.0 1.0 0.0 0.0 0.0

-1 -2 -1 -2 -2 -2 -3

-1 1 7 4 5 2 1

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 40 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------SODIUM (MMOL/L) SRT2104 1.0 g 11 Follow-up 10 0.4 2.12 0.0 -2 5 TRIGLYCERIDES (MMOL/L)

Placebo

7 Day 42

7

-0.077

0.2753

-0.140

-0.32

0.46

Day 84

6

0.160

0.4385

-0.020

-0.34

0.84

SRT2104 0.25 g

9 Day 42 Day 84

7 5

-0.009 0.420

0.5879 0.5566

0.000 0.300

-0.72 -0.30

1.00 1.00

SRT2104 0.5 g

12 Day 42 Day 84

10 9

0.428 -0.107

0.9561 0.4892

0.330 -0.100

-0.88 -0.92

1.88 0.52

SRT2104 1.0 g

11 Day 1 Day 42 Day 84

1 11 10

-1.040 -0.822 -0.364

1.1929 0.6521

-1.040 -0.480 -0.220

-1.04 -2.96 -1.68

-1.04 0.52 0.58

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 41 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------UREA NITROGEN Placebo 7 Day 14 7 1.00 1.472 0.50 -0.5 3.5 (MMOL/L) Day 28 7 -0.57 1.742 -0.50 -4.0 1.0 Day 42 7 0.36 1.842 -0.50 -1.5 3.5 Day 56 7 0.29 1.220 0.50 -1.5 2.0 Day 70 7 0.29 1.410 0.50 -2.0 2.0 Day 84 7 -0.50 1.915 0.00 -4.0 1.5 Follow-up 7 0.43 0.886 0.50 -1.0 1.5 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

0.33 0.17 0.86 0.25 0.13 0.40 0.00

1.061 0.935 0.988 0.689 0.854 1.084 1.275

0.50 0.00 1.50 0.00 0.25 0.00 0.00

-1.0 -1.5 -0.5 -0.5 -1.0 -1.0 -1.5

2.5 1.5 2.0 1.5 1.0 1.5 2.0

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-0.04 -0.05 0.25 0.22 0.29 0.11 0.13

0.498 0.986 1.379 1.176 0.488 0.858 1.598

0.00 0.00 0.00 0.50 0.00 0.00 0.25

-1.0 -2.0 -2.0 -1.5 0.0 -1.0 -2.5

0.5 1.5 2.5 2.5 1.0 1.5 2.5

SRT2104 1.0 g

11 Day Day Day Day Day Day

1 11 11 11 11 10

-0.50 0.36 -0.05 -0.18 -0.23 -0.15

0.674 0.789 0.717 0.786 1.081

-0.50 0.50 0.00 -0.50 0.00 0.00

-0.5 -1.5 -1.0 -1.0 -1.5 -1.5

-0.5 1.0 1.0 1.0 0.5 1.5

1 14 28 42 56 70

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 42 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------UREA NITROGEN SRT2104 1.0 g 11 Day 84 10 -0.30 0.753 -0.25 -1.5 1.0 (MMOL/L) Follow-up 10 -0.50 0.745 -0.50 -1.5 0.5

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 43 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------URIC ACID (UMOL/L) Placebo 7 Day 14 7 -4.3 69.97 -20.0 -120 90 Day 28 7 -5.7 49.28 -20.0 -70 60 Day 42 7 10.0 48.99 20.0 -70 80 Day 56 7 22.9 51.22 30.0 -80 90 Day 70 7 11.4 56.10 20.0 -80 70 Day 84 7 -12.9 51.87 0.0 -90 50 Follow-up 7 8.6 65.68 20.0 -130 60 SRT2104 0.25 g

9 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

9 9 7 6 4 5 5

-5.6 21.1 11.4 -1.7 7.5 20.0 36.0

52.70 61.73 78.83 77.05 23.63 25.50 53.67

10.0 30.0 30.0 20.0 0.0 20.0 40.0

-130 -120 -130 -150 -10 -20 -20

50 90 120 60 40 50 120

SRT2104 0.5 g

12 Day 14 Day 28 Day 42 Day 56 Day 70 Day 84 Follow-up

12 11 10 9 7 9 8

-28.3 -14.5 1.0 7.8 5.7 -14.4 20.0

63.51 85.37 77.95 69.42 63.99 81.10 51.27

-20.0 -20.0 25.0 40.0 30.0 -60.0 20.0

-140 -170 -120 -110 -100 -120 -60

90 140 90 80 70 120 100

SRT2104 1.0 g

11 Day Day Day Day Day Day Day

1 11 11 11 11 10 10

70.0 -28.2 -26.4 -27.3 -8.2 -9.0 -13.0

76.27 76.59 70.01 70.40 66.41 38.89

70.0 -20.0 -10.0 -30.0 0.0 -5.0 0.0

70 -220 -170 -200 -120 -140 -100

70 60 70 90 90 100 30

1 14 28 42 56 70 84

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 44 of 44 Clinical Study Report SRT-2104-013

Table 14.3.3.7 Summary of Change from Baseline for Clinical Chemistry Data Safety Analysis Set Population Lab Test Planned (Unit) Treatment N Visit n Mean SD Median Min. Max. -----------------------------------------------------------------------------------------------------------URIC ACID (UMOL/L) SRT2104 1.0 g 11 Follow-up 10 -7.0 31.29 -10.0 -40 60

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 8 Clinical Study Report SRT-2104-013

Table 14.3.3.8 Listing of Clinical Chemistry Abnormalities of Potential Clinical Importance Safety Analysis Set Population Treatment: Placebo Age(y)/ Sex/ Subj. Race

Lab Test (Units)

Planned Visit

Date/ Time

Study Day

Flag[1] PCI BL This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. Value

Normal Range

NR

[1] NR for Normal Range flag, PCI for Potential Clinical Importance flag, BL for Change from Baseline flag. H=Above range, L=Below range.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 321 Clinical Study Report SRT-2104-013

Table 14.3.3.9 Listing of All Clinical Chemistry Data for Subjects with Abnormalities of Potential Clinical Importance Safety Analysis Set Population Treatment: Placebo Age(y)/ Sex/ Subj. Race

Lab Test (Units)

Planned Visit

Date/ Time

Study Day

Flag[1] PCI BL This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. Value

Normal Range

NR

[1] NR for Normal Range flag, PCI for Potential Clinical Importance flag, BL for Change from Baseline flag. H=Above range, L=Below range.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------AMORPHOUS Screening n 1 3 2 0 SEDIMENT FEW 1 (100%) 2 (67%) 2 (100%) 0 MODERATE 0 1 (33%) 0 0 Day 1

n FEW MANY

0 0 0

1 1 (100%) 0

0 0 0

2 0 2 (100%)

Day 14

n FEW MODERATE

0 0 0

4 4 (100%) 0

0 0 0

1 0 1 (100%)

Day 28

n FEW MANY

1 1 (100%) 0

4 2 2

(50%) (50%)

3 2 1

(67%) (33%)

1 1 (100%) 0

n FEW MANY MODERATE

0 0 0 0

3 2 1 0

(67%) (33%)

2 1 0 1

(50%) (50%)

2 0 2 (100%) 0

Day 56

n FEW

0 0

0 0

1 1 (100%)

1 1 (100%)

Day 84

n FEW

1 1 (100%)

2 2 (100%)

1 1 (100%)

0 0

Follow-up

n FEW MODERATE

0 0 0

2 1 1

0 0 0

0 0 0

Day 42

(50%) (50%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------APPEARANCE Screening n 5 9 11 6 CLEAR 5 (100%) 6 (67%) 9 (82%) 3 (50%) CLOUDY 0 3 (33%) 2 (18%) 2 (33%) TURBID 0 0 0 1 (17%) Day 1

Day 14

Day 28

Day 42

Day 56

Day 70

n CLEAR CLOUDY TURBID

4 3 1 0

(75%) (25%)

8 7 1 0

(88%) (13%)

8 5 2 1

(63%) (25%) (13%)

5 1 2 2

(20%) (40%) (40%)

n CLEAR CLOUDY TURBID

5 3 2 0

(60%) (40%)

6 4 2 0

(67%) (33%)

9 5 2 2

(56%) (22%) (22%)

3 2 1 0

(67%) (33%)

n CLEAR CLOUDY TURBID

5 5 (100%) 0 0

9 6 1 2

(67%) (11%) (22%)

9 8 0 1

(89%)

3 2 1 0

(67%) (33%)

n CLEAR CLOUDY TURBID

4 4 (100%) 0 0

6 4 1 1

(67%) (17%) (17%)

4 3 0 1

(75%) (25%)

5 1 2 2

(20%) (40%) (40%)

n CLEAR CLOUDY

4 4 (100%) 0

6 4 2

(67%) (33%)

2 1 1

(50%) (50%)

3 2 1

(67%) (33%)

n CLEAR

2 1

4 3

(75%)

2 2 (100%)

3 1

(33%)

(50%)

(11%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------APPEARANCE Day 70 CLOUDY 1 (50%) 1 (25%) 0 2 (67%) Day 84

n CLEAR CLOUDY

2 1 1

(50%) (50%)

4 3 1

(75%) (25%)

2 2 (100%) 0

2 1 1

n CLEAR CLOUDY TURBID

4 4 (100%) 0 0

5 3 1 1

(60%) (20%) (20%)

3 3 (100%) 0 0

3 3 (100%) 0 0

Screening

n MANY

0 0

0 0

1 1 (100%)

0 0

Day 1

n MODERATE

0 0

0 0

0 0

1 1 (100%)

Day 14

n FEW MODERATE

0 0 0

0 0 0

1 1 (100%) 0

1 0 1 (100%)

Screening

n NEGATIVE

5 5 (100%)

9 9 (100%)

11 11 (100%)

6 6 (100%)

Day 1

n NEGATIVE

4 4 (100%)

8 8 (100%)

8 8 (100%)

5 5 (100%)

Day 14

n NEGATIVE

5 5 (100%)

6 6 (100%)

9 9 (100%)

3 3 (100%)

Day 28

n

5

9

9

3

Follow-up

BACTERIA

BILIRUBIN

(50%) (50%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------BILIRUBIN Day 28 NEGATIVE 5 (100%) 9 (100%) 9 (100%) 3 (100%)

CALCIUM OXALATE CRYS

COLOR

Day 42

n NEGATIVE

4 4 (100%)

6 6 (100%)

4 4 (100%)

5 5 (100%)

Day 56

n NEGATIVE

4 4 (100%)

6 6 (100%)

2 2 (100%)

3 3 (100%)

Day 70

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

3 3 (100%)

Day 84

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

2 2 (100%)

Follow-up

n NEGATIVE

4 4 (100%)

5 5 (100%)

3 3 (100%)

3 3 (100%)

Screening

n

0

0

1

0

FEW

0

0

1 (100%)

0

Day 14

n FEW

0 0

1 1 (100%)

0 0

0 0

Day 42

n FEW

0 0

0 0

1 1 (100%)

0 0

Screening

n DARK YELLOW YELLOW

5 0 5 (100%)

9 5 4

11 0 11 (100%)

6 1 5

(56%) (44%)

(17%) (83%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------COLOR Day 1 n 4 8 8 5 DARK YELLOW 1 (25%) 3 (38%) 0 2 (40%) YELLOW 3 (75%) 5 (63%) 8 (100%) 3 (60%) Day 14

Day 28

Day 42

Day 56

Day 70

Day 84

Follow-up

n DARK YELLOW YELLOW

5 0 5 (100%)

6 4 2

(67%) (33%)

9 2 7

(22%) (78%)

3 0 3 (100%)

n DARK YELLOW YELLOW

5 1 4

(20%) (80%)

9 5 4

(56%) (44%)

9 1 8

(11%) (89%)

3 0 3 (100%)

n DARK YELLOW ORANGE YELLOW

4 1 0 3

(25%) (75%)

6 3 1 2

(50%) (17%) (33%)

4 0 0 4 (100%)

5 3 1 1

n DARK YELLOW YELLOW

4 0 4 (100%)

6 5 1

(83%) (17%)

2 0 2 (100%)

3 0 3 (100%)

n DARK YELLOW YELLOW

2 0 2 (100%)

4 1 3

(25%) (75%)

2 0 2 (100%)

3 0 3 (100%)

n DARK YELLOW YELLOW

2 1 1

(50%) (50%)

4 1 3

(25%) (75%)

2 0 2 (100%)

2 1 1

n DARK YELLOW

4 1

(25%)

5 1

(20%)

3 0

3 0

(60%) (20%) (20%)

(50%) (50%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------COLOR Follow-up YELLOW 3 (75%) 4 (80%) 3 (100%) 3 (100%) GLUCOSE

Screening

Day 1

Day 14

Day 28

Day 42

n 2+ OR 1/2 G/DL (%) 3+ OR 1 G/DL (%) NEGATIVE

5 0

9 0

0

1

(11%)

0

5 (100%)

8

(89%)

10

n 3+ OR 1 G/DL (%) NEGATIVE

4 0

8 1

(13%)

8 0

5 0

4 (100%)

7

(88%)

8 (100%)

5 (100%)

n 3+ OR 1 G/DL (%) NEGATIVE

5 0

6 1

(17%)

9 1

(11%)

3 0

5 (100%)

5

(83%)

8

(89%)

3 (100%)

n 1+ OR 1/4 G/DL (%) 3+ OR 1 G/DL (%) NEGATIVE TRACE

5 0

9 1

(11%)

9 0

0

0

n 1+ OR 1/4 G/DL (%)

4 0

4 1

(80%) (20%)

11 1

(9%)

6 0 0

(91%)

6 (100%)

3 0

1

(11%)

0

(89%)

3 (100%) 0

8 0

(89%)

8 0

6 1

(17%)

4 0

5 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------GLUCOSE Day 42 2+ OR 1/2 0 1 (17%) 2 (50%) 0 G/DL (%) NEGATIVE 4 (100%) 4 (67%) 2 (50%) 5 (100%) Day 56

n 3+ OR 1 G/DL (%) NEGATIVE

4 0

6 1

(17%)

2 1

(50%)

3 0

4 (100%)

5

(83%)

1

(50%)

3 (100%)

n NEGATIVE TRACE

2 2 (100%) 0

4 4 (100%) 0

2 1 1

(50%) (50%)

3 3 (100%) 0

n 2+ OR 1/2 G/DL (%) NEGATIVE

2 0

4 0

2 1

(50%)

2 0

2 (100%)

4 (100%)

1

(50%)

2 (100%)

Follow-up

n NEGATIVE

4 4 (100%)

5 5 (100%)

3 3 (100%)

3 3 (100%)

Screening

n NEGATIVE

5 5 (100%)

9 9 (100%)

11 11 (100%)

6 6 (100%)

Day 1

n NEGATIVE TRACE

4 4 (100%) 0

8 8 (100%) 0

8 8 (100%) 0

5 4 1

(80%) (20%)

n NEGATIVE TRACE

5 5 (100%) 0

6 5 1

9 9 (100%) 0

3 2 1

(67%) (33%)

Day 70

Day 84

KETONE

Day 14

(83%) (17%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------KETONE Day 28 n 5 9 9 3 NEGATIVE 5 (100%) 9 (100%) 9 (100%) 3 (100%) Day 42

LEUKOCYTES

n NEGATIVE TRACE

4 4 (100%) 0

6 4 2

(67%) (33%)

4 4 (100%) 0

5 4 1

Day 56

n NEGATIVE

4 4 (100%)

6 6 (100%)

2 2 (100%)

3 3 (100%)

Day 70

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

3 3 (100%)

Day 84

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

2 2 (100%)

Follow-up

n NEGATIVE TRACE

4 4 (100%) 0

5 5 (100%) 0

3 3 (100%) 0

3 2 1

n 2+ NEGATIVE TRACE

5 1 4 0

9 1 8 0

n 2+ NEGATIVE

4 0 4 (100%)

8 0 8 (100%)

8 0 8 (100%)

5 1 4

(20%) (80%)

n NEGATIVE

5 5 (100%)

6 6 (100%)

9 9 (100%)

3 2

(67%)

Screening

Day 1

Day 14

(20%) (80%)

(11%) (89%)

11 0 10 1

(91%) (9%)

(80%) (20%)

(67%) (33%)

6 0 6 (100%) 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------LEUKOCYTES Day 14 TRACE 0 0 0 1 (33%) Day 28

n 2+ NEGATIVE

5 0 5 (100%)

9 1 8

(11%) (89%)

9 0 9 (100%)

3 0 3 (100%)

n 1+ 2+ NEGATIVE TRACE

4 0 0 4 (100%) 0

6 0 1 5 0

(17%) (83%)

4 0 0 4 (100%) 0

5 1 0 3 1

n 1+ NEGATIVE TRACE

4 0 4 (100%) 0

6 1 5 0

(17%) (83%)

2 0 2 (100%) 0

3 0 2 1

Day 70

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

3 3 (100%)

Day 84

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

2 2 (100%)

Follow-up

n NEGATIVE

4 4 (100%)

5 5 (100%)

3 3 (100%)

3 3 (100%)

Screening

n

1

5

3

1

FEW MODERATE

1 (100%) 0

3 2

3 (100%) 0

1 (100%) 0

Day 42

Day 56

MUCOUS THREADS

(60%) (40%)

(20%) (60%) (20%)

(67%) (33%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------MUCOUS Day 1 n 0 3 1 2 THREADS FEW 0 1 (33%) 1 (100%) 2 (100%) MODERATE 0 2 (67%) 0 0 Day 14

n FEW MODERATE

1 1 (100%) 0

4 3 1

(75%) (25%)

2 2 (100%) 0

1 1 (100%) 0

n FEW MODERATE

1 1 (100%) 0

4 3 1

(75%) (25%)

2 2 (100%) 0

1 1 (100%) 0

n FEW MODERATE

2 2 (100%) 0

5 4 1

(80%) (20%)

0 0 0

1 1 (100%) 0

Day 56

n FEW

0 0

2 2 (100%)

0 0

1 1 (100%)

Day 70

n FEW

1 1 (100%)

2 2 (100%)

0 0

1 1 (100%)

Day 84

n FEW

1 1 (100%)

1 1 (100%)

1 1 (100%)

0 0

Follow-up

n FEW

1 1 (100%)

2 2 (100%)

0 0

0 0

Screening

n NEGATIVE

5 5 (100%)

9 9 (100%)

11 10

Day 28

Day 42

NITRITE

(91%)

6 6 (100%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------NITRITE Screening POSITIVE 0 0 1 (9%) 0 Day 1

n NEGATIVE POSITIVE

4 4 (100%) 0

8 8 (100%) 0

8 8 (100%) 0

5 4 1

(80%) (20%)

n NEGATIVE POSITIVE

5 5 (100%) 0

6 6 (100%) 0

9 9 (100%) 0

3 2 1

(67%) (33%)

Day 28

n NEGATIVE

5 5 (100%)

9 9 (100%)

9 9 (100%)

3 3 (100%)

Day 42

n NEGATIVE POSITIVE

4 4 (100%) 0

6 6 (100%) 0

4 4 (100%) 0

5 4 1

Day 56

n NEGATIVE

4 4 (100%)

6 6 (100%)

2 2 (100%)

3 3 (100%)

Day 70

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

3 3 (100%)

Day 84

n NEGATIVE

2 2 (100%)

4 4 (100%)

2 2 (100%)

2 2 (100%)

Follow-up

n NEGATIVE

4 4 (100%)

5 5 (100%)

3 3 (100%)

3 3 (100%)

Screening

n 1+

5 0

9 0

Day 14

OCCULT BLOOD

11 0

6 1

(80%) (20%)

(17%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------OCCULT BLOOD Screening 3+ 0 0 1 (9%) 0 NEGATIVE 5 (100%) 9 (100%) 8 (73%) 5 (83%) TRACE 0 0 2 (18%) 0 Day 1

n 3+ NEGATIVE TRACE

4 0 4 (100%) 0

8 0 8 (100%) 0

8 1 7 0

(13%) (88%)

5 0 4 1

n 3+ NEGATIVE

5 0 5 (100%)

6 0 6 (100%)

9 1 8

(11%) (89%)

3 0 3 (100%)

n 1+ 3+ NEGATIVE TRACE

5 0 0 5 (100%) 0

9 0 0 9 (100%) 0

9 0 1 7 1

(11%) (78%) (11%)

3 1 0 2 0

n 1+ 3+ NEGATIVE TRACE

4 0 0 4 (100%) 0

6 0 0 6 (100%) 0

4 0 0 3 1

(75%) (25%)

5 1 1 3 0

Day 56

n NEGATIVE

4 4 (100%)

6 6 (100%)

2 2 (100%)

3 3 (100%)

Day 70

n NEGATIVE TRACE

2 2 (100%) 0

4 4 (100%) 0

2 2 (100%) 0

3 2 1

Day 14

Day 28

Day 42

(80%) (20%)

(33%) (67%)

(20%) (20%) (60%)

(67%) (33%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------OCCULT BLOOD Day 84 n 2 4 2 2 NEGATIVE 2 (100%) 4 (100%) 2 (100%) 2 (100%) Follow-up

RBC/HPF

Screening

Day 1

Day 14

Day 28

n 1+ NEGATIVE

4 0 4 (100%)

5 0 5 (100%)

3 0 3 (100%)

3 1 2

n 0-1 1-3 15-25 3-5 NONE SEEN

2 1 0 0 0 1

(50%)

5 2 1 0 0 2

5 1 1 1 0 2

(40%)

1 0 0 0 1 (100%) 0

n 0-1 1-3 3-5 5-10 NONE SEEN

1 0 0 0 0 1 (100%)

3 1 0 0 0 2

(50%) (50%)

3 0 1 1 0 1

n 0-1 10-15 NONE SEEN

1 0 0 1 (100%)

4 1 0 3

(50%) (50%)

1 1 (100%) 0 0

n 0-1 1-3 15-25 3-5

2 0 0 0 0

5 3 0 0 0

(50%)

(40%) (20%) (40%) (33%)

(67%) (25%) (75%) (60%)

2 0 0 0 1 1 2 0 1 1 4 1 1 1 0

(20%) (20%) (20%)

(25%) (25%) (25%)

(33%) (67%)

(33%) (33%) (33%)

1 0 0 0 1 (100%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------RBC/HPF Day 28 NONE SEEN 2 (100%) 2 (40%) 1 (25%) 0 Day 42

n 0-1 3-5 INNUMERABLE NONE SEEN

2 1 0 0 1

(50%)

5 3 0 0 2

(40%)

3 1 1 0 1

n 1-3 NONE SEEN

1 0 1 (100%)

3 1 2

(33%) (67%)

1 0 1 (100%)

1 0 1 (100%)

Day 70

n 1-3 NONE SEEN

1 0 1 (100%)

2 0 2 (100%)

1 0 1 (100%)

1 1 (100%) 0

Day 84

n 0-1 NONE SEEN

1 1 (100%) 0

2 1 1

1 0 1 (100%)

0 0 0

Follow-up

n 0-1 3-5 NONE SEEN

1 1 (100%) 0 0

2 0 0 2 (100%)

0 0 0 0

1 0 1 (100%) 0

Screening

n

1

4

4

1

FEW (1-5) MANY (21 OR GREATER) OCCASIONAL

0 0

2 0

(50%)

2 1

(50%) (25%)

1 (100%) 0

1 (100%)

2

(50%)

1

(25%)

0

Day 56

SQUAMOUS EPITH CELLS

(50%)

(60%)

(50%) (50%)

(33%) (33%) (33%)

3 0 1 1 1

(33%) (33%) (33%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------SQUAMOUS Day 1 n 0 2 1 2 EPITH CELLS FEW (1-5) 0 1 (50%) 1 (100%) 2 (100%) OCCASIONAL 0 1 (50%) 0 0 Day 14

n FEW (1-5) OCCASIONAL

0 0 0

3 0 3 (100%)

1 1 (100%) 0

0 0 0

Day 28

n FEW (1-5) OCCASIONAL

2 2 (100%) 0

4 3 1

(75%) (25%)

1 1 (100%) 0

0 0 0

n FEW (1-5) MODERATE (6-20) OCCASIONAL

1 1 (100%) 0

3 0 1

(33%)

1 1 (100%) 0

2 1 1

0

2

(67%)

0

0

Day 56

n FEW (1-5) OCCASIONAL

0 0 0

1 1 (100%) 0

1 0 1 (100%)

1 0 1 (100%)

Day 70

n FEW (1-5)

0 0

0 0

0 0

1 1 (100%)

Day 84

n FEW (1-5) OCCASIONAL

1 1 (100%) 0

2 1 1

1 0 1 (100%)

0 0 0

n

1

2

0

0

Day 42

Follow-up

(50%) (50%)

(50%) (50%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------SQUAMOUS Follow-up FEW (1-5) 1 (100%) 0 0 0 EPITH CELLS OCCASIONAL 0 2 (100%) 0 0 URIC ACID CRYSTALS

WBC/HPF

Screening

n

0

0

1

0

MODERATE

0

0

1 (100%)

0

Day 28

n FEW

1 1 (100%)

0 0

0 0

0 0

Screening

n 0-1 1-3 15-25 3-5 5-10 NONE SEEN

2 1 0 1 0 0 0

5 1 1 0 0 2 1

n 1-3 10-15 NONE SEEN

1 0 0 1 (100%)

3 1 0 2

(33%)

n 0-1 3-5 NONE SEEN

1 0 0 1 (100%)

4 3 0 1

(75%)

n 0-1

2 0

5 1

Day 1

Day 14

Day 28

(50%) (50%)

(20%) (20%) (40%) (20%)

5 1 2 0 1 0 1

(20%) (40%) (20%) (20%)

1 1 (100%) 0 0 0 0 0

2 0 0 2 (100%)

3 0 1 2

(50%)

(25%)

2 1 0 1

(50%)

1 0 1 (100%) 0

(20%)

4 1

(25%)

1 0

(67%)

(33%) (67%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------WBC/HPF Day 28 1-3 0 1 (20%) 0 0 5-10 0 1 (20%) 0 0 NONE SEEN 2 (100%) 2 (40%) 3 (75%) 1 (100%) Day 42

n 0-1 1-3 10-15 3-5 NONE SEEN

2 1 0 0 0 1

(50%)

5 2 0 1 0 2

(40%)

3 1 0 0 0 2

n 0-1 5-10 NONE SEEN

1 0 0 1 (100%)

3 0 1 2

(33%) (67%)

1 1 (100%) 0 0

1 1 (100%) 0 0

Day 70

n 0-1 NONE SEEN

1 0 1 (100%)

2 0 2 (100%)

1 0 1 (100%)

1 1 (100%) 0

Day 84

n 0-1

1 1 (100%)

2 2 (100%)

1 1 (100%)

0 0

Follow-up

n 0-1 NONE SEEN

1 1 (100%) 0

2 2 (100%) 0

0 0 0

1 0 1 (100%)

Screening

n

5

9

11

6

1.0230 0.00854

1.0293 0.00740

1.0219 0.00656

1.0190 0.00885

Day 56

SPECIFIC GRAVITY

Mean SD

(50%)

(40%) (20%)

(33%)

(67%)

3 0 1 0 1 1

(33%) (33%) (33%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------SPECIFIC Screening Median 1.0240 1.0280 1.0210 1.0200 GRAVITY Min. 1.010 1.019 1.010 1.008 Max. 1.034 1.042 1.030 1.030 Day 1

n Mean SD Median Min. Max.

4 1.0208 0.00465 1.0200 1.016 1.027

8 1.0274 0.00713 1.0250 1.022 1.044

8 1.0200 0.00545 1.0220 1.012 1.025

5 1.0232 0.00901 1.0260 1.012 1.034

Day 14

n Mean SD Median Min. Max.

5 1.0216 0.00706 1.0250 1.013 1.028

6 1.0258 0.00847 1.0275 1.013 1.036

9 1.0227 0.00823 1.0200 1.011 1.037

3 1.0243 0.01102 1.0250 1.013 1.035

Day 28

n Mean SD Median Min. Max.

5 1.0222 0.00455 1.0240 1.016 1.027

9 1.0258 0.00519 1.0240 1.020 1.035

9 1.0203 0.00474 1.0220 1.013 1.026

3 1.0227 0.01150 1.0230 1.011 1.034

Day 42

n Mean SD Median Min.

4 1.0253 0.00411 1.0260 1.020

6 1.0272 0.00728 1.0260 1.019

4 1.0238 0.00814 1.0255 1.013

5 1.0248 0.00729 1.0270 1.013

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 19 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------SPECIFIC Day 42 Max. 1.029 1.036 1.031 1.031 GRAVITY Day 56

n Mean SD Median Min. Max.

4 1.0213 0.00655 1.0215 1.013 1.029

6 1.0273 0.00455 1.0270 1.022 1.035

2 1.0200 0.01131 1.0200 1.012 1.028

3 1.0170 0.00600 1.0170 1.011 1.023

Day 70

n Mean SD Median Min. Max.

2 1.0240 0.00283 1.0240 1.022 1.026

4 1.0213 0.00435 1.0225 1.015 1.025

2 1.0200 0.01273 1.0200 1.011 1.029

3 1.0200 0.00954 1.0190 1.011 1.030

Day 84

n Mean SD Median Min. Max.

2 1.0285 0.00212 1.0285 1.027 1.030

4 1.0188 0.00665 1.0185 1.013 1.025

2 1.0170 0.01273 1.0170 1.008 1.026

2 1.0195 0.00919 1.0195 1.013 1.026

Follow-up

n Mean SD Median Min. Max.

4 1.0260 0.00216 1.0265 1.023 1.028

5 1.0222 0.00259 1.0230 1.018 1.025

3 1.0213 0.01002 1.0250 1.010 1.029

3 1.0230 0.00173 1.0220 1.022 1.025

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 20 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------REACTION PH Screening n 5 9 11 6 Mean 5.80 6.00 6.05 5.83 SD 0.274 0.433 0.723 0.606 Median 6.00 6.00 6.00 5.50 Min. 5.5 5.0 5.5 5.5 Max. 6.0 6.5 8.0 7.0 Day 1

n Mean SD Median Min. Max.

4 6.38 0.479 6.25 6.0 7.0

8 6.13 0.518 6.00 5.5 7.0

8 5.81 0.372 5.75 5.5 6.5

5 5.70 0.447 5.50 5.5 6.5

Day 14

n Mean SD Median Min. Max.

5 6.10 0.224 6.00 6.0 6.5

6 5.83 0.408 5.75 5.5 6.5

9 5.78 0.507 5.50 5.5 7.0

3 5.67 0.289 5.50 5.5 6.0

Day 28

n Mean SD Median Min. Max.

5 5.80 0.274 6.00 5.5 6.0

9 6.11 0.333 6.00 5.5 6.5

9 5.83 0.250 6.00 5.5 6.0

3 5.83 0.289 6.00 5.5 6.0

Day 42

n Mean SD

4 6.00 0.408

6 5.83 0.683

4 5.75 0.500

5 5.70 0.274

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 21 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------REACTION PH Day 42 Median 6.00 5.75 5.50 5.50 Min. 5.5 5.0 5.5 5.5 Max. 6.5 7.0 6.5 6.0 Day 56

n Mean SD Median Min. Max.

4 5.88 0.750 6.00 5.0 6.5

6 5.67 0.408 5.75 5.0 6.0

2 5.75 0.354 5.75 5.5 6.0

3 5.67 0.289 5.50 5.5 6.0

Day 70

n Mean SD Median Min. Max.

2 5.75 0.354 5.75 5.5 6.0

4 5.75 0.289 5.75 5.5 6.0

2 5.50 0.000 5.50 5.5 5.5

3 5.83 0.289 6.00 5.5 6.0

Day 84

n Mean SD Median Min. Max.

2 5.75 0.354 5.75 5.5 6.0

4 5.63 0.250 5.50 5.5 6.0

2 5.75 0.354 5.75 5.5 6.0

2 5.75 0.354 5.75 5.5 6.0

Follow-up

n Mean SD Median Min. Max.

4 5.75 0.289 5.75 5.5 6.0

5 6.30 0.758 6.50 5.0 7.0

3 5.33 0.289 5.50 5.0 5.5

3 5.67 0.289 5.50 5.5 6.0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 22 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------PROTEIN Screening n 5 9 11 6 1+ 1 (20%) 0 1 (9%) 0 2+ 0 1 (11%) 0 0 3+ 0 1 (11%) 0 0 NEGATIVE 4 (80%) 5 (56%) 10 (91%) 6 (100%) TRACE 0 2 (22%) 0 0 Day 1

Day 14

Day 28

Day 42

n 2+ 3+ NEGATIVE TRACE

4 1 0 3 0

n 1+ 2+ 3+ NEGATIVE TRACE

5 1 0 0 4 0

n 1+ 2+ 3+ NEGATIVE TRACE

5 1 0 0 4 0

n 1+ 2+ 3+

4 1 0 0

(25%) (75%)

(20%) (80%)

(20%) (80%)

(25%)

8 1 1 6 0

(13%) (13%) (75%)

8 0 0 7 1

6 0 1 1 3 1

(17%) (17%) (50%) (17%)

9 0 1 0 8 0

9 1 1 1 5 1

(11%) (11%) (11%) (56%) (11%)

9 1 0 0 7 1

6 1 1 1

(17%) (17%) (17%)

4 1 0 0

(88%) (13%)

(11%) (89%)

(11%) (78%) (11%) (25%)

5 0 0 4 1 3 1 0 0 2 0

(80%) (20%) (33%) (67%)

3 0 0 0 3 (100%) 0 5 1 0 0

(20%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 23 of 23 Clinical Study Report SRT-2104-013 Table 14.3.3.10 Summary of Urinalysis Data Safety Analysis Set Population

0.25 g 0.5 g 1.0 g Placebo SRT2379 SRT2379 SRT2379 Lab Test Visit Result (N=7) (N=9) (N=12) (N=11) --------------------------------------------------------------------------------------------PROTEIN Day 42 NEGATIVE 2 (50%) 1 (17%) 3 (75%) 3 (60%) TRACE 1 (25%) 2 (33%) 0 1 (20%) Day 56

Day 70

Day 84

Follow-up

n 1+ 3+ NEGATIVE TRACE

4 1 0 3 0

n 1+ 2+ 3+ NEGATIVE

2 1 0 0 1

n 1+ 2+ 3+ NEGATIVE

2 1 0 0 1

n 1+ 2+ 3+ NEGATIVE

4 1 0 0 3

(25%) (75%)

(50%) (50%) (50%) (50%) (25%) (75%)

6 1 1 3 1 4 0 1 1 2 4 0 1 1 2 5 0 1 1 3

(17%) (17%) (50%) (17%)

2 0 0 2 (100%) 0

3 0 0 3 (100%) 0

(25%) (25%) (50%)

2 0 0 0 2 (100%)

3 0 0 0 3 (100%)

(25%) (25%) (50%)

2 0 0 0 2 (100%)

2 0 0 0 2 (100%)

(20%) (20%) (60%)

3 0 0 0 3 (100%)

3 0 0 0 3 (100%)

Page 1 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = ALAT (SGPT) (U/L)

ALAT (SGPT) (U/L)

30

-20 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 2 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = ALBUMIN (G/L)

3 2 1

ALBUMIN (G/L)

0 -1 -2 -3 -4 -5 -6 -7 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 3 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = ALKALINE PHOSPHATASE (U/L)

10

ALKALINE PHOSPHATASE (U/L)

8 6 4 2 0 -2 -4 -6 -8 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 4 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = ASAT (SGOT) (U/L)

15 10

ASAT (SGOT) (U/L)

5 0 -5 -10 -15 -20 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 5 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = DIRECT BILIRUBIN (UMOL/L)

3.0

DIRECT BILIRUBIN (UMOL/L)

2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 6 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = INDIRECT BILIRUBIN (UMOL/L)

12

INDIRECT BILIRUBIN (UMOL/L)

10 8 6 4 2 0 -2 -4 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 7 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = TOTAL BILIRUBIN (UMOL/L)

14

TOTAL BILIRUBIN (UMOL/L)

12 10 8 6 4 2 0 -2 -4 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 8 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = CALCIUM (MMOL/L)

0.4 0.3

CALCIUM (MMOL/L)

0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 9 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = CHLORIDE (MMOL/L)

12 10

CHLORIDE (MMOL/L)

8 6 4 2 0 -2 -4 -6 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 10 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = TOTAL CHOLESTEROL (MMOL/L)

1.0

TOTAL CHOLESTEROL (MMOL/L)

0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 11 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = CO2 CONTENT (MMOL/L)

4

CO2 CONTENT (MMOL/L)

2 0 -2 -4 -6 -8 -10 -12 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 12 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = TOTAL CPK (U/L)

600 500

TOTAL CPK (U/L)

400 300 200 100 0 -100 -200 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 13 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = CREATININE (UMOL/L)

20

CREATININE (UMOL/L)

16 12 8 4 0 -4 -8 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 14 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = GGT (U/L)

10 8 6

GGT (U/L)

4 2 0 -2 -4 -6 -8 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 15 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = PLASMA GLUCOSE (MMOL/L)

5

PLASMA GLUCOSE (MMOL/L)

4 3 2 1 0 -1 -2 -3 -4 -5 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 16 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = HDL CHOL DIRECT (MMOL/L)

0.4 0.3

HDL CHOL DIRECT (MMOL/L)

0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 17 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = LACTIC DEHYDROGENASE (U/L)

50

LACTIC DEHYDROGENASE (U/L)

40 30 20 10 0 -10 -20 -30 -40 -50 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 18 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = LDL-CHOL CALCULATION (MMOL/L)

1.0

LDL-CHOL CALCULATION (MMOL/L)

0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 19 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = MAGNESIUM (MMOL/L)

1.0 0.8

MAGNESIUM (MMOL/L)

0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 20 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = NEFA (MMOL/L)

1.0 0.8 0.6

NEFA (MMOL/L)

0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 21 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = PHOSPHORUS INORGANIC (MMOL/L)

1.0

PHOSPHORUS INORGANIC (MMOL/L)

0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 22 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = POTASSIUM (MMOL/L)

1.0 0.8

POTASSIUM (MMOL/L)

0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 23 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = SODIUM (MMOL/L)

6

SODIUM (MMOL/L)

4

2

0

-2

-4

-6 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 24 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = TRIGLYCERIDES (MMOL/L)

1.6 1.4

TRIGLYCERIDES (MMOL/L)

1.2 1.0 0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 25 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = UREA NITROGEN (MMOL/L)

3

UREA NITROGEN (MMOL/L)

2 1 0 -1 -2 -3 -4 -5 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 26 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Chemistry Parameter = URIC ACID (UMOL/L)

100 80

URIC ACID (UMOL/L)

60 40 20 0 -20 -40 -60 -80 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 27 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = BASOPHILS (%)

1.0 0.8 0.6

BASOPHILS (%)

0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 28 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = BASOPHILS ABSOLUTE (GI/L)

0.10

BASOPHILS ABSOLUTE (GI/L)

0.08 0.06 0.04 0.02 0.00 -0.02 -0.04 -0.06 -0.08 -0.10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 29 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time

CRP HIGH SENSITIVITY (MG/L)

Hematology Parameter = CRP HIGH SENSITIVITY (MG/L)

10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 30 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = EOSINOPHILS (%)

3 2

EOSINOPHILS (%)

1 0 -1 -2 -3 -4 -5 -6 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 31 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = EOSINOPHILS ABSOLUTE (GI/L)

1.0

EOSINOPHILS ABSOLUTE (GI/L)

0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 32 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = HEMATOCRIT (1)

0.10 0.08 0.06

HEMATOCRIT (1)

0.04 0.02 0.00 -0.02 -0.04 -0.06 -0.08 -0.10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 33 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = HEMOGLOBIN (G/L)

10 8

HEMOGLOBIN (G/L)

6 4 2 0 -2 -4 -6 -8 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 34 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = LYMPHOCYTES (%)

10 5

LYMPHOCYTES (%)

0 -5 -10 -15 -20 -25 -30 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 35 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = LYMPHOCYTES ABSOLUTE (GI/L)

LYMPHOCYTES ABSOLUTE (GI/L)

2

1

0

-1

-2

-3 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 36 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = MCH (PG)

2.0 1.5 1.0

MCH (PG)

0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 37 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = MCHC (G/L)

10

5

MCHC (G/L)

0

-5

-10

-15

-20 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 38 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = MCV (FL)

5 4 3 2

MCV (FL)

1 0 -1 -2 -3 -4 -5 -6 -7 -8 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 39 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = MONOCYTES (%)

5 4

MONOCYTES (%)

3 2 1 0 -1 -2 -3 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 40 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = MONOCYTES ABSOLUTE (GI/L)

1.0

MONOCYTES ABSOLUTE (GI/L)

0.8 0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 41 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = NEUTROPHIL SEGS (%)

30

NEUTROPHIL SEGS (%)

25 20 15 10 5 0 -5 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 42 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = NEUTROPHILS ABSOLUTE (GI/L)

5

NEUTROPHILS ABSOLUTE (GI/L)

4 3 2 1 0 -1 -2 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 43 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = PLATELET COUNT (GI/L)

60

PLATELET COUNT (GI/L)

50 40 30 20 10 0 -10 -20 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 44 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time

RDW (%)

Hematology Parameter = RDW (%)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0 -1.1 -1.2 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 45 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = RED CELL COUNT (TI/L)

1.0 0.8

RED CELL COUNT (TI/L)

0.6 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 46 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = TOTAL NEUTROPHILS (%)

35 30

TOTAL NEUTROPHILS (%)

25 20 15 10 5 0 -5 -10 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 47 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = TOTAL NEUTROPHILS AB (GI/L)

5

TOTAL NEUTROPHILS AB (GI/L)

4 3 2 1 0 -1 -2 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 48 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Hematology Parameter = WHITE CELL COUNT (GI/L)

4

WHITE CELL COUNT (GI/L)

3

2

1

0

-1

-2 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 49 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Coagulation Parameter = INR

0.5 0.4 0.3

INR

0.2 0.1 0.0 -0.1 -0.2 -0.3 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 50 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Coagulation Parameter = PROTHROMBIN TIME (SECONDS)

2.5

PROTHROMBIN TIME (SECONDS)

2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 51 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Coagulation Parameter = APTT

2.0 1.5

APTT

1.0 0.5 0.0 -0.5 -1.0 -1.5 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 52 of 52

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Report SRT-2104-013

Figure 14.3.3.11 Plot of Mean Change from Baseline Lab Parameters Vs Time Urinalysis Parameter = URINE SPECIFIC GRAVITY

0.03

URINE SPECIFIC GRAVITY

0.02

0.01

0.00

-0.01

-0.02

-0.03 14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 1 of 4 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.12 Plot of Mean Change from Baseline Vital Signs Vs Time by Treatment Systolic Blood Pressure Change from Baseline (mmHg)

Systolic Blood Pressure Change from Baseline (mmHg)

14 12 10 8 6 4 2 0 -2 -4 -6 1

14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 2 of 4 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.12 Plot of Mean Change from Baseline Vital Signs Vs Time by Treatment

Diastolic Blood Pressure Change from Baseline (mmHg)

Diastolic Blood Pressure Change from Baseline (mmHg)

3

1

-1

-3

-5

-7 1

14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 3 of 4 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.12 Plot of Mean Change from Baseline Vital Signs Vs Time by Treatment Heart Rate Change from Baseline (beats/min)

Heart Rate Change from Baseline (beats/min)

12 10 8 6 4 2 0 -2 1

14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 4 of 4 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.12 Plot of Mean Change from Baseline Vital Signs Vs Time by Treatment Respiratory Rate Change from Baseline (breaths/min)

Respiratory Rate Change from Baseline (breaths/min)

2

0

-2 1

14

28

42

56

70

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

84

Page 1 of 5 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.13 Plot of Mean Change from Baseline ECG Measure Vs Time by Treatment PR Interval Change from Baseline (MSEC)

22 PR Interval Change from Baseline (MSEC)

20 18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 28

56

84

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

Page 2 of 5 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.13 Plot of Mean Change from Baseline ECG Measure Vs Time by Treatment QRS Duration Change from Baseline (MSEC)

QRS Duration Change from Baseline (MSEC)

6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 28

56

84

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

Page 3 of 5 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.13 Plot of Mean Change from Baseline ECG Measure Vs Time by Treatment

QT Interval Change from Baseline (MSEC)

QT Interval Change from Baseline (MSEC)

60 55 50 45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 28

56

84

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

Page 4 of 5 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.13 Plot of Mean Change from Baseline ECG Measure Vs Time by Treatment

QTcB Change from Baseline (MSEC)

QTcB Change from Baseline (MSEC)

60 55 50 45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 28

56

84

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

Page 5 of 5 Clinical Study Report SRT-2104-013

SRT2104

Sirtris Pharmaceuticals, Inc.

Figure 14.3.3.13 Plot of Mean Change from Baseline ECG Measure Vs Time by Treatment

QTcF Change from Baseline (MSEC)

QTcF Change from Baseline (MSEC)

60 55 50 45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 28

56

84

Planned Time (Days) Treatment:

P

A

B

C

P = Placebo; A = SRT2104 0.25g; B = SRT2104 0.5g; C = SRT2104 1.0g. Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Systolic blood pressure Placebo 7 Screening 7 114.9 12.38 118.0 98 128 (mmHg)

SRT2104 0.25 g

9

Day 1

7

120.7

11.03

120.0

100

135

Day 14

7

121.7

10.16

122.0

110

140

Day 28

7

119.0

9.92

118.0

110

135

Day 42

7

120.9

11.25

126.0

100

130

Day 56

7

119.1

13.66

120.0

104

140

Day 70

7

127.1

5.27

130.0

120

132

Day 84

7

122.3

12.19

128.0

100

136

Follow-up

7

120.3

14.02

120.0

100

142

Screening

9

122.4

14.31

112.0

110

142

Day 1

9

121.1

8.67

120.0

110

138

Day 14

9

124.2

16.41

122.0

100

148

Day 28

9

122.0

8.72

122.0

112

136

Day 42

7

127.7

17.72

128.0

100

150

Day 56

6

123.0

14.46

117.0

110

150

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Systolic blood pressure SRT2104 0.25 g 9 Day 70 5 125.2 19.88 120.0 104 158 (mmHg)

SRT2104 0.5 g

SRT2104 1.0 g

12

11

Day 84

8

122.0

19.68

114.0

102

160

Follow-up

6

125.0

16.28

118.0

112

148

Screening

12

122.0

9.07

122.0

108

138

Day 1

12

120.8

12.31

118.0

106

144

Day 14

12

121.2

11.39

122.0

104

138

Day 28

12

125.5

8.91

125.0

112

138

Day 42

11

120.1

9.15

122.0

100

136

Day 56

9

120.0

4.69

120.0

112

126

Day 70

9

121.6

3.97

122.0

116

128

Day 84

12

120.5

9.69

122.0

100

134

Follow-up

10

124.0

14.30

123.0

98

152

Screening

11

127.3

18.60

124.0

98

160

Day 1

11

126.3

19.65

120.0

108

166

Day 14

11

121.5

17.47

120.0

100

155

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Systolic blood pressure SRT2104 1.0 g 11 Day 28 11 121.2 17.49 120.0 98 148 (mmHg)

Diastolic Blood Pressure (mmHg)

Placebo

7

Day 42

11

125.0

17.81

120.0

98

165

Day 56

11

125.1

20.43

120.0

102

165

Day 70

11

122.2

14.63

118.0

108

150

Day 84

11

123.0

14.99

120.0

100

150

Follow-up

10

119.2

16.23

119.0

100

150

Screening

7

79.1

7.73

80.0

68

90

Day 1

7

77.1

7.56

76.0

68

90

Day 14

7

75.4

7.37

74.0

70

90

Day 28

7

77.6

8.32

80.0

60

84

Day 42

7

78.7

4.86

80.0

70

84

Day 56

7

77.0

9.29

80.0

64

90

Day 70

7

77.4

5.86

78.0

70

84

Day 84

7

79.7

7.70

84.0

64

86

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Diastolic Blood Placebo 7 Follow-up 7 78.4 6.78 80.0 68 86 Pressure (mmHg) SRT2104 0.25 g

SRT2104 0.5 g

9

12

Screening

9

78.4

11.39

80.0

60

94

Day 1

9

76.9

11.19

78.0

60

92

Day 14

9

76.2

12.31

78.0

60

100

Day 28

9

79.1

10.20

78.0

60

94

Day 42

7

78.3

13.59

78.0

60

100

Day 56

6

72.3

7.84

70.0

64

86

Day 70

5

75.6

16.40

70.0

60

100

Day 84

8

77.8

11.68

76.0

60

100

Follow-up

6

78.3

14.61

79.0

60

98

Screening

12

76.7

7.45

79.0

64

88

Day 1

12

75.2

8.02

76.0

60

88

Day 14

12

75.5

7.09

78.0

58

80

Day 28

12

77.2

8.16

80.0

64

90

Day 42

11

74.4

6.56

76.0

60

80

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Diastolic Blood SRT2104 0.5 g 12 Day 56 9 76.4 5.17 78.0 68 82 Pressure (mmHg)

SRT2104 1.0 g

Heart rate (bpm)

Placebo

11

7

Day 70

9

78.7

7.87

80.0

64

88

Day 84

12

76.2

8.80

79.0

58

88

Follow-up

10

79.8

6.96

80.0

70

94

Screening

11

81.5

6.82

80.0

70

90

Day 1

11

81.4

8.37

80.0

70

96

Day 14

11

79.3

7.95

80.0

60

90

Day 28

11

74.7

8.40

80.0

60

82

Day 42

11

80.3

9.06

80.0

66

90

Day 56

11

78.6

6.38

78.0

68

90

Day 70

11

83.2

7.81

80.0

72

100

Day 84

11

80.1

7.65

78.0

70

92

Follow-up

10

76.9

7.13

77.0

70

90

Screening

7

70.3

9.76

68.0

52

80

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Heart rate Placebo 7 Day 1 7 72.6 15.86 74.0 50 100 (bpm)

SRT2104 0.25 g

9

Day 14

7

71.4

9.71

70.0

60

88

Day 28

7

70.0

15.79

72.0

48

96

Day 42

7

71.1

16.96

74.0

48

100

Day 56

7

68.3

14.07

68.0

52

88

Day 70

7

70.3

13.24

64.0

56

88

Day 84

7

72.9

14.04

68.0

60

100

Follow-up

7

72.3

8.98

72.0

60

84

Screening

9

72.9

11.92

72.0

56

96

Day 1

9

69.3

9.43

68.0

56

82

Day 14

9

72.4

7.54

72.0

64

86

Day 28

9

69.8

8.69

72.0

60

84

Day 42

7

76.0

8.25

80.0

66

84

Day 56

6

71.7

11.34

72.0

56

88

Day 70

5

78.8

11.97

84.0

58

88

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Heart rate SRT2104 0.25 g 9 Day 84 8 70.5 13.68 70.0 56 96 (bpm)

SRT2104 0.5 g

SRT2104 1.0 g

12

11

Follow-up

6

73.3

9.35

76.0

60

84

Screening

12

72.7

12.16

75.0

54

96

Day 1

12

67.8

13.47

63.0

52

88

Day 14

12

72.3

10.58

72.0

56

86

Day 28

12

68.8

11.40

67.5

56

90

Day 42

11

71.3

10.67

72.0

60

92

Day 56

9

71.0

8.89

70.0

60

86

Day 70

9

72.4

8.93

70.0

60

88

Day 84

12

69.2

13.76

69.0

44

94

Follow-up

10

73.2

9.25

74.0

52

88

Screening

11

69.3

8.59

72.0

56

84

Day 1

11

69.8

10.90

72.0

56

90

Day 14

11

68.4

10.50

72.0

56

88

Day 28

11

70.4

15.92

64.0

56

108

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Heart rate SRT2104 1.0 g 11 Day 42 11 74.5 13.68 74.0 56 98 (bpm)

Respiratory Rate (breaths/min)

Placebo

SRT2104 0.25 g

7

9

Day 56

11

72.5

15.72

74.0

50

96

Day 70

11

72.4

14.33

72.0

46

94

Day 84

11

71.1

11.33

72.0

56

84

Follow-up

10

72.0

11.51

73.0

56

94

Screening

7

15.4

3.60

16.0

12

20

Day 1

7

16.0

3.27

16.0

12

20

Day 14

7

15.1

3.24

16.0

12

20

Day 28

7

15.4

3.60

16.0

12

20

Day 42

7

14.6

2.51

16.0

12

18

Day 56

7

15.4

3.60

16.0

12

20

Day 70

7

15.4

3.60

16.0

12

20

Day 84

7

14.9

3.24

14.0

12

20

Follow-up

7

16.3

4.07

16.0

12

24

Screening

9

14.9

2.47

14.0

12

20

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Respiratory Rate SRT2104 0.25 g 9 Day 1 9 14.2 2.73 14.0 12 20 (breaths/min)

SRT2104 0.5 g

12

Day 14

9

15.6

2.40

16.0

12

20

Day 28

9

14.9

2.67

14.0

12

20

Day 42

7

15.7

2.14

16.0

14

20

Day 56

6

14.0

3.10

13.0

12

20

Day 70

5

15.6

2.61

14.0

14

20

Day 84

8

13.8

2.71

13.0

12

20

Follow-up

6

14.7

2.73

14.0

12

20

Screening

12

16.3

2.67

18.0

12

20

Day 1

12

16.2

3.01

17.0

12

20

Day 14

12

17.0

3.13

18.0

12

20

Day 28

12

15.8

2.56

16.5

12

18

Day 42

11

17.3

3.61

18.0

12

22

Day 56

9

17.3

3.16

18.0

12

20

Day 70

9

16.9

3.02

18.0

12

20

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Respiratory Rate SRT2104 0.5 g 12 Day 84 12 16.2 2.89 18.0 12 20 (breaths/min)

SRT2104 1.0 g

Temperature (Celsius)

Placebo

11

7

Follow-up

10

17.6

3.10

19.0

12

20

Screening

11

15.6

2.66

16.0

12

20

Day 1

11

15.8

2.09

16.0

12

18

Day 14

11

16.4

2.66

16.0

12

20

Day 28

11

16.5

2.70

16.0

12

20

Day 42

11

16.8

2.86

17.0

12

20

Day 56

11

16.0

3.79

16.0

12

24

Day 70

11

16.3

3.17

16.0

12

20

Day 84

11

16.5

3.70

16.0

12

24

Follow-up

10

15.2

3.55

14.0

12

20

Screening

7

36.50

0.361

36.60

35.8

36.9

Day 1

7

36.43

0.515

36.70

35.4

36.8

Day 14

7

36.46

0.443

36.60

35.7

36.9

Day 28

7

36.41

0.453

36.40

35.8

37.1

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Temperature Placebo 7 Day 42 7 36.40 0.638 36.60 35.1 37.0 (Celsius)

SRT2104 0.25 g

SRT2104 0.5 g

9

12

Day 56

7

36.49

0.508

36.60

35.6

37.2

Day 70

7

36.46

0.355

36.60

35.8

36.8

Day 84

7

36.44

0.544

36.60

35.6

37.1

Follow-up

7

36.44

0.399

36.60

35.9

36.9

Screening

9

36.69

0.518

36.60

36.0

37.9

Day 1

9

36.57

0.260

36.60

36.0

36.9

Day 14

9

36.46

0.378

36.50

35.8

36.9

Day 28

9

36.66

0.384

36.60

36.1

37.1

Day 42

7

36.61

0.308

36.60

36.2

37.0

Day 56

6

36.75

0.207

36.75

36.5

37.1

Day 70

5

36.86

0.365

36.90

36.3

37.3

Day 84

8

36.65

0.262

36.60

36.4

37.1

Follow-up

6

36.73

0.234

36.75

36.4

37.0

Screening

12

36.61

0.496

36.75

35.1

37.0

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Temperature SRT2104 0.5 g 12 Day 1 12 36.73 0.156 36.75 36.5 37.0 (Celsius)

SRT2104 1.0 g

11

Day 14

12

36.73

0.230

36.80

36.1

37.0

Day 28

12

36.70

0.176

36.70

36.4

37.1

Day 42

11

36.81

0.202

36.80

36.5

37.2

Day 56

9

36.72

0.156

36.70

36.4

36.9

Day 70

9

36.69

0.314

36.70

36.1

37.3

Day 84

12

36.76

0.284

36.70

36.4

37.4

Follow-up

10

36.71

0.296

36.70

36.1

37.3

Screening

11

36.67

0.473

36.70

35.4

37.2

Day 1

11

36.66

0.450

36.80

35.6

37.2

Day 14

11

36.77

0.338

36.80

35.9

37.2

Day 28

11

36.55

0.639

36.80

35.2

37.3

Day 42

11

36.71

0.532

36.80

35.4

37.4

Day 56

11

36.75

0.396

36.70

36.1

37.6

Day 70

11

36.75

0.364

36.80

36.2

37.2

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Temperature SRT2104 1.0 g 11 Day 84 11 36.64 0.403 36.70 35.6 37.2 (Celsius)

Weight (kg)

Placebo

SRT2104 0.25 g

7

9

Follow-up

10

36.81

0.360

36.80

36.0

37.2

Screening

7

93.07

11.537

93.40

75.3

104.3

Day 1

7

92.71

11.173

91.90

76.7

104.3

Day 14

7

93.80

11.297

92.10

77.6

106.0

Day 28

7

94.11

11.251

93.50

77.9

106.0

Day 42

7

94.07

11.776

93.50

77.6

105.7

Day 56

7

92.84

12.438

91.20

75.8

106.0

Day 70

7

93.79

10.999

90.00

78.9

105.2

Day 84

7

93.56

11.554

90.30

78.5

106.4

Follow-up

7

93.16

11.826

88.60

76.7

107.0

Screening

9

105.28

24.880

104.70

74.0

157.1

Day 1

9

104.90

24.484

105.60

73.7

156.2

Day 14

9

104.99

22.924

107.90

74.0

150.9

Day 28

9

104.79

22.558

108.00

74.5

148.0

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Weight SRT2104 0.25 g 9 Day 42 7 109.44 20.929 110.00 75.5 146.0 (kg)

SRT2104 0.5 g

SRT2104 1.0 g

12

11

Day 56

6

109.58

23.600

111.05

74.4

147.1

Day 70

5

109.52

26.100

111.00

76.6

148.5

Day 84

8

103.58

22.942

104.95

74.0

146.4

Follow-up

6

104.23

27.566

106.80

74.3

148.9

Screening

12

87.97

15.477

81.25

70.3

115.1

Day 1

12

88.11

15.626

81.10

70.3

115.6

Day 14

12

88.03

15.591

81.65

70.3

115.2

Day 28

12

87.72

15.691

80.80

70.3

115.3

Day 42

11

88.28

16.183

82.80

70.3

115.2

Day 56

9

88.17

17.539

79.40

70.3

112.0

Day 70

9

88.02

17.447

79.40

70.3

112.5

Day 84

12

87.33

15.450

81.65

70.3

111.9

Follow-up

10

88.15

16.905

80.90

70.3

114.0

Screening

11

84.36

27.999

81.60

61.2

158.8

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 15 Clinical Study Report SRT-2104-013

Table 14.3.4.1 Summary of Vital Signs and Body Weight Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------Weight SRT2104 1.0 g 11 Day 1 11 84.93 27.787 81.60 62.1 158.3 (kg) Day 14

11

84.80

28.185

81.60

61.2

159.7

Day 28

11

84.45

28.430

81.20

60.3

159.7

Day 42

11

84.74

28.497

82.10

61.2

158.8

Day 56

11

84.32

28.594

81.60

60.3

158.8

Day 70

11

84.61

28.215

81.60

61.2

157.9

Day 84

11

84.68

28.312

83.50

61.2

157.9

Follow-up

10

86.64

28.685

83.25

59.9

156.9

Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Systolic blood pressure Placebo 7 Day 1 2 13.5 30.41 13.5 -8 35 (mmHg)

SRT2104 0.25 g

9

Day 14

7

4.9

5.87

4.0

-6

10

Day 28

7

2.1

17.25

-2.0

-18

35

Day 42

7

4.0

12.49

0.0

-8

30

Day 56

7

2.3

18.35

2.0

-16

40

Day 70

7

10.3

10.86

8.0

0

30

Day 84

7

5.4

11.18

6.0

-8

28

Follow-up

7

3.4

22.02

2.0

-20

42

Day 14

9

3.1

11.67

4.0

-18

24

Day 28

9

0.9

6.79

2.0

-6

12

Day 42

7

5.1

13.66

8.0

-18

24

Day 56

6

1.7

7.09

1.0

-8

12

Day 70

5

3.2

12.70

0.0

-14

20

Day 84

8

2.0

13.77

-3.0

-16

22

Follow-up

6

4.7

12.31

2.0

-8

24

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Systolic blood pressure SRT2104 0.5 g 12 Day 1 1 -2.0 -2.0 -2 -2 (mmHg)

SRT2104 1.0 g

11

Day 14

12

0.2

10.29

-2.0

-16

18

Day 28

12

4.5

10.55

3.0

-12

28

Day 42

11

-1.9

7.05

0.0

-18

7

Day 56

9

-4.2

13.21

0.0

-30

12

Day 70

9

-2.7

12.00

0.0

-26

10

Day 84

12

-0.5

10.02

2.0

-22

14

Follow-up

10

1.4

9.34

-1.0

-10

22

Day 1

3

-2.0

2.00

-2.0

-4

0

Day 14

11

-5.3

9.36

-4.0

-28

9

Day 28

11

-5.6

5.80

-5.0

-18

0

Day 42

11

-1.8

10.34

0.0

-26

10

Day 56

11

-1.7

5.14

-2.0

-10

10

Day 70

11

-4.6

5.97

-2.0

-16

2

Day 84

11

-3.8

8.86

-2.0

-26

10

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Systolic blood pressure SRT2104 1.0 g 11 Follow-up 10 -3.7 5.23 -5.0 -10 8 (mmHg) Diastolic Blood Pressure (mmHg)

Placebo

SRT2104 0.25 g

7

9

Day 1

2

1.0

12.73

1.0

-8

10

Day 14

7

-1.4

9.14

0.0

-10

14

Day 28

7

0.7

8.18

4.0

-10

10

Day 42

7

1.9

6.69

2.0

-8

12

Day 56

7

0.1

6.28

0.0

-6

10

Day 70

7

0.6

6.40

4.0

-10

8

Day 84

7

2.9

7.20

2.0

-6

14

Follow-up

7

1.6

6.00

3.0

-10

8

Day 14

9

-0.7

10.05

-2.0

-14

16

Day 28

9

2.2

8.57

0.0

-12

20

Day 42

7

1.1

14.23

4.0

-18

24

Day 56

6

-3.7

10.54

-5.0

-18

12

Day 70

5

-1.2

9.01

0.0

-14

8

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Diastolic Blood SRT2104 0.25 g 9 Day 84 8 1.8 6.96 1.0 -8 14 Pressure (mmHg)

SRT2104 0.5 g

SRT2104 1.0 g

12

11

Follow-up

6

2.7

Day 1

1

-2.0

Day 14

12

0.2

Day 28

12

Day 42

15.32

5.0

-18

26

-2.0

-2

-2

6.69

0.0

-12

10

1.8

5.42

2.0

-8

10

11

-2.4

9.50

0.0

-20

10

Day 56

9

-0.7

9.43

0.0

-20

12

Day 70

9

1.6

10.53

4.0

-24

12

Day 84

12

0.8

7.79

-1.0

-8

18

Follow-up

10

2.2

5.45

0.0

-4

14

Day 1

3

-0.7

3.06

0.0

-4

2

Day 14

11

-2.3

7.24

-2.0

-18

8

Day 28

11

-6.8

7.11

-6.0

-18

2

Day 42

11

-1.3

6.36

-2.0

-12

12

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Diastolic Blood SRT2104 1.0 g 11 Day 56 11 -2.9 5.30 -4.0 -10 5 Pressure (mmHg)

Heart rate (bpm)

Placebo

SRT2104 0.25 g

7

9

Day 70

11

1.6

8.61

0.0

-8

20

Day 84

11

-1.5

6.41

-4.0

-10

10

Follow-up

10

-3.2

8.66

-4.5

-18

8

Day 1

2

12.0

11.31

12.0

4

20

Day 14

7

2.3

5.71

4.0

-4

10

Day 28

7

0.9

7.29

-2.0

-4

16

Day 42

7

2.0

8.72

0.0

-8

20

Day 56

7

-0.9

8.32

-4.0

-8

12

Day 70

7

1.1

8.93

4.0

-16

10

Day 84

7

3.7

10.92

2.0

-14

20

Follow-up

7

3.1

7.20

6.0

-8

10

Day 14

9

3.1

6.41

4.0

-8

14

Day 28

9

0.4

10.04

4.0

-22

12

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Heart rate SRT2104 0.25 g 9 Day 42 7 4.6 9.78 4.0 -14 16 (bpm)

SRT2104 0.5 g

SRT2104 1.0 g

12

11

Day 56

6

-1.0

9.10

0.0

-16

8

Day 70

5

7.6

5.55

8.0

2

14

Day 84

8

0.5

10.84

2.0

-22

16

Follow-up

6

3.3

7.87

4.0

-6

16

Day 1

1

8.0

8.0

8

8

Day 14

12

5.2

10.77

4.0

-12

24

Day 28

12

1.6

7.30

2.5

-16

10

Day 42

11

2.7

7.60

2.0

-10

14

Day 56

9

2.3

5.87

0.0

-6

14

Day 70

9

3.8

6.12

4.0

-8

12

Day 84

12

2.0

11.05

6.0

-16

16

Follow-up

10

3.4

11.35

8.0

-12

18

Day 1

3

-1.3

2.31

0.0

-4

0

Day 14

11

-1.8

3.40

-2.0

-8

4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Heart rate SRT2104 1.0 g 11 Day 28 11 0.2 9.01 -4.0 -8 24 (bpm)

Respiratory Rate (breaths/min)

Placebo

7

Day 42

11

4.3

6.13

4.0

-4

14

Day 56

11

2.4

10.19

4.0

-16

20

Day 70

11

2.2

11.64

2.0

-20

18

Day 84

11

0.9

10.05

0.0

-12

24

Follow-up

10

3.8

6.83

2.0

-4

20

Day 1

2

-2.0

2.83

-2.0

-4

0

Day 14

7

-1.4

1.90

0.0

-4

0

Day 28

7

-1.1

1.95

0.0

-4

0

Day 42

7

-2.0

2.00

-2.0

-4

0

Day 56

7

-1.1

1.95

0.0

-4

0

Day 70

7

-1.1

1.95

0.0

-4

0

Day 84

7

-1.7

1.80

-2.0

-4

0

Follow-up

7

-0.3

2.43

0.0

-4

4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Respiratory Rate SRT2104 0.25 g 9 Day 14 9 1.3 2.00 0.0 0 6 (breaths/min)

SRT2104 0.5 g

12

Day 28

9

0.7

2.65

0.0

-4

6

Day 42

7

0.9

1.07

0.0

0

2

Day 56

6

-0.7

1.63

0.0

-4

0

Day 70

5

1.2

1.10

2.0

0

2

Day 84

8

-0.3

1.67

0.0

-4

2

Follow-up

6

0.7

1.03

0.0

0

2

Day 1

1

0.0

0.0

0

0

Day 14

12

0.8

1.03

0.0

0

2

Day 28

12

-0.4

1.78

0.0

-4

2

Day 42

11

1.3

2.05

2.0

-2

6

Day 56

9

1.3

1.73

0.0

0

4

Day 70

9

0.9

2.26

0.0

-2

4

Day 84

12

0.0

1.48

0.0

-2

2

Follow-up

10

1.2

2.15

2.0

-2

4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Respiratory Rate SRT2104 1.0 g 11 Day 1 3 1.3 2.31 0.0 0 4 (breaths/min)

Temperature (Celsius)

Placebo

7

Day 14

11

0.9

1.64

0.0

0

4

Day 28

11

1.1

1.64

0.0

0

4

Day 42

11

1.4

2.62

0.0

-1

8

Day 56

11

0.5

3.36

0.0

-4

8

Day 70

11

0.8

1.47

0.0

-1

4

Day 84

11

1.1

3.02

0.0

-4

8

Follow-up

10

-0.2

3.71

0.0

-4

8

Day 1

2

0.05

0.212

0.05

-0.1

0.2

Day 14

7

0.04

0.305

0.10

-0.5

0.4

Day 28

7

0.00

0.416

-0.10

-0.6

0.5

Day 42

7

-0.01

0.438

0.00

-0.4

0.9

Day 56

7

0.07

0.298

0.10

-0.4

0.4

Day 70

7

0.04

0.190

0.00

-0.2

0.4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Temperature Placebo 7 Day 84 7 0.03 0.486 0.00 -0.9 0.5 (Celsius)

SRT2104 0.25 g

SRT2104 0.5 g

9

12

Follow-up

7

0.03

0.395

0.00

-0.6

0.7

Day 14

9

-0.11

0.257

-0.10

-0.5

0.3

Day 28

9

0.09

0.322

0.10

-0.3

0.5

Day 42

7

0.04

0.207

0.00

-0.2

0.4

Day 56

6

0.08

0.147

0.05

-0.1

0.3

Day 70

5

0.14

0.472

0.20

-0.6

0.7

Day 84

8

0.01

0.280

0.00

-0.4

0.5

Follow-up

6

0.03

0.175

0.05

-0.2

0.3

Day 1

1

0.50

0.50

0.5

0.5

Day 14

12

0.03

0.264

0.05

-0.4

0.4

Day 28

12

0.01

0.156

0.00

-0.2

0.2

Day 42

11

0.13

0.224

0.10

-0.2

0.7

Day 56

9

0.02

0.130

0.00

-0.1

0.3

Day 70

9

-0.01

0.262

0.00

-0.4

0.4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Temperature SRT2104 0.5 g 12 Day 84 12 0.07 0.314 0.00 -0.3 0.9 (Celsius) Follow-up SRT2104 1.0 g

Weight (kg)

Placebo

11

7

10

0.03

0.316

0.00

-0.4

0.8

Day 1

3

0.20

0.436

0.00

-0.1

0.7

Day 14

11

0.16

0.367

0.10

-0.2

1.2

Day 28

11

-0.06

0.175

0.00

-0.4

0.2

Day 42

11

0.10

0.257

0.10

-0.2

0.7

Day 56

11

0.15

0.380

0.10

-0.4

0.7

Day 70

11

0.14

0.314

0.00

-0.3

0.8

Day 84

11

0.03

0.307

0.00

-0.3

0.9

Follow-up

10

0.22

0.575

0.05

-0.1

1.8

Day 1

2

-1.15

0.212

-1.15

-1.3

-1.0

Day 14

7

0.76

0.660

0.90

0.0

2.0

Day 28

7

1.07

0.776

1.30

0.0

2.0

Day 42

7

1.03

0.826

1.40

-0.2

1.8

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Weight Placebo 7 Day 56 7 -0.20 1.654 0.00 -3.2 2.0 (kg)

SRT2104 0.25 g

SRT2104 0.5 g

9

12

Day 70

7

0.74

1.429

0.90

-2.3

2.2

Day 84

7

0.51

1.356

0.50

-1.6

2.4

Follow-up

7

0.11

1.925

0.00

-3.3

3.0

Day 14

9

0.09

2.230

0.40

-5.3

2.3

Day 28

9

-0.11

3.451

1.00

-8.2

2.4

Day 42

7

-0.80

4.544

0.20

-10.2

3.4

Day 56

6

-0.55

4.794

-0.05

-9.1

4.7

Day 70

5

0.62

4.930

1.50

-7.7

5.4

Day 84

8

-0.57

4.643

0.75

-9.8

5.1

Follow-up

6

1.20

4.806

1.15

-7.3

6.2

Day 1

1

-0.30

-0.30

-0.3

-0.3

Day 14

12

-0.10

0.536

0.00

-1.3

0.8

Day 28

12

-0.42

0.642

-0.15

-1.5

0.5

Day 42

11

-0.69

0.929

-0.40

-3.1

0.0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 13 Clinical Study Report SRT-2104-013

Table 14.3.4.2 Summary of Change from Baseline for Vital Signs Safety Analysis Set Population VS Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------Weight SRT2104 0.5 g 12 Day 56 9 -0.98 1.364 -0.30 -3.6 0.0 (kg)

SRT2104 1.0 g

11

Day 70

9

-1.12

1.247

-0.50

-3.1

0.0

Day 84

12

-0.80

1.715

0.00

-3.8

1.0

Follow-up

10

-0.39

1.081

-0.35

-1.6

1.5

Day 1

3

-0.17

1.159

0.00

-1.4

0.9

Day 14

11

-0.17

1.217

0.00

-2.3

1.4

Day 28

11

-0.52

1.272

-0.40

-2.3

1.4

Day 42

11

-0.24

1.627

0.00

-2.7

2.7

Day 56

11

-0.65

1.728

-0.90

-3.7

2.3

Day 70

11

-0.36

1.564

-0.40

-2.7

2.7

Day 84

11

-0.29

2.309

-0.40

-4.3

3.2

Follow-up

10

-0.16

2.455

-1.10

-4.1

3.7

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013

Table 14.3.4.3 Listing of Vital Signs of Potential Clinical Importance Treatment: SRT2104 1.0 g

Subj.

Age(y)/ Sex/ Race

Planned Relative Time

Actual Date/ Time

Study Day

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Heart Rate (bpm)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

Note: L=Low, H=High.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Table 14.3.4.4 Listing of All Vital Signs for Subjects with Values of Potential Clinical Importance Treatment: SRT2104 1.0 g

Subj.

Age(y)/ Sex/ Race

Planned Relative Time

Actual Date/ Time

Study Day

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Heart Rate (bpm)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

Note: L=Low, H=High.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Systolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-40 -40
7

0

0

7 (100%)

0

Day 28

7

0

0

6

(86%)

1

(14%)

0

Day 42

7

0

0

6

(86%)

1

(14%)

0

Day 56

7

0

0

6

(86%)

0

Day 70

7

0

0

5

(71%)

2

(29%)

0

Day 84

7

0

0

6

(86%)

1

(14%)

0

Follow-up

7

0

1

4

(57%)

1

(14%)

1

(14%)

0

1

(14%)

(14%)

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Systolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-40 -40
9

0

0

9 (100%)

0

0

Day 42

7

0

0

6

(86%)

1

Day 56

6

0

0

6 (100%)

0

Day 70

5

0

0

4

(80%)

1

(20%)

0

Day 84

8

0

0

6

(75%)

2

(25%)

0

Follow-up

6

0

0

5

(83%)

1

(17%)

0

(14%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Systolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-40 -40
12

0

0

12 (100%)

0

0

Day 28

12

0

0

11

(92%)

1

Day 42

11

0

0

11 (100%)

0

0

Day 56

9

0

2

(22%)

7

(78%)

0

0

Day 70

9

0

1

(11%)

8

(89%)

0

0

Day 84

12

0

1

(8%)

11

(92%)

0

0

Follow-up

10

0

0

9

(90%)

1

(8%)

(10%)

0

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Systolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-40 -40
11

0

1

Day 28

11

0

0

Day 42

11

0

1

Day 56

11

0

Day 70

11

Day 84 Follow-up

(9%)

(91%)

0

0

11 (100%)

0

0

10

(91%)

0

0

0

11 (100%)

0

0

0

0

11 (100%)

0

0

11

0

1

10

(91%)

0

0

10

0

0

10 (100%)

0

0

(9%)

(9%)

10

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Diastolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-20 -20
7

0

3

(43%)

3

(43%)

1

(14%)

0

Day 28

7

0

1

(14%)

5

(71%)

1

(14%)

0

Day 42

7

0

0

6

(86%)

1

(14%)

0

Day 56

7

0

0

6

(86%)

1

(14%)

0

Day 70

7

0

1

6

(86%)

0

Day 84

7

0

0

5

(71%)

2

Follow-up

7

0

1

6

(86%)

0

(14%)

(14%)

0 (29%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Diastolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-20 -20
9

0

1

(11%)

7

(78%)

0

1

(11%)

Day 42

7

0

2

(29%)

4

(57%)

0

1

(14%)

Day 56

6

0

2

(33%)

3

(50%)

1

Day 70

5

0

1

(20%)

4

(80%)

0

Day 84

8

0

0

7

(88%)

1

Follow-up

6

0

2

3

(50%)

0

(33%)

(17%)

0 0

(13%)

0 1

(17%)

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Diastolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-20 -20
12

0

2

Day 28

12

0

0

Day 42

11

1

(9%)

1

Day 56

9

1

(11%)

Day 70

9

1

(11%)

Day 84

12

Follow-up

10

(17%)

9

(75%)

1

(8%)

0

10

(83%)

2

(17%)

0

8

(73%)

1

(9%)

0

0

6

(67%)

2

(22%)

0

0

6

(67%)

2

(22%)

0

0

0

10

(83%)

2

(17%)

0

0

0

9

(90%)

1

(10%)

0

(9%)

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Diastolic blood pressure (mmHg) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-20 -20
11

0

2

(18%)

9

(82%)

0

0

Day 28

11

0

4

(36%)

7

(64%)

0

0

Day 42

11

0

1

(9%)

9

(82%)

1

Day 56

11

0

2

(18%)

9

(82%)

0

Day 70

11

0

0

9

(82%)

1

(9%)

1

Day 84

11

0

1

(9%)

9

(82%)

1

(9%)

0

Follow-up

10

0

2

(20%)

8

(80%)

0

(9%)

0 0 (9%)

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Heart rate (bpm) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-30 -30
7

0

0

7 (100%)

0

Day 28

7

0

0

6

(86%)

1

(14%)

0

Day 42

7

0

0

6

(86%)

1

(14%)

0

Day 56

7

0

0

7 (100%)

0

0

Day 70

7

0

1

6

(86%)

0

0

Day 84

7

0

0

6

(86%)

1

Follow-up

7

0

0

7 (100%)

0

(14%)

0

(14%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Heart rate (bpm) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-30 -30
9

0

1

Day 42

7

0

0

Day 56

6

0

1

Day 70

5

0

0

Day 84

8

0

1

Follow-up

6

0

0

(11%)

(17%)

(13%)

8

(89%)

0

0

6

(86%)

1

5

(83%)

0

0

5 (100%)

0

0

6

(75%)

1

(13%)

0

5

(83%)

1

(17%)

0

(14%)

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Heart rate (bpm) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-30 -30
12

0

0

9

(75%)

3

Day 28

12

0

1

11

(92%)

0

0

Day 42

11

0

0

11 (100%)

0

0

Day 56

9

0

0

9 (100%)

0

0

Day 70

9

0

0

9 (100%)

0

0

Day 84

12

0

2

9

(75%)

1

(8%)

0

Follow-up

10

0

0

8

(80%)

2

(20%)

0

(8%)

(17%)

(25%)

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 12 Clinical Study Report SRT-2104-013

Table 14.3.4.5 Summary of Category of Increase from Baseline Vital Signs Interval Data by Treatment and Time Safety Analysis Set Population Parameter : Heart rate (bpm) Planned Category Relative _______________________________________________________________________ Trt. N Time n Value<=-30 -30
11

0

0

11 (100%)

0

0

Day 28

11

0

0

10

(91%)

1

Day 42

11

0

0

11 (100%)

0

Day 56

11

0

1

(9%)

9

(82%)

1

(9%)

0

Day 70

11

0

1

(9%)

9

(82%)

1

(9%)

0

Day 84

11

0

0

10

(91%)

1

(9%)

0

Follow-up

10

0

0

9

(90%)

1

(10%)

0

(9%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: The position was not consistent for all subjects.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Screening SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 7 9 12 10 Normal 7 (100%) 9 (100%) 12 (100%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Eyes/ ears/ nose & throat n 7 9 12 10 Normal 6 (86%) 9 (100%) 11 (92%) 10 (100%) Abnormal 1 (14%) 0 1 (8%) 0 Not Done 0 0 0 0 Extremities n 7 9 12 10 Normal 5 (71%) 9 (100%) 11 (92%) 8 (80%) Abnormal 2 (29%) 0 1 (8%) 2 (20%) Not Done 0 0 0 0 General Appearance n 7 9 12 10 Normal 7 (100%) 9 (100%) 12 (100%) 9 (90%) Abnormal 0 0 0 1 (10%) Not Done 0 0 0 0 Genitourinary n 7 9 12 10 Normal 2 (29%) 3 (33%) 2 (17%) 1 (10%) Abnormal 1 (14%) 0 0 0 Not Done 4 (57%) 6 (67%) 10 (83%) 9 (90%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Screening SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 7 9 12 10 Normal 6 (86%) 9 (100%) 12 (100%) 10 (100%) Abnormal 1 (14%) 0 0 0 Not Done 0 0 0 0 Head and Neck n 7 9 12 10 Normal 7 (100%) 9 (100%) 12 (100%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Lymphatic n 7 9 12 10 Normal 7 (100%) 9 (100%) 12 (100%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Musculoskeletal n 7 9 12 10 Normal 7 (100%) 9 (100%) 12 (100%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Neurological n 7 9 12 10 Normal 6 (86%) 9 (100%) 12 (100%) 10 (100%) Abnormal 1 (14%) 0 0 0 Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Screening SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 5 6 6 9 Normal 0 0 0 1 (11%) Abnormal 0 0 0 0 Not Done 5 (100%) 6 (100%) 6 (100%) 8 (89%) Respiratory n 7 9 12 10 Normal 6 (86%) 9 (100%) 12 (100%) 10 (100%) Abnormal 1 (14%) 0 0 0 Not Done 0 0 0 0 Skin and Mucosa n 7 9 12 10 Normal 0 0 0 0 Abnormal 7 (100%) 9 (100%) 12 (100%) 10 (100%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 1 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 6 8 12 11 Normal 6 (100%) 8 (100%) 12 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Eyes/ ears/ nose & throat n 6 8 12 11 Normal 6 (100%) 8 (100%) 11 (92%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (8%) 0 Extremities n 6 8 12 11 Normal 5 (83%) 8 (100%) 11 (92%) 10 (91%) Abnormal 1 (17%) 0 0 1 (9%) Not Done 0 0 1 (8%) 0 General Appearance n 6 8 12 11 Normal 6 (100%) 8 (100%) 12 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 Genitourinary n 6 8 12 11 Normal 2 (33%) 3 (38%) 1 (8%) 1 (9%) Abnormal 0 0 0 0 Not Done 4 (67%) 5 (63%) 11 (92%) 10 (91%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 1 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 6 8 12 11 Normal 6 (100%) 8 (100%) 11 (92%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (8%) 0 Head and Neck n 6 8 12 11 Normal 6 (100%) 8 (100%) 11 (92%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (8%) 0 Lymphatic n 6 8 12 11 Normal 6 (100%) 7 (88%) 11 (92%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 1 (8%) 0 Musculoskeletal n 6 8 12 11 Normal 6 (100%) 7 (88%) 10 (83%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 2 (17%) 0 Neurological n 6 8 12 11 Normal 6 (100%) 7 (88%) 11 (92%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 1 (8%) 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 1 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 4 6 7 10 Normal 0 0 0 2 (20%) Abnormal 0 0 0 0 Not Done 4 (100%) 6 (100%) 7 (100%) 8 (80%) Respiratory n 6 8 12 11 Normal 5 (83%) 8 (100%) 12 (100%) 11 (100%) Abnormal 1 (17%) 0 0 0 Not Done 0 0 0 0 Skin and Mucosa n 6 8 12 11 Normal 0 0 0 0 Abnormal 6 (100%) 8 (100%) 12 (100%) 11 (100%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 28 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 5 8 10 11 Normal 5 (100%) 8 (100%) 9 (90%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Eyes/ ears/ nose & throat n 5 8 10 11 Normal 5 (100%) 7 (88%) 10 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 0 0 Extremities n 5 8 10 11 Normal 4 (80%) 7 (88%) 9 (90%) 10 (91%) Abnormal 1 (20%) 0 0 1 (9%) Not Done 0 1 (13%) 1 (10%) 0 General Appearance n 5 8 10 11 Normal 5 (100%) 8 (100%) 10 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 Genitourinary n 5 8 10 11 Normal 0 2 (25%) 1 (10%) 0 Abnormal 0 0 0 0 Not Done 5 (100%) 6 (75%) 9 (90%) 11 (100%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 28 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 5 8 10 11 Normal 4 (80%) 7 (88%) 9 (90%) 11 (100%) Abnormal 1 (20%) 0 0 0 Not Done 0 1 (13%) 1 (10%) 0 Head and Neck n 5 8 10 11 Normal 5 (100%) 7 (88%) 9 (90%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 1 (10%) 0 Lymphatic n 5 8 10 11 Normal 4 (80%) 7 (88%) 9 (90%) 11 (100%) Abnormal 1 (20%) 0 0 0 Not Done 0 1 (13%) 1 (10%) 0 Musculoskeletal n 5 8 10 11 Normal 5 (100%) 7 (88%) 9 (90%) 9 (82%) Abnormal 0 0 0 2 (18%) Not Done 0 1 (13%) 1 (10%) 0 Neurological n 5 8 10 11 Normal 5 (100%) 7 (88%) 9 (90%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (13%) 1 (10%) 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 28 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 4 5 6 11 Normal 1 (25%) 0 0 1 (9%) Abnormal 0 0 0 0 Not Done 3 (75%) 5 (100%) 6 (100%) 10 (91%) Respiratory n 5 8 10 11 Normal 4 (80%) 8 (100%) 9 (90%) 11 (100%) Abnormal 1 (20%) 0 0 0 Not Done 0 0 1 (10%) 0 Skin and Mucosa n 5 8 10 11 Normal 0 0 0 0 Abnormal 5 (100%) 8 (100%) 10 (100%) 11 (100%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 56 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 7 6 8 11 Normal 7 (100%) 6 (100%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (13%) 0 Eyes/ ears/ nose & throat n 7 6 8 11 Normal 7 (100%) 5 (83%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (17%) 1 (13%) 0 Extremities n 7 6 8 11 Normal 7 (100%) 5 (83%) 7 (88%) 9 (82%) Abnormal 0 0 0 2 (18%) Not Done 0 1 (17%) 1 (13%) 0 General Appearance n 7 6 8 11 Normal 7 (100%) 6 (100%) 8 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 Genitourinary n 7 6 8 11 Normal 2 (29%) 1 (17%) 0 0 Abnormal 0 0 0 0 Not Done 5 (71%) 5 (83%) 8 (100%) 11 (100%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 56 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 7 6 8 11 Normal 6 (86%) 6 (100%) 7 (88%) 11 (100%) Abnormal 1 (14%) 0 0 0 Not Done 0 0 1 (13%) 0 Head and Neck n 7 6 8 11 Normal 7 (100%) 5 (83%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (17%) 1 (13%) 0 Lymphatic n 7 6 8 11 Normal 7 (100%) 5 (83%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (17%) 1 (13%) 0 Musculoskeletal n 7 6 8 11 Normal 7 (100%) 5 (83%) 6 (75%) 11 (100%) Abnormal 0 0 1 (13%) 0 Not Done 0 1 (17%) 1 (13%) 0 Neurological n 7 6 8 11 Normal 7 (100%) 5 (83%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 1 (17%) 1 (13%) 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 12 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 56 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 6 4 7 11 Normal 0 0 0 0 Abnormal 0 0 0 0 Not Done 6 (100%) 4 (100%) 7 (100%) 11 (100%) Respiratory n 7 6 8 11 Normal 7 (100%) 6 (100%) 7 (88%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (13%) 0 Skin and Mucosa n 7 6 8 11 Normal 0 0 0 1 (9%) Abnormal 7 (100%) 6 (100%) 8 (100%) 10 (91%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 13 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 84 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Eyes/ ears/ nose & throat n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 Extremities n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 General Appearance n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0 Genitourinary n 5 8 11 11 Normal 0 2 (25%) 1 (9%) 0 Abnormal 0 0 0 0 Not Done 5 (100%) 6 (75%) 10 (91%) 11 (100%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 14 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 84 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 5 8 11 11 Normal 5 (100%) 7 (88%) 11 (100%) 10 (91%) Abnormal 0 1 (13%) 0 1 (9%) Not Done 0 0 0 0 Head and Neck n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Lymphatic n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Musculoskeletal n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Neurological n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 10 (91%) Abnormal 0 0 0 1 (9%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 15 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Day 84 SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 5 5 8 11 Normal 0 0 0 0 Abnormal 0 0 0 0 Not Done 5 (100%) 5 (100%) 8 (100%) 11 (100%) Respiratory n 5 8 11 11 Normal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Abnormal 0 0 0 0 Not Done 0 0 0 0 Skin and Mucosa n 5 8 11 11 Normal 0 0 0 0 Abnormal 5 (100%) 8 (100%) 11 (100%) 11 (100%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 16 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Follow-up SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Cardiovascular n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Eyes/ ears/ nose & throat n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Extremities n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 8 (80%) Abnormal 0 0 0 2 (20%) Not Done 0 0 1 (10%) 0 General Appearance n 6 6 10 10 Normal 6 (100%) 6 (100%) 10 (100%) 9 (90%) Abnormal 0 0 0 1 (10%) Not Done 0 0 0 0 Genitourinary n 6 6 10 10 Normal 0 0 0 0 Abnormal 0 0 0 0 Not Done 6 (100%) 6 (100%) 10 (100%) 10 (100%)

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 17 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Follow-up SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Gastrointestinal n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Head and Neck n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Lymphatic n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 9 (90%) Abnormal 0 0 0 1 (10%) Not Done 0 0 1 (10%) 0 Musculoskeletal n 6 6 10 10 Normal 6 (100%) 5 (83%) 9 (90%) 10 (100%) Abnormal 0 0 1 (10%) 0 Not Done 0 1 (17%) 0 0 Neurological n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 18 of 18 Clinical Study Report SRT-2104-013 Table 14.3.5 Summary of Physical Exam Safety Analysis Set Population

Visit: Follow-up SRT2104 SRT2104 SRT2104 Body System Examined Placebo 0.25 g 0.5 g 1.0 g Category (N=7) (N=9) (N=12) (N=11) -----------------------------------------------------------------------------Other n 6 5 8 10 Normal 1 (17%) 0 0 0 Abnormal 0 0 0 0 Not Done 5 (83%) 5 (100%) 8 (100%) 10 (100%) Respiratory n 6 6 10 10 Normal 6 (100%) 6 (100%) 9 (90%) 10 (100%) Abnormal 0 0 0 0 Not Done 0 0 1 (10%) 0 Skin and Mucosa n 6 6 10 10 Normal 0 0 0 0 Abnormal 6 (100%) 6 (100%) 10 (100%) 10 (100%) Not Done 0 0 0 0

Note: Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 1 Clinical Study Report SRT-2104-013 Table 14.3.6.1 Summary of ECG Overall Impressions Safety Analysis Set Population

Visit Planned Time Point Placebo SRT2104 0.25 g SRT2104 0.5 g SRT2104 1.0 g Category (N=7) (N=9) (N=12) (N=11) ------------------------------------------------------------------------------------------------------Screening n 7 9 12 11 Normal 2 (29%) 4 (44%) 6 (50%) 7 (64%) Abnormal (Not Clinically 5 (71%) 5 (56%) 6 (50%) 4 (36%) Significant) Day 1 n Normal Abnormal (Not Clinically Significant)

7 2 (29%) 5 (71%)

8 5 (63%) 3 (38%)

12 6 (50%) 6 (50%)

11 6 (55%) 5 (45%)

Day 28 n Normal Abnormal (Not Clinically Significant)

7 2 (29%) 5 (71%)

9 3 (33%) 6 (67%)

12 6 (50%) 6 (50%)

11 4 (36%) 7 (64%)

Day 56 n Normal Abnormal (Not Clinically Significant)

7 3 (43%) 4 (57%)

6 3 (50%) 3 (50%)

9 4 (44%) 5 (56%)

11 5 (45%) 6 (55%)

Day 84 n Normal Abnormal (Not Clinically Significant)

7 3 (43%) 4 (57%)

8 3 (38%) 5 (63%)

11 5 (45%) 6 (55%)

11 7 (64%) 4 (36%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------PR (msec) Placebo 7 Screening 6 165.7 24.32 161.0 140 203 Day 1 6 161.7 23.70 161.0 133 197 Day 28 6 171.3 31.90 171.0 131 209 Day 56 6 166.3 25.07 170.0 136 203 Day 84 6 158.7 27.41 150.0 132 200 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

166.8 167.3 164.2 176.5 172.3

17.01 16.99 19.82 10.71 15.79

169.0 170.5 172.0 175.0 173.5

138 140 132 163 140

186 184 184 193 188

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

156.6 159.1 157.3 166.5 164.0

15.18 16.72 17.94 9.15 20.51

152.0 156.0 156.0 166.0 164.0

138 134 131 156 142

178 184 182 178 198

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

152.8 150.3 144.4 152.8 146.4

20.54 20.22 28.30 27.63 22.22

154.0 145.0 147.0 149.0 147.0

116 122 104 116 114

175 178 176 190 181

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QRS (msec) Placebo 7 Screening 6 100.2 8.30 101.0 88 109 Day 1 6 98.2 10.93 100.0 80 110 Day 28 6 98.8 9.09 96.5 88 114 Day 56 6 97.5 9.99 94.5 86 114 Day 84 6 101.5 8.43 102.0 88 113 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

91.6 92.0 87.6 84.3 91.0

7.75 7.39 9.77 13.14 7.09

94.0 91.0 90.0 88.0 92.0

76 80 66 61 76

101 106 98 96 99

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

96.3 104.4 104.7 103.8 104.8

24.07 8.20 8.67 6.13 9.91

105.0 109.0 109.0 104.5 108.5

43 91 92 96 90

113 110 114 110 117

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

88.0 89.8 91.8 88.5 89.9

11.87 15.14 13.96 13.90 14.17

89.0 89.0 90.0 87.0 90.0

72 72 74 72 72

107 112 112 109 110

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QT (msec) Placebo 7 Screening 6 407.0 39.52 400.5 354 466 Day 1 6 397.2 35.53 404.5 341 440 Day 28 6 401.7 41.75 402.0 329 443 Day 56 6 412.7 56.03 413.5 336 494 Day 84 6 391.7 37.38 397.0 332 436 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

386.8 388.6 386.1 376.2 386.8

28.98 30.41 32.15 31.87 32.05

388.0 392.0 394.0 370.5 387.0

342 340 330 336 334

426 432 441 434 425

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

399.9 410.1 410.7 409.8 407.2

21.13 27.18 42.74 48.21 47.20

392.0 400.0 400.0 387.0 404.0

373 390 369 383 364

434 468 479 482 495

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

402.0 393.0 399.8 402.5 400.5

32.37 37.91 42.36 38.00 30.10

406.0 397.0 415.5 410.0 405.0

346 334 312 344 350

442 438 453 446 438

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QTCB (msec) Placebo 7 Screening 6 412.8 25.83 411.5 379 448 Day 1 6 419.2 29.18 426.5 383 447 Day 28 6 408.7 28.10 399.0 382 446 Day 56 6 424.7 34.29 409.5 393 485 Day 84 6 405.2 28.81 400.5 377 445 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

417.6 409.5 419.1 414.8 413.0

25.18 21.49 16.01 9.58 15.40

426.0 411.0 413.0 417.0 410.5

375 374 394 403 399

440 437 445 429 446

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

410.3 409.4 419.9 416.3 412.7

24.83 26.92 37.14 24.51 29.38

421.0 408.0 425.0 411.5 418.0

370 370 357 393 367

439 448 470 449 448

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

399.6 410.8 408.3 408.6 417.5

11.40 13.41 13.80 19.65 18.71

402.5 409.5 415.0 412.5 417.5

379 391 383 371 391

412 430 420 430 444

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QTCF (msec) Placebo 7 Screening 6 410.8 25.80 409.5 384 454 Day 1 6 411.0 22.14 408.5 387 440 Day 28 6 406.0 27.94 403.5 363 445 Day 56 6 420.3 37.46 415.0 373 488 Day 84 6 400.3 22.75 403.5 369 427 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

406.4 402.1 407.7 401.3 403.8

17.57 19.36 17.35 13.81 17.53

413.0 401.5 407.0 401.0 404.0

372 381 383 381 378

426 431 432 422 431

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

406.6 409.3 416.3 413.8 410.0

20.30 19.18 31.97 23.64 25.06

412.0 411.0 427.0 412.5 415.5

371 378 361 390 378

429 428 445 440 443

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

400.0 404.1 404.8 405.9 411.5

9.43 8.64 11.55 11.69 15.27

402.5 402.5 405.0 405.5 410.5

386 390 380 393 388

410 419 420 429 430

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 6 Clinical Study Report SRT-2104-013 Table 14.3.6.2 Summary of ECG Values Safety Analysis Set Population

EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------Ventricular Rate (bpm) Placebo 7 Screening 6 64.0 15.11 61.0 49 88 Day 1 6 68.0 17.05 66.5 50 88 Day 28 6 65.5 17.32 63.0 45 95 Day 56 6 67.7 20.31 58.5 49 99 Day 84 6 68.5 20.87 62.0 44 100 SRT2104 0.25 g

9

Screening Day 1 Day 28 Day 56 Day 84

9 8 9 6 8

70.9 67.5 71.4 73.8 69.3

15.23 11.87 11.71 10.91 10.81

72.0 66.5 73.0 77.0 72.0

48 53 56 55 53

97 85 92 86 86

SRT2104 0.5 g

12

Screening Day 1 Day 28 Day 56 Day 84

7 7 7 4 6

63.9 60.4 63.9 63.5 63.7

8.63 11.76 14.01 14.73 16.68

59.0 59.0 63.0 64.0 65.0

54 44 47 45 43

78 79 83 81 91

SRT2104 1.0 g

11

Screening Day 1 Day 28 Day 56 Day 84

8 8 8 8 8

60.9 69.5 65.5 64.3 66.6

12.54 17.38 20.03 17.43 12.25

60.5 65.5 60.0 60.5 68.5

44 48 43 41 51

84 96 109 94 82

Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------PR (msec) Placebo 7 Day 28 6 9.7 16.66 8.0 -8 40 Day 56 6 4.7 7.97 4.0 -4 18 Day 84 6 -3.0 8.44 -1.5 -16 6 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

-4.4 -1.3 0.5

13.27 10.54 9.47

-8.0 -2.0 1.0

-32 -14 -19

13 13 13

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

-1.9 2.8 3.2

6.31 8.38 9.68

-2.0 1.5 5.5

-12 -6 -12

9 14 14

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

-5.9 2.5 -3.9

12.94 12.83 11.84

-2.5 0.0 -3.0

-32 -18 -18

10 21 12

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QRS (msec) Placebo 7 Day 28 6 0.7 5.47 1.0 -8 8 Day 56 6 -0.7 5.92 -0.5 -11 6 Day 84 6 3.3 5.85 2.5 -6 11 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

-4.7 -7.8 -0.8

9.21 13.50 5.15

-2.0 -3.5 -2.0

-28 -33 -7

3 6 8

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

0.3 -1.8 1.2

4.46 4.11 3.06

1.0 -1.0 0.0

-9 -7 -1

5 2 7

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

2.0 -1.3 0.1

2.14 2.31 2.75

2.0 -0.5 0.0

0 -5 -5

6 2 4

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QT (msec) Placebo 7 Day 28 6 4.5 16.75 -0.5 -12 28 Day 56 6 15.5 22.21 9.0 -5 54 Day 84 6 -5.5 14.76 -5.5 -22 15 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

1.6 2.3 4.6

22.47 13.22 23.80

-2.0 3.5 -2.5

-32 -19 -16

40 20 57

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

0.6 7.8 6.7

30.76 43.41 42.26

-4.0 -4.0 -0.5

-26 -31 -36

67 70 83

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

6.8 9.5 7.5

20.25 17.14 20.98

7.0 10.5 3.5

-22 -24 -16

34 36 52

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QTCB (msec) Placebo 7 Day 28 6 -10.5 19.65 -3.0 -39 7 Day 56 6 5.5 29.66 10.0 -35 45 Day 84 6 -14.0 12.98 -9.5 -35 0 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

7.8 -1.0 -0.3

26.71 7.87 18.44

8.0 -0.5 -4.0

-18 -11 -17

59 11 38

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

10.4 2.8 2.3

14.95 13.18 9.42

14.0 5.5 6.0

-13 -15 -14

32 15 10

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

-2.5 -2.1 6.8

10.95 13.52 14.47

-3.5 -1.5 7.0

-16 -28 -13

12 12 30

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------QTCF (msec) Placebo 7 Day 28 6 -5.0 16.35 4.5 -28 7 Day 56 6 9.3 25.56 9.5 -20 48 Day 84 6 -10.7 8.19 -12.0 -20 0 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

5.8 0.3 1.5

19.85 9.03 15.50

1.0 -0.5 -2.0

-23 -14 -15

39 11 30

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

7.0 4.3 3.2

16.16 20.42 14.61

8.0 4.0 -1.5

-17 -20 -7

31 29 32

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

0.6 1.8 7.4

6.91 11.23 13.24

1.0 8.0 6.5

-10 -16 -10

13 10 28

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 6 Clinical Study Report SRT-2104-013

Table 14.3.6.3 Summary of Change from Baseline for ECG Values Safety Analysis Set Population EG Test (Unit) Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------Ventricular Rate (bpm) Placebo 7 Day 28 6 -2.5 7.74 -1.5 -13 7 Day 56 6 -0.3 8.14 0.0 -14 11 Day 84 6 0.5 8.83 2.5 -13 12 SRT2104 0.25 g

9

Day 28 Day 56 Day 84

9 6 8

1.7 -1.5 -2.0

12.07 4.32 10.31

5.0 -0.5 1.5

-21 -8 -22

19 4 9

SRT2104 0.5 g

12

Day 28 Day 56 Day 84

7 4 6

3.4 -0.3 0.5

7.37 9.32 13.19

5.0 3.5 1.5

-12 -14 -16

11 6 19

SRT2104 1.0 g

11

Day 28 Day 56 Day 84

8 8 8

-4.0 -5.3 -2.9

10.86 9.07 10.93

-3.5 -4.5 2.5

-21 -19 -18

13 6 10

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose. Note: Values for QTcN not included in summary table.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 7 Clinical Study Report SRT-2104-013

Table 14.3.6.4 Listing of ECG Values of Potential Clinical Importance Safety Analysis Set Population Treatment: Placebo QTcF (msec)/ Age(y)/ Planned Change from Sex/ Relative ECG Date/ baseline of QTcN Subj. Race Time Time QTcF (msec) This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. Ventricular Study Rate PR QRS QT Day (bpm) (msec) (msec) (msec)

QTcB (msec)/ Change from baseline of QTcB

Note: L=Low, H=High. Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 10 Clinical Study Report SRT-2104-013

Table 14.3.6.5 Listing of All ECG Values for Subjects with Values of Potential Clinical Importance Safety Analysis Set Population Treatment: Placebo

Subj.

Age(y)/ Planned Sex/ Relative Race Time

ECG Date/ Time

Ventricular Study Rate PR QRS QT Day (bpm) (msec) (msec) (msec)

QTcB (msec)/ Change from baseline of QTcB

QTcF (msec)/ Change from baseline of QTcN QTcF (msec)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

Note: L=Low, H=High. Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcB (msec) Placebo 7 Screening 6 6 (100%) 0 0 0 Day 1

6

6 (100%)

0

0

0

Day 28

6

6 (100%)

0

0

0

Day 56

6

5

(83%)

0

1

Day 84

6

6 (100%)

0

0

(17%)

0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcB (msec) SRT2104 9 Screening 9 9 (100%) 0 0 0 0.25 g Day 1

8

8 (100%)

0

0

0

Day 28

9

9 (100%)

0

0

0

Day 56

6

6 (100%)

0

0

0

Day 84

8

8 (100%)

0

0

0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcB (msec) SRT2104 12 Screening 7 7 (100%) 0 0 0 0.5 g Day 1

7

7 (100%)

0

0

0

Day 28

7

6

(86%)

1

0

0

Day 56

4

4 (100%)

0

0

0

Day 84

6

6 (100%)

0

0

0

(14%)

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcB (msec) SRT2104 11 Screening 8 8 (100%) 0 0 0 1.0 g Day 1

8

8 (100%)

0

0

0

Day 28

8

8 (100%)

0

0

0

Day 56

8

8 (100%)

0

0

0

Day 84

8

8 (100%)

0

0

0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcF (msec) Placebo 7 Screening 6 5 (83%) 1 (17%) 0 0 Day 1

6

6 (100%)

0

0

0

Day 28

6

6 (100%)

0

0

0

Day 56

6

5

(83%)

0

1

Day 84

6

6 (100%)

0

0

(17%)

0 0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcF (msec) SRT2104 9 Screening 9 9 (100%) 0 0 0 0.25 g Day 1

8

8 (100%)

0

0

0

Day 28

9

9 (100%)

0

0

0

Day 56

6

6 (100%)

0

0

0

Day 84

8

8 (100%)

0

0

0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcF (msec) SRT2104 12 Screening 7 7 (100%) 0 0 0 0.5 g Day 1

7

7 (100%)

0

0

0

Day 28

7

7 (100%)

0

0

0

Day 56

4

4 (100%)

0

0

0

Day 84

6

6 (100%)

0

0

0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.6 Summary of Category of QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative __________________________________________________________ Parameter Trt. N Time n Value<=450 450500 ---------------------------------------------------------------------------------------------------------QTcF (msec) SRT2104 11 Screening 8 8 (100%) 0 0 0 1.0 g Day 1

8

8 (100%)

0

0

0

Day 28

8

8 (100%)

0

0

0

Day 56

8

8 (100%)

0

0

0

Day 84

8

8 (100%)

0

0

0

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcB (msec) Placebo 7 Day 28 6 6 (100%) 0 0 Day 56

6

5

(83%)

1

Day 84

6

6 (100%)

0

(17%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcB (msec) SRT2104 9 Day 28 9 7 (78%) 2 (22%) 0 0.25 g Day 56

6

6 (100%)

0

Day 84

8

7

1

(88%)

0 (13%)

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcB (msec) SRT2104 12 Day 28 7 6 (86%) 1 (14%) 0 0.5 g Day 56

4

4 (100%)

0

0

Day 84

6

6 (100%)

0

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcB (msec) SRT2104 11 Day 28 8 8 (100%) 0 0 1.0 g Day 56

8

8 (100%)

0

0

Day 84

8

8 (100%)

0

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcF (msec) Placebo 7 Day 28 6 6 (100%) 0 0 Day 56

6

5

(83%)

1

Day 84

6

6 (100%)

0

(17%)

0 0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcF (msec) SRT2104 9 Day 28 9 7 (78%) 2 (22%) 0 0.25 g Day 56

6

6 (100%)

0

0

Day 84

8

8 (100%)

0

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcF (msec) SRT2104 12 Day 28 7 6 (86%) 1 (14%) 0 0.5 g Day 56

4

4 (100%)

0

Day 84

6

5

1

(83%)

0 (17%)

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 8 Clinical Study Report SRT-2104-013

Table 14.3.6.7 Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time Safety Analysis Set Population Planned Category Relative ______________________________________________ Parameter Trt. N Time n Value<=30 3060 -----------------------------------------------------------------------------------------------QTcF (msec) SRT2104 11 Day 28 8 8 (100%) 0 0 1.0 g Day 56

8

8 (100%)

0

0

Day 84

8

8 (100%)

0

0

Note: Baseline is defined as the last non-missing value before administration of the SRT2104/placebo dose.

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------CCL20 Placebo 7 Day 1 7 13.9 15.05 15.1 0 37 Day 84 7 28.4 43.21 0.0 0 99

CCL20 repeat

SRT2104 0.25 g

9

Day 1 Day 84

9 9

7.9 6.1

12.46 9.57

0.0 0.0

0 0

30 25

SRT2104 0.5 g

12

Day 1 Day 84

11 11

20.8 6.9

32.30 17.15

0.0 0.0

0 0

86 55

SRT2104 1.0 g

11

Day 1 Day 84

11 6

20.7 11.6

50.42 18.16

0.0 0.0

0 0

167 39

Overall

39

Day 1 Day 84

38 33

16.4 12.1

32.70 24.37

0.0 0.0

0 0

167 99

Placebo

7

Day 1 Day 84

7 7

17.5 11.1

8.75 7.92

16.7 10.4

6 2

34 24

SRT2104 0.25 g

9

Day 1 Day 84

9 6

16.1 12.6

8.45 11.17

13.5 11.7

6 1

33 31

SRT2104 0.5 g

12

Day 1 Day 84

11 10

16.5 14.6

14.86 25.26

10.4 8.3

2 2

41 86

SRT2104 1.0 g

11

Day 1 Day 84

11 10

15.7 17.5

22.38 15.77

6.1 10.8

2 3

78 49

Overall

39

Day 1 Day 84

38 33

16.4 14.4

14.94 16.93

13.1 9.5

2 1

78 86

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------CXCL1 Placebo 7 Day 1 7 71.4 60.22 62.8 22 203 Day 84 7 28.0 26.37 14.3 5 76

DEFB4A

SRT2104 0.25 g

9

Day 1 Day 84

9 6

80.7 25.8

77.35 28.54

48.1 18.3

25 3

223 81

SRT2104 0.5 g

12

Day 1 Day 84

11 10

58.8 28.2

57.73 19.78

40.4 22.1

7 4

214 68

SRT2104 1.0 g

11

Day 1 Day 84

11 10

67.3 82.8

75.72 109.94

31.5 51.3

7 4

208 373

Overall

39

Day 1 Day 84

38 33

68.8 44.3

66.32 66.58

47.2 21.6

7 3

223 373

Placebo

7

Day 1 Day 84

7 7

5131.8 2419.9

2914.93 1782.24

3828.8 2909.4

1864 0

10486 4102

SRT2104 0.25 g

9

Day 1 Day 84

9 6

6099.5 2892.1

4251.53 3409.97

4965.2 2077.5

306 0

15852 8008

SRT2104 0.5 g

12

Day 1 Day 84

11 10

7221.7 5010.0

5017.58 5427.34

6598.4 4104.7

860 0

14200 18116

SRT2104 1.0 g

11

Day 1 Day 84

11 10

7257.4 8381.9

4147.08 4452.28

7373.5 8668.2

2657 910

14930 15101

Overall

39

Day 1 Day 84

38 33

6581.3 5097.3

4177.37 4703.81

5141.9 4155.0

306 0

15852 18116

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IFNg Placebo 7 Day 1 7 0.8 0.56 1.0 0 2 Day 84 7 0.5 0.31 0.5 0 1

IFNg(custom)

SRT2104 0.25 g

9

Day 1 Day 84

9 6

4.4 0.9

9.18 0.32

1.2 0.8

1 1

29 1

SRT2104 0.5 g

12

Day 1 Day 84

11 10

0.8 0.8

0.56 0.67

0.8 0.6

0 0

2 3

SRT2104 1.0 g

11

Day 1 Day 84

11 10

0.8 0.9

0.56 0.53

0.8 0.9

0 0

2 2

Overall

39

Day 1 Day 84

38 33

1.7 0.8

4.57 0.52

0.8 0.7

0 0

29 3

Placebo

7

Day 1 Day 84

7 7

222.3 179.0

65.59 45.30

202.3 170.0

158 118

334 260

SRT2104 0.25 g

9

Day 1 Day 84

9 6

234.4 192.0

77.69 38.78

193.9 204.1

157 141

386 230

SRT2104 0.5 g

12

Day 1 Day 84

11 10

222.1 232.9

40.94 113.18

232.7 197.2

155 125

277 520

SRT2104 1.0 g

11

Day 1 Day 84

11 10

236.0 202.0

93.71 53.31

234.4 198.0

110 122

409 280

Overall

39

Day 1 Day 84

38 33

229.1 204.7

69.81 73.81

231.2 195.9

110 118

409 520

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IL12B Placebo 7 Day 1 7 0.8 0.59 0.7 0 1 Day 84 7 0.6 0.39 0.5 0 1

IL13

SRT2104 0.25 g

9

Day 1 Day 84

9 6

1.6 0.6

0.95 0.56

1.3 0.3

1 0

4 2

SRT2104 0.5 g

12

Day 1 Day 84

11 10

1.3 1.1

0.97 1.34

1.4 0.6

0 0

3 4

SRT2104 1.0 g

11

Day 1 Day 84

11 10

1.1 1.4

0.79 1.79

1.1 0.7

0 0

3 6

Overall

39

Day 1 Day 84

38 33

1.2 1.0

0.87 1.27

1.2 0.7

0 0

4 6

Placebo

7

Day 1 Day 84

7 7

0.0 0.0

0.00 0.00

0.0 0.0

0 0

0 0

SRT2104 0.25 g

9

Day 1 Day 84

9 6

0.5 0.0

1.45 0.00

0.0 0.0

0 0

4 0

SRT2104 0.5 g

12

Day 1 Day 84

11 10

0.0 0.0

0.00 0.00

0.0 0.0

0 0

0 0

SRT2104 1.0 g

11

Day 1 Day 84

11 10

0.1 0.1

0.11 0.30

0.0 0.0

0 0

0 1

Overall

39

Day 1 Day 84

38 33

0.1 0.0

0.71 0.17

0.0 0.0

0 0

4 1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IL17A Placebo 7 Day 1 7 2.9 2.58 2.4 0 8 Day 84 7 1.4 0.96 1.2 0 3

IL1B

SRT2104 0.25 g

9

Day 1 Day 84

9 6

2.5 1.5

1.69 1.24

2.3 1.8

0 0

5 3

SRT2104 0.5 g

12

Day 1 Day 84

11 10

3.4 3.2

2.77 3.69

3.1 1.6

1 0

10 12

SRT2104 1.0 g

11

Day 1 Day 84

11 10

2.8 2.3

2.08 1.14

2.0 2.0

0 1

7 5

Overall

39

Day 1 Day 84

38 33

2.9 2.2

2.25 2.27

2.3 1.7

0 0

10 12

Placebo

7

Day 1 Day 84

7 7

91.5 36.9

59.84 34.10

68.1 19.4

28 8

210 98

SRT2104 0.25 g

9

Day 1 Day 84

9 6

99.5 29.9

92.09 30.94

63.4 22.4

30 5

264 90

SRT2104 0.5 g

12

Day 1 Day 84

11 10

72.2 38.3

62.64 28.05

60.5 28.6

7 7

230 96

SRT2104 1.0 g

11

Day 1 Day 84

11 10

75.9 88.0

84.47 94.99

36.3 64.9

11 6

258 319

Overall

39

Day 1 Day 84

38 33

83.3 51.6

74.38 61.09

62.0 28.2

7 5

264 319

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IL1B repeat Placebo 7 Day 1 7 25.1 21.11 15.8 10 69 Day 84 7 14.2 10.87 9.0 3 32

IL22

SRT2104 0.25 g

9

Day 1 Day 84

9 6

35.2 10.5

29.14 9.20

20.5 7.7

9 3

92 26

SRT2104 0.5 g

12

Day 1 Day 84

11 10

20.8 13.6

17.03 17.09

14.7 7.6

3 0

54 54

SRT2104 1.0 g

11

Day 1 Day 84

11 10

18.2 19.7

17.54 17.59

9.8 14.7

0 4

55 64

Overall

39

Day 1 Day 84

38 33

24.2 15.0

21.48 14.70

17.1 9.8

0 0

92 64

Placebo

7

Day 1 Day 84

7 7

0.5 0.2

0.39 0.16

0.3 0.2

0 0

1 0

SRT2104 0.25 g

9

Day 1 Day 84

9 6

6.7 0.2

18.50 0.23

0.6 0.1

0 0

56 1

SRT2104 0.5 g

12

Day 1 Day 84

11 10

0.4 0.3

0.36 0.48

0.4 0.2

0 0

1 2

SRT2104 1.0 g

11

Day 1 Day 84

11 10

1.1 0.4

2.27 0.39

0.5 0.3

0 0

8 2

Overall

39

Day 1 Day 84

38 33

2.1 0.3

9.06 0.36

0.4 0.2

0 0

56 2

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IL23A Placebo 7 Day 1 7 1.6 1.00 1.6 0 3 Day 84 7 1.3 0.85 1.3 0 2

IL6

SRT2104 0.25 g

9

Day 1 Day 84

9 6

3.1 1.6

1.48 1.04

3.1 1.6

1 0

5 3

SRT2104 0.5 g

12

Day 1 Day 84

11 10

1.7 1.9

1.25 2.58

1.5 1.3

0 0

4 9

SRT2104 1.0 g

11

Day 1 Day 84

11 10

1.6 2.2

0.94 1.30

1.7 2.0

0 1

3 4

Overall

39

Day 1 Day 84

38 33

2.0 1.8

1.31 1.66

1.7 1.5

0 0

5 9

Placebo

7

Day 1 Day 84

7 7

0.8 0.9

0.38 0.58

0.9 0.8

0 0

1 2

SRT2104 0.25 g

9

Day 1 Day 84

9 6

1.3 0.7

0.97 0.30

1.1 0.8

0 0

4 1

SRT2104 0.5 g

12

Day 1 Day 84

11 10

1.6 0.9

1.67 0.57

0.7 0.6

0 0

5 2

SRT2104 1.0 g

11

Day 1 Day 84

11 10

2.4 1.1

5.31 0.57

0.7 0.9

0 0

18 2

Overall

39

Day 1 Day 84

38 33

1.6 0.9

2.99 0.52

0.9 0.8

0 0

18 2

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 8 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------IL8 Placebo 7 Day 1 7 243.9 438.55 72.4 26 1234 Day 84 7 111.0 133.82 52.4 2 332

K16

SRT2104 0.25 g

9

Day 1 Day 84

9 6

133.4 25.8

165.17 26.81

31.9 17.6

18 1

431 73

SRT2104 0.5 g

12

Day 1 Day 84

11 10

80.5 55.9

100.06 88.52

53.5 23.4

2 3

322 294

SRT2104 1.0 g

11

Day 1 Day 84

11 10

69.5 68.1

81.62 77.21

25.7 54.3

6 7

251 269

Overall

39

Day 1 Day 84

38 33

120.0 65.8

213.92 90.16

49.0 28.5

2 1

1234 332

Placebo

7

Day 1 Day 84

7 7

4511.6 3206.8

3886.34 1726.85

2242.1 2180.0

951 1464

11148 5939

SRT2104 0.25 g

9

Day 1 Day 84

9 6

7079.2 2968.7

5526.59 3112.55

5569.5 1727.0

1802 384

18530 7371

SRT2104 0.5 g

12

Day 1 Day 84

11 10

6511.9 5086.9

3901.59 4603.16

6591.6 4700.0

2425 419

15367 16679

SRT2104 1.0 g

11

Day 1 Day 84

11 10

8374.3 8849.6

4087.46 7983.89

6656.7 6870.6

3353 1910

14769 28841

Overall

39

Day 1 Day 84

38 33

6816.9 5443.2

4410.65 5645.15

5832.4 4321.4

951 384

18530 28841

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 9 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------LCN2 Placebo 7 Day 1 7 2462.3 1267.03 2060.8 1197 4616 Day 84 7 1572.8 1092.15 1775.0 87 3499

P50

SRT2104 0.25 g

9

Day 1 Day 84

9 6

2656.1 1612.6

1665.71 1415.30

2510.2 1530.4

252 105

5933 3358

SRT2104 0.5 g

12

Day 1 Day 84

11 10

2990.6 1957.9

1665.97 1461.56

2932.3 1325.4

685 398

6585 4932

SRT2104 1.0 g

11

Day 1 Day 84

11 10

2099.4 2510.6

1304.33 1621.31

1752.0 1968.2

673 428

4288 5642

Overall

39

Day 1 Day 84

38 33

2556.1 1980.9

1480.68 1423.53

2198.7 1746.3

252 87

6585 5642

Placebo

7

Day 1 Day 84

7 7

29.5 27.1

10.79 4.88

25.5 26.5

16 21

48 34

SRT2104 0.25 g

9

Day 1 Day 84

9 6

45.0 31.9

12.21 14.03

42.9 26.2

31 20

72 54

SRT2104 0.5 g

12

Day 1 Day 84

11 10

34.0 35.4

11.49 11.43

34.6 33.0

17 20

57 59

SRT2104 1.0 g

11

Day 1 Day 84

11 10

33.8 32.1

9.40 6.81

33.1 32.6

20 20

47 40

Overall

39

Day 1 Day 84

38 33

35.7 32.0

11.88 9.69

35.1 29.1

16 20

72 59

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 10 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------S100A7 Placebo 7 Day 1 7 19482.3 4999.87 17271.0 15557 27258 Day 84 7 15137.2 9943.29 14310.4 1812 26878

TNF(a)

SRT2104 0.25 g

9

Day 1 Day 84

9 6

26372.6 17677.8

12600.45 15049.98

28711.1 17337.8

8163 991

41332 34273

SRT2104 0.5 g

12

Day 1 Day 84

11 10

23696.4 15112.5

10386.99 11335.24

25792.0 14946.1

8809 1608

39510 32565

SRT2104 1.0 g

11

Day 1 Day 84

11 10

18311.7 25933.2

7800.62 10842.24

18093.1 25393.0

5577 4176

28869 43697

Overall

39

Day 1 Day 84

38 33

21995.2 18863.1

9733.33 12101.44

21091.7 21141.4

5577 991

41332 43697

Placebo

7

Day 1 Day 84

7 7

3.2 3.4

1.49 1.46

2.7 3.0

1 2

5 5

SRT2104 0.25 g

9

Day 1 Day 84

9 6

4.9 3.3

2.93 1.72

3.4 2.6

2 2

10 6

SRT2104 0.5 g

12

Day 1 Day 84

11 10

4.5 3.8

2.53 1.54

3.8 4.0

1 1

10 7

SRT2104 1.0 g

11

Day 1 Day 84

11 10

4.1 3.1

2.03 0.94

3.1 3.0

2 2

7 5

Overall

39

Day 1 Day 84

38 33

4.2 3.4

2.32 1.36

3.4 3.3

1 1

10 7

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 11 of 11 Clinical Study Report SRT-2104-013 Table 14.4.1.1 Summary of Gene Expression Data Efficacy Analysis Population

Gene Name Treatment N Visit n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------p65 Placebo 7 Day 1 7 399.7 155.74 340.9 244 716 Day 84 7 526.4 236.29 465.8 280 1028 SRT2104 0.25 g

9

Day 1 Day 84

9 6

619.0 537.3

191.63 56.51

586.3 529.0

285 460

915 623

SRT2104 0.5 g

12

Day 1 Day 84

11 10

636.0 718.2

86.92 370.03

624.1 560.0

491 437

748 1525

SRT2104 1.0 g

11

Day 1 Day 84

11 10

642.1 580.6

237.00 195.82

598.6 595.6

391 341

1180 925

Overall

39

Day 1 Day 84

38 33

590.2 602.9

193.88 258.18

585.4 528.0

244 280

1180 1525

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------CCL20 Placebo 7 Day 84 7 14.4 49.89 0.0 -37 83

CCL20 repeat

CXCL1

SRT2104 0.25 g

9

Day 84

9

-1.8

12.60

0.0

-26

17

SRT2104 0.5 g

12

Day 84

11

-13.9

26.43

0.0

-86

0

SRT2104 1.0 g

11

Day 84

6

-26.2

71.78

-6.0

-167

39

Overall

39

Day 84

33

-6.8

41.51

0.0

-167

83

Placebo

7

Day 84

7

-6.3

10.83

-11.3

-18

7

SRT2104 0.25 g

9

Day 84

6

-3.9

11.21

-6.1

-14

17

SRT2104 0.5 g

12

Day 84

10

-3.4

21.80

-4.1

-32

49

SRT2104 1.0 g

11

Day 84

10

1.7

12.14

4.3

-30

14

Overall

39

Day 84

33

-2.5

15.04

-1.3

-32

49

Placebo

7

Day 84

7

-43.4

53.49

-28.8

-150

13

SRT2104 0.25 g

9

Day 84

6

-12.5

39.11

-20.7

-53

56

SRT2104 0.5 g

12

Day 84

10

-33.0

58.31

-32.3

-167

34

SRT2104 1.0 g

11

Day 84

10

14.0

90.15

13.8

-195

165

Overall

39

Day 84

33

-17.2

67.49

-11.6

-195

165

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------DEFB4A Placebo 7 Day 84 7 -2711.8 3270.39 -977.4 -7461 334

IFNg

IFNg(custom)

SRT2104 0.25 g

9

Day 84

6

-1323.2

3803.37

-337.9

-6640

3660

SRT2104 0.5 g

12

Day 84

10

-1513.8

7464.59

-1293.6

-13431

11517

SRT2104 1.0 g

11

Day 84

10

1692.7

5563.87

1422.2

-5162

10613

Overall

39

Day 84

33

-761.6

5620.84

-859.8

-13431

11517

Placebo

7

Day 84

7

-0.3

0.65

-0.2

-1

1

SRT2104 0.25 g

9

Day 84

6

-5.2

11.27

-0.9

-28

0

SRT2104 0.5 g

12

Day 84

10

-0.1

0.82

-0.1

-1

2

SRT2104 1.0 g

11

Day 84

10

0.3

0.56

0.3

-1

1

Overall

39

Day 84

33

-1.0

4.94

0.0

-28

2

Placebo

7

Day 84

7

-43.3

42.90

-57.7

-78

37

SRT2104 0.25 g

9

Day 84

6

-41.5

95.52

-41.6

-161

68

SRT2104 0.5 g

12

Day 84

10

13.8

103.33

-26.6

-100

247

SRT2104 1.0 g

11

Day 84

10

-30.7

113.24

-20.8

-205

154

Overall

39

Day 84

33

-21.9

94.74

-42.5

-205

247

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 3 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------IL12B Placebo 7 Day 84 7 -0.2 0.46 -0.1 -1 1

IL13

IL17A

SRT2104 0.25 g

9

Day 84

6

-0.8

1.06

-0.5

-2

1

SRT2104 0.5 g

12

Day 84

10

-0.2

1.50

-0.4

-3

2

SRT2104 1.0 g

11

Day 84

10

0.4

2.10

-0.0

-1

6

Overall

39

Day 84

33

-0.1

1.50

-0.3

-3

6

Placebo

7

Day 84

7

0.0

0.00

0.0

0

0

SRT2104 0.25 g

9

Day 84

6

-0.7

1.78

0.0

-4

0

SRT2104 0.5 g

12

Day 84

10

0.0

0.00

0.0

0

0

SRT2104 1.0 g

11

Day 84

10

0.0

0.23

0.0

-0

1

Overall

39

Day 84

33

-0.1

0.77

0.0

-4

1

Placebo

7

Day 84

7

-1.5

2.18

-0.4

-6

0

SRT2104 0.25 g

9

Day 84

6

-0.4

1.12

-0.4

-2

1

SRT2104 0.5 g

12

Day 84

10

-0.4

3.55

-1.1

-4

8

SRT2104 1.0 g

11

Day 84

10

-0.3

2.17

-0.1

-5

3

Overall

39

Day 84

33

-0.6

2.49

-0.4

-6

8

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 4 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------IL1B Placebo 7 Day 84 7 -54.6 53.69 -47.4 -141 5

IL1B repeat

IL22

SRT2104 0.25 g

9

Day 84

6

-18.8

42.64

-25.7

-59

53

SRT2104 0.5 g

12

Day 84

10

-36.9

68.31

-34.8

-162

50

SRT2104 1.0 g

11

Day 84

10

10.6

80.73

28.8

-199

88

Overall

39

Day 84

33

-23.0

67.85

-16.0

-199

88

Placebo

7

Day 84

7

-10.9

24.19

-6.8

-53

23

SRT2104 0.25 g

9

Day 84

6

-9.4

16.05

-6.5

-39

10

SRT2104 0.5 g

12

Day 84

10

-8.8

16.21

-4.2

-45

13

SRT2104 1.0 g

11

Day 84

10

1.5

18.85

3.3

-42

24

Overall

39

Day 84

33

-6.2

18.74

-4.1

-53

24

Placebo

7

Day 84

7

-0.3

0.42

-0.2

-1

0

SRT2104 0.25 g

9

Day 84

6

-9.4

22.62

-0.2

-56

0

SRT2104 0.5 g

12

Day 84

10

-0.1

0.41

-0.2

-1

1

SRT2104 1.0 g

11

Day 84

10

-0.8

2.43

-0.1

-8

0

Overall

39

Day 84

33

-2.0

9.70

-0.2

-56

1

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 5 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------IL23A Placebo 7 Day 84 7 -0.4 1.11 0.0 -2 1

IL6

IL8

SRT2104 0.25 g

9

Day 84

6

-1.3

2.29

-1.1

-4

2

SRT2104 0.5 g

12

Day 84

10

0.1

2.54

0.0

-4

6

SRT2104 1.0 g

11

Day 84

10

0.7

1.25

0.5

-1

3

Overall

39

Day 84

33

-0.1

1.95

0.1

-4

6

Placebo

7

Day 84

7

0.0

0.64

-0.0

-1

1

SRT2104 0.25 g

9

Day 84

6

-0.6

1.05

-0.5

-3

0

SRT2104 0.5 g

12

Day 84

10

-0.9

1.86

-0.6

-4

2

SRT2104 1.0 g

11

Day 84

10

-1.5

5.82

0.4

-18

1

Overall

39

Day 84

33

-0.8

3.33

-0.1

-18

2

Placebo

7

Day 84

7

-132.9

458.32

-23.7

-1134

206

SRT2104 0.25 g

9

Day 84

6

-21.2

65.74

-12.9

-141

55

SRT2104 0.5 g

12

Day 84

10

-31.7

75.78

-8.6

-192

47

SRT2104 1.0 g

11

Day 84

10

-5.8

102.57

-3.4

-228

156

Overall

39

Day 84

33

-43.4

216.71

-18.3

-1134

206

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 6 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------K16 Placebo 7 Day 84 7 -1304.8 2347.19 -290.4 -5209 1229

LCN2

P50

SRT2104 0.25 g

9

Day 84

6

-2671.5

6129.17

-1382.9

-13687

3149

SRT2104 0.5 g

12

Day 84

10

-539.5

4599.99

-934.1

-5496

8920

SRT2104 1.0 g

11

Day 84

10

898.5

7774.74

424.0

-12236

15585

Overall

39

Day 84

33

-653.7

5609.61

-290.4

-13687

15585

Placebo

7

Day 84

7

-889.6

1084.25

-646.5

-3088

209

SRT2104 0.25 g

9

Day 84

6

-475.2

1845.42

-45.4

-3650

1582

SRT2104 0.5 g

12

Day 84

10

-904.1

1833.95

-610.0

-3832

2000

SRT2104 1.0 g

11

Day 84

10

592.3

1690.80

591.7

-1645

4900

Overall

39

Day 84

33

-369.6

1715.29

-254.9

-3832

4900

Placebo

7

Day 84

7

-2.4

14.13

0.3

-27

19

SRT2104 0.25 g

9

Day 84

6

-15.1

25.95

-17.9

-48

23

SRT2104 0.5 g

12

Day 84

10

0.1

10.21

-0.7

-15

18

SRT2104 1.0 g

11

Day 84

10

-0.9

10.82

-0.5

-27

12

Overall

39

Day 84

33

-3.5

15.38

-1.4

-48

23

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 7 of 7 Clinical Study Report SRT-2104-013

Table 14.4.1.2 Summary of Change from Baseline Gene Expression Data Efficacy Analysis Population Gene Name Treatment N Visit n Mean SD Median Min. Max. --------------------------------------------------------------------------------------------------S100A7 Placebo 7 Day 84 7 -4345.1 10228.42 -1518.1 -16440 9160

TNF(a)

p65

SRT2104 0.25 g

9

Day 84

6

-4985.1

16027.12

-2652.7

-35031

9030

SRT2104 0.5 g

12

Day 84

10

-9468.6

13090.94

-6934.7

-35159

7567

SRT2104 1.0 g

11

Day 84

10

8530.6

9428.61

6544.1

-5426

30383

Overall

39

Day 84

33

-2112.3

13707.65

-885.0

-35159

30383

Placebo

7

Day 84

7

0.2

2.02

-0.6

-2

4

SRT2104 0.25 g

9

Day 84

6

-2.4

2.72

-1.1

-8

-1

SRT2104 0.5 g

12

Day 84

10

-0.8

2.28

-0.1

-6

2

SRT2104 1.0 g

11

Day 84

10

-0.8

2.07

0.0

-5

2

Overall

39

Day 84

33

-0.9

2.30

-0.6

-8

4

Placebo

7

Day 84

7

126.7

145.57

72.4

-57

313

SRT2104 0.25 g

9

Day 84

6

-153.9

201.03

-94.7

-422

67

SRT2104 0.5 g

12

Day 84

10

78.4

342.77

-61.2

-218

845

SRT2104 1.0 g

11

Day 84

10

-51.1

260.83

-14.3

-465

257

Overall

39

Day 84

33

7.2

270.38

-34.6

-465

845

SRT2104 Sirtris Pharmaceuticals, Inc.

1

Clinical Study Protocol SRT-2104-013 February 12, 2009

PROTOCOL SUMMARY

Study Title: A Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis Number of Study Center(s): Approximately five centers located in the United States are planned for this study. Study Phase: Phase IIa Study Period: Approximately 18 weeks Study Objectives: Primary: 1. To assess the effects of 500 mg and 2000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis Secondary: 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 500 mg and 2000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque-type psoriasis Exploratory: 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of depression and anxiety in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Mentor Psoriasis Instrument, PQOL-12.

Page 2 of 69

CONFIDENTIAL

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Protocol SRT-2104-013 February 12, 2009

Study Design: This phase IIa, proof of concept, randomized, double-blind, placebo-controlled study will be conducted in approximately 30 subjects with moderate to severe plaque-type psoriasis. There will be a screening period, a 12-week treatment period with 7 on-treatment visits (Days 1, 14, 28, 42, 56, 70 and 84) and a follow-up safety assessment (Day 114). Subjects who provide informed consent will undergo screening procedures within 21days of randomization. Subjects will be enrolled and randomized into the study on approximately Day – 6 and receive investigational product on Day 1. Subjects will take blinded investigational product on a daily basis from Day 1 through Day 84. For the safety evaluation, adverse events (AEs) will be monitored from Day 1 through a follow-up visit that will occur 30 days after discontinuation of investigational product on Day 84. Vital signs, clinical laboratory results (hematology, chemistry, urinalysis), ECGs and physical examinations will be assessed at periodic intervals from Day 1 through Day 84. Skin biopsies of the same designated psoriatic lesion will be conducted on Days 1 and 84 to assess the effects of SRT2104 on histologic markers of inflammation. Disease assessments using the PASI score and the PGA will be conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. Sense of well-being will be assessed using depression and anxiety scales (PHQ-9 and HADS respectively) which will be completed on Days 1, 28, 56 and 84. Quality of Life (QOL) will be assessed on Days 1 and 84 using the PQOL-12. Blood will be obtained on Days 28, 56 and 84 for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Subjects who prematurely discontinue from the study will complete Day 84 assessments at the time of discontinuation. Number of Subjects: Approximately 30 subjects will be enrolled. Duration of Subjects Participation/Duration of Study/Duration of Treatment: Subject participation will include a screening period of up to 21 days and an 84-day dosing period. Subjects will return to the clinic 30 days after their last dose of investigational product for a follow up visit. The duration of each subject’s participation is expected to be approximately 18 weeks. The study duration (first subject’s first visit through last subject’s last visit) is anticipated to last approximately 8-10 months. Drug Supply, Dosage, and Mode of Administration: Subjects will be randomized 2:2:1 to receive either 500 or 2000 mg/day of SRT2104 or placebo, respectively. Investigational product will be supplied as 250 mg capsules of SRT2104 along with matching placebo capsules. Investigational product will be administered orally once daily for 84 consecutive days. Eight capsules (SRT2104, SRT2104 and placebo or all placebos) will be taken daily. The subjects and the investigator will be blinded to treatment assignment. Dosing with SRT2104 or placebo is to take place at approximately the same time every day, approximately 15 minutes following consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories. Page 3 of 69

CONFIDENTIAL

SRT2104 Sirtris Pharmaceuticals, Inc.

Clinical Study Protocol SRT-2104-013 February 12, 2009

CRITERIA FOR EVALUATION Safety and Tolerability: The incidence of AEs and clinically significant abnormal laboratory values will be recorded based upon investigator observation and subject reporting. Safety will be monitored by reports of AEs (at all visits after the first dose has been administered through 30 days after the last dose), vital sign measurements, physical examinations, laboratory parameters and electrocardiograms. Concomitant medications and AEs will be recorded at every visit. Additional visits will be permitted for safety follow-up as required. Pharmacokinetics: Blood will be obtained using a sparse sampling technique for PK and PD assessments. Pharmacodynamics: Biomarkers for psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose and may include, but may not be limited to, hsCRP and FGF21. Activity: The primary clinical activity endpoint is change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks. Skin biopsy samples will be evaluated for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD68+ monocytes, CD11c+ dendritic cells, CD38+ cells, CD3+ T-cells, and TH17+ T cells), and keratinocyte expression of K-16 and ICAM-l. Secondary clinical activity endpoints are PASI-50 and PASI-75 response rates, defined as the proportion of subjects who achieve a PASI-50 or PASI-75, mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. RT-PCR will be used to assess expression of specific genes at baseline and after 12 weeks which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPAR alpha, PPAR delta, and p53. In addition, global changes in gene expression may be assessed using gene micro-array techniques. Exploratory clinical activity endpoints include assessments of the subject’s sense of well-being (PHQ-9 and HADS) and health-related quality of life (PQOL-12).

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Clinical Study Protocol SRT-2104-013 February 12, 2009

General Analysis Plan: Response will be compared between active treatment groups and the null placebo response of 10% using a single sided, one sample binomial test. Other activity analyses (PASI response, sense of well-being and QOL) will be performed between treatments using analysis of covariance on the change between day of assessment and baseline using the baseline value as the covariate. Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. Listing of individual subject and summary statistics for plasma SRT2104 concentrations, blood sampling times, and for other PK parameters and graphs of concentration vs. time will be prepared by dosing cohort. Rationale for Number of Subjects: A sample size of 10 evaluable subjects per active treatment group and 5 evaluable subjects per placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 one-sided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (response of excellent) of 30.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2) therefore, based on an estimated dropout rate of approximately 17%, enrollment of approximately 12 subjects per active group and 6 subjects per placebo group is planned.

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1.1

Clinical Study Protocol SRT-2104-013 February 12, 2009

Schedule of Events

A full description of the study procedures is provided in Section 6. Study Period

Screening

Visit Number Study Day(s) Clinic Visit Informed Consent Medical History1 Viral Serology Photographs (total body surface area involvement) Randomization2 Investigational Product Dispensed Physical Examination3 (including height at Screening and weight at all subsequent visits) Vital Signs Chest X-Ray 12-lead ECG Clinical Chemistry/Hematology4 Urinalysis Pregnancy Test5 Adverse Event/Concomitant Medication Assessment PK Sampling6 PASI & PGA QOL assessments (PHQ-9, HADS, PQOL-127) Biomarkers Pharmacogenetics Sample9 Skin Biopsy (Immunohistochemistry and Gene Expression Profiling)

1 -21 to -6 X X X X X X X X X X X X

Dosing Period 2 18 X

3 14 X

4 28 X

5 42 X

6 56 X

7 70 X

8 8410 X

Follow Up 114 X

X

X

X

X

X X

X X

X X

X

X

X

X

X X X X X

X X X X

X X X X X X X X X X X

X X X X

X X X X X X

X X X X

X X X X X X

X X X X

X X X

X X X

X X X

X

X

X

X

X

Footnotes: 1. Medical events occurring prior to the first dose will be collected on the medical history case report form (CRF). AEs occurring after the first dose will be recorded on the AE CRF. AEs and concomitant medications will be followed for 30 days after the last dose of study medication. 2. Subjects will be randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of investigational product. 3. A complete physical examination (PE) will be conducted at the Screening Visit. A symptom-driven, directed PE will be performed as needed at all other timepoints. 4. See Section 6.2 for a complete listing of safety lab parameters to be measured/analyzed. Lipid profiling and coagulation studies will be performed in fasting samples at Screening, and on Days 1, 42 and 84 only. 5. Serum pregnancy test to be performed at Screening; urine screen for pregnancy at all other timepoints. 6. PK sampling will be performed according to the schedule described in Section 6.2. 7. PQOL-12 to be performed on Days 1 and 84 only 8. The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1. 9. See Appendix 2 for a description of the pharmacogenetic assessment. 10. Subjects withdrawing from the study prior to the study assessments on Day 84 will undergo all Day 84 assessments and return for a follow-up visit 30 days following the last dose of investigational product.

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TABLE OF CONTENTS 1

PROTOCOL SUMMARY 1.1 Schedule of Events

2 6

LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS

10

2

INTRODUCTION AND STUDY RATIONALE 2.1 Disease Background 2.2 Scientific Background 2.3 SRT2104 Non-Clinical Experience 2.4 SRT2104 Clinical Experience

13 13 13 14 16

3

STUDY RATIONALE

20

4

STUDY OBJECTIVES 4.1 Primary 4.2 Secondary 4.3 Exploratory

21 21 21 21

5

INVESTIGATIONAL PLAN 5.1 Overall Study Design 5.2 Selection of Study Population 5.2.1 Number of Subjects 5.2.2 Replacement of Subjects 5.2.3 Inclusion Criteria 5.2.4 Exclusion Criteria 5.2.5 Definition of Treatment Failure 5.2.6 Removal of Subjects from the Study 5.3 Selection of Doses in the Study 5.4 Identity of Investigational Product 5.5 Treatments to be Administered 5.6 Method of Assigning Subjects to Treatment Groups 5.7 Individuals Who Will Be Unblinded to Treatment Assignments 5.8 Unblinding Procedures 5.9 Duration of Treatment 5.10 Prior Treatments 5.11 Proscribed Medications and Other Study Restrictions 5.12 Contraceptive Use 5.13 Treatment Compliance 5.14 Missed Doses of Investigational Product 5.15 Schedule of Events

22 22 22 22 22 22 23 24 24 25 26 26 27 27 27 27 28 28 28 29 29 29

6

STUDY PROCEDURES 6.1 Study Procedures 6.1.1 Visit 1 (Screening) 6.1.2 Visit 2 6.1.3 Visits 3, 5 and 7 6.1.4 Visits 4 and 6 6.1.5 Visit 8 6.1.6 Follow-Up Procedures 6.2 Pharmacokinetic Sampling

30 33 33 33 34 34 34 34 34

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6.3 6.4 6.5 6.6

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Laboratory Assessments Skin Biopsy Evaluation and Scoring Appropriateness of Measurements Data Quality Assurance

35 37 37 38

7

ADVERSE EVENTS 7.1 Definitions 7.1.1 Adverse Event Definition 7.1.2 Serious Adverse Event Definition 7.1.3 Suspected Unexpected Serious Adverse Reaction Definition 7.1.4 QTc Withdrawal Criteria 7.1.5 Liver Chemistry Stopping Rules and Follow-up 7.2 Procedures for Recording and Reporting AEs and SAEs 7.3 Monitoring of Adverse Events and Period of Observation 7.4 Pregnancy Reporting

39 39 39 39 41 41 41 45 48 48

8

STATISTICAL PROCEDURES 8.1 Randomization and Stratification 8.2 Sample Size 8.3 Populations for Analysis 8.4 Procedures for Handling Missing, Unused, and Spurious Data 8.5 Statistical Methods 8.5.1 Subject Disposition 8.5.2 Subjects Baseline Characteristics 8.5.3 Exposure to Investigational Product 8.5.4 Safety Analysis 8.5.5 Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 8.5.6 Activity Analysis 8.6 Procedures for Reporting Deviations to Original Statistical Analysis Plan

50 50 50 50 51 51 51 52 52 52 53 53 55

9

ADMINISTRATIVE REQUIREMENTS 9.1 Good Clinical Practice 9.2 Ethical Considerations 9.3 Subject Information and Informed Consent 9.4 Subject Confidentiality 9.5 Protocol Compliance 9.6 Study Monitoring 9.7 On-site Audits 9.8 Case Report Form Completion 9.9 Drug Accountability 9.10 Premature Closure of the Study 9.11 Record Retention 9.12 Liability and Insurance

56 56 56 56 56 57 57 58 58 58 59 59 59

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10

USE OF INFORMATION

61

11

INVESTIGATOR AGREEMENT

62

12

REFERENCES

63

13

Appendix 1 List of Permitted Rescue Medications

66

14

Appendix 2 Pharmacogenetic Research

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS AE

Adverse Event

ALT

Alanine Aminotransferase

ANCOVA

Analyses of Covariance

AUC

Area Under the Plasma Concentration Time Curve

◦

C

Degrees Celsius

CFR

Code of Federal Regulations

CL

Clearance

Cmax

Maximum (plasma) Concentration

CR

Calorie Restriction

CRP

C-reactive Protein

CRF

Case Report Form

CRO

Contract Research Organization

CTC

Common Toxicity Criteria

DIO

Diet-Induced Obesity

DNA

Deoxyribonucleic Acid

DSS

Dextran Sulphate Sodium

EAE

Experimental Autoimmune Encephalitis

ECG

Electrocardiogram

FAS

Full Analysis Set

FDA

Food and Drug Administration (U.S.)

FGF21

Fibroblast Growth Factor 21

FOXO

Forkhead Transcription Factors

GCP

Good Clinical Practice

GSK

GlaxoSmithKline

HADS

Hospital Anxiety and Depression Scale

HCV

Hepatitis C Virus

HIV

Human Immunodeficiency Virus

hr

Hour

hsCRP

High sensitivity C-reactive protein

ICH

International Conference on Harmonization

IEC

Independent Ethics Committee

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IRB

Institutional Review Board

IL

Interleukin

IV

Intravenous

Km

Michaelis-Menten Constant

LPS

Lipopolysaccharide

MedDRA

Medical Dictionary for Regulatory Activities

NCI

National Cancer Institute

NCoR

Nuclear Receptor Co-repressor

NFκβ

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells

NOAEL

No Observable Adverse Effect Level

ob/ob

Genetically Obese Mouse Model, Lepob/ob

PASI

Psoriasis Area and Severity Index

PD

Pharmacodynamics

PGA

Physician’s Global Assessment

PGC-1α

PPAR Gamma Coactivator-1α

PGx

Pharmacogenetics

PHQ-9

Patient Health Questionnaire

PINP

Procollagen-I-N-Terminal Propeptide

PK

Pharmacokinetics

PPS

Per-Protocol Analysis Set

PQOL-12

Koo-Mentor Psoriasis Quality of Life Instrument

PUVA

Psoralen and Ultraviolet Light A

QOL

Quality of Life

SAE

Serious Adverse Event

SAF

Safety Analysis Set

SIRT

Silent Information Regulator Transcript; Sirtuin

SIRT1

Sirtuin Enzyme 1

SRT2104

A SIRT1 Activator

SD

Standard Deviation

SUSAR

Suspected Unexpected Serious Adverse Reaction

t

Time

Tmax

Time of Maximum Concentration

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t1/2

Terminal Elimination Half –Life

TGF

Transforming Growth Factor

TMF

Trial Master File

TNF

Tumor Necrosing Factor

ULN

Upper Limit of Normal

UVB

Ultraviolet light B

V

Volume of distribution

WBC

White Blood Cell

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Clinical Study Protocol SRT-2104-013 February 12, 2009

INTRODUCTION AND STUDY RATIONALE

2.1 Disease Background Psoriasis is a chronic inflammatory skin disorder that impacts approximately 2-3% of the world’s population. [Schon, 2005; Koo J, 1996]. It is typically characterized by sharply demarcated, raised, erythematous plaques covered by silvery white scales. Psoriasis impacts both the physical and emotional well-being of the patient. Its effect on quality of life is comparable to that of other chronic medical disorders [Rapp, 1999]. Significant unmet medical need remains for safe, effective, and convenient treatments. Psoriasis is a complex, immune-mediated disease in which T-lymphocytes, neutrophils, and dendritic cells play a major role. Numerous cytokines are over-expressed in psoriatic skin lesions including TNF-α, IL-17, and IL-23 [Krueger JG, 2007]. Several growth factors are also over-expressed including transforming growth factor type alpha (TGF-α). The result is an epidermis characterized by hyperproliferation, inflammatory cell infiltrates, and vascular changes. Current treatments are primarily geared at reducing the excessive cellular proliferation and/or blocking the inflammatory response. 2.2

Scientific Background

One novel therapeutic approach to treating psoriasis and other diseases of inflammation has come from the study of aging and calorie restriction (CR). CR is a dietary regimen in which 30%-40% fewer calories than those required to maintain ideal body weight are consumed. It has been demonstrated that CR extends lifespan in lower organisms and mammals and improves a number of metabolic and inflammatory parameters [Heilbronn, 2003; Roth, 2001, Fontana, 2009]. As such the molecular components of the aging pathways downstream of CR may provide relevant intervention points for the development of therapeutic drugs to treat inflammatory and metabolic disease [Weindruch, 2001; Ingram, 2006]. Sirtuin Enzyme 1 (SIRT1) is a member of the sirtuin family of NAD+-dependent deacetylases [Frye, 1999; Frye, 2000; Imai, 2000]. There are seven human sirtuins (SIRT1-7) with different subcellular compartmentalization and downstream targets [Blander, 2004]. SIRT1 is predominantly nuclear and is upregulated in tissues of calorically restricted animals [Cohen, 2004]. The precise biological pathway whereby SIRT1 promotes the beneficial effects of CR is an area of intense study, but it appears that the ability of SIRT1 to interact and deacetylate PGC-1α is an important component [Rodgers, 2005]. PGC1α controls energy metabolism and muscle function with an inhibitory role in pro-inflammatory cytokine production [Handschin, 2008] and has been implicated as a key mediator of the effects of CR [Corton, Page 13 of 69

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2005]. Additionally, a number of other cellular substrates for SIRT1 have been identified including NCoR, p300, NFκβ, FOXO, and p53 [Bouras, 2005; Brunet, 2004; Luo, 2001; Motta, 2004; Nemoto, 2005; Picard, 2004; Rodgers, 2005; van der Horst, 2004; Vaziri, 2001; Yeung, 2004].

For example,

SIRT1 has been shown to physically interact with and deacetylate the RelA/p65 subunit of NFκβ, and thereby inhibit NFκβ-induced transcription [Yeung, 2004; Sirtris unpublished data] which is involved in up regulation of proinflammatory cytokines such as TNF-α and IL-6. Furthermore, SIRT1 activators have been shown to inhibit TNF-α secretion in both in vitro [Smith 2009; Yoshizaki 2009] and in vivo (Sirtris unpublished data) LPS-induced cellular and animal models. Through modulation of the activities of these proteins, SIRT1 regulates inflammation, cellular differentiation and survival, mitochondrial biogenesis, and glucose metabolism [Cohen, 2004; Heilbronn, 2005; Nisoli, 2005; Picard, 2004]. SRT2104 is a potent and selective small molecule activator of SIRT1. SRT2104 was identified as a SIRT1 activator in a high throughput screen of a diverse library of 290,000 compounds [Milne, 2007]. SIRT1 activity is increased by SRT2104 due to a lowering of the Km for its acetylated protein substrate, resulting in an approximately two-fold increase in activity. SRT2104 is selective for SIRT1 activation over the two most closely related sirtuin homologs, SIRT2 and SIRT3. 2.3

SRT2104 Non-Clinical Experience

The effect of once daily oral administration of SRT2104 on fasting blood glucose and fed insulin levels, body weight, triglyceride and plasma lipid levels was evaluated in a number of animal models of diabetes and obesity (DIO mice and ob/ob mice). In general, SRT2104 lowered fasting blood glucose and fed insulin and enhanced the response to a glucose tolerance test. No effect on body weight was observed with SRT2104. Activity in the diabetes models was seen following daily doses of 100-3000 mg/kg/day of SRT2104. SRT2104 has also shown efficacy following once daily oral administration in a number of in vivo inflammation models including LPS-induced TNF-α production, dextran sulphate sodium (DSS) and trinitrobenzesulphonic acid-induced colitis, cecal ligation and puncture-induced sepsis as well as in experimental autoimmune encephalomyelitis (EAE). The efficacy of SRT2104 in these inflammation studies was seen at doses of 10 – 1000 mg/kg/day given orally once daily for five to ten days depending on the model studied. In the DSS and EAE models SRT2104 was given therapeutically, that is after the diseases had been induced in the mice. SRT2104 was tested in vitro in counter-receptor binding studies and showed no significant inhibitory activity against 39 common receptors. SRT2104 was not an inhibitor of five major cytochrome P450 Page 14 of 69

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Clinical Study Protocol SRT-2104-013 February 12, 2009

isoforms tested (CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), and is not a significant inducer of cytochrome P450 isoforms CYP1A and CYP3A4 at the concentrations tested. The non-clinical safety of SRT2104 was investigated in the Ames and mouse micronucleus genetic toxicology models, and in safety pharmacology studies in rats and dogs. SRT2104 was not genotoxic at the doses investigated. No central nervous system (CNS), cardiovascular system (CVS), or pulmonary effects were observed in the safety pharmacology studies at the doses tested (300-2000 mg/kg). SRT2104 has been dosed up to 2000 mg /kg/day in two species (rat and dog) for 28 days. The compound was well tolerated at all doses in both species. Toxicity studies showed a no observable adverse effect level (NOAEL) of 2000 mg/kg/day in male rats and 1000 mg/kg/day in female rats and 1000 mg/kg/day in male and female dogs. In the male rat, the NOAEL was 2000 mg/kg/day, the highest dose tested. In the female rat, the NOAEL was considered to be 1000 mg/kg/day, due to a vacuolation of pancreatic acinar cells in 3 of 10 animals on Day 29 which was not seen after 4 weeks in the recovery animals. The physiological significance of this finding is unclear. Furthermore, this effect was not seen in the rat 90 day study or in the 28 or 90 day dog studies. The NOAEL in the female dog was determined to be 1000 mg/kg/day due to a mild increase in indirect bilirubin in the 2000 mg/kg/day group and microscopic bilirubin accumulation in the liver of one female dog at 2000 mg/kg/day. No adverse findings were seen in male dogs. SRT2104 has also been dosed in two species (rat and dog) for 90 days. In the 90 day studies no toxicologically relevant adverse events were seen at the highest doses tested in rats (2,000 mg/kg/day males, 1,000 mg/kg/day females) and in dogs (300 mg/kg/day in fed males and females). In the 90 day rat study there were reductions in mean body weights primarily due to a reduction in food consumption during the first week of the study. There were reversible increases in bilirubin in both male and female rats with no corresponding histopathological changes in the liver. Minor histopathology findings of increased acinar cell apoptosis in the pancreas and accumulation of amorphous material in the basal pits of the stomach were judged to be non-adverse since neither were associated with overt degenerative changes and/or were also seen in control rats. In the 90 day dog study there were mild, reversible increases in serum total/direct/indirect bilirubin in males and females at 300 mg/kg/day and reversible mild increases in serum alkaline phosphatase (males) or cholesterol (females) at 300 mg/kg/day. The increased serum bilirubin levels corresponded with pigment accumulation in the canaliculi of the liver on Day 91 for the 100 and 300 mg/kg/day males and females. However, the pigment accumulation and increased serum bilirubin, suggestive of impaired Page 15 of 69

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excretion or stasis, were not associated with any microscopic effect (degeneration or necrosis) on bile duct epithelium or hepatocytes. Furthermore, the clinical pathology results were reversible and well within the normalized historical control ranges. The findings seen in the 90 day studies reflect what was seen in the 28 day studies with an increase in bilirubin being the most notable finding in both the dog and rat studies. The stasis finding at 2000 mg/kg/day in female dogs was judged to be adverse in the 28 day study but not adverse in the 90 day study due to the observation that there was no progression from 28 to 90 days and no evidence of necrosis, inflammation or any damage associated with the stasis. From a safety perspective, the 2000 mg/day dose, the highest dose to be tested in future studies, is supported by the pre-clinical safety toxicology package and by the cumulative human safety experience gathered to date. From the pre-clinical 90-day toxicology studies, the safety intervals are 0.50-1.37 based on Cmax and 0.93-3.40 based on AUC at the NOAELs. However, it should be pointed out that there were no adverse findings at the highest doses tested in the 90-day studies, so these safety intervals are likely to be an under-estimate of the true values. 2.4

SRT2104 Clinical Experience

As of December 31 2009, approximately 85 subjects have been dosed in completed clinical trials with SRT2104. Based on currently available clinical data, the investigational product appeared well tolerated and no safety concerns have been identified with the administration of SRT2104 in healthy volunteers at doses up to 3.0 g per day for 7 consecutive days in the fasted state and up to 2.0 g per day for 7 days in the fed state. Completed and Reported Trials The first administration of SRT2104 to humans was performed as part of clinical study SRT-2104-001, a randomized, placebo-controlled, single-blind, multiple-dose, dose-escalation study (EudraCT Number: 2007-007598-22). A total of 28 healthy male volunteers received SRT2104 in the form of a liquid suspension as both a single dose and during a separate multiple dose period (once per day for 7 days) at the following dose levels: 30, 100, 250, 500, 1000, 2000, and 3000 mg/day (4 volunteers at each dose level). SRT2104 was well-tolerated following both the single- and multiple-dose periods at all dose levels investigated and all adverse events (AEs) recorded were either mild or moderate in severity and were predominantly gastrointestinal in nature. Treatment-emergent AEs observed in more than one subject were flatulence, headache, nausea, and diarrhea. All AEs were short in duration and resolved without sequelae. No dose-related AEs were identified. There were no serious adverse events. The pharmacokinetic parameters AUC(0-t) and Cmax exhibited dose proportionality over the dose range of 30 to Page 16 of 69

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1000 mg/day in healthy volunteers. At doses greater than 1000 mg /day increases in AUC(0-t) and Cmax were less than proportional to the increase in dose. The terminal elimination half-life (t½) ranged from 8 to 24 hours and was not affected by dose. There was no evidence to suggest saturation of any elimination pathways over the dose range investigated (30 to 3000 mg /day). A second administration of SRT2104 to human volunteers was performed as part of a single-center, combined intravenous (IV) and oral dosing study to evaluate the PK and absolute bioavailability of SRT2104 (Clinical Protocol SRT-2104-002; EudraCT Number 2008-006283-10). SRT2104 was administered as a 250 mg oral suspension and IV microdose of 100 µg 14C-SRT2104 to eight healthy male subjects. SRT2104 was well tolerated by all subjects. No serious adverse events (SAEs) were recorded. The AEs assessed as related to SRT2104 were aching at infusion site and paresthesia. All AEs were of mild severity and resolved without sequelae. The maximal drug concentrations generally occurred at the end of the 15-minute IV infusion. The terminal elimination half-life for total radioactivity after intravenous dosing was similar to that for the parent drug. The mean t½ for 14C-SRT2104 was 23.7 ± 9.37 hours following a 15-minute IV infusion of approximately 100 μg 14C-SRT2104 and mean t½ for SRT2104 was 25.5 ± 6.45 hours following oral administration of 250 mg SRT2104. Absolute bioavailability of SRT2104, when dosed as a 250 mg oral suspension in a fasted state, was approximately 14%. A third clinical study was conducted to assess the effect of food and gender on the PK of SRT2104 (Clinical Protocol SRT-2104-004; EudraCT Number: 2008-007364-41). This Phase I, randomized, openlabel study enrolled 10 male and 10 female healthy volunteers to characterize the PK profile of a single 500 mg dose of SRT2104 when administered as an oral suspension and as a capsule formulation in both the fed and fasted states. SRT2104 was well tolerated at the dose level tested. The absorption of SRT2104 administered as capsules and oral suspension was significantly increased when administered to subjects in the fed versus fasted state. There was a very slight decrease in absorption when SRT2104 was administered as a capsule. No gender effects were noted. Clinical Protocol SRT-2104-009 (EudraCT Number: 2009-010829-39) was a prospective, randomized study to assess the safety and PK of SRT2104 in healthy male volunteers. Ten male subjects were randomized to receive 2000 mg SRT2104 or placebo capsules under fed conditions on eight occasions during the study, once as a single dose and once per day for seven consecutive days. SRT2104 was considered to be safe and well tolerated at the dose levels tested. The mean AUC(0-τ) following once daily dosing for seven days was found to be increased when compared with the mean AUC(0-∞) following single Page 17 of 69

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dose administration, providing evidence for accumulation of SRT2104 following once daily dosing at 2000 mg for seven days. Evaluation of the pre-dose plasma SRT2104 concentrations during the multiple dose period suggested that steady state had likely not been achieved by all subjects at the end of the 7-day dosing interval. However, review of the individual subject plasma concentrations over the multiple dose period indicated that some subjects appeared to have reached steady state plasma SRT2104 concentrations within seven days of daily dosing. Following 7 days of dosing of 2 g SRT2104 to fed volunteers the mean Cmax was 1,874 ng/ml and the mean AUC was 13,997 ng.h/mL. The safety intervals from the 90 day study are 0.50-1.37 ng/mL based on Cmax and 0.93-3.40 ng.hr/mL based on AUC. It should be pointed out that there were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals are likely to be an under-estimate of the true values. Clinical Protocol SRT-2104-008 (EudraCT Number 2009-010620-25) was conducted to assess the pharmacodynamic effect of single oral doses of SRT2104 and prednisolone as measured by levels of ex vivo LPS-induced TNF-α production in whole blood of healthy adult subjects. This was a prospective, single center, non-therapeutic, randomized, double-blind study. Twenty male subjects were enrolled in the study and randomized to receive single doses of SRT2104 (250, 500, 1000, and 2000 mg) and/or placebo on 5 separate occasions followed by a single 30 mg dose of prednisolone on the sixth dosing occasion. Although Cmax increased with SRT2104 dose, the relationship between dose and Cmax was less than proportional. Median Tmax did not appear to vary significantly according to dose. Ongoing Trials Clinical Protocol SRT-2104-005 (EudraCT Number: 2009-010720-26) is a randomized, placebocontrolled, double-blind, multiple-dose, inpatient/outpatient study to assess the safety and PK of SRT2104 in male and female subjects with type 2 diabetes on an existing, stable, background metformin therapy. Approximately 225 subjects will be enrolled in this study. Subjects will be evenly randomized to receive SRT2104 or placebo in one of five cohorts: placebo (A); 250 mg/day SRT2104 (B); 500 mg/day SRT2104 (C); 1000 mg/day SRT2104 (D); or 2000 mg/day SRT2104 (E). Subjects will be dosed once a day for 28 consecutive days, approximately 15 minutes following the consumption of a standardized meal. Subjects will remain on a fixed dose of investigational product for all dosing days in the study. As of December 31, 2009, 51 subjects had been randomized into the study, 17 subjects had completed the study, 2 subjects had withdrawn (due to voluntary consent withdrawal), and 13 subjects had experienced treatment-emergent adverse events. A review of blinded safety data showed the most commonly reported Page 18 of 69

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adverse events were dyspepsia and hyperglycemia, each of which was reported twice and by different subjects. Two additional studies of SRT2104 are currently ongoing. Clinical Protocol SRT-2104-007 (EudraCT Number 2009-011918-21) is a randomized, placebo-controlled, double-blind, study to assess the safety, tolerability and pharmacokinetics of oral SRT2104 capsules administered to healthy elderly subjects for 28 days. Twenty-four subjects will be randomized to receive one of the following three treatments: SRT2104 500 mg/day, SRT2104 2000 mg/day or placebo. This study is currently enrolling as is Clinical Protocol SRT-2104-010 (EudraCT Number 2009-011918-21). Protocol SRT-2104-010 is being conducted to determine if single or multiple doses of SRT2104 attenuate the inflammatory response in normal healthy male subjects after exposure to low-dose endotoxin. Twenty-four healthy male subjects will be randomized to receive single or multiple doses of 2000 mg of SRT2104 and/or placebo for 7 days. Study endpoints include safety, PK and clinical signs and symptoms and laboratory parameters for inflammation.

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STUDY RATIONALE

A direct role for SIRT1 in promoting keratinocyte differentiation was elucidated [Blander, 2004] and is supportive of earlier findings that resveratrol, a natural plant-derived polyphenol that has been shown to activate SIRT1, inhibited the proliferation of human keratinocytes in vitro [Holian, 2001] and suppressed angiogenesis [Brakenhielm, 2001]. Taken together with the finding that SIRT1 activators are potent inhibitors of cytokine production, including TNF-α [Smith, 2009], the therapeutic potential for SIRT1 activators in the treatment of psoriasis will be explored as part of this clinical protocol. We hypothesize that SIRT1 activators may demonstrate anti-psoriatic action by promoting keratinocyte differentiation, reducing inflammation and/or inhibiting angiogenesis.

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4 4.1

Clinical Study Protocol SRT-2104-013 February 12, 2009

STUDY OBJECTIVES Primary 1. To assess the effects of 500 mg and 2000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis

4.2

Secondary 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 500 mg and 2000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaquetype psoriasis

4.3

Exploratory 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Mentor Psoriasis Instrument, PQOL-12.

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5

Clinical Study Protocol SRT-2104-013 February 12, 2009

INVESTIGATIONAL PLAN

5.1 Overall Study Design Subjects will receive either SRT2104 and/or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety will be assessed on an ongoing basis. The study consists of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Potential subjects will sign the IRB-approved informed consent form at the Screening Visit, and will undergo screening assessments to verify eligibility for the study. If eligible and willing to participate, subjects will return to the clinic within 21 days of the Screening Visit to participate in the dosing phase of the study. For the dosing phase of the study, starting on Day 1, subjects will be randomized on approximately Day -6 to receive either 500 mg or 2000 mg of SRT2104 or placebo once daily for 84 consecutive days. PK sampling will occur on Days 28, 56 and 84. 5.2 5.2.1

Selection of Study Population Number of Subjects

A sample size of 10 evaluable subjects per active treatment group and 5 evaluable subjects per placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 one-sided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (response of excellent) of 30.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may be replaced (see Section 5.2.2). Enrollment of approximately 12 subjects per active group and 6 subjects per placebo group is planned. 5.2.2

Replacement of Subjects

Subjects who withdraw from the study prior to completing 8 weeks of treatment may be replaced. 5.2.3

Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following Screening criteria are met: 1. Able and willing to provide written informed consent to participate in the study 2. Be male or female aged 18 to 80 years (inclusive) 3. Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving >10% of body surface area 4. Have a baseline PASI of >10 Page 22 of 69

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5. Be a candidate for systemic psoriasis therapy, in the opinion of the investigator 6. If a female subject of child-bearing potential, be willing to use reliable contraception (see Section 5.13) for the duration of the study, through the 30 day safety follow up telephone call 7. Be willing and able to comply with the protocol for the duration of the study. 5.2.4

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria are met at Screening: 1. Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit 2. Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 3. Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study 4. Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period is prohibited 5. Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit 6. Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 7. Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 8. Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation 9. Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit 10. Has a positive test for HIV antibody 11. Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial 12. Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: •

QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period)

•

QTcB ≥480 msec in subjects with Bundle Branch Block

13. Has renal or liver impairment, defined as: •

Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males

•

AST and ALT ≥ 2xULN or

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Alkaline phosphatase and bilirubin > 1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)

•

14. Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) 15. Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 16. Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine 17. History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation 18. Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. 5.2.5

Definition of Treatment Failure

A subject who experiences a treatment failure is anyone who demonstrates a score of “no improvement” based on the Krueger criteria defined in Section 6.4, or any subject who is prematurely withdrawn from the study due to lack of efficacy as judged by the investigator. 5.2.6

Removal of Subjects from the Study

Subjects will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The investigator can withdraw subjects from the study for any of the following reasons: •

QT interval changes as defined in Section 7.1.4

•

Liver event (see Section 7.1.5)

•

Treatment failure

•

Subject request

•

Failure to return for follow-up

•

Administrative reasons

•

General non-compliance with the protocol

•

Positive pregnancy test result

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The investigator also reserves the right to withdraw subjects in the interest of subject safety and welfare. If a subject is withdrawn from the study, the subject must complete Day 84 assessments at the time of discontinuation and return to the clinic approximately 30 days after the last dose to conduct a safety and activity (PASI and PGA) evaluation. The sponsor reserves the right to terminate the study at any time for administrative reasons. 5.3

Selection of Doses in the Study

Two different doses of SRT2104 were selected for study in this protocol, 500 mg/day and 2000 mg/day. These doses should be distinct enough to give different systemic exposures and both could be in pharmacologically active ranges based on the pre-clinical animal efficacy models. Comparing two different doses may allow establishment of some pharmacokinetic/pharmacodynamic relationship for SRT2104 and will assist in understanding whether a dose effect exists with regard to the psoriatic efficacy parameters being tested. This will provide valuable information in choosing doses for future trials. In prior human clinical trials, subjects have received doses of SRT2104 as high as 3000 mg/day with good tolerability. Pharmacokinetic data demonstrated dose-related increases in exposure up to 2000 mg/day, but not beyond, establishing 2000 mg/day as the highest dose to be considered for further studies. No in vivo pharmacodynamic parameters were collected in the normal volunteer studies, thus no human pharmacokinetic/pharmacodynamic relationship has been established to date. In preclinical testing, SRT2104 has been shown to positively impact a variety of animal models, including those of both metabolic and inflammatory disorders, at daily doses ranging from 10 - 300 mg/kg/day. The most consistent doses associated with good efficacy results in these models range from 100 - 300 mg/kg/day. Adjusting for body surface area between human and mouse, these equilibrate to potential pharmacologically active doses in man of 500 mg to 1500 mg, respectively. It is unclear as to how the mouse efficacy ranges will translate to efficacy ranges in humans, therefore testing doses above this range, up to 2000 mg/day, is justified. From a safety perspective, the 2000 mg/day dose, the highest dose to be tested, is supported by the preclinical safety toxicology package described in Section 2.3 and by the cumulative human safety experience gathered to date. From the pre-clinical 90 day toxicology studies, the safety intervals are 0.501.37ng/mL based on Cmax and 0.93-3.40 ng.hr/mL based on AUC. However, it should be pointed out that there were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals are likely to be an under-estimate of the true values. The most notable finding in the rat and dog toxicity studies has been a small, reversible increase in serum bilirubin. Bilirubin levels will be closely monitored Page 25 of 69

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in the proposed clinical trial. The entry criteria are written to exclude subjects with elevated bilirubin levels. Subjects developing elevated bilirubin values that meet the criteria for stopping investigational product will be withdrawn from the study (see Section 7.1.5, Liver Chemistry Stopping Rules and Follow-Up). In the completed and ongoing clinical trials with SRT2104, there have been no serious adverse events reported to date. In addition, no specific safety signals have been identified at this time. 5.4

Identity of Investigational Product

SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged as multiple capsules in dosing bottles. For the matching placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product. All subjects will be provided with one dosing bottle per day that contains eight capsules for oral ingestion. Prior to being dispensed, the investigational product should be stored at 15 – 25 oC and protected from light. Subjects will be instructed to store investigational product at room temperature away from direct light. 5.5

Treatments to be Administered

Investigational product will be dispensed only to eligible subjects under the supervision of the investigator or identified sub-investigator(s). A trained investigative site member will administer the investigational product to subjects when they are in the clinic, where applicable. As shown in study SRT-2104-004, the administration of SRT2104 with food increased exposure levels and reduced variability in exposure levels in humans. For this reason, subjects participating in this study are required to take SRT2104 approximately 15 minutes following the consumption of food. Investigational product should be administered with approximately 250 to 500 cc of water at approximately the same time every dosing day. Subjects should refrain from eating or drinking anything other than water for 1 hour after dosing. Dietary recommendations for the meal that precedes dosing will be included in the study reference manual and provided to the study subjects by the clinical site staff.

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5.6

Clinical Study Protocol SRT-2104-013 February 12, 2009

Method of Assigning Subjects to Treatment Groups

Subjects will be randomized to receive 500 mg or 2000 mg of SRT2104 or placebo in a 2:2:1 fashion. Treatments will be administered as follows for the duration of the study:

5.7

•

SRT2104 500 mg/day administered as two 250 mg capsules and six matching placebo capsules

•

SRT2104 2000 mg/day administered as eight 250 mg capsules

•

Matching placebo administered as eight matching placebo capsules

Individuals Who Will Be Unblinded to Treatment Assignments

Designated individuals of Sirtris Pharmaceutics Research will be unblinded for purposes of assigning the treatment assignments according to a randomization schema that will be retained in a secure location with limited access. In addition, selected personnel at the bioanalytical laboratory will be unblinded to treatment assignments for purposes of data analysis. 5.8

Unblinding Procedures

Procedures for obtaining unblinded treatment information will be provided to the clinical sites in the study operations manual. If it is medically imperative to know the treatment that a subject is receiving, the investigator shall, prior to requesting the treatment information, make every attempt to contact the medical monitor for the study to discuss the rationale for breaking the blind. In situations where the investigator is unable to contact the medical monitor as described above (e.g., a medical emergency on the part of the subject), the investigator must contact the medical monitor within 24 hours after the code break to inform him/her of the rationale for the code break. The investigator must provide a written narrative describing the event(s) that led to the code break to the medical monitor within 48 hours following the code break. In addition, the investigator must record the date of the code break and the reasons for breaking the blind in the CRF and in the subject’s medical records. 5.9

Duration of Treatment

All subjects enrolled in the study will receive SRT2104 and/or placebo once daily for up to 84 days during the study period.

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5.10 Prior Treatments See the exclusion criteria (Section 5.2.4) for details regarding medications that are prohibited prior to entry into the study. 5.11 Proscribed Medications In addition to the restrictions described in Section 5.2.4, no other concomitant medications, dietary supplements, or herbal products are permitted for the duration of this trial except as described in Section 5.12. Over-the-counter antacids should not be taken within four hours of investigational product administration as they may interfere with the absorption of investigational product. 5.12 Permitted Medications The following concomitant medications are permitted during the study: •

Non-prescription medications administered to treat an AE (e.g., acetaminophen, or non-steroidal anti-inflammatory agents taken for headache)

•

Topical Class 6 and/or 7 “rescue” corticosteroid treatment for psoriasis flares may be used, but use must be limited to the face, axillae and groin regions. See Section 13 for a list of permitted topical corticosteroid treatments. NOTE: Topical treatments should not be applied to other areas and in particular the plaque being assessed for efficacy, at or near the biopsy site

•

Any chronically prescribed non-psoriatic medication or herbal or dietary supplements administered at a stable dose for at least 6 weeks prior to enrollment with the exception of proton pump inhibitors. Potential subjects taking proton pump inhibitors at the time of the Screening Visit must be willing and able to discontinue these medications prior to taking investigational product and for the duration of the dosing period.

All medications administered during the study must be recorded in the subject’s CRF and in the source documents. 5.13 Contraceptive Use All female subjects of child-bearing potential must use two adequate forms of contraception for the duration of the trial (from the Screening Visit through Day 114). Adequate forms of contraception are defined as: Page 28 of 69

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Clinical Study Protocol SRT-2104-013 February 12, 2009

•

Abstinence

•

Oral Contraceptive, either combined or progestogen alone

•

Injectable progestogen

•

Implants of levonorgestrel

•

Estrogenic vaginal ring

•

Percutaneous contraceptive patches

•

Intrauterine device or intrauterine system

•

Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject (“documentation” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records)

•

Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

5.14 Treatment Compliance Compliance with the investigational product dosing regimen will be assessed by trained study personnel. Subjects are required to bring all study medication (both empty and full containers) to study visits. Study medication containers will be reviewed by the site staff at each study visit to verify treatment compliance. Subjects who do not comply with the investigational product dosing regimen and who consequently miss either three consecutive doses or six individual doses of investigational product at any time point during the study may be withdrawn from the study. The Investigator must call the medical monitor to discuss the disposition of subjects who miss doses as described above. 5.15 Missed Doses of Investigational Product Subjects who inadvertently miss a dose of investigational product should skip that dose and recommence dosing on the next dosing day. 5.16 Schedule of Events A detailed visit-by-visit schedule of study procedures is provided in Section 1.1. Prior to engaging in any study procedure, each subject must sign and date an IRB-approved informed consent form.

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6

Clinical Study Protocol SRT-2104-013 February 12, 2009

STUDY PROCEDURES

The timepoints for all study procedures are reflected in the Schedule of Events (see Section 1.1). All visits and telephone contacts will be scheduled to take place as near as possible to the scheduled day. The date of the visit will be recorded in the CRF. Descriptions of the required study procedures are provided below: Physical Examination A complete physical examination should be performed at Screening. A symptom-driven, directed physical examination will be performed at other timepoints as defined in the schedule of events. Body systems that will be included are the following: general appearance, musculoskeletal, skin and mucosa, head and neck, lymphatic, respiratory, breast, gastrointestinal, cardiovascular, extremities, neurological, psychological, eyes, ears, nose and throat. Other body systems may be examined as needed, at the discretion of the investigator. Body Weight/Height Height is measured once at the Screening visit. Body weight will be measured at all other clinic visits. The clinical staff will be instructed to use calibrated scales to measure subjects’ body weight. Vital Signs Vital sign assessments will include measurements of resting pulse rate, blood pressure, respiration rate, and temperature. Electrocardiogram A 12-lead ECG will be performed in the rested state. The subject should be lying comfortably in the supine position with ECG leads on for at least 5 minutes prior to the ECG recording. The ECGs will be read locally by the clinical site. The ECG will include the assessment of PR (PQ), QRS, QT, and QTc intervals and heart rate. Identification of any conduction abnormalities will be recorded in the CRF. If a subject’s QTc intervals are prolonged, then the ECG should be done in triplicate with results reported as an average of the three ECGs. Copies of the ECG graphs and available reports will be collected by the study sponsor at the end of the study. Prolonged QTc intervals will be managed according to the QTc withdrawal criteria described in Section 7.1.4. Page 30 of 69

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Pregnancy Testing Serum pregnancy testing will be performed at the Screening Visit; urine pregnancy tests will be performed at all other visits where a pregnancy test is performed (see Section 1.1). Blood and Urine Sample Collection for Clinical Laboratory Testing Blood and urine samples will be collected as outlined in the Schedule of Events (see Section 1.1) for clinical laboratory safety testing, serology and biomarker analyses. See Section 6.3 for a complete listing of blood and urine parameters. Sample collection, processing, and shipping instructions for samples that will not be analyzed in the local laboratory at the clinical site will be provided in the study operations manual. Pharmacokinetics Approximately 20 mL of blood will be collected throughout the duration of the trial for PK analyses. Samples will be collected on Days 28, 56 and 84 using sparse sampling techniques as described in Section 6.2. Analyses may include metabolite profiling in a subset of samples. Collected samples will be transferred for analysis to Simbec Research Ltd., South Wales, United Kingdom. Additional sample collection, processing, and shipping instructions will be provided in the study operations manual. Pharmacodynamics Biomarkers of psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21. Pharmacogenetics A single blood sample will be obtained on Day 1 for potential pharmacogenetic analysis. The sample is labelled (or “coded”) with a study-specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers such as name or social security number. A full description of the pharmacogenetic assessment is included in Appendix 2. Subject participation in the pharmacogenetic portion of the study is voluntary and refusal to participate will not preclude participation in the clinical study. Page 31 of 69

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Clinical Study Protocol SRT-2104-013 February 12, 2009

Photography Subjects who provide consent to photography procedures will have full body photographs taken from the neck down at timepoints outlined in the Schedule of Events (see Section 1.1). Identifying marks such as tattoos that might reveal the identity of a subject will be covered. Skin Biopsy A skin biopsy will be collected on Days 1 and 84 and transferred to the USA, for evaluation by a central reader. Biopsy tissue analyses are described in detail in Section 6.4. Skin biopsy collection, processing, and shipping instructions will be provided in the study operations manual. Quality of Life Assessments Some authors have noted that the psychosocial consequences of psoriasis can be as disruptive to the individual's life as the physical aspects of the illness itself [Fortune DG, 1997]. As part of an effort to explore whether improvements in the psychosocial consequences of psoriasis represent potential independent targets for treatment with SRT2104, the present study includes the three patient-reported outcome instruments described below. The Patient Health Questionnaire 9 (PHQ-9) is a 9-item, validated self-rating instrument that assesses eight core symptoms of depression in addition to an item that assesses functioning. The PHQ-9 has been validated as a diagnostic instrument for major depression, and it also provides an assessment of the severity of depression [Kroenke K, 2001]. The Hospital Anxiety and Depression Scale (HADS) is a 14-item, validated self-rating instrument of symptoms of anxiety and depression [Mykletun A, 2001]. It is intended to provide a crosssectional assessment of anxiety and depressive symptoms whether or not subjects meet formal criteria for anxiety and depressive disorders. As such, the HADS could provide a signal of efficacy in a broad-based population of psoriasis sufferers. The 12-item Psoriasis Quality of Life questionnaire (PQOL-12) is a brief, validated instrument derived from a 41-item instrument covering both psychosocial and physical domains [Feldman SR, 2005; Koo J, 2002]. The focus of the PQOL-12 on patient reports of psychosocial and physical

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effects specifically related to psoriasis reflects the growing emphasis among dermatologists on the major impact of the illness on patients' quality of life. Adverse Event Monitoring AE assessment (including SAEs) will be assessed on an ongoing basis throughout the study starting from the time of first dose. All SAEs/SUSARs should be monitored until they are resolved or clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Definitions, documentation, and reporting of AEs are described in detail in Section 7. Concomitant Medications Concomitant medication usage will be assessed throughout the study. See Section 5.11 for a description of permitted and restricted concomitant medications. 6.1 6.1.1

Study Procedures Visit 1 (Screening)

Potential subjects will be given an opportunity to have any questions about the study or their participation in it answered by the principal investigator or his designate. Prior to engaging in any study procedure, each potential subject must sign and date an IRB-approved informed consent form. When the consent form is signed, each subject will be assigned a unique screening number and screening procedures will be performed. 6.1.2

Visit 2

Those subjects meeting the study entry criteria who agree to participate in the study will return to the clinical site on Day 1. The investigator may, at his/her discretion choose to conduct a portion of the Day 1 visit procedures (exclusive of investigational product administration) on Day -1. Study procedures including safety, activity (PASI and PGA) and QOL assessments will be performed as outlined in the Schedule of Events (Section 1.1). Blood samples for biomarker analysis, pharmacogenetics and skin biopsies will be obtained. In addition, a photograph will be taken to document the body surface area affected by psoriatic lesions. Subjects will be randomized to a treatment group approximately 6 days prior to this visit to allow sufficient time for delivery of investigational product. The first dose of study medication will be administered in the clinic following consumption of food. Prior to leaving the clinic, subjects will receive a kit containing study medication and will be instructed to continue once daily dosing after eating, and to store the Page 33 of 69

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Clinical Study Protocol SRT-2104-013 February 12, 2009

study medication under ambient conditions (between 15 and 25 ºC), protected from direct light for the remainder of the dosing period. 6.1.3

Visits 3, 5 and 7

On Days 14, 42 and 70 subjects will return to the clinic for safety assessments as outlined in the Schedule of Events (Section 1.1). 6.1.4

Visits 4 and 6

On Days 28 and 56 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.5

Visit 8

On Day 84 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Skin biopsies and blood samples for biomarker analysis will be obtained. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.6

Follow-Up Procedures

On Day 114 subjects will return to the clinic for safety and activity assessments, and pregnancy testing as outlined in the Schedule of Events (Section 1.1). 6.2

Pharmacokinetic Sampling

PK measurements will be required for all subjects at all participating centers. Accurate recording of dosing and sample collection times is critical. The actual dosing and sample collection times must be recorded in the CRF.

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Clinical Study Protocol SRT-2104-013 February 12, 2009

A total of five blood samples (4 mL each) will be obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. The following samples can be taken over the course of Visits 4, 6, and 8. Multiple PK samples can be taken during one visit provided the sampling windows as described below are observed and no 2 samples are separated by less than 1 hour. •

One pre-dose sample will be collected prior to taking investigational product (30 minutes or less before dosing). This sample must be collected on any ONE of the following: Visit 4, 6 or 8. It is recommended that the dose associated with this sample be administered in the clinic.

•

A single PK sample will be collected in the time interval of 0.5 to 2 hours post-dose. It is recommended that the dose associated with this sample be administered in the clinic. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

A single PK sample will be collected in the time interval of 3 to 6 hours post-dose. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

Two PK samples will be collected in the time interval of 6 to 22 hours post-dose. These 2 samples must be collected on any of the following: Visit 4, 6 or 8.

PK samples may be collected at any time during the defined sampling intervals. An effort should be made to ensure that samples are not consistently collected at the same time point within a defined collection interval. This study provides flexible options for scheduling of most PK samples. This flexibility is incorporated to improve subject convenience for sampling at later time points. 6.3

Laboratory Assessments

Safety (e.g., hematology, chemistry, and urinalysis) and screening (e.g., serum β-HCG and serology) samples will be analyzed by a central laboratory. A subset of samples (e.g., PK and FGF21 samples) may be transferred for analysis to Sirtris, GlaxoSmithKline (GSK), or other designated representative working with GSK and/or Sirtris.

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The following clinical laboratory parameters will be evaluated at the time points specified in the Schedule of Events (see Section 1.1). Collected samples may be transferred for analysis to Sirtris, GSK, or other designated representatives working with GSK or Sirtris. Hematology White blood cell count (WBC)

Complete WBC differential

Hemoglobin

Platelets

Hematocrit

Mean corpuscular volume

Red blood cell count

Mean Corpuscular Hemoglobin Concentration

Red Cell Distribution Width

Mean Corpuscular Hemoglobin

Clinical Chemistry Sodium

Alanine aminotransferase

Potassium

Aspartate aminotransferase

Chloride

Total, direct, and indirect bilirubin

Blood Urea Nitrogen

Alkaline phosphatase

Serum creatinine

Lactate dehydrogenase

Plasma Glucose

Gamma-glutamyl transferase

Calcium

Amylase

Magnesium

Bicarbonate

Uric acid

Albumin

ProthrombinTime/International Normalized

Phosphate

Ratio

1

Activated Partial Thromboplastin Time 1

Creatine Kinase

Lipid Profile (Total Cholesterol, Low Density Lipoprotein, High Density Lipoprotein, Free Fatty Acids, Triglycerides)2 1

Coagulation studies will be performed at Screening and on Days 1, 42 and 84 only.

2

Lipid profiling will be performed in fasting samples at Screening, Days 1, 42 and 84 only.

Pregnancy Monitoring Serum β-HCG at Screening

Urine testing at other timepoints as defined in the Schedule of Events (Section 1.1)

Urinalysis Dipstick

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Clinical Study Protocol SRT-2104-013 February 12, 2009

Serology HCV ab

HBsAg

HIV 1 & 2 Biomarkers* hsCRP

FGF21

*Biomarker analysis will be performed in fasting samples according to the timepoints displayed in the Schedule of Events (Section 1.1). Additional biomarkers thought to be associated with SIRT1 activation may be assessed.

6.4

Skin Biopsy Evaluation and Scoring

Skin biopsies will be obtained from the same designated plaque on Days 1 and 84. The central reader at

(who will be blinded to treatment assignments) will evaluate the

biopsy tissue for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD68+ monocytes, CD11c+ dendritic cells, CD38+ cells, CD3+ T-cells, and TH17+ T cells). Keratinocyte expression of K-16 and ICAM-l will be measured. RT-PCR will be used to assess for expression of specific genes which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPARα, PPAR-delta, and p53.

In

addition, global changes in gene expression may be assessed using gene micro-array techniques. Skin biopsies will be assigned an improvement score according to the Krueger criteria defined below: Improvement Score

Definition

No improvement

defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes

Good improvement

defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16

Excellent improvement

defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16.

6.5 Appropriateness of Measurements Per the U.S. Food and Drug Administration (FDA) guidance, “Collection of Race and Ethnicity Data in Clinical Trials, September 2005”, demographic data and complete subject medical histories will be documented for all subjects during screening. Investigational product Page 37 of 69

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administration data, including dose interruptions and modifications and the associated reason(s), also will be documented. AEs and SAEs will be monitored in this study in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines to ensure the safety of subjects. 6.6

Data Quality Assurance

Sirtris or its designated representative will conduct a clinical site visit to verify the qualifications of the investigator, inspect clinical site facilities, and inform the investigator of responsibilities and procedures for ensuring adequate and correct study documentation. The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. All information recorded on the CRFs for this study must be consistent with the subject’s source documentation. During the course of the study, the study monitor will conduct clinical site visits to review protocol compliance, compare CRFs and individual subject’s medical records (source documents), assess investigational product accountability, and ensure that the study is being conducted according to pertinent regulatory requirements. CRFs will be verified with source documentation. The review of medical records will be performed in a manner to ensure that subject confidentiality is maintained. A hardcopy of the final CRFs will be placed in the investigator’s study file and Sirtris’ Trial Master File (TMF). Instances of missing or uninterpretable data will be discussed with the investigator for resolution. Study data will be entered into a secure, validated data processing system and a backup will be maintained. Any changes to study data will be documented. A quality assurance audit will be performed on the database.

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7

Clinical Study Protocol SRT-2104-013 February 12, 2009

ADVERSE EVENTS

The principal investigator and designated study staff are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE/SUSARs. 7.1 7.1.1

Definitions Adverse Event Definition

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational product, whether or not it is considered to be investigational product-related. This includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of investigational product. 7.1.2

Serious Adverse Event Definition

A serious adverse event (SAE) is any AE, occurring at any dose and regardless of causality that: •

Results in death.

•

Is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.

•

Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry, are not considered AEs if the illness or disease existed before the subject was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the study (e.g., surgery performed earlier than planned).

•

Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions.

•

Is a congenital anomaly/birth defect.

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•

Clinical Study Protocol SRT-2104-013 February 12, 2009

Is an important medical event. An important medical event is an event that may not result in death, be life-threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. See Section 7.1.5 for guidance on liver events that would be considered SAEs.

•

Is associated with liver injury and impaired liver function defined as: • ALT ≥ 3xULN, and • total bilirubin ≥ 2xULN or INR > 1.5. NOTES: (1) Bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury). (2) INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

•

Pregnancy complications: spontaneous abortions in subjects exposed to investigational product must be reported as SAEs. NOTE: Any SAE occurring in association with a pregnancy that is brought to the investigator’s attention after the subject has completed the study and that is considered by the investigator as possibly related to the investigational product, must be promptly reported to Sirtris.

Clarification should be made between the terms “serious” and “severe” as they ARE NOT synonymous. The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a severe headache). This is NOT the same as “serious,” which is based on subject/event outcome or action criteria described above, and is Page 40 of 69

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usually associated with events that pose a threat to a subject’s life or functioning. A severe AE does not necessarily need to be considered serious. For example, persistent nausea of several hours’ duration may be considered severe nausea but not an SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild, but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 7.1.3

Suspected Unexpected Serious Adverse Reaction Definition

A suspected unexpected serious adverse reaction (SUSAR) is any adverse drug reaction (i.e., any AE that is assessed by the Investigator as associated with [i.e., unlikely, possibly or probably related to] SRT2104, the specificity or severity of which is not consistent with those noted in the current protocol and/or Investigator’s Brochure (IB). This refers to any adverse reaction that has not been previously observed (e.g., included in the IB), rather than from the perspective of such an event not being anticipated from the pharmacological properties of the product. 7.1.4

QTc Withdrawal Criteria

A subject that meets the criteria below will be withdrawn from the study. •

QTcB > 500 msec (machine or manual overread). If the subject has bundle branch block then the criterion is QTcB > 530 msec

•

Prolongation of QTcB > 60 msec as compared to baseline

These criteria are based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, 2 additional ECGs are to be obtained over a brief period and the averaged QTc values of the 3 ECGs is used to determine whether the subject should be discontinued from the study. All ECGs with a machine-read QTcB value of > 500 msec collected during the study (including at Screening) will be manually over-read by a cardiologist to verify the QTcB value. 7.1.5

Liver Chemistry Stopping Rules and Follow-up

Liver Chemistry Stopping Rules Investigational product will be stopped if any of the following liver chemistry stopping criteria is met: 1.

ALT ≥ 3xULN and bilirubin ≥ 2xULN (or ALT ≥ 3xULN and INR > 1.5)

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NOTE: serum bilirubin fractionation should be performed if testing is available.

If

fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury). 2.

ALT ≥ 5xULN

3.

ALT ≥ 3xULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia)

4.

ALT ≥ 3xULN persists for ≥ 4 weeks

5.

ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks

6.

Alkaline phosphatase ≥ 3xULN and bilirubin ≥ 2xULN.

7.

Subjects with ALT ≥ 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash, can continue investigational product as long as they can be monitored weekly for 4 weeks. Liver Chemistry Follow-up If any of criteria 1 through 5 above are met, the following actions should be taken: •

Immediately withdraw investigational product

•

Report the event to Sirtris and Akos Ltd. within 24 hours of learning its occurrence

•

Complete the SAE reporting form if the event also meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR >1.5, if INR measured; INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE.

NOTE: if serum bilirubin fractionation is not immediately available, investigational product should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. •

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below

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•

Clinical Study Protocol SRT-2104-013 February 12, 2009

Withdraw the subject from the study (unless further safety follow up is required) after completion of the liver chemistry monitoring as described below

•

Do not re-challenge with investigational product.

In addition, for criterion 1: •

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

•

A specialist or hepatology consultation is recommended

•

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values

For criteria 2, 3, 4 and 5: •

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

•

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.

For criteria 6 and 7: •

Notify the Sirtris medical monitor within 24 hours of learning of the abnormality to discuss subject safety

•

Can continue investigational product

•

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline

•

If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

•

If, after 4 weeks of monitoring, ALT < 3xULN and alkaline phosphatase < 3xULN and bilirubin < 2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.

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For criteria 1-5, make every attempt to carry out the assessments described below: •

Viral hepatitis serology including: o Hepatitis A IgM antibody; o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); o Hepatitis C RNA; o Cytomegalovirus IgM antibody; o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); o Hepatitis E IgM antibody (if subject has travelled outside US in past 3 months);

•

Blood sample for PK analysis, obtained as soon as possible following last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for PK sample handling and shipping are in the study operations manual.

•

Serum creatine phosphokinase and lactate dehydrogenase

•

Fractionate bilirubin, if total bilirubin ≥ 2xULN

•

Obtain complete blood count with differential to assess eosinophilia

•

Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia as relevant on the AE report form

•

Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form

•

Record alcohol use on the liver event alcohol intake case report form

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The following are required for subjects with ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) but are optional for other abnormal liver chemistries: •

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies

•

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

7.2

Procedures for Recording and Reporting AEs and SAEs

All AEs spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures will be recorded on the appropriate page of the CRF. Any clinically relevant change in laboratory assessments or other clinical findings is considered an AE and must be recorded on the appropriate pages of the CRF. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event. All SAEs and SUSARs that occur during the course of the study, as defined by the protocol, must be reported by the investigator to Sirtris and Akos Ltd. by faxing the SAE/SUSAR form within 1 working day from the point in time when the investigator becomes aware of the SAE/SUSAR. In addition, all SAEs/SUSARs, including all deaths, which occur up to and including 30 days after administration of the last dose of investigational product, must be reported to Sirtris and Akos Ltd. within 1 working day. All SAEs/SUSARs and deaths must be reported whether or not considered causally related to the investigational product. The information collected using the SAE/SUSAR form will include a minimum of the following: subject number, a narrative description of the event and an assessment by the investigator as to the intensity of the event and relatedness to investigational product. A sample of the SAE/SUSAR form can be found in the study operations manual. Follow-up information on the SAE/SUSAR may be requested by Sirtris or Akos Ltd.

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SAE/SUSAR Reporting Contact Information: Akos Limited The Coach House, Pipers Lane Harpenden, Hertfordshire AL5 1AH United Kingdom SAE Reporting Line: or Telephone: And to the Sponsor: MD Chief Medical Officer Sirtris Pharmaceuticals 200 Technology Square Cambridge, MA 02139 USA Direct Line: Extension Fax Line: If there are suspected, unexpected, serious adverse drug reactions (SUSARs) associated with the use of the investigational product, Sirtris or its designee will notify the appropriate regulatory agency(ies) and all participating investigators on an expedited basis (7 days for fatal or lifethreatening suspected, unexpected, serious adverse drug reactions). Sirtris has delegated the responsibility to promptly notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all SUSARs involving risk to human subjects in accordance with the rules and regulations of the IRB/IEC to the principal investigator. An unexpected event is one that is not reported in the Investigator’s Brochure. Planned hospital admissions or surgical procedures for an illness or disease that was diagnosed before the subject was enrolled in the study or before investigational product was given, are not to be considered AEs. For both serious and non-serious AEs, the investigator must determine both the intensity and the relationship of the event to investigational product administration. Intensity for each AE will be determined by using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 4.0 as a guideline, wherever possible. Dose-limiting toxicities will be defined as those AEs of Grade 3 or greater that are seen to occur with an evident temporal Page 46 of 69

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relationship to SRT2104 dosing. In those cases where the NCI CTC criteria do not apply, intensity should be defined according to the following criteria: Mild

Awareness of sign or symptom, but easily tolerated

Moderate

Discomfort enough to cause interference with normal daily activities

Severe

Inability to perform normal daily activities

Life Threatening or Disabling

Immediate risk of death from the reaction as it occurred

Death

The event resulted in death

Relationship to investigational product administration will be determined as follows: Not Related

No relationship between the experience and the administration of investigational product; related to other etiologies, such as concomitant medications or subject’s clinical state.

Unlikely Related

The current state of knowledge indicates that a relationship is unlikely.

Possibly Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product. The reaction might have been produced by the subject’s clinical state or other modes of therapy administered to the subject.

Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product and can be confirmed with a positive re-challenge test or supporting laboratory data.

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7.3

Clinical Study Protocol SRT-2104-013 February 12, 2009

Monitoring of Adverse Events and Period of Observation

AEs, both serious and non-serious, and deaths will be recorded on the CRFs throughout the study from the time of first dose until the final follow-up contact. However, any SAEs assessed as related to study participation (e.g., investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs should be monitored until they are resolved or are clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Any SAE that occurs at any time after completion of the study including the designated follow-up period, which the investigator considers to be related to study medication, must be reported to Sirtris. AEs or SAEs requiring therapy must be treated by recognized standards of medical care to protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines must be available to ensure the best possible treatment of an emergency situation. The outcome of AEs will be rated as: • Recovered/Resolved; • Recovering/Resolving; • Not Recovered/Not Resolved; • Recovered/Resolved with Sequelae; • Fatal; • Unknown. Any non-serious AE which occurs in the course of the study should be monitored and followed for up to 30 days following the last dose of investigational product. 7.4

Pregnancy Reporting

The investigator will attempt to collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to Sirtris within 2 weeks of learning of the pregnancy. The outcome of the pregnancy will also be followed. Information on the status of the mother and child

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will be forwarded to Sirtris. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported. Pregnancy complications, including spontaneous abortions, and elective terminations for medical reasons must be reported as AEs or SAEs.

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8

Clinical Study Protocol SRT-2104-013 February 12, 2009

STATISTICAL PROCEDURES

The sample size has been chosen based on the probability of overall response to treatment and feasibility to allow preliminary characterization of safety, tolerability, and PK and to explore pharmacodynamic measures. Alphas will be two-tailed in nature and set at 0.05 for all analyses unless otherwise stated. As this is a proof of concept study, no adjustment for multiple analyses will be made. 8.1

Randomization and Stratification

On entry into the study subjects will be randomized to 500 mg or 2000 mg SRT2104 or placebo in a 2:2:1 fashion using a predetermined randomization schedule. All subjects will receive the assigned, double-blind study medication for 84 days. 8.2

Sample Size

A sample size of 10 evaluable subjects per active treatment group and 5 evaluable subjects per placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 one-sided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (an improvement score of “excellent improvement” based on the Krueger criteria [see Section 6.4]) of 30.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2), therefore, based on an estimated dropout rate of approximately 17%, enrollment of approximately 12 subjects per active group and 6 subjects per placebo group is planned. In addition, with a sample size of 12 for active dose groups, the probability of observing at least one adverse event of a given type will be 85.8% when the probability of such an adverse event is actually 15.0%. 8.3

Populations for Analysis

All subjects randomized will be included in the Randomized Set. The population for all safety analyses is the Safety Analysis Set (SAF). All subjects who receive at least one dose of any investigational product during the study will be included in the SAF population. Subjects will be analyzed according to the treatment received. Subjects will be included in the Full Analysis Set (FAS) for the primary assessment of activity according to the intent-to-treat principle. The FAS will include all randomized subjects who take Page 50 of 69

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at least one dose of investigational product and have at least one activity measurement at baseline and at least one post-randomization study visit. Subjects will be included in the treatment group to which they were randomized. The Per-Protocol Analysis Set (PPS) is defined as all subjects from the FAS set who complete the study and are deemed to be protocol-compliant. To be protocol-compliant, a subject must not have any major protocol deviations during the study period. Protocol deviations will be identified prior to database lock and will be listed by treatment group in the clinical study report. The PPS will be used for a secondary assessment of activity endpoints. Pharmacokinetics Population is defined as all subjects who receive at least one dose of SRT2104 and have PK data available. 8.4 Procedures for Handling Missing, Unused, and Spurious Data All available data will be included in data listings and tabulations. No imputation of values for missing data will be performed. Percentages of subjects with AEs or laboratory toxicities will be based on non-missing values. Data that are potentially spurious or erroneous will be examined under the auspices of standard data management operating procedures. 8.5 8.5.1

Statistical Methods Subject Disposition

The total number of subjects screened, randomized, completed, and prematurely discontinued from the study will be summarized by treatment group and overall. The reason for termination for all subjects who discontinued will be summarized by treatment group and overall. A listing of subjects who discontinued from the study by reason for termination will also be presented. A table summarizing the analysis sets will be presented, with the number of randomized subjects who satisfy the requirements for inclusion and frequencies of exclusion from the respective SAF, FAS, PPS, and PK analysis sets. A listing of subjects with major protocol deviations will also be presented.

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8.5.2

Clinical Study Protocol SRT-2104-013 February 12, 2009

Subjects Baseline Characteristics

Descriptive summaries of demographic and baseline characteristics will be presented by treatment group for all subjects randomized. Baseline characteristics will include a summary of the following: •

Subject demographics including age, gender, race;

•

Baseline disease characteristics, including duration since diagnosis;

•

Pre-existing medical conditions;

•

Prior therapies.

8.5.3

Exposure to Investigational Product

Exposure to SRT2104 will be tabulated by group by presenting number of days on study, defined as number of days from day of first dose to day of last dose taken. Total amount of investigational product taken using a similar calculation method will be presented by group. 8.5.4

Safety Analysis

Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) AE coding system for purposes of summarization. All AEs occurring on study will be listed in by-subject data listings. Treatment-emergent events will be tabulated, where treatment-emergent is defined as any AE that occurs after administration of the first dose of investigational product through 30 days after the last dose of SRT2104, any event that is considered causally drug-related regardless of the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered drug-related by the investigator. Events that are considered related to treatment (unlikely related, possibly related, or related) will also be tabulated. Tabulation will also be provided that enumerates AEs by maximum severity. Deaths, other SAEs, and events resulting in study discontinuation will be tabulated. Page 52 of 69

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Change from baseline in clinical laboratory parameters will be summarized across time on study. Shift tables may be produced for selected laboratory parameters if implied by the data. Changes in vital sign parameters will be summarized over time in a similar fashion to laboratory parameters, and any abnormal values will be tabulated. Additional safety analyses may be determined at any time without prejudice, in order to most clearly enumerate rates of toxicities and to further define the safety profile of SRT2104. 8.5.5

Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses

The PK population includes all subjects for which SRT2104 concentration data are available. For the current study, plasma concentrations of SRT2104 for each subject will be listed on the basis of the dose level, time and day at which each sample was collected relative to the first dose. Relevant data from the current study, which may be combined with historical data, will be analyzed using a non-linear mixed effects modeling approach (population PK). Population PK parameters including clearance (CL), volume of distribution (V) and AUC will be estimated. Dependent on the final structural PK model additional PK parameters also may be estimated. Sources of variability in PK parameters will be investigated during population modeling. Demographic or clinical variables including, but not limited to, age, sex, race, and body weight will be evaluated as potential predictors of inter- and intra-subject variability for PK parameters. Results of the population PK model may be used in additional PK/PD analyses. Population modeling will be performed using the non-linear mixed effects modeling software (NONMEM, Globomax LLC; Ellicott City, MD). Further details of population PK analyses will be described under a separate analysis plan to be completed prior to database lock. Results of the population PK analysis will be included in a report separate from the clinical study report. Measures of individual exposure to SRT2104, such as AUC, may be correlated with selected efficacy endpoints, biomarkers, and measures of safety and tolerability as exploratory analyses of pharmacokinetic/pharmacodynamic relationships. Specific analyses that may be conducted are not specified a priori; they will be determined on the basis of study outcome. 8.5.6

Activity Analysis

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of skin biopsies after 12 weeks of exposure. Analyses will also assess the effects of SRT2104 on the PASI in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. The effects of SRT2104 on the PGA score in subjects with moderate to severe plaquetype psoriasis after 4, 8, and 12 weeks of exposure will also be analyzed. Exploratory analyses will be performed to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. Analyses will also be performed in order to assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the PHQ-9 and the HADS. The potential effects of SRT2104 on healthrelated quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the PQOL-12 will also be analyzed. Analyses of activity will be performed on both the FAS and PPS populations. Summary statistics for activity variables will be presented for each planned assessment and, for continuous variables, change plus percent change will be presented at each assessment by treatment group. For all subject reported outcomes, appropriate calculations will be made to produce each factor or subscore for each instrument as well as the overall or total instrument score. The primary clinical activity outcome will be on histology (i.e., skin pathology) using the Krueger criteria (see Section 6.4). The proportion of subjects with an improvement score of “excellent improvement” will be compared against the null placebo response of 10% using single-sided, one sample binomial tests. In secondary efficacy assessments, “response” to treatment will be determined by PASI-50 and PASI-75 response rates. Response is defined as the proportion of subjects who achieve a PASI-50 or PASI-75. Comparisons will also be made for mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. Response rates for the active treatment groups will be compared against the null placebo response of 10% using single sided, one sample binomial tests.

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For all other activity assessments, analysis of baseline to each assessment differences will be performed employing analyses of covariance (ANCOVA) on values, changes, and percent changes. Baseline values will be used as the covariate for these analyses. If distributions are found to deviate significantly from normal, non-parametric analyses will be substituted for ANCOVA. For variables where change from baseline and percent change from baseline are not appropriate, t-tests will be performed to assess difference between groups. The number and percentage of subjects who experience treatment failure as defined in Section 5.2.5 will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between treatment pairs. Subjects experiencing treatment failure will be identified in the data listings. The number and percentage of subjects receiving at least one rescue medication (see Section 5.11), will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between treatment pairs. All rescue medication administrations will be provided in the data listings. 8.6

Procedures for Reporting Deviations to Original Statistical Analysis Plan

A formal statistical analysis plan for the analysis and presentation of data from this study will be prepared before database lock. Deviations from the statistical analyses outlined in this protocol will be indicated in this plan; any further modifications will be noted in the final clinical study report.

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ADMINISTRATIVE REQUIREMENTS Good Clinical Practice

The study will be conducted in accordance with the ICH for GCP and the appropriate regulatory requirement(s). The investigator will be thoroughly familiar with the appropriate use of the investigational product as described in the protocol and IB. Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. The investigator site file and associated study documentation will be archived for up to 30 years. The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the sponsor delegates the set-up and maintenance of the sponsor TMF, the TMF will be returned to the sponsor at the end of the study and the sponsor will archive it for up to 30 years after initial marketing approval or termination of development. 9.2

Ethical Considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki (see Section 12) and the relevant regulations under 21 CFR parts 312, 50 and 56. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety, and well-being of the subjects. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written information given to the subjects, safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator. 9.3

Subject Information and Informed Consent

After the study has been fully explained, written informed consent will be obtained from either the subject or their guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s). 9.4

Subject Confidentiality

In order to maintain subject privacy, all CRFs, investigational product accountability records, study reports, and communications will identify the subject by initials and the assigned subject number. The investigator will grant monitor(s) and auditor(s) from Sirtris or its designee and regulatory authority(ies) access to the subject’s original medical records for verification of data gathered on the CRFs and to audit the data collection process. The subject’s confidentiality will be Page 56 of 69

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maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations. 9.5

Protocol Compliance

The investigator will conduct the study in compliance with the protocol provided by Sirtris, and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). Modifications to the protocol should not be made without agreement by both the investigator and Sirtris. Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to implementation, except when the modification is needed to eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC. Sirtris or its designee will submit all protocol modifications to the regulatory authority(ies) in accordance with the governing regulations. When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to subjects, the investigator will contact Sirtris, if circumstances permit, to discuss the planned course of action. Any departures from the protocol must be fully documented in the CRF and source documentation. 9.6

Study Monitoring

Monitoring and auditing procedures developed by Sirtris will be followed, in order to comply with GCP guidelines. On-site checking of the CRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative matters will be performed. The study will be monitored by Sirtris or its designee. Monitoring will be done by personal visits from a representative of the sponsor (site monitor) who will review the CRFs and source documents. The site monitor will ensure that the investigation is conducted according to protocol design and regulatory requirements by frequent communications (letter, telephone, and fax). All unused investigational product and other study materials are to be returned to Sirtris or its designee, or destroyed on site after the clinical phase of the study has been completed (see Section 9.9).

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On-site Audits

Regulatory authorities, the IEC/IRB, and/or Sirtris’ clinical quality assurance group may request access to all source documents, CRFs, and other study documentation for on-site audit or inspection. Direct access to these documents must be guaranteed by the investigator, who must provide support at all times for these activities. 9.8

Case Report Form Completion

Case report forms will be completed for each study subject. It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported in the subject’s CRF. Source documentation supporting the CRF data should indicate the subject’s participation in the study and should document the dates and details of study procedures, AEs, and subject status. The investigator, or designated representative, should complete the CRF pages as soon as possible after information is collected, preferably on the same day that a study subject is seen for an examination, treatment, or any other study procedure. Any outstanding entries must be completed immediately after the final examination. An explanation should be given for all missing data. 9.9

Drug Accountability

Accountability for the investigational product at the study site and with the subject is the responsibility of the investigator. The investigator will ensure that the investigational product is used only in accordance with this protocol. Where allowed, the investigator may choose to assign some of the drug accountability responsibilities to a pharmacist or other appropriate individual. Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, use by each subject, and return to Sirtris (or destruction and disposal of the drug, if approved by Sirtris) will be maintained by the clinical site. These records will adequately document that the subjects were provided the doses as specified in the protocol and should reconcile all investigational product received from Sirtris. Accountability records will include dates, quantities, batch/serial numbers, expiration dates (if applicable), and subject numbers. The sponsor or its designee will assign a site monitor to review drug accountability at the site on an ongoing basis during monitoring visits. All unused and used investigational product will be retained at the site until they are inventoried by the site monitor. All used, unused or expired investigational product will be returned to Sirtris or its designee, or if authorized, disposed of at the study site and documented. All material Page 58 of 69

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containing SRT2104 will be treated and disposed of as hazardous waste in accordance with governing regulations. 9.10 Premature Closure of the Study This study may be prematurely terminated, if in the opinion of the investigator or Sirtris, there is sufficient reasonable cause. Written notification documenting the reason for study termination will be provided to the investigator or Sirtris by the terminating party. Circumstances that may warrant termination include, but are not limited to: • Determination of unexpected, significant, or unacceptable risk to subjects; • Failure to enter subjects at an acceptable rate; • Insufficient adherence to protocol requirements; • Insufficient complete and/or evaluable data; • Plans to modify, suspend or discontinue the development of the investigational product. Should the study be closed prematurely, all study materials must be returned to Sirtris. 9.11 Record Retention The investigator will maintain all study records according to ICH-GCP, applicable regulatory requirement(s) and Sirtris’ record retention policy. Records will be retained for 30 years after the last marketing application approval or 30 years after formal discontinuation of the clinical development of the investigational product or according to applicable regulatory requirement(s). The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the investigator withdraws from the responsibility of keeping the study records, custody must be transferred to a person willing to accept the responsibility. Sirtris must be notified in writing in advance of any change in disposition of the study records, including if a custodial change occurs. 9.12 Liability and Insurance Sirtris will be subscribed to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to participating persons and arising out of this research performed

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strictly in accordance with the scientific protocol as well as with applicable law and professional standards.

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10 USE OF INFORMATION All information regarding SRT2104 supplied by Sirtris to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Sirtris. It is understood that there is an obligation to provide Sirtris with complete data obtained during the study. The information obtained from the clinical study will be used towards the development of SRT2104 and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required. Publication of the results of the study, whether in whole or in part, shall be within the sole and absolute discretion of Sirtris. Investigators, sites, CROs and/or designees shall not be entitled to publish any of the data or information arising during or out of the provision of the services without the prior written consent of Sirtris. For the avoidance of doubt Sirtris reserves the unqualified right to reject any paper or article utilizing any data generated from this study before such paper or article is presented or submitted for publication.

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11 INVESTIGATOR AGREEMENT I have read the Protocol entitled, “A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis” I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform all who assist me in the conduct of this study of their responsibilities and obligations.

Principal Investigator (Printed Name)

Principal Investigator Signature

Date

Investigational site or name of institution and location (printed)

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12 REFERENCES Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417435. Bouras T, Fu M, Sauve AA, et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem. 2005 Mar; 280:10264-76. Brunet A, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303:2011-2015. Brakenhielm, E, et al. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. Faseb J. 2001 Aug, 15:1798-1800. Cohen H, Miller C, Bitterman K, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul; 305(5682):390-392. Corton JC, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci. 2005 Dec; 60:14941509. Feldman SR, et al. Decision points for the initiation of systemic treatment for psoriasis. Journal of the American Academy of Dermatology. 2005; 53:101 Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Experimental Gastroenterology. 2009; 44:41-45. Fortune DG, et al. Quality of life in patients with psoriasis: the contribution of clinical variables and psoriasis. British Journal of Dermatology. 1997; 137: 755-760 Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 1999; 260:273-279. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 2000; 273:793-798. Handschin C, Spiegelman, BM. The role of exercise and PGC1-α in inflammation and chronic disease. Nature. 2008; 454(7203):463-469 Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep; 78:361-369. Heilbronn LK, Ravussin E. Calorie restriction extends life span-but which calories? PLoS Med. 2005 Aug; 2:e231. Holian, O, Walter RJ. Resveratrol inhibits the proliferation of normal human keatinocytes in vitro. J Page 63 of 69

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Cell Biol. 2001; Supplement 36:55-62 Imai S, Armstrong CM, Kaeberlein M. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb; 403:795-800. Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimetics: an emerging research field.Aging Cell. 2006; 5:97-108. Koo J, Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996; 485-96) Koo J, et al. The Development of a Disease-Specific Questionnaire to Assess Quality of Life for Psoriasis Patients: An Analysis of the Reliability, Validity, and Responsiveness of the Psoriasis Quality of Life Questionnaire. Dermatol. Psychosom. 2002; 3:171–179. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a Brief Depression Severity Measure. J Gen Intern Med; 2001 16(9): 606–613. Krueger JG, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. NEJM. 2007; 356:580 Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001 Oct; 107:137-148. Mykletun A, et.al.. Hospital Anxiety and Depression (HAD) scale: factor structure, item analyses and internal consistency in a large population. British Journal of Psychiatry, 2001; 179: 540 Milne J, Lambert P, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov; 450:712-716. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb; 116:551-563. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem. 2005 Apr; 280:16456-16460. Nisoli E, Tonello C, Cardile A, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005 Oct; 310:314-317. Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun; 429:771-776. Rapp SR, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41:401-7 Rodgers J, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through complex of PGCPage 64 of 69

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1α and SIRT1. Nature. 2005 Mar; 434(7029):113-118. Roth, G. S., Ingram, D. K. & Lane, M. A. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001; 928:305-315. Schon MP, Boehncke WH. Psoriasis. NEJM. 2005; 352:1899 Smith J, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Systems Biology. 2009; 3:31. van der Horst A, et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279, 28873-28879. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001 Oct; 107:149-159. Weindruch R, Keenan KP, Carney JM et al. Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci. 2001 Mar; 56 Spec No 1:20-33. World Medical Association Declaration of Helsinki : Ehtical Principles for Medical Research Involving Human Subjects. October, 2008. http://www.wma.net/en/30publications/10policies/b3/index.html Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun; 23:2369-80. Yoshizaki T, et al. SIRT1 Inhibits Inflammatory Pathways in Macrophages and Modulates Insulin Sensitivity. Am J Physiol Endocrinol Metab. Dec, 2009.

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13 Appendix 1 List of Permitted Rescue Medications Class 6 steroids Alclometasone dipropionate 0.05% cream and 0.05% ointment Desonide 0.05% cream, 0.05% foam, 0.05% gel and 0.05% lotion Fluocinolone acetonide 0.01% shampoo and 0.01% solution Flurandrenolide 0.025% cream Triamcinolone acetonide 0.025% cream and 0.025% lotion Class 7 steroids Hydrocortisone 0.5% cream and 0.5% ointment Hydrocortisone 1% cream, 1% lotion and 1% ointment Hydrocortisone 2.5% cream, 2.5% lotion and 2.5% ointment

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14 Appendix 2 Pharmacogenetic Research Background Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, and elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include: Drug Abacavir

Tranilast

ABT-761

Disease HIV [Hetherington, 2002; Mallal, 2002] Restenosis prevention following coronary bypass [Roses, 2002] Asthma [Drazen, 1999]

Gene HLA (human leukocyte antigen)

Outcome Caucasian males with HLA B57 variant were at increased risk for experiencing hypersensitivity to abacavir

UGT1A1

Drug induced hyperbilirubinemia explained by high proportion of affected patients having 7/7 TA repeat genotype, consistent with clinically benign Gilbert’s Syndrome

ALOX5

ALOX5 Sp1 promoter genotype (x,x) associated with reduced response to 5-lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priory hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to SRT2104. Pharmacogenetics Research Objectives The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to SRT2104. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with SRT2104 that may be attributable to genetic variations of subjects, the following objectives may be investigated: •

Relationship between genetic variants and the pharmacokinetics of investigational product

•

Relationship between genetic variants and safety and/or tolerability of investigational product

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•

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Relationship between genetic variants and efficacy of investigational product.

Study Population Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research. Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled. Study Assessments and Procedures In addition to any blood samples taken for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labelled (or coded) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed. The need to conduct PGx analysis may be identified after a study (or set of studies) of SRT2104 has been completed and the study data reviewed. In some cases, the samples may not be studied e.g., no questions are raised about how people respond to SRT2104. Samples will be stored securely and may be kept for up to 30 years after the last subject completes the study or Sirtris may destroy the samples sooner. Sirtris or those working with Sirtris (for Page 68 of 69

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example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time. Provision of Study Results and Confidentiality of Subject’s PGx Data Sirtris may summarize the cumulative PGx research results in the clinical study report. In general, Sirtris does not inform the investigator, subject or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of the PGx research results because the information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research, under any circumstance unless required by law. References Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

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PROTOCOL SUMMARY

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis Number of Study Center(s): Approximately five centers located in the United States are planned for this study. Study Phase: Phase IIa Study Period: Approximately 18 weeks for each dose cohort Study Objectives: Primary: 1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis Secondary: 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque-type psoriasis Exploratory: 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of depression and anxiety in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Mentor Psoriasis Instrument, PQOL-12.

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Study Design: This phase IIa, proof of concept, randomized, double-blind, placebo-controlled, dose-escalation study will be conducted in approximately 30 subjects with moderate to severe plaque-type psoriasis. For each dose cohort there will be a screening period, a 12-week treatment period with 7 on-treatment visits (Days 1, 14, 28, 42, 56, 70 and 84) and a follow-up safety assessment (Day 114). Three cohorts of ten subjects each will be enrolled. Subjects within each cohort will be randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects will be dosed sequentially. Dosing in the second and third cohort will not commence until subjects in the previous cohort have completed at least 28 days of dosing, and a review of key safety parameters has been completed by an Independent Safety Review Committee (ISRC). Subjects who provide informed consent will undergo screening procedures within 21days of randomization. Subjects will be enrolled and randomized into the study on approximately Day – 6 and receive investigational product on Day 1. Subjects will take blinded investigational product on a daily basis from Day 1 through Day 84. For the safety evaluation, adverse events (AEs) will be monitored from Day 1 through a follow-up visit that will occur 30 days after discontinuation of investigational product on Day 84. Vital signs, clinical laboratory results (hematology, chemistry, urinalysis), ECGs and physical examinations will be assessed at periodic intervals from Day 1 through Day 84. Skin biopsies of the same designated psoriatic lesion will be conducted on Days 1 and 84 to assess the effects of SRT2104 on histologic markers of inflammation. Disease assessments using the PASI score and the PGA will be conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. Sense of well-being will be assessed using depression and anxiety scales (PHQ-9 and HADS respectively) which will be completed on Days 1, 28, 56 and 84. Quality of Life (QOL) will be assessed on Days 1 and 84 using the PQOL-12. Blood will be obtained on Days 28, 56 and 84 for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Subjects who prematurely discontinue from the study will complete Day 84 assessments at the time of discontinuation. Number of Subjects: Approximately 30 subjects will be enrolled.

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Duration of Subjects Participation/Duration of Study/Duration of Treatment: Subject participation will include a screening period of up to 21 days and an 84-day dosing period. Subjects will return to the clinic 30 days after their last dose of investigational product for a follow up visit. The duration of each subject’s participation is expected to be approximately 18 weeks. The study duration (first subject’s first visit through last subject’s last visit) is anticipated to last approximately 10 12 months. Drug Supply, Dosage, and Mode of Administration: Subjects will be randomized 4:1 to receive active SRT2104 at one of three dose levels (250, 500, or 1000 mg/day) or placebo. Investigational product will be supplied as 250 mg capsules of SRT2104 along with matching placebo capsules that will be administered orally once daily for 84 consecutive days. The subjects and the investigator will be blinded to active vs. placebo treatment assignment. Dosing with SRT2104 or placebo is to take place at approximately the same time every day, approximately 15 minutes following consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories.

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CRITERIA FOR EVALUATION Safety and Tolerability: The incidence of AEs and clinically significant abnormal laboratory values will be recorded based upon investigator observation and subject reporting. Safety will be monitored by reports of AEs (at all visits after the first dose has been administered through 30 days after the last dose), vital sign measurements, physical examinations, laboratory parameters and electrocardiograms. Concomitant medications and AEs will be recorded at every visit. Additional visits will be permitted for safety follow-up as required. Pharmacokinetics: Blood will be obtained using a sparse sampling technique for PK and PD assessments. Pharmacodynamics: Biomarkers for psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose and may include, but may not be limited to, hsCRP and FGF21. Activity: The primary clinical activity endpoint is change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks. Skin biopsy samples will be evaluated for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells), and keratinocyte expression of K-16 and ICAM-l. Secondary clinical activity endpoints are PASI-50 and PASI-75 response rates, defined as the proportion of subjects who achieve a PASI-50 or PASI-75, mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. RT-PCR will be used to assess expression of specific genes at baseline and after 12 weeks which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPAR alpha, PPAR delta, and p53. In addition, global changes in gene expression may be assessed using gene micro-array techniques. Exploratory clinical activity endpoints include assessments of the subject’s sense of well-being (PHQ-9 and HADS) and health-related quality of life (PQOL-12).

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General Analysis Plan: Response will be compared between active treatment groups and the null placebo response of 10% using a single sided, one sample binomial test. Other activity analyses (PASI response, sense of well-being and QOL) will be performed between treatments using analysis of covariance on the change between day of assessment and baseline using the baseline value as the covariate. Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. Listing of individual subject and summary statistics for plasma SRT2104 concentrations, blood sampling times, and for other PK parameters and graphs of concentration vs. time will be prepared by dosing cohort. Rationale for Number of Subjects: A sample size of 10 evaluable subjects per active treatment group and 6 evaluable subjects in the merged placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 onesided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (response of excellent) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2).

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Schedule of Events

A full description of the study procedures is provided in Section 6. Study Period

Screening

Visit Number Study Day(s) Clinic Visit Informed Consent Medical History1 Viral Serology Photographs (total body surface area involvement) Randomization2 Investigational Product Dispensed Physical Examination3 (including height at Screening and weight at all subsequent visits) Vital Signs Chest X-Ray 12-lead ECG Clinical Chemistry/Hematology4 Urinalysis Pregnancy Test5 Adverse Event/Concomitant Medication Assessment PK Sampling6 PASI & PGA QOL assessments (PHQ-9, HADS, PQOL-127) Biomarkers Pharmacogenetics Sample9 Skin Biopsy (Immunohistochemistry and Gene Expression Profiling)

1 -21 to -6 X X X X X X X X X X X X

Dosing Period 2 18 X

3 14 X

4 28 X

5 42 X

6 56 X

7 70 X

8 8410 X

Follow Up 114 X

X

X

X

X

X X

X X

X X

X

X

X

X

X X X X X

X X X X

X X X X X X X X X X X

X X X X

X X X X X X

X X X X

X X X X X X

X X X X

X X X

X X X

X X X

X

X

X

X

X

Footnotes: 1. Medical events occurring prior to the first dose will be collected on the medical history case report form (CRF). AEs occurring after the first dose will be recorded on the AE CRF. AEs and concomitant medications will be followed for 30 days after the last dose of study medication. 2. Subjects will be randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of investigational product. 3. A complete physical examination (PE) will be conducted at the Screening Visit. A symptom-driven, directed PE will be performed as needed at all other timepoints. 4. See Section 6.2 for a complete listing of safety lab parameters to be measured/analyzed. Lipid profiling and coagulation studies will be performed in fasting samples at Screening, and on Days 1, 42 and 84 only. 5. Serum pregnancy test to be performed at Screening; urine screen for pregnancy at all other timepoints. 6. PK sampling will be performed according to the schedule described in Section 6.2. 7. PQOL-12 to be performed on Days 1 and 84 only 8. The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1. 9. See Appendix 2 for a description of the pharmacogenetic assessment. 10. Subjects withdrawing from the study prior to the study assessments on Day 84 will undergo all Day 84 assessments and return for a follow-up visit 30 days following the last dose of investigational product.

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Clinical Study Protocol SRT-2104-013 March 19, 2010

Schematic Diagram of Study Design

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TABLE OF CONTENTS 1

PROTOCOL SUMMARY 1.1 Schedule of Events 1.2 Schematic Diagram of Study Design

2 7 8

LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS

12

2

INTRODUCTION AND STUDY RATIONALE 2.1 Disease Background 2.2 Scientific Background 2.3 SRT2104 Non-Clinical Experience 2.4 SRT2104 Clinical Experience

15 15 15 16 18

3

STUDY RATIONALE

22

4

STUDY OBJECTIVES 4.1 Primary 4.2 Secondary 4.3 Exploratory

23 23 23 23

5

INVESTIGATIONAL PLAN 5.1 Overall Study Design 5.2 Selection of Study Population 5.2.1 Number of Subjects 5.2.2 Replacement of Subjects 5.2.3 Inclusion Criteria 5.2.4 Exclusion Criteria 5.2.5 Definition of Treatment Failure 5.2.6 Removal of Subjects from the Study 5.3 Selection of Doses in the Study 5.4 Identity of Investigational Product 5.5 Treatments to be Administered 5.6 Method of Assigning Subjects to Treatment Groups 5.7 Individuals Who Will Be Unblinded to Treatment Assignments 5.8 Unblinding Procedures 5.9 Duration of Treatment 5.10 Independent Safety Review Committee 5.11 Safety Review and Dose Escalation or Cessation 5.11.1 Criteria for discontinuing dosing/dose escalation 5.12 Prior Treatments 5.13 Proscribed Medications 5.14 Permitted Medications 5.15 Contraceptive Use 5.16 Treatment Compliance 5.17 Missed Doses of Investigational Product 5.18 Schedule of Events

24 24 24 24 24 25 25 26 26 27 28 28 29 29 29 30 30 30 30 31 31 31 32 32 33 33

6

STUDY PROCEDURES 6.1 Study Procedures

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6.1.1 Visit 1 (Screening) 6.1.2 Visit 2 6.1.3 Visits 3, 5 and 7 6.1.4 Visits 4 and 6 6.1.5 Visit 8 6.1.6 Follow-Up Procedures Pharmacokinetic Sampling Laboratory Assessments Skin Biopsy Evaluation and Scoring Appropriateness of Measurements Data Quality Assurance

37 37 38 38 38 38 38 39 41 41 42

7

ADVERSE EVENTS 7.1 Definitions 7.1.1 Adverse Event Definition 7.1.2 Serious Adverse Event Definition 7.1.3 Suspected Unexpected Serious Adverse Reaction Definition 7.1.4 QTc Withdrawal Criteria 7.1.5 Liver Chemistry Stopping Rules and Follow-up 7.2 Procedures for Recording and Reporting AEs and SAEs 7.3 Monitoring of Adverse Events and Period of Observation 7.4 Pregnancy Reporting

43 43 43 43 45 45 45 49 52 52

8

STATISTICAL PROCEDURES 8.1 Randomization and Stratification 8.2 Sample Size 8.3 Populations for Analysis 8.4 Procedures for Handling Missing, Unused, and Spurious Data 8.5 Statistical Methods 8.5.1 Subject Disposition 8.5.2 Subjects Baseline Characteristics 8.5.3 Exposure to Investigational Product 8.5.4 Safety Analysis 8.5.5 Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 8.5.6 Activity Analysis 8.6 Procedures for Reporting Deviations to Original Statistical Analysis Plan

54 54 54 54 55 55 55 56 56 56 57 57 59

9

ADMINISTRATIVE REQUIREMENTS 9.1 Good Clinical Practice 9.2 Ethical Considerations 9.3 Subject Information and Informed Consent 9.4 Subject Confidentiality 9.5 Protocol Compliance 9.6 Study Monitoring 9.7 On-site Audits 9.8 Case Report Form Completion 9.9 Drug Accountability 9.10 Premature Closure of the Study

60 60 60 60 60 61 61 61 62 62 63

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Record Retention Liability and Insurance

63 63

10

USE OF INFORMATION

64

11

INVESTIGATOR AGREEMENT

65

12

REFERENCES

66

13

Appendix 1 List of Permitted Rescue Medications

69

14

Appendix 2 Pharmacogenetic Research

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS AE

Adverse Event

ALT

Alanine Aminotransferase

ANCOVA

Analyses of Covariance

AUC

Area Under the Plasma Concentration Time Curve

◦

C

Degrees Celsius

CFR

Code of Federal Regulations

CL

Clearance

Cmax

Maximum (plasma) Concentration

CR

Calorie Restriction

CRP

C-reactive Protein

CRF

Case Report Form

CRO

Contract Research Organization

CTC

Common Toxicity Criteria

DIO

Diet-Induced Obesity

DNA

Deoxyribonucleic Acid

DSS

Dextran Sulphate Sodium

EAE

Experimental Autoimmune Encephalitis

ECG

Electrocardiogram

FAS

Full Analysis Set

FDA

Food and Drug Administration (U.S.)

FGF21

Fibroblast Growth Factor 21

FOXO

Forkhead Transcription Factors

GCP

Good Clinical Practice

GSK

GlaxoSmithKline

HADS

Hospital Anxiety and Depression Scale

HCV

Hepatitis C Virus

HIV

Human Immunodeficiency Virus

hr

Hour

hsCRP

High sensitivity C-reactive protein

ICH

International Conference on Harmonization

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IEC

Independent Ethics Committee

IL

Interleukin

IRB

Institutional Review Board

ISRC

Independent Safety Review Committee

IV

Intravenous

Km

Michaelis-Menten Constant

LPS

Lipopolysaccharide

MedDRA

Medical Dictionary for Regulatory Activities

NCI

National Cancer Institute

NCoR

Nuclear Receptor Co-repressor

NFκβ

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells

NOAEL

No Observable Adverse Effect Level

ob/ob

Genetically Obese Mouse Model, Lepob/ob

PASI

Psoriasis Area and Severity Index

PD

Pharmacodynamics

PGA

Physician’s Global Assessment

PGC-1α

PPAR Gamma Coactivator-1α

PGx

Pharmacogenetics

PHQ-9

Patient Health Questionnaire

PINP

Procollagen-I-N-Terminal Propeptide

PK

Pharmacokinetics

PPS

Per-Protocol Analysis Set

PQOL-12

Koo-Mentor Psoriasis Quality of Life Instrument

PUVA

Psoralen and Ultraviolet Light A

QOL

Quality of Life

SAE

Serious Adverse Event

SAF

Safety Analysis Set

SIRT

Silent Information Regulator Transcript; Sirtuin

SIRT1

Sirtuin Enzyme 1

SRT2104

A SIRT1 Activator

SD

Standard Deviation

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SUSAR

Suspected Unexpected Serious Adverse Reaction

t

Time

Tmax

Time of Maximum Concentration

t1/2

Terminal Elimination Half –Life

TGF

Transforming Growth Factor

TMF

Trial Master File

TNF

Tumor Necrosing Factor

ULN

Upper Limit of Normal

UVB

Ultraviolet light B

V

Volume of distribution

WBC

White Blood Cell

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INTRODUCTION AND STUDY RATIONALE Disease Background

Psoriasis is a chronic inflammatory skin disorder that impacts approximately 2-3% of the world’s population. [Schon, 2005; Koo J, 1996]. It is typically characterized by sharply demarcated, raised, erythematous plaques covered by silvery white scales. Psoriasis impacts both the physical and emotional well-being of the patient. Its effect on quality of life is comparable to that of other chronic medical disorders [Rapp, 1999]. Significant unmet medical need remains for safe, effective, and convenient treatments. Psoriasis is a complex, immune-mediated disease in which T-lymphocytes, neutrophils, and dendritic cells play a major role. Numerous cytokines are over-expressed in psoriatic skin lesions including TNF-α, IL-17, and IL-23 [Krueger JG, 2007]. Several growth factors are also over-expressed including transforming growth factor type alpha (TGF-α). The result is an epidermis characterized by hyperproliferation, inflammatory cell infiltrates, and vascular changes. Current treatments are primarily geared at reducing the excessive cellular proliferation and/or blocking the inflammatory response. 2.2

Scientific Background

One novel therapeutic approach to treating psoriasis and other diseases of inflammation has come from the study of aging and calorie restriction (CR). CR is a dietary regimen in which 30%-40% fewer calories than those required to maintain ideal body weight are consumed. It has been demonstrated that CR extends lifespan in lower organisms and mammals and improves a number of metabolic and inflammatory parameters [Heilbronn, 2003; Roth, 2001, Fontana, 2009]. As such the molecular components of the aging pathways downstream of CR may provide relevant intervention points for the development of therapeutic drugs to treat inflammatory and metabolic disease [Weindruch, 2001; Ingram, 2006]. Sirtuin Enzyme 1 (SIRT1) is a member of the sirtuin family of NAD+-dependent deacetylases [Frye, 1999; Frye, 2000; Imai, 2000]. There are seven human sirtuins (SIRT1-7) with different subcellular compartmentalization and downstream targets [Blander, 2004]. SIRT1 is predominantly nuclear and is upregulated in tissues of calorically restricted animals [Cohen, 2004]. The precise biological pathway whereby SIRT1 promotes the beneficial effects of CR is an area of intense study, but it appears that the ability of SIRT1 to interact and deacetylate PGC-1α is an important component [Rodgers, 2005]. PGC1α controls energy metabolism and muscle function with an inhibitory role in pro-inflammatory cytokine production [Handschin, 2008] and has been implicated as a key mediator of the effects of CR [Corton, SRT-2104-013 Version 2.0

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2005]. Additionally, a number of other cellular substrates for SIRT1 have been identified including NCoR, p300, NFκβ, FOXO, and p53 [Bouras, 2005; Brunet, 2004; Luo, 2001; Motta, 2004; Nemoto, 2005; Picard, 2004; Rodgers, 2005; van der Horst, 2004; Vaziri, 2001; Yeung, 2004].

For example,

SIRT1 has been shown to physically interact with and deacetylate the RelA/p65 subunit of NFκβ, and thereby inhibit NFκβ-induced transcription [Yeung, 2004; Sirtris unpublished data] which is involved in up regulation of proinflammatory cytokines such as TNF-α and IL-6. Furthermore, SIRT1 activators have been shown to inhibit TNF-α secretion in both in vitro [Smith 2009; Yoshizaki 2009] and in vivo (Sirtris unpublished data) LPS-induced cellular and animal models. Through modulation of the activities of these proteins, SIRT1 regulates inflammation, cellular differentiation and survival, mitochondrial biogenesis, and glucose metabolism [Cohen, 2004; Heilbronn, 2005; Nisoli, 2005; Picard, 2004]. SRT2104 is a potent and selective small molecule activator of SIRT1. SRT2104 was identified as a SIRT1 activator in a high throughput screen of a diverse library of 290,000 compounds [Milne, 2007]. SIRT1 activity is increased by SRT2104 due to a lowering of the Km for its acetylated protein substrate, resulting in an approximately two-fold increase in activity. SRT2104 is selective for SIRT1 activation over the two most closely related sirtuin homologs, SIRT2 and SIRT3. 2.3

SRT2104 Non-Clinical Experience

The effect of once daily oral administration of SRT2104 on fasting blood glucose and fed insulin levels, body weight, triglyceride and plasma lipid levels was evaluated in a number of animal models of diabetes and obesity (DIO mice and ob/ob mice). In general, SRT2104 lowered fasting blood glucose and fed insulin and enhanced the response to a glucose tolerance test. No effect on body weight was observed with SRT2104. Activity in the diabetes models was seen following daily doses of 100-3000 mg/kg/day of SRT2104. SRT2104 has also shown efficacy following once daily oral administration in a number of in vivo inflammation models including LPS-induced TNF-α production, dextran sulphate sodium (DSS) and trinitrobenzesulphonic acid-induced colitis, cecal ligation and puncture-induced sepsis as well as in experimental autoimmune encephalomyelitis (EAE). The efficacy of SRT2104 in these inflammation studies was seen at doses of 10 – 300 mg/kg/day given orally once daily for five to twenty eight days depending on the model studied. In the DSS and EAE models SRT2104 was given therapeutically, that is after the diseases had been induced in the mice.

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SRT2104 was tested in vitro in counter-receptor binding studies and showed no significant inhibitory activity against 39 common receptors. SRT2104 was not an inhibitor of five major cytochrome P450 isoforms tested (CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), and is not a significant inducer of cytochrome P450 isoforms CYP1A and CYP3A4 at the concentrations tested. The non-clinical safety of SRT2104 was investigated in the Ames and mouse micronucleus genetic toxicology models, and in safety pharmacology studies in rats and dogs. SRT2104 was not genotoxic at the doses investigated. No central nervous system (CNS), cardiovascular system (CVS), or pulmonary effects were observed in the safety pharmacology studies at the doses tested (300-2000 mg/kg). SRT2104 has been dosed up to 2000 mg /kg/day in two species (rat and dog) for 28 days. The compound was well tolerated at all doses in both species. Toxicity studies showed a no observable adverse effect level (NOAEL) of 2000 mg/kg/day in male rats and 1000 mg/kg/day in female rats and 1000 mg/kg/day in male and female dogs. In the male rat, the NOAEL was 2000 mg/kg/day, the highest dose tested. In the female rat, the NOAEL was considered to be 1000 mg/kg/day, due to a vacuolation of pancreatic acinar cells in 3 of 10 animals on Day 29 which was not seen after 4 weeks in the recovery animals. The physiological significance of this finding is unclear. Furthermore, this effect was not seen in the rat 90 day study or in the 28 or 90 day dog studies. The NOAEL in the female dog was determined to be 1000 mg/kg/day due to a mild increase in indirect bilirubin in the 2000 mg/kg/day group and microscopic bilirubin accumulation in the liver of one female dog at 2000 mg/kg/day. No adverse findings were seen in male dogs. SRT2104 has also been dosed in two species (rat and dog) for 90 days. In the 90 day studies no toxicologically relevant adverse events were seen at the highest doses tested in rats (2,000 mg/kg/day males, 1,000 mg/kg/day females) and in dogs (300 mg/kg/day in fed males and females). In the 90 day rat study there were reductions in mean body weights primarily due to a reduction in food consumption during the first week of the study. There were reversible increases in bilirubin in both male and female rats with no corresponding histopathological changes in the liver. Minor histopathology findings of increased acinar cell apoptosis in the pancreas and accumulation of amorphous material in the basal pits of the stomach were judged to be non-adverse since neither were associated with overt degenerative changes and/or were also seen in control rats. In the 90 day dog study there were mild, reversible increases in serum total/direct/indirect bilirubin in males and females at 300 mg/kg/day and reversible mild increases in serum alkaline phosphatase (males) SRT-2104-013 Version 2.0

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or cholesterol (females) at 300 mg/kg/day. The increased serum bilirubin levels corresponded with pigment accumulation in the canaliculi of the liver on Day 91 for the 100 and 300 mg/kg/day males and females. However, the pigment accumulation and increased serum bilirubin, suggestive of impaired excretion or stasis, were not associated with any microscopic effect (degeneration or necrosis) on bile duct epithelium or hepatocytes. Furthermore, the clinical pathology results were reversible and well within the normalized historical control ranges. The findings seen in the 90 day studies reflect what was seen in the 28 day studies with an increase in bilirubin being the most notable finding in both the dog and rat studies. The stasis finding at 2000 mg/kg/day in female dogs was judged to be adverse in the 28 day study but not adverse in the 90 day study due to the observation that there was no progression from 28 to 90 days and no evidence of necrosis, inflammation or any damage associated with the stasis. From a safety perspective, the 1000 mg/day dose, the highest dose to be tested in this SRT-2104-013 protocol, is supported by the pre-clinical safety toxicology package and by the cumulative human safety experience gathered to date. From the pre-clinical 90-day toxicology studies, the safety intervals are 1.33.6 based on Cmax and 1.9-6.8 based on AUC at the NOAELs. There were no adverse findings at the highest doses tested in the 90-day studies so these safety intervals may be an under-estimate of the true values. 2.4

SRT2104 Clinical Experience

As of December 31 2009, approximately 85 subjects have been dosed in completed clinical trials with SRT2104. Based on currently available clinical data, the investigational product appeared well tolerated and no safety concerns have been identified with the administration of SRT2104 in healthy volunteers at doses up to 3.0 g per day for 7 consecutive days in the fasted state and up to 2.0 g per day for 7 days in the fed state. Completed and Reported Trials The first administration of SRT2104 to humans was performed as part of clinical study SRT-2104-001, a randomized, placebo-controlled, single-blind, multiple-dose, dose-escalation study (EudraCT Number: 2007-007598-22). A total of 28 healthy male volunteers received SRT2104 in the form of a liquid suspension as both a single dose and during a separate multiple dose period (once per day for 7 days) at the following dose levels: 30, 100, 250, 500, 1000, 2000, and 3000 mg/day (4 volunteers at each dose level). SRT2104 was well-tolerated following both the single- and multiple-dose periods at all dose levels investigated and all adverse events (AEs) recorded were either mild or moderate in severity and SRT-2104-013 Version 2.0

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were predominantly gastrointestinal in nature. Treatment-emergent AEs observed in more than one subject were flatulence, headache, nausea, and diarrhea. All AEs were short in duration and resolved without sequelae. No dose-related AEs were identified. There were no serious adverse events. The pharmacokinetic parameters AUC(0-t) and Cmax exhibited dose proportionality over the dose range of 30 to 1000 mg/day in healthy volunteers. At doses greater than 1000 mg /day increases in AUC(0-t) and Cmax were less than proportional to the increase in dose. The terminal elimination half-life (t½) ranged from 8 to 24 hours and was not affected by dose. There was no evidence to suggest saturation of any elimination pathways over the dose range investigated (30 to 3000 mg /day). A second administration of SRT2104 to human volunteers was performed as part of a single-center, combined intravenous (IV) and oral dosing study to evaluate the PK and absolute bioavailability of SRT2104 (Clinical Protocol SRT-2104-002; EudraCT Number 2008-006283-10). SRT2104 was administered as a single dose of 250 mg administered as an oral suspension and an IV microdose of 100 µg 14C-SRT2104 to eight healthy male subjects. SRT2104 was well tolerated by all subjects. No serious adverse events (SAEs) were recorded. The AEs assessed as related to SRT2104 were aching at infusion site and paresthesia. All AEs were of mild severity and resolved without sequelae. The maximal drug concentrations generally occurred at the end of the 15-minute IV infusion. The terminal elimination half-life for total radioactivity after intravenous dosing was similar to that for the parent drug. The mean t½ for 14C-SRT2104 was 23.7 ± 9.37 hours following a 15-minute IV infusion of approximately 100 μg 14

C-SRT2104 and mean t½ for SRT2104 was 25.5 ± 6.45 hours following oral administration of 250 mg

SRT2104. Absolute bioavailability of SRT2104, when dosed as a 250 mg oral suspension in a fasted state, was approximately 14%. A third clinical study was conducted to assess the effect of food and gender on the PK of SRT2104 (Clinical Protocol SRT-2104-004; EudraCT Number: 2008-007364-41). This Phase I, randomized, openlabel study enrolled 10 male and 10 female healthy volunteers to characterize the PK profile of a single 500 mg dose of SRT2104 when administered as an oral suspension and as a capsule formulation in both the fed and fasted states. SRT2104 was well tolerated at the dose level tested. The absorption of SRT2104 administered as capsules and oral suspension was significantly increased when administered to subjects in the fed versus fasted state. There was a very slight decrease in absorption when SRT2104 was administered as a capsule. No gender effects were noted.

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Clinical Protocol SRT-2104-009 (EudraCT Number: 2009-010829-39) was a prospective, randomized study to assess the safety and PK of SRT2104 in healthy male volunteers. Ten male subjects were randomized to receive 2000 mg SRT2104 or placebo capsules under fed conditions on eight occasions during the study, once as a single dose and once per day for seven consecutive days. SRT2104 was considered to be safe and well tolerated at the dose levels tested. The mean AUC(0-τ) following once daily dosing for seven days was found to be increased when compared with the mean AUC(0-∞) following single dose administration, providing evidence for accumulation of SRT2104 following once daily dosing at 2000 mg for seven days. Evaluation of the pre-dose plasma SRT2104 concentrations during the multiple dose period suggested that steady state had likely not been achieved by all subjects at the end of the 7-day dosing interval. However, review of the individual subject plasma concentrations over the multiple dose period indicated that some subjects appeared to have reached steady state plasma SRT2104 concentrations within seven days of daily dosing. Following 7 days of dosing of 2 g SRT2104 to fed volunteers the mean Cmax was 1,874 ng/ml and the mean AUC was 13,997 ng.h/mL. The safety intervals from the 90 day study are 0.50-1.37 ng/mL based on Cmax and 0.93-3.40 ng.hr/mL based on AUC. It should be pointed out that there were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals are likely to be an under-estimate of the true values. Clinical Protocol SRT-2104-008 (EudraCT Number 2009-010620-25) was conducted to assess the pharmacodynamic effect of single oral doses of SRT2104 and prednisolone as measured by levels of ex vivo LPS-induced TNF-α production in whole blood of healthy adult subjects. This was a prospective, single center, non-therapeutic, randomized, double-blind study. Twenty male subjects were enrolled in the study and randomized to receive single doses of SRT2104 (250, 500, 1000, and 2000 mg) and/or placebo on 5 separate occasions followed by a single 30 mg dose of prednisolone on the sixth dosing occasion. Although Cmax increased with SRT2104 dose, the relationship between dose and Cmax was less than proportional. Median Tmax did not appear to vary significantly according to dose. Ongoing Trials Clinical Protocol SRT-2104-005 (EudraCT Number: 2009-010720-26) is a randomized, placebocontrolled, double-blind, multiple-dose, inpatient/outpatient study to assess the safety and PK of SRT2104 in male and female subjects with type 2 diabetes on an existing, stable, background metformin therapy. Approximately 225 subjects will be enrolled in this study. Subjects will be evenly randomized to receive SRT-2104-013 Version 2.0

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SRT2104 or placebo in one of five cohorts: placebo (A); 250 mg/day SRT2104 (B); 500 mg/day SRT2104 (C); 1000 mg/day SRT2104 (D); or 2000 mg/day SRT2104 (E). Subjects will be dosed once a day for 28 consecutive days, approximately 15 minutes following the consumption of a standardized meal. Subjects will remain on a fixed dose of investigational product for all dosing days in the study. As of December 31, 2009, 51 subjects had been randomized into the study, 17 subjects had completed the study, 2 subjects had withdrawn (due to voluntary consent withdrawal), and 13 subjects had experienced treatment-emergent adverse events. A review of blinded safety data showed the most commonly reported adverse events were dyspepsia and hyperglycemia, each of which was reported twice and by different subjects. Two additional studies of SRT2104 are currently ongoing. Clinical Protocol SRT-2104-007 (EudraCT Number 2009-011918-21) is a randomized, placebo-controlled, double-blind, study to assess the safety, tolerability and pharmacokinetics of oral SRT2104 capsules administered to healthy elderly subjects for 28 days. Twenty-four subjects will be randomized to receive one of the following three treatments: SRT2104 500 mg/day, SRT2104 2000 mg/day or placebo. This study is currently enrolling as is Clinical Protocol SRT-2104-010 (EudraCT Number 2009-011918-21). Protocol SRT-2104-010 is being conducted to determine if single or multiple doses of SRT2104 attenuate the inflammatory response in normal healthy male subjects after exposure to low-dose endotoxin. Twenty-four healthy male subjects will be randomized to receive single or multiple doses of 2000 mg of SRT2104 and/or placebo for 7 days. Study endpoints include safety, PK and clinical signs and symptoms and laboratory parameters for inflammation.

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STUDY RATIONALE

A direct role for SIRT1 in promoting keratinocyte differentiation was elucidated [Blander, 2004] and is supportive of earlier findings that resveratrol, a natural plant-derived polyphenol that has been shown to activate SIRT1, inhibited the proliferation of human keratinocytes in vitro [Holian, 2001] and suppressed angiogenesis [Brakenhielm, 2001]. Taken together with the finding that SIRT1 activators are potent inhibitors of cytokine production, including TNF-α [Smith, 2009], the therapeutic potential for SIRT1 activators in the treatment of psoriasis will be explored as part of this clinical protocol. We hypothesize that SIRT1 activators may demonstrate anti-psoriatic action by promoting keratinocyte differentiation, reducing inflammation and/or inhibiting angiogenesis.

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STUDY OBJECTIVES Primary 1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis

4.2

Secondary 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg, and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaquetype psoriasis

4.3

Exploratory 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Mentor Psoriasis Instrument, PQOL-12.

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INVESTIGATIONAL PLAN

5.1 Overall Study Design Three cohorts of ten subjects each will be enrolled. Subjects within each cohort will be randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects will be dosed sequentially. Dosing in the second and third cohort will not commence until subjects in the previous cohort have completed at least 28 days of dosing, and a review of safety parameters (physical examination findings, vital signs, electrocardiograms, adverse events and laboratory values) has been completed by an Independent Safety Review Committee (ISRC). Subjects will receive either SRT2104 or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety will be assessed on an ongoing basis. The study consists of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Potential subjects will sign the IRB-approved informed consent form at the Screening Visit, and will undergo screening assessments to verify eligibility for the study. If eligible and willing to participate, subjects will return to the clinic within 21 days of the Screening Visit to participate in the dosing phase of the study. For the dosing phase of the study, starting on Day 1, subjects will be randomized on approximately Day -6 to receive either 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo once daily for 84 consecutive days. PK sampling will occur on Days 28, 56 and 84. 5.2 5.2.1

Selection of Study Population Number of Subjects

A sample size of 10 evaluable subjects per active treatment group and 6 evaluable subjects in the merged placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 onesided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (response of excellent) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2). 5.2.2

Replacement of Subjects

Subjects who withdraw from the study prior to completing 8 weeks of treatment may be replaced.

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5.2.3

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Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following Screening criteria are met: 1. Able and willing to provide written informed consent to participate in the study 2. Be male or female aged 18 to 80 years (inclusive) 3. Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving >10% of body surface area 4. Have a baseline PASI of >10 5. Be a candidate for systemic psoriasis therapy, in the opinion of the investigator 6. If a female subject of child-bearing potential, be willing to use reliable contraception (see Section 5.15) for the duration of the study, through the 30 day safety follow up telephone call 7. Be willing and able to comply with the protocol for the duration of the study. 5.2.4

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria are met at Screening: 1. Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit 2. Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 3. Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study 4. Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period is prohibited 5. Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit 6. Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 7. Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 8. Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation 9. Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit 10. Has a positive test for HIV antibody SRT-2104-013 Version 2.0

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11. Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial 12. Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: •

QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period)

•

QTcB ≥480 msec in subjects with Bundle Branch Block

13. Has renal or liver impairment, defined as: •

Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males

•

AST and ALT ≥ 2xULN or

•

Alkaline phosphatase and bilirubin > 1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)

14. Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) 15. Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 16. Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine 17. History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation 18. Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. 5.2.5

Definition of Treatment Failure

A subject who experiences a treatment failure is anyone who demonstrates a score of “no improvement” based on the Krueger criteria defined in Section 6.4, or any subject who is prematurely withdrawn from the study due to lack of efficacy as judged by the investigator. 5.2.6

Removal of Subjects from the Study

Subjects will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The investigator can withdraw subjects from the study for any of the following reasons: •

QT interval changes as defined in Section 7.1.4

•

Liver event (see Section 7.1.5)

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•

Treatment failure

•

Subject request

•

Failure to return for follow-up

•

Administrative reasons

•

General non-compliance with the protocol

•

Positive pregnancy test result

The investigator also reserves the right to withdraw subjects in the interest of subject safety and welfare. If a subject is withdrawn from the study, the subject must complete Day 84 assessments at the time of discontinuation and return to the clinic approximately 30 days after the last dose to conduct a safety and activity (PASI and PGA) evaluation. The sponsor reserves the right to terminate the study in the interest of subject safety as defined in Section 5.11. The sponsor also reserves the right to terminate the study at any time for administrative reasons. 5.3

Selection of Doses in the Study

Three different doses of SRT2104 were selected for study in this protocol, 250 mg/day, 500 mg/day, and 1000 mg/day. These doses should be distinct enough to give different systemic exposures. Comparing three different doses may allow establishment of a pharmacokinetic/pharmacodynamic relationship for SRT2104 and will assist in understanding whether a dose effect exists with regard to the psoriatic efficacy parameters being tested. This will provide valuable information in choosing doses for future trials. In prior human clinical trials, subjects have received doses of SRT2104 as high as 3000 mg/day with good tolerability. Pharmacokinetic data demonstrated dose-related increases in exposure up to 2000 mg/day, but not beyond. No in vivo pharmacodynamic parameters were collected in the normal volunteer studies, thus no human pharmacokinetic/pharmacodynamic relationship has been established to date. In preclinical testing, SRT2104 has been shown to positively impact a variety of animal models, including those of both metabolic and inflammatory disorders, at daily doses ranging from 10 - 300 mg/kg/day. The most consistent doses associated with good efficacy results in these models range from 100 - 200 mg/kg/day. Adjusting for body surface area between human and mouse, these equilibrate to potential pharmacologically active doses in man of 500 mg to 1000 mg, respectively.

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From a safety perspective, the 1000 mg/day dose, the highest dose to be tested, is supported by the preclinical safety toxicology package described in Section 2.3 and by the cumulative human safety experience gathered to date. From the pre-clinical 90 day toxicology studies, the safety intervals are 1.33.6 based on Cmax and 1.9-6.8 based on AUC. There were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals may be an under-estimate of the true values. The most notable finding in the rat and dog toxicity studies has been a small, reversible increase in serum bilirubin. Bilirubin levels will be closely monitored in the proposed clinical trial. The entry criteria are written to exclude subjects with elevated bilirubin levels. Subjects developing elevated bilirubin values that meet the criteria for stopping investigational product will be withdrawn from the study (see Section 7.1.5, Liver Chemistry Stopping Rules and Follow-Up). In the completed and ongoing clinical trials with SRT2104, there have been no serious adverse events reported to date. In addition, no specific safety signals have been identified at this time. 5.4

Identity of Investigational Product

SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged as one, two or four capsules in dosing bottles. For the matching placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product. All subjects will be provided with one dosing bottle per day that contains one, two or four capsules for oral ingestion as described in Section 5.5. Prior to being dispensed, the investigational product should be stored at 15 – 25 oC and protected from light. Subjects will be instructed to store investigational product at room temperature away from direct light. 5.5

Treatments to be Administered

Investigational product will be dispensed only to eligible subjects under the supervision of the investigator or identified sub-investigator(s). A trained investigative site member will administer the investigational product to subjects when they are in the clinic, where applicable. As shown in study SRT-2104-004, the administration of SRT2104 with food increased exposure levels and reduced variability in exposure levels in humans. For this reason, subjects participating in this study SRT-2104-013 Version 2.0

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are required to take SRT2104 approximately 15 minutes following the consumption of food. Investigational product should be administered with approximately 250 to 500 cc of water at approximately the same time every dosing day. Subjects should refrain from eating or drinking anything other than water for 1 hour after dosing. Dietary recommendations for the meal that precedes dosing will be included in the study reference manual and provided to the study subjects by the clinical site staff. 5.6

Method of Assigning Subjects to Treatment Groups

Subjects will be randomized to receive 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo in a 4:1 fashion. Treatments will be administered as follows for the duration of the study:

5.7

•

Arm 1: 250 mg/day administered as one 250 mg capsule (active or placebo)

•

Arm 2: 500 mg/day administered as two 250 mg capsules (active or placebo)

•

Arm 3: 1000 mg/day administered as four 250 mg capsules (active or placebo)

Individuals Who Will Be Unblinded to Treatment Assignments

Designated individuals of Sirtris’ Pharmaceutics Research Department will be unblinded for purposes of assigning the treatment assignments according to a randomization schema that will be retained in a secure location with limited access. In addition, selected personnel at the bioanalytical laboratory will be unblinded to treatment assignments for purposes of data analysis. Members of the ISRC will be unblinded for purposes of conducting the cohort safety assessments. 5.8

Unblinding Procedures

Procedures for obtaining unblinded treatment information will be provided to the clinical sites in the study operations manual. If it is medically imperative to know the treatment that a subject is receiving, the investigator shall, prior to requesting the treatment information, make every attempt to contact the medical monitor for the study to discuss the rationale for breaking the blind. In situations where the investigator is unable to contact the medical monitor as described above (e.g., a medical emergency on the part of the subject), the investigator must contact the medical monitor within 24 hours after the code break to inform him/her of the rationale for the code break. SRT-2104-013 Version 2.0

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The investigator must provide a written narrative describing the event(s) that led to the code break to the medical monitor within 48 hours following the code break. In addition, the investigator must record the date of the code break and the reasons for breaking the blind in the CRF and in the subject’s medical records. 5.9

Duration of Treatment

All subjects enrolled in the study will receive SRT2104 or placebo once daily for up to 84 days during the study period. 5.10 Independent Safety Review Committee An ISRC will be utilized during the conduct of this study to assess safety and advise on dose escalation as described in Section 5.11. The membership of the ISRC and the plan for the safety data review are described in detail in the ISRC charter. A copy of the ISRC charter is available upon request. 5.11 Safety Review and Dose Escalation or Cessation Subject safety will be monitored on an ongoing basis. Dose escalation will be dependent upon the review of the unblinded safety data by the ISRC. All safety data generated for all subjects in every cohort who have completed at least 28 days of dosing will be reviewed by the ISRC. In the event of clinically significant adverse events deemed to be of sufficient severity to pause dosing, a full analysis of all safety data will be conducted before continuing with a given dose or with dose escalation. When the last subject in a cohort has completed 28 days of dosing, the data for each subject will be manually entered into an electronic data capture system. The laboratory data will be transferred electronically into the database. The safety data will then be listed and presented to the ISRC for review. If the safety data is acceptable, any subjects still active in the current cohort will continue dosing, and the ISRC will authorize the initiation of dosing to the next cohort of subjects at the higher dose level. This will be repeated until all three dosing cohorts have completed at least 28 days of dosing. 5.11.1 Criteria for discontinuing dosing/dose escalation In the event that there are any serious adverse events or moderate to severe adverse event toxicities reported in a cohort, one of the following procedures will be applied: •

If one subject receiving test material in a cohort is intolerant of the test material, but the other subjects receiving that same dose are tolerant of that dose, the ISRC and Sponsor will determine

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whether the nature, severity, or the number of toxicities permit continuing the dosing cohort, or if dosing and/or dose escalation will stop. •

If at least two subjects are intolerant of a given dose of SRT2104, but similar toxicities are recorded for subjects on placebo, the ISRC and Sponsor will determine whether the nature, severity, or the number of toxicities permit continuing the dosing cohort, or if dosing and/or dose escalation will stop.

•

If at least two subjects are intolerant of SRT2104 at a given dose level, and no toxicities are seen in placebo subjects, the dose escalation will stop.

5.12 Prior Treatments See the exclusion criteria (Section 5.2.4) for details regarding medications that are prohibited prior to entry into the study. 5.13 Proscribed Medications In addition to the restrictions described in Section 5.2.4, no other concomitant medications, dietary supplements, or herbal products are permitted for the duration of this trial except as described in Section 5.14. 5.14 Permitted Medications The following concomitant medications are permitted during the study: •

Non-prescription medications administered to treat an AE (e.g., acetaminophen, or non-steroidal anti-inflammatory agents taken for headache) NOTE: Over-the-counter antacids should not be taken within four hours of investigational product administration as they may interfere with the absorption of investigational product.

•

Topical Class 6 and/or 7 “rescue” corticosteroid treatment for psoriasis flares may be used, but use must be limited to the face, axillae and groin regions. See Section 13 for a list of permitted topical corticosteroid treatments. NOTE: Topical treatments should not be applied to other areas and in particular the plaque being assessed for efficacy, at or near the biopsy site

•

Any chronically prescribed non-psoriatic medication or herbal or dietary supplements administered at a stable dose for at least 6 weeks prior to enrollment with the exception of proton

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pump inhibitors. Potential subjects taking proton pump inhibitors at the time of the Screening Visit must be willing and able to discontinue these medications prior to taking investigational product and for the duration of the dosing period. All medications administered during the study must be recorded in the subject’s CRF and in the source documents. 5.15 Contraceptive Use All female subjects of child-bearing potential must use two adequate forms of contraception for the duration of the trial (from the Screening Visit through Day 114). Adequate forms of contraception are defined as: •

Abstinence

•

Oral Contraceptive, either combined or progestogen alone

•

Injectable progestogen

•

Implants of levonorgestrel

•

Estrogenic vaginal ring

•

Percutaneous contraceptive patches

•

Intrauterine device or intrauterine system

•

Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject (“documentation” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records)

•

Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

5.16 Treatment Compliance Compliance with the investigational product dosing regimen will be assessed by trained study personnel. Subjects are required to bring all study medication (both empty and full containers) to study visits. Study medication containers will be reviewed by the site staff at each study visit to verify treatment compliance. Subjects who do not comply with the investigational product dosing regimen and who consequently miss either three consecutive doses or six individual doses of investigational product at any time point during

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the study may be withdrawn from the study. The Investigator must call the medical monitor to discuss the disposition of subjects who miss doses as described above. 5.17 Missed Doses of Investigational Product Subjects who inadvertently miss a dose of investigational product should skip that dose and recommence dosing on the next dosing day. 5.18 Schedule of Events A detailed visit-by-visit schedule of study procedures is provided in Section 1.1. Prior to engaging in any study procedure, each subject must sign and date an IRB-approved informed consent form.

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STUDY PROCEDURES

The timepoints for all study procedures are reflected in the Schedule of Events (see Section 1.1). All visits and telephone contacts will be scheduled to take place as near as possible to the scheduled day. The date of the visit will be recorded in the CRF. Descriptions of the required study procedures are provided below: Physical Examination A complete physical examination should be performed at Screening. A symptom-driven, directed physical examination will be performed at other timepoints as defined in the schedule of events. Body systems that will be included are the following: general appearance, musculoskeletal, skin and mucosa, head and neck, lymphatic, respiratory, breast, gastrointestinal, cardiovascular, extremities, neurological, psychological, eyes, ears, nose and throat. Other body systems may be examined as needed, at the discretion of the investigator. Body Weight/Height Height is measured once at the Screening visit. Body weight will be measured at all other clinic visits. The clinical staff will be instructed to use calibrated scales to measure subjects’ body weight. Vital Signs Vital sign assessments will include measurements of resting pulse rate, blood pressure, respiration rate, and temperature. Electrocardiogram A 12-lead ECG will be performed in the rested state. The subject should be lying comfortably in the supine position with ECG leads on for at least 5 minutes prior to the ECG recording. The ECGs will be read locally by the clinical site. The ECG will include the assessment of PR (PQ), QRS, QT, and QTc intervals and heart rate. Identification of any conduction abnormalities will be recorded in the CRF. If a subject’s QTc intervals are prolonged, then the ECG should be done in triplicate with results reported as an average of the three ECGs. Copies of the ECG graphs and available reports will be collected by the study sponsor at the end of the study. Prolonged QTc intervals will be managed according to the QTc withdrawal criteria described in Section 7.1.4. SRT-2104-013 Version 2.0

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Pregnancy Testing Serum pregnancy testing will be performed at the Screening Visit; urine pregnancy tests will be performed at all other visits where a pregnancy test is performed (see Section 1.1). Blood and Urine Sample Collection for Clinical Laboratory Testing Blood and urine samples will be collected as outlined in the Schedule of Events (see Section 1.1) for clinical laboratory safety testing, serology and biomarker analyses. See Section 6.3 for a complete listing of blood and urine parameters. Sample collection, processing, and shipping instructions for samples that will not be analyzed in the local laboratory at the clinical site will be provided in the study operations manual. Pharmacokinetics Approximately 20 mL of blood will be collected throughout the duration of the trial for PK analyses. Samples will be collected on Days 28, 56 and 84 using sparse sampling techniques as described in Section 6.2. Analyses may include metabolite profiling in a subset of samples. Collected samples will be transferred for analysis to Simbec Research Ltd., South Wales, United Kingdom. Additional sample collection, processing, and shipping instructions will be provided in the study operations manual. Pharmacodynamics Biomarkers of psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21. Pharmacogenetics A single blood sample will be obtained on Day 1 for potential pharmacogenetic analysis. The sample is labelled (or “coded”) with a study-specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers such as name or social security number. A full description of the pharmacogenetic assessment is included in Appendix 2. Subject participation in the pharmacogenetic portion of the study is voluntary and refusal to participate will not preclude participation in the clinical study.

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Photography Subjects who provide consent to photography procedures will have full body photographs taken from the neck down at timepoints outlined in the Schedule of Events (see Section 1.1).

Identifying marks such as

tattoos that might reveal the identity of a subject will be covered. Skin Biopsy A skin biopsy will be collected on Days 1 and 84 and transferred to the USA, for evaluation by a central reader. Biopsy tissue analyses are described in detail in Section 6.4. Skin biopsy collection, processing, and shipping instructions will be provided in the study operations manual. Quality of Life Assessments Some authors have noted that the psychosocial consequences of psoriasis can be as disruptive to the individual's life as the physical aspects of the illness itself [Fortune DG, 1997]. As part of an effort to explore whether improvements in the psychosocial consequences of psoriasis represent potential independent targets for treatment with SRT2104, the present study includes the three patient-reported outcome instruments described below. The Patient Health Questionnaire 9 (PHQ-9) is a 9-item, validated self-rating instrument that assesses eight core symptoms of depression in addition to an item that assesses functioning. The PHQ-9 has been validated as a diagnostic instrument for major depression, and it also provides an assessment of the severity of depression [Kroenke K, 2001]. The Hospital Anxiety and Depression Scale (HADS) is a 14-item, validated self-rating instrument of symptoms of anxiety and depression [Mykletun A, 2001]. It is intended to provide a cross-sectional assessment of anxiety and depressive symptoms whether or not subjects meet formal criteria for anxiety and depressive disorders. As such, the HADS could provide a signal of efficacy in a broad-based population of psoriasis sufferers. The 12-item Psoriasis Quality of Life questionnaire (PQOL-12) is a brief, validated instrument derived from a 41-item instrument covering both psychosocial and physical domains [Feldman SR, 2005; Koo J, 2002]. The focus of the PQOL-12 on patient reports of psychosocial and physical effects specifically

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related to psoriasis reflects the growing emphasis among dermatologists on the major impact of the illness on patients' quality of life. Adverse Event Monitoring AE assessment (including SAEs) will be assessed on an ongoing basis throughout the study starting from the time of first dose. All SAEs/SUSARs should be monitored until they are resolved or clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Definitions, documentation, and reporting of AEs are described in detail in Section 7. Concomitant Medications Concomitant medication usage will be assessed throughout the study. See Section 5.13 for a description of permitted and restricted concomitant medications. 6.1 6.1.1

Study Procedures Visit 1 (Screening)

Potential subjects will be given an opportunity to have any questions about the study or their participation in it answered by the principal investigator or his designate. Prior to engaging in any study procedure, each potential subject must sign and date an IRB-approved informed consent form. When the consent form is signed, each subject will be assigned a unique screening number and screening procedures will be performed. 6.1.2

Visit 2

Those subjects meeting the study entry criteria who agree to participate in the study will return to the clinical site on Day 1. The investigator may, at his/her discretion choose to conduct a portion of the Day 1 visit procedures (exclusive of investigational product administration) on Day -1. Study procedures including safety, activity (PASI and PGA) and QOL assessments will be performed as outlined in the Schedule of Events (Section 1.1). Blood samples for biomarker analysis, pharmacogenetics and skin biopsies will be obtained. In addition, a photograph will be taken to document the body surface area affected by psoriatic lesions. Subjects will be randomized to a treatment group approximately 6 days prior to this visit to allow sufficient time for delivery of investigational product. The first dose of study medication will be administered in the clinic following consumption of food. Prior to leaving the clinic, subjects will receive a kit containing study medication and will be instructed to continue once daily SRT-2104-013 Version 2.0

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dosing after eating, and to store the study medication under ambient conditions (between 15 and 25 ºC), protected from direct light for the remainder of the dosing period. 6.1.3

Visits 3, 5 and 7

On Days 14, 42 and 70 subjects will return to the clinic for safety assessments as outlined in the Schedule of Events (Section 1.1). 6.1.4

Visits 4 and 6

On Days 28 and 56 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.5

Visit 8

On Day 84 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Skin biopsies and blood samples for biomarker analysis will be obtained. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.6

Follow-Up Procedures

On Day 114 subjects will return to the clinic for safety and activity assessments, and pregnancy testing as outlined in the Schedule of Events (Section 1.1). 6.2

Pharmacokinetic Sampling

PK measurements will be required for all subjects at all participating centers. Accurate recording of dosing and sample collection times is critical. The actual dosing and sample collection times must be recorded in the CRF.

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A total of five blood samples (4 mL each) will be obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. The following samples can be taken over the course of Visits 4, 6, and 8. Multiple PK samples can be taken during one visit provided the sampling windows as described below are observed and no 2 samples are separated by less than 1 hour. •

One pre-dose sample will be collected prior to taking investigational product (30 minutes or less before dosing). This sample must be collected on any ONE of the following: Visit 4, 6 or 8. It is recommended that the dose associated with this sample be administered in the clinic.

•

A single PK sample will be collected in the time interval of 0.5 to 2 hours post-dose. It is recommended that the dose associated with this sample be administered in the clinic. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

A single PK sample will be collected in the time interval of 3 to 6 hours post-dose. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

Two PK samples will be collected in the time interval of 6 to 22 hours post-dose. These 2 samples must be collected on any of the following: Visit 4, 6 or 8.

PK samples may be collected at any time during the defined sampling intervals. An effort should be made to ensure that samples are not consistently collected at the same time point within a defined collection interval. This study provides flexible options for scheduling of most PK samples. This flexibility is incorporated to improve subject convenience for sampling at later time points. 6.3

Laboratory Assessments

Safety (e.g., hematology, chemistry, and urinalysis) and screening (e.g., serum β-HCG and serology) samples will be analyzed by a central laboratory. A subset of samples (e.g., PK and FGF21 samples) may be transferred for analysis to Sirtris, GlaxoSmithKline (GSK), or other designated representative working with GSK and/or Sirtris. The following clinical laboratory parameters will be evaluated at the time points specified in the Schedule of Events (see Section 1.1). Collected samples may be transferred for analysis to Sirtris, GSK, or other designated representatives working with GSK or Sirtris. SRT-2104-013 Version 2.0

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Hematology White blood cell count (WBC)

Complete WBC differential

Hemoglobin

Platelets

Hematocrit

Mean corpuscular volume

Red blood cell count

Mean Corpuscular Hemoglobin Concentration

Red Cell Distribution Width

Mean Corpuscular Hemoglobin

Clinical Chemistry Sodium

Alanine aminotransferase

Potassium

Aspartate aminotransferase

Chloride

Total, direct, and indirect bilirubin

Blood Urea Nitrogen

Alkaline phosphatase

Serum creatinine

Lactate dehydrogenase

Plasma Glucose

Gamma-glutamyl transferase

Calcium

Amylase

Magnesium

Bicarbonate

Uric acid

Albumin

ProthrombinTime/International Normalized

Phosphate

Ratio

1

Activated Partial Thromboplastin Time 1

Creatine Kinase

Lipid Profile (Total Cholesterol, Low Density Lipoprotein, High Density Lipoprotein, Free Fatty Acids, Triglycerides)2 1

Coagulation studies will be performed at Screening and on Days 1, 42 and 84 only.

2

Lipid profiling will be performed in fasting samples at Screening, Days 1, 42 and 84 only.

Pregnancy Monitoring Serum β-HCG at Screening

Urine testing at other timepoints as defined in the Schedule of Events (Section 1.1)

Urinalysis Dipstick

Microscopic exam only if dipstick abnormal

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Serology HCV ab

HBsAg

HIV 1 & 2

Biomarkers* hsCRP

FGF21

*Biomarker analysis will be performed in fasting samples according to the timepoints displayed in the Schedule of Events (Section 1.1). Additional biomarkers thought to be associated with SIRT1 activation may be assessed.

6.4

Skin Biopsy Evaluation and Scoring

Skin biopsies will be obtained from the same designated plaque on Days 1 and 84. The central reader at (who will be blinded to treatment assignments) will evaluate the biopsy tissue for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells). Keratinocyte expression of K-16 and ICAM-l will be measured. RT-PCR will be used to assess for expression of specific genes which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPARα, PPAR-delta, and p53.

In addition, global changes in gene expression may be assessed using

gene micro-array techniques. Skin biopsies will be assigned an improvement score according to the Krueger criteria defined below: Improvement Score

Definition

No improvement

defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes

Good improvement

defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16

Excellent improvement

defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16.

6.5 Appropriateness of Measurements Per the U.S. Food and Drug Administration (FDA) guidance, “Collection of Race and Ethnicity Data in Clinical Trials, September 2005”, demographic data and complete subject medical histories will be

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documented for all subjects during screening. Investigational product administration data, including dose interruptions and modifications and the associated reason(s), also will be documented. AEs and SAEs will be monitored in this study in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines to ensure the safety of subjects. 6.6

Data Quality Assurance

Sirtris or its designated representative will conduct a clinical site visit to verify the qualifications of the investigator, inspect clinical site facilities, and inform the investigator of responsibilities and procedures for ensuring adequate and correct study documentation. The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. All information recorded on the CRFs for this study must be consistent with the subject’s source documentation. During the course of the study, the study monitor will conduct clinical site visits to review protocol compliance, compare CRFs and individual subject’s medical records (source documents), assess investigational product accountability, and ensure that the study is being conducted according to pertinent regulatory requirements. CRFs will be verified with source documentation. The review of medical records will be performed in a manner to ensure that subject confidentiality is maintained. A hardcopy of the final CRFs will be placed in the investigator’s study file and Sirtris’ Trial Master File (TMF). Instances of missing or uninterpretable data will be discussed with the investigator for resolution. Study data will be entered into a secure, validated data processing system and a backup will be maintained. Any changes to study data will be documented. A quality assurance audit will be performed on the database.

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Clinical Study Protocol SRT-2104-013 March 19, 2010

ADVERSE EVENTS

The principal investigator and designated study staff are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE/SUSARs. 7.1 7.1.1

Definitions Adverse Event Definition

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational product, whether or not it is considered to be investigational product-related. This includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of investigational product. 7.1.2

Serious Adverse Event Definition

A serious adverse event (SAE) is any AE, occurring at any dose and regardless of causality that: •

Results in death.

•

Is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.

•

Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry, are not considered AEs if the illness or disease existed before the subject was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the study (e.g., surgery performed earlier than planned).

•

Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions.

•

Is a congenital anomaly/birth defect.

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Is an important medical event. An important medical event is an event that may not result in death, be life-threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. See Section 7.1.5 for guidance on liver events that would be considered SAEs.

•

Is associated with liver injury and impaired liver function defined as: • ALT ≥ 3xULN, and • total bilirubin ≥ 2xULN or INR > 1.5. NOTES: (1) Bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury). (2) INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

•

Pregnancy complications: spontaneous abortions in subjects exposed to investigational product must be reported as SAEs. NOTE: Any SAE occurring in association with a pregnancy that is brought to the investigator’s attention after the subject has completed the study and that is considered by the investigator as possibly related to the investigational product, must be promptly reported to Sirtris.

Clarification should be made between the terms “serious” and “severe” as they ARE NOT synonymous. The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a severe headache). This is NOT the same as “serious,” which is based on subject/event outcome or action criteria described above, and is usually associated with events that pose a threat to a subject’s life or functioning. A severe AE does not necessarily need to be considered serious. For example, persistent nausea of several hours’ duration may be considered severe nausea but not an SRT-2104-013 Version 2.0

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SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild, but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 7.1.3

Suspected Unexpected Serious Adverse Reaction Definition

A suspected unexpected serious adverse reaction (SUSAR) is any adverse drug reaction (i.e., any AE that is assessed by the Investigator as associated with [i.e., unlikely, possibly or probably related to] SRT2104, the specificity or severity of which is not consistent with those noted in the current protocol and/or Investigator’s Brochure (IB). This refers to any adverse reaction that has not been previously observed (e.g., included in the IB), rather than from the perspective of such an event not being anticipated from the pharmacological properties of the product. 7.1.4

QTc Withdrawal Criteria

A subject that meets the criteria below will be withdrawn from the study. •

QTcB > 500 msec (machine or manual overread). If the subject has bundle branch block then the criterion is QTcB > 530 msec

•

Prolongation of QTcB > 60 msec as compared to baseline

These criteria are based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, 2 additional ECGs are to be obtained over a brief period and the averaged QTc values of the 3 ECGs is used to determine whether the subject should be discontinued from the study. All ECGs with a machine-read QTcB value of > 500 msec collected during the study (including at Screening) will be manually over-read by a cardiologist to verify the QTcB value. 7.1.5

Liver Chemistry Stopping Rules and Follow-up

Liver Chemistry Stopping Rules Investigational product will be stopped if any of the following liver chemistry stopping criteria is met: 1.

ALT ≥ 3xULN and bilirubin ≥ 2xULN (or ALT ≥ 3xULN and INR > 1.5) NOTE: serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

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2.

ALT ≥ 5xULN

3.

ALT ≥ 3xULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia)

4.

ALT ≥ 3xULN persists for ≥ 4 weeks

5.

ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks

6.

Alkaline phosphatase ≥ 3xULN and bilirubin ≥ 2xULN.

7.

Subjects with ALT ≥ 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash, can continue investigational product as long as they can be monitored weekly for 4 weeks. Liver Chemistry Follow-up If any of criteria 1 through 5 above are met, the following actions should be taken: •

Immediately withdraw investigational product

•

Report the event to Sirtris and Akos Ltd. within 24 hours of learning its occurrence

•

Complete the SAE reporting form if the event also meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR >1.5, if INR measured; INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE.

NOTE: if serum bilirubin fractionation is not immediately available, investigational product should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. •

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below

•

Withdraw the subject from the study (unless further safety follow up is required) after completion of the liver chemistry monitoring as described below

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Clinical Study Protocol SRT-2104-013 March 19, 2010

Do not re-challenge with investigational product.

In addition, for criterion 1: •

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

•

A specialist or hepatology consultation is recommended

•

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values

For criteria 2, 3, 4 and 5: •

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

•

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.

For criteria 6 and 7: •

Notify the Sirtris medical monitor within 24 hours of learning of the abnormality to discuss subject safety

•

Can continue investigational product

•

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline

•

If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

•

If, after 4 weeks of monitoring, ALT < 3xULN and alkaline phosphatase < 3xULN and bilirubin < 2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.

For criteria 1-5, make every attempt to carry out the assessments described below:

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Viral hepatitis serology including: o Hepatitis A IgM antibody; o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); o Hepatitis C RNA; o Cytomegalovirus IgM antibody; o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); o Hepatitis E IgM antibody (if subject has travelled outside US in past 3 months);

•

Blood sample for PK analysis, obtained as soon as possible but no later than 5 days following last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for PK sample handling and shipping are in the study operations manual.

•

Serum creatine phosphokinase and lactate dehydrogenase

•

Fractionate bilirubin, if total bilirubin ≥ 2xULN

•

Obtain complete blood count with differential to assess eosinophilia

•

Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia as relevant on the AE report form

•

Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form

•

Record alcohol use on the liver event alcohol intake case report form

The following are required for subjects with ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) but are optional for other abnormal liver chemistries: SRT-2104-013 Version 2.0

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Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies

•

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

7.2

Procedures for Recording and Reporting AEs and SAEs

All AEs spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures will be recorded on the appropriate page of the CRF. Any clinically relevant change in laboratory assessments or other clinical findings is considered an AE and must be recorded on the appropriate pages of the CRF. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event. All SAEs and SUSARs that occur during the course of the study, as defined by the protocol, must be reported by the investigator to Sirtris and Akos Ltd. by faxing the SAE/SUSAR form within 1 working day from the point in time when the investigator becomes aware of the SAE/SUSAR. In addition, all SAEs/SUSARs, including all deaths, which occur up to and including 30 days after administration of the last dose of investigational product, must be reported to Sirtris and Akos Ltd. within 1 working day. All SAEs/SUSARs and deaths must be reported whether or not considered causally related to the investigational product. The information collected using the SAE/SUSAR form will include a minimum of the following: subject number, a narrative description of the event and an assessment by the investigator as to the intensity of the event and relatedness to investigational product. A sample of the SAE/SUSAR form can be found in the study operations manual. Follow-up information on the SAE/SUSAR may be requested by Sirtris or Akos Ltd.

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SAE/SUSAR Reporting Contact Information: Akos Limited The Coach House, Pipers Lane Harpenden, Hertfordshire AL5 1AH United Kingdom SAE Reporting Line: or Telephone: And to the Sponsor: MD Chief Medical Officer Sirtris Pharmaceuticals 200 Technology Square Cambridge, MA 02139 USA Direct Line: Extension Fax Line: If there are suspected, unexpected, serious adverse drug reactions (SUSARs) associated with the use of the investigational product, Sirtris or its designee will notify the appropriate regulatory agency(ies) and all participating investigators on an expedited basis (7 days for fatal or life-threatening suspected, unexpected, serious adverse drug reactions). Sirtris has delegated the responsibility to promptly notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all SUSARs involving risk to human subjects in accordance with the rules and regulations of the IRB/IEC to the principal investigator. An unexpected event is one that is not reported in the Investigator’s Brochure. Planned hospital admissions or surgical procedures for an illness or disease that was diagnosed before the subject was enrolled in the study or before investigational product was given, are not to be considered AEs. For both serious and non-serious AEs, the investigator must determine both the intensity and the relationship of the event to investigational product administration. Intensity for each AE will be determined by using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 4.0 as a guideline, wherever possible. Dose-limiting toxicities will be defined as those AEs of Grade 3 or greater that are seen to occur with an evident temporal relationship to SRT2104 SRT-2104-013 Version 2.0

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dosing. In those cases where the NCI CTC criteria do not apply, intensity should be defined according to the following criteria: Mild

Awareness of sign or symptom, but easily tolerated

Moderate

Discomfort enough to cause interference with normal daily activities

Severe

Inability to perform normal daily activities

Life Threatening or Disabling

Immediate risk of death from the reaction as it occurred

Death

The event resulted in death

Relationship to investigational product administration will be determined as follows: Not Related

No relationship between the experience and the administration of investigational product; related to other etiologies, such as concomitant medications or subject’s clinical state.

Unlikely Related

The current state of knowledge indicates that a relationship is unlikely.

Possibly Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product. The reaction might have been produced by the subject’s clinical state or other modes of therapy administered to the subject.

Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product and can be confirmed with a positive re-challenge test or supporting laboratory data.

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7.3

Clinical Study Protocol SRT-2104-013 March 19, 2010

Monitoring of Adverse Events and Period of Observation

AEs, both serious and non-serious, and deaths will be recorded on the CRFs throughout the study from the time of first dose until the final follow-up contact. However, any SAEs assessed as related to study participation (e.g., investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs should be monitored until they are resolved or are clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Any SAE that occurs at any time after completion of the study including the designated follow-up period, which the investigator considers to be related to study medication, must be reported to Sirtris. AEs or SAEs requiring therapy must be treated by recognized standards of medical care to protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines must be available to ensure the best possible treatment of an emergency situation. The outcome of AEs will be rated as: • Recovered/Resolved; • Recovering/Resolving; • Not Recovered/Not Resolved; • Recovered/Resolved with Sequelae; • Fatal; • Unknown. Any non-serious AE which occurs in the course of the study should be monitored and followed for up to 30 days following the last dose of investigational product. 7.4

Pregnancy Reporting

The investigator will attempt to collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to Sirtris within 2 weeks of learning of the pregnancy. The outcome of the pregnancy will also be followed. Information on the status of the mother and child will be forwarded to Sirtris. Generally, follow-up will occur at approximately 3-month intervals and will be no longer than 12 SRT-2104-013 Version 2.0

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months following the estimated delivery date. Any premature termination of the pregnancy will be reported. Pregnancy complications, including spontaneous abortions, and the medical reason(s) for elective terminations must be reported as AEs or SAEs.

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STATISTICAL PROCEDURES

The sample size has been chosen based on the probability of overall response to treatment and feasibility to allow preliminary characterization of safety, tolerability, and PK and to explore pharmacodynamic measures. Alphas will be two-tailed in nature and set at 0.05 for all analyses unless otherwise stated. As this is a proof of concept study, no adjustment for multiple analyses will be made. 8.1

Randomization and Stratification

On entry into each of the three cohorts, the study subjects will be randomized to active SRT2104 (250mg, 500 mg, or 1000 mg) or placebo in a 4:1 fashion using a predetermined randomization schedule. All subjects will receive the assigned, double-blind study medication for 84 days. 8.2

Sample Size

A sample size of 8 evaluable subjects per active treatment group and 6 evaluable subjects in the merged placebo group is based on the following assumptions: an exact binomial test with a nominal 0.05 onesided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (an improvement score of “excellent improvement” based on the Krueger criteria [see Section 6.4]) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2). In addition, with a sample size of 8 for active dose groups, the probability of observing at least one adverse event of a given type will be 72.8% when the probability of such an adverse event is actually 15.0%. Based on the results of the second cohort (SRT2104 500 mg) the sample size of the last cohort (SRT2104 1000 mg) may be slightly increased. 8.3

Populations for Analysis

All subjects randomized will be included in the Randomized Set. The population for all safety analyses is the Safety Analysis Set (SAF). All subjects who receive at least one dose of any investigational product during the study will be included in the SAF population. Subjects will be analyzed according to the treatment received.

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Subjects will be included in the Full Analysis Set (FAS) for the primary assessment of activity according to the intent-to-treat principle. The FAS will include all randomized subjects who take at least one dose of investigational product and have at least one activity measurement at baseline and at least one postrandomization study visit. Subjects will be included in the treatment group to which they were randomized. The Per-Protocol Analysis Set (PPS) is defined as all subjects from the FAS set who complete the study and are deemed to be protocol-compliant. To be protocol-compliant, a subject must not have any major protocol deviations during the study period. Protocol deviations will be identified prior to database lock and will be listed by treatment group in the clinical study report. The PPS will be used for a secondary assessment of activity endpoints. Pharmacokinetics Population is defined as all subjects who receive at least one dose of SRT2104 and have PK data available. 8.4

Procedures for Handling Missing, Unused, and Spurious Data

All available data will be included in data listings and tabulations. No imputation of values for missing data will be performed. Percentages of subjects with AEs or laboratory toxicities will be based on non-missing values. Data that are potentially spurious or erroneous will be examined under the auspices of standard data management operating procedures. 8.5 8.5.1

Statistical Methods Subject Disposition

The total number of subjects screened, randomized, completed, and prematurely discontinued from the study will be summarized by treatment group and overall. The reason for termination for all subjects who discontinued will be summarized by treatment group and overall. A listing of subjects who discontinued from the study by reason for termination will also be presented. A table summarizing the analysis sets will be presented, with the number of randomized subjects who satisfy the requirements for inclusion and frequencies of exclusion from the respective SAF, FAS, PPS, and PK analysis sets. A listing of subjects with major protocol deviations will also be presented. SRT-2104-013 Version 2.0

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Subjects Baseline Characteristics

Descriptive summaries of demographic and baseline characteristics will be presented by treatment group for all subjects randomized. Baseline characteristics will include a summary of the following: •

Subject demographics including age, gender, race;

•

Baseline disease characteristics, including duration since diagnosis;

•

Pre-existing medical conditions;

•

Prior therapies.

8.5.3

Exposure to Investigational Product

Exposure to SRT2104 will be tabulated by group by presenting number of days on study, defined as number of days from day of first dose to day of last dose taken. Total amount of investigational product taken using a similar calculation method will be presented by group. 8.5.4

Safety Analysis

Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) AE coding system for purposes of summarization. All AEs occurring on study will be listed in by-subject data listings. Treatment-emergent events will be tabulated, where treatment-emergent is defined as any AE that occurs after administration of the first dose of investigational product through 30 days after the last dose of SRT2104, any event that is considered causally drug-related regardless of the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered drug-related by the investigator. Events that are considered related to treatment (unlikely related, possibly related, or related) will also be tabulated. Tabulation will also be provided that enumerates AEs by maximum severity. Deaths, other SAEs, and events resulting in study discontinuation will be tabulated. SRT-2104-013 Version 2.0

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Change from baseline in clinical laboratory parameters will be summarized across time on study. Shift tables may be produced for selected laboratory parameters if implied by the data. Changes in vital sign parameters will be summarized over time in a similar fashion to laboratory parameters, and any abnormal values will be tabulated. Additional safety analyses may be determined at any time without prejudice, in order to most clearly enumerate rates of toxicities and to further define the safety profile of SRT2104. 8.5.5

Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses

The PK population includes all subjects for which SRT2104 concentration data are available. For the current study, plasma concentrations of SRT2104 for each subject will be listed on the basis of the dose level, time and day at which each sample was collected relative to the first dose. Relevant data from the current study, which may be combined with historical data, will be analyzed using a non-linear mixed effects modeling approach (population PK). Population PK parameters including clearance (CL), volume of distribution (V) and AUC will be estimated. Dependent on the final structural PK model additional PK parameters also may be estimated. Sources of variability in PK parameters will be investigated during population modeling. Demographic or clinical variables including, but not limited to, age, sex, race, and body weight will be evaluated as potential predictors of inter- and intra-subject variability for PK parameters. Results of the population PK model may be used in additional PK/PD analyses. Population modeling will be performed using the non-linear mixed effects modeling software (NONMEM, Globomax LLC; Ellicott City, MD). Further details of population PK analyses will be described under a separate analysis plan to be completed prior to database lock. Results of the population PK analysis will be included in a report separate from the clinical study report. Measures of individual exposure to SRT2104, such as AUC, may be correlated with selected efficacy endpoints, biomarkers, and measures of safety and tolerability as exploratory analyses of pharmacokinetic/pharmacodynamic relationships. Specific analyses that may be conducted are not specified a priori; they will be determined on the basis of study outcome. 8.5.6

Activity Analysis

Activity analyses will be performed to examine the effect of daily doses of SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin SRT-2104-013 Version 2.0

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biopsies after 12 weeks of exposure. Analyses will also assess the effects of SRT2104 on the PASI in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. The effects of SRT2104 on the PGA score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure will also be analyzed. Exploratory analyses will be performed to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. Analyses will also be performed in order to assess the effects of SRT2104 on sense of wellbeing in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the PHQ-9 and the HADS. The potential effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the PQOL-12 will also be analyzed. Analyses of activity will be performed on both the FAS and PPS populations. Summary statistics for activity variables will be presented for each planned assessment and, for continuous variables, change plus percent change will be presented at each assessment by treatment group. For all subject reported outcomes, appropriate calculations will be made to produce each factor or subscore for each instrument as well as the overall or total instrument score. For all assessments of activity, the placebo groups will be merged from the 3 cohorts prior to inferential comparisons against active treatments. In addition, the two highest SRT2104 dose cohorts may be merged and serve as an additional group of treated subjects for all activity comparisons. The primary clinical activity outcome will be on histology (i.e., skin pathology) using the Krueger criteria (see Section 6.4). The proportion of subjects with an improvement score of “excellent improvement” will be compared against the null placebo response of 10% using single-sided, one sample binomial tests. In secondary efficacy assessments, “response” to treatment will be determined by PASI-50 and PASI-75 response rates. Response is defined as the proportion of subjects who achieve a PASI-50 or PASI-75. Comparisons will also be made for mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. Response rates for the active treatment groups will be compared against the null placebo response of 10% using single sided, one sample binomial tests. SRT-2104-013 Version 2.0

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For all other activity assessments, analysis of baseline to each assessment differences will be performed employing analyses of covariance (ANCOVA) on values, changes, and percent changes. Baseline values will be used as the covariate for these analyses. If distributions are found to deviate significantly from normal, non-parametric analyses will be substituted for ANCOVA. For variables where change from baseline and percent change from baseline are not appropriate, t-tests will be performed to assess difference between groups. The number and percentage of subjects who experience treatment failure as defined in Section 5.2.5 will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between groups. Subjects experiencing treatment failure will be identified in the data listings. The number and percentage of subjects receiving at least one rescue medication (see Section 5.13), will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between groups. All rescue medication administrations will be provided in the data listings. 8.6

Procedures for Reporting Deviations to Original Statistical Analysis Plan

A formal statistical analysis plan for the analysis and presentation of data from this study will be prepared before database lock. Deviations from the statistical analyses outlined in this protocol will be indicated in this plan; any further modifications will be noted in the final clinical study report.

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ADMINISTRATIVE REQUIREMENTS Good Clinical Practice

The study will be conducted in accordance with the ICH for GCP and the appropriate regulatory requirement(s). The investigator will be thoroughly familiar with the appropriate use of the investigational product as described in the protocol and IB. Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. The investigator site file and associated study documentation will be archived for up to 30 years. The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the sponsor delegates the set-up and maintenance of the sponsor TMF, the TMF will be returned to the sponsor at the end of the study and the sponsor will archive it for up to 30 years after initial marketing approval or termination of development. 9.2

Ethical Considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki (see Section 12) and the relevant regulations under 21 CFR parts 312, 50 and 56. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety, and well-being of the subjects. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written information given to the subjects, safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator. 9.3

Subject Information and Informed Consent

After the study has been fully explained, written informed consent will be obtained from either the subject or their guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s). 9.4

Subject Confidentiality

In order to maintain subject privacy, all CRFs, investigational product accountability records, study reports, and communications will identify the subject by initials and the assigned subject number. The investigator will grant monitor(s) and auditor(s) from Sirtris or its designee and regulatory authority(ies) access to the subject’s original medical records for verification of data gathered on the CRFs and to audit SRT-2104-013 Version 2.0

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the data collection process. The subject’s confidentiality will be maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations. 9.5

Protocol Compliance

The investigator will conduct the study in compliance with the protocol provided by Sirtris, and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). Modifications to the protocol should not be made without agreement by both the investigator and Sirtris. Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to implementation, except when the modification is needed to eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC. Sirtris or its designee will submit all protocol modifications to the regulatory authority(ies) in accordance with the governing regulations. When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to subjects, the investigator will contact Sirtris, if circumstances permit, to discuss the planned course of action. Any departures from the protocol must be fully documented in the CRF and source documentation. 9.6

Study Monitoring

Monitoring and auditing procedures developed by Sirtris will be followed, in order to comply with GCP guidelines. On-site checking of the CRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative matters will be performed. The study will be monitored by Sirtris or its designee. Monitoring will be done by personal visits from a representative of the sponsor (site monitor) who will review the CRFs and source documents. The site monitor will ensure that the investigation is conducted according to protocol design and regulatory requirements by frequent communications (letter, telephone, and fax). All unused investigational product and other study materials are to be returned to Sirtris or its designee, or destroyed on site after the clinical phase of the study has been completed (see Section 9.9). 9.7

On-site Audits

Regulatory authorities, the IEC/IRB, and/or Sirtris’ clinical quality assurance group may request access to all source documents, CRFs, and other study documentation for on-site audit or inspection. Direct access SRT-2104-013 Version 2.0

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to these documents must be guaranteed by the investigator, who must provide support at all times for these activities. 9.8

Case Report Form Completion

Case report forms will be completed for each study subject. It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported in the subject’s CRF. Source documentation supporting the CRF data should indicate the subject’s participation in the study and should document the dates and details of study procedures, AEs, and subject status. The investigator, or designated representative, should complete the CRF pages as soon as possible after information is collected, preferably on the same day that a study subject is seen for an examination, treatment, or any other study procedure. Any outstanding entries must be completed immediately after the final examination. An explanation should be given for all missing data. 9.9

Drug Accountability

Accountability for the investigational product at the study site and with the subject is the responsibility of the investigator. The investigator will ensure that the investigational product is used only in accordance with this protocol. Where allowed, the investigator may choose to assign some of the drug accountability responsibilities to a pharmacist or other appropriate individual. Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, use by each subject, and return to Sirtris (or destruction and disposal of the drug, if approved by Sirtris) will be maintained by the clinical site. These records will adequately document that the subjects were provided the doses as specified in the protocol and should reconcile all investigational product received from Sirtris. Accountability records will include dates, quantities, batch/serial numbers, expiration dates (if applicable), and subject numbers. The sponsor or its designee will assign a site monitor to review drug accountability at the site on an ongoing basis during monitoring visits. All unused and used investigational product will be retained at the site until they are inventoried by the site monitor. All used, unused or expired investigational product will be returned to Sirtris or its designee, or if authorized, disposed of at the study site and documented. All material containing SRT2104 will be treated and disposed of as hazardous waste in accordance with governing regulations.

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9.10 Premature Closure of the Study This study may be prematurely terminated, if in the opinion of the investigator or Sirtris, there is sufficient reasonable cause. Written notification documenting the reason for study termination will be provided to the investigator or Sirtris by the terminating party. Circumstances that may warrant termination include, but are not limited to: • Determination of unexpected, significant, or unacceptable risk to subjects; • Failure to enter subjects at an acceptable rate; • Insufficient adherence to protocol requirements; • Insufficient complete and/or evaluable data; • Plans to modify, suspend or discontinue the development of the investigational product. Should the study be closed prematurely, all study materials must be returned to Sirtris. 9.11 Record Retention The investigator will maintain all study records according to ICH-GCP, applicable regulatory requirement(s) and Sirtris’ record retention policy. Records will be retained for 30 years after the last marketing application approval or 30 years after formal discontinuation of the clinical development of the investigational product or according to applicable regulatory requirement(s). The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the investigator withdraws from the responsibility of keeping the study records, custody must be transferred to a person willing to accept the responsibility. Sirtris must be notified in writing in advance of any change in disposition of the study records, including if a custodial change occurs. 9.12 Liability and Insurance Sirtris will be subscribed to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to participating persons and arising out of this research performed strictly in accordance with the scientific protocol as well as with applicable law and professional standards.

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10 USE OF INFORMATION All information regarding SRT2104 supplied by Sirtris to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Sirtris. It is understood that there is an obligation to provide Sirtris with complete data obtained during the study. The information obtained from the clinical study will be used towards the development of SRT2104 and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required. Publication of the results of the study, whether in whole or in part, shall be within the sole and absolute discretion of Sirtris. Investigators, sites, CROs and/or designees shall not be entitled to publish any of the data or information arising during or out of the provision of the services without the prior written consent of Sirtris. For the avoidance of doubt Sirtris reserves the unqualified right to reject any paper or article utilizing any data generated from this study before such paper or article is presented or submitted for publication.

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11 INVESTIGATOR AGREEMENT I have read the Protocol entitled, “A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe PlaqueType Psoriasis” I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform all who assist me in the conduct of this study of their responsibilities and obligations.

Principal Investigator (Printed Name)

Principal Investigator Signature

Date

Investigational site or name of institution and location (printed)

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12 REFERENCES Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417435. Bouras T, Fu M, Sauve AA, et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem. 2005 Mar; 280:10264-76. Brunet A, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303:2011-2015. Brakenhielm, E, et al. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. Faseb J. 2001 Aug, 15:1798-1800. Cohen H, Miller C, Bitterman K, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul; 305(5682):390-392. Corton JC, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci. 2005 Dec; 60:14941509. Feldman SR, et al. Decision points for the initiation of systemic treatment for psoriasis. Journal of the American Academy of Dermatology. 2005; 53:101 Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Experimental Gastroenterology. 2009; 44:41-45. Fortune DG, et al. Quality of life in patients with psoriasis: the contribution of clinical variables and psoriasis. British Journal of Dermatology. 1997; 137: 755-760 Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 1999; 260:273-279. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 2000; 273:793-798. Handschin C, Spiegelman, BM. The role of exercise and PGC1-α in inflammation and chronic disease. Nature. 2008; 454(7203):463-469 Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep; 78:361-369. Heilbronn LK, Ravussin E. Calorie restriction extends life span-but which calories? PLoS Med. 2005 Aug; 2:e231.

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Holian, O, Walter RJ. Resveratrol inhibits the proliferation of normal human keatinocytes in vitro. J Cell Biol. 2001; Supplement 36:55-62 Imai S, Armstrong CM, Kaeberlein M. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb; 403:795-800. Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006; 5:97-108. Koo J, Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996; 485-96) Koo J, et al. The Development of a Disease-Specific Questionnaire to Assess Quality of Life for Psoriasis Patients: An Analysis of the Reliability, Validity, and Responsiveness of the Psoriasis Quality of Life Questionnaire. Dermatol. Psychosom. 2002; 3:171–179. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a Brief Depression Severity Measure. J Gen Intern Med; 2001 16(9): 606–613. Krueger JG, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. NEJM. 2007; 356:580 Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001 Oct; 107:137-148. Mykletun A, et.al.. Hospital Anxiety and Depression (HAD) scale: factor structure, item analyses and internal consistency in a large population. British Journal of Psychiatry, 2001; 179: 540 Milne J, Lambert P, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov; 450:712-716. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb; 116:551-563. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem. 2005 Apr; 280:16456-16460. Nisoli E, Tonello C, Cardile A, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005 Oct; 310:314-317. Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun; 429:771-776. Rapp SR, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41:401-7 SRT-2104-013 Version 2.0

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Rodgers J, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through complex of PGC1α and SIRT1. Nature. 2005 Mar; 434(7029):113-118. Roth, G. S., Ingram, D. K. & Lane, M. A. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001; 928:305-315. Schon MP, Boehncke WH. Psoriasis. NEJM. 2005; 352:1899 Smith J, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Systems Biology. 2009; 3:31. van der Horst A, et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279, 28873-28879. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001 Oct; 107:149-159. Weindruch R, Keenan KP, Carney JM et al. Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci. 2001 Mar; 56 Spec No 1:20-33. World Medical Association Declaration of Helsinki : Ehtical Principles for Medical Research Involving Human Subjects. October, 2008. http://www.wma.net/en/30publications/10policies/b3/index.html Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun; 23:2369-80. Yoshizaki T, et al. SIRT1 Inhibits Inflammatory Pathways in Macrophages and Modulates Insulin Sensitivity. Am J Physiol Endocrinol Metab. Dec, 2009.

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13 Appendix 1 List of Permitted Rescue Medications Class 6 steroids Alclometasone dipropionate 0.05% cream and 0.05% ointment Desonide 0.05% cream, 0.05% foam, 0.05% gel and 0.05% lotion Fluocinolone acetonide 0.01% shampoo and 0.01% solution Flurandrenolide 0.025% cream Triamcinolone acetonide 0.025% cream and 0.025% lotion Class 7 steroids Hydrocortisone 0.5% cream and 0.5% ointment Hydrocortisone 1% cream, 1% lotion and 1% ointment Hydrocortisone 2.5% cream, 2.5% lotion and 2.5% ointment

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14 Appendix 2 Pharmacogenetic Research Background Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, and elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include: Drug Abacavir

Tranilast

ABT-761

Disease HIV [Hetherington, 2002; Mallal, 2002] Restenosis prevention following coronary bypass [Roses, 2002] Asthma [Drazen, 1999]

Gene HLA (human leukocyte antigen)

Outcome Caucasian males with HLA B57 variant were at increased risk for experiencing hypersensitivity to abacavir

UGT1A1

Drug induced hyperbilirubinemia explained by high proportion of affected patients having 7/7 TA repeat genotype, consistent with clinically benign Gilbert’s Syndrome

ALOX5

ALOX5 Sp1 promoter genotype (x,x) associated with reduced response to 5-lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priory hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to SRT2104. Pharmacogenetics Research Objectives The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to SRT2104. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with SRT2104 that may be attributable to genetic variations of subjects, the following objectives may be investigated: •

Relationship between genetic variants and the pharmacokinetics of investigational product

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•

Relationship between genetic variants and safety and/or tolerability of investigational product

•

Relationship between genetic variants and efficacy of investigational product.

Study Population Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research. Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled. Study Assessments and Procedures In addition to any blood samples taken for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labelled (or coded) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed. The need to conduct PGx analysis may be identified after a study (or set of studies) of SRT2104 has been completed and the study data reviewed. In some cases, the samples may not be studied e.g., no questions are raised about how people respond to SRT2104. Samples will be stored securely and may be kept for up to 30 years after the last subject completes the study or Sirtris may destroy the samples sooner. Sirtris or those working with Sirtris (for example, other SRT-2104-013 Version 2.0

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researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time. Provision of Study Results and Confidentiality of Subject’s PGx Data Sirtris may summarize the cumulative PGx research results in the clinical study report. In general, Sirtris does not inform the investigator, subject or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of the PGx research results because the information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research, under any circumstance unless required by law. References Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

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Clinical Study Protocol SRT-2104-013 October 22 , 2010

PROTOCOL SUMMARY

Study Title: A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis Number of Study Center(s): Approximately five centers located in the United States are planned for this study. Study Phase: Phase IIa Study Period: Approximately 18 weeks for each dose cohort Study Objectives: Primary: 1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis Secondary: 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque-type psoriasis Exploratory: 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of depression and anxiety in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Menter Psoriasis Instrument, PQOL-12.

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Clinical Study Protocol SRT-2104-013 October 22 , 2010

Study Design: This phase IIa, proof of concept, randomized, double-blind, placebo-controlled, dose-escalation study will be conducted in approximately 30 subjects with moderate to severe plaque-type psoriasis. For each dose cohort there will be a screening period, a 12-week treatment period with 7 on-treatment visits (Days 1, 14, 28, 42, 56, 70 and 84) and a follow-up safety assessment (Day 114). Three cohorts of ten subjects each will be enrolled. Subjects within each cohort will be randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects will be dosed sequentially. Dosing in the second and third cohort will not commence until subjects in the previous cohort have completed at least 28 days of dosing, and a review of key safety parameters has been completed by an Internal Safety Review Committee (ISRC). Subjects who provide informed consent will undergo screening procedures within 21days of randomization. Subjects will be enrolled and randomized into the study on approximately Day – 6 and receive investigational product on Day 1. Subjects will take blinded investigational product on a daily basis from Day 1 through Day 84. For the safety evaluation, adverse events (AEs) will be monitored from Day 1 through a follow-up visit that will occur 30 days after discontinuation of investigational product on Day 84. Vital signs, clinical laboratory results (hematology, chemistry, urinalysis), ECGs and physical examinations will be assessed at periodic intervals from Day 1 through Day 84. Skin biopsies of the same designated psoriatic lesion will be conducted on Days 1 and 84 to assess the effects of SRT2104 on histologic markers of inflammation. Disease assessments using the PASI score and the PGA will be conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. Sense of well-being will be assessed using depression and anxiety scales (PHQ-9 and HADS respectively) which will be completed on Days 1, 28, 56 and 84. Quality of Life (QOL) will be assessed on Days 1 and 84 using the PQOL-12. Blood will be obtained on Days 28, 56 and 84 for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Subjects who prematurely discontinue from the study will complete Day 84 assessments at the time of discontinuation. Number of Subjects: Approximately 30 subjects will be enrolled.

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Duration of Subjects Participation/Duration of Study/Duration of Treatment: Subject participation will include a screening period of up to 21 days and an 84-day dosing period. Subjects will return to the clinic 30 days after their last dose of investigational product for a follow up visit. The duration of each subject’s participation is expected to be approximately 18 weeks. The study duration (first subject’s first visit through last subject’s last visit) is anticipated to last approximately 10 12 months. Drug Supply, Dosage, and Mode of Administration: Subjects will be randomized 4:1 to receive active SRT2104 at one of three dose levels (250, 500, or 1000 mg/day) or placebo. Investigational product will be supplied as 250 mg capsules of SRT2104 along with matching placebo capsules that will be administered orally once daily for 84 consecutive days. The subjects and the investigator will be blinded to active vs. placebo treatment assignment. Dosing with SRT2104 or placebo is to take place at approximately the same time every day, approximately 15 minutes following consumption of food. Subjects must wait at least 1 hour after dosing before consuming additional calories.

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Clinical Study Protocol SRT-2104-013 October 22 , 2010

CRITERIA FOR EVALUATION Safety and Tolerability: The incidence of AEs and clinically significant abnormal laboratory values will be recorded based upon investigator observation and subject reporting. Safety will be monitored by reports of AEs (at all visits after the first dose has been administered through 30 days after the last dose), vital sign measurements, physical examinations, laboratory parameters and electrocardiograms. Concomitant medications and AEs will be recorded at every visit. Additional visits will be permitted for safety follow-up as required. Pharmacokinetics: Blood will be obtained using a sparse sampling technique for PK and PD assessments. Pharmacodynamics: Biomarkers for psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose and may include, but may not be limited to, hsCRP and FGF21. Activity: The primary clinical activity endpoint is change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks. Skin biopsy samples will be evaluated for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells), and keratinocyte expression of K-16 and ICAM-l. Secondary clinical activity endpoints are PASI-50 and PASI-75 response rates, defined as the proportion of subjects who achieve a PASI-50 or PASI-75, mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. RT-PCR will be used to assess expression of specific genes at baseline and after 12 weeks which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPAR alpha, PPAR delta, and p53. In addition, global changes in gene expression may be assessed using gene micro-array techniques. Exploratory clinical activity endpoints include assessments of the subject’s sense of well-being (PHQ-9 and HADS) and health-related quality of life (PQOL-12).

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General Analysis Plan: The primary objectives are (1) to assess the effects of SRT2104 on clinical activity, based on the Krueger criteria, relative to a historical placebo response rate of 5% and (2) to assess safety and tolerability of SRT 2104. The first objective will be accomplished based on an exposure-response analysis. Previous studies have indicated that the pharmcokinetic exposure is relatively variable. For this reason, the active treatments will be combined and then dichotomized into low and high drug exposure groups. The cut-off point will likely be the midpoint of exposure but the selection of the final cut-off point will be dependent on the distribution of exposure. Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responders, defined as “good” or “excellent” Krueger improvement score, for each of the exposure groups and the historical null placebo response of 5%. No formal hypothesis testing will be performed. The second primary objective will be accomplished by review of individual subject data and descriptive summaries of the safety data. Safety displays will be summarized by treatment group (placebo, 250mg, 500mg, and 1000mg) Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity ( PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the differences between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. The clinical activity endpoints will also be summarized by treatment group, as a secondary analysis. All other pharmacodynamic endpoints will summarized by treatment group. Point estimates and corresponding 90% confidence intervals will be constructed for PK comparisons. A repeated measures analysis of covariance using baseline as a covariate will be performed on the PASI response. Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. Listing of individual subject plasma SRT2104 concentrations and blood sampling times will be prepared. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. Rationale for Number of Subjects: Sample size is based on feasibility. A sample size of 8 evaluable subjects per active treatment group and 6 evaluable placebo subjects in a merged placebo group will be assessed. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2).

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Clinical Study Protocol SRT-2104-013 October 22 , 2010

Schedule of Events

A full description of the study procedures and applicable visit windows is provided in Section 6. Study Period

Screening

Visit Number Study Day(s) Clinic Visit Informed Consent Medical History1 Viral Serology Photographs (total body surface area involvement) Randomization2 Investigational Product Dispensed Physical Examination3 (including height at Screening and weight at all subsequent visits) Vital Signs Chest X-Ray 12-lead ECG Clinical Chemistry/Hematology4 Urinalysis Pregnancy Test5 Tuberculosis Test

1 -21 to -6 X X X X

Adverse Event/Concomitant Medication Assessment PK Sampling6 PASI & PGA QOL assessments (PHQ-9, HADS, PQOL-127) Biomarkers Pharmacogenetics Sample9 Skin Biopsy (Immunohistochemistry and Gene Expression Profiling)

X X X X X X X X X

Dosing Period 2 18 X

3 14 X

4 28 X

5 42 X

6 56 X

7 70 X

8 8410 X

Follow Up 114 X

X

X

X

X

X X

X X

X X

X

X

X

X

X

X

X

X

X

X

X X X X

X X

X X X X

X X

X X X X

X X

X X X X

X X X

X

X

X

X

X

X

X

X X

X X X X X

X X X

X X X

X X X

X

X

X X

Footnotes: 1. Medical events occurring prior to the first dose will be collected on the medical history case report form (CRF). AEs occurring after the first dose will be recorded on the AE CRF. AEs and concomitant medications will be followed for 30 days after the last dose of study medication. 2. Subjects will be randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of investigational product. 3. A complete physical examination (PE) will be conducted at the Screening Visit. A symptom-driven, directed PE will be performed as needed at all other timepoints. 4. See Section 6.3 for a complete listing of safety lab parameters to be measured/analyzed. Lipid profiling and coagulation studies will be performed in fasting samples at Screening, and on Days 1, 42 and 84 only. 5. Serum pregnancy test to be performed at Screening; urine screen for pregnancy at all other timepoints. 6. PK sampling will be performed according to the schedule described in Section 6.2. 7. PQOL-12 to be performed on Days 1 and 84 only 8. The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1. 9. See Appendix 2 for a description of the pharmacogenetic assessment. 10. Subjects withdrawing from the study prior to the study assessments on Day 84 will undergo all Day 84 assessments and return for a follow-up visit 30 days following the last dose of investigational product.

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Clinical Study Protocol SRT-2104-013 October 22, 2010

Schematic Diagram of Study Design

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TABLE OF CONTENTS 1

PROTOCOL SUMMARY 1.1 Schedule of Events 1.2 Schematic Diagram of Study Design

2 7 8

LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS

12

2

INTRODUCTION AND STUDY RATIONALE 2.1 Disease Background 2.2 Scientific Background 2.3 SRT2104 Non-Clinical Experience 2.4 SRT2104 Clinical Experience

15 15 15 16 18

3

STUDY RATIONALE

22

4

STUDY OBJECTIVES 4.1 Primary 4.2 Secondary 4.3 Exploratory

23 23 23 23

5

INVESTIGATIONAL PLAN 5.1 Overall Study Design 5.2 Selection of Study Population 5.2.1 Number of Subjects 5.2.2 Replacement of Subjects 5.2.3 Inclusion Criteria 5.2.4 Exclusion Criteria 5.2.5 Definition of Treatment Failure 5.2.6 Removal of Subjects from the Study 5.3 Selection of Doses in the Study 5.4 Identity of Investigational Product 5.5 Treatments to be Administered 5.6 Method of Assigning Subjects to Treatment Groups 5.7 Individuals Who Will Be Unblinded to Treatment Assignments 5.8 Unblinding Procedures 5.9 Duration of Treatment 5.10 Internal Safety Review Committee 5.11 Safety Review and Dose Escalation or Cessation 5.11.1 Criteria for discontinuing dosing/dose escalation 5.12 Prior Treatments 5.13 Proscribed Medications 5.14 Permitted Medications 5.15 Contraceptive Use 5.16 Treatment Compliance 5.17 Missed Doses of Investigational Product 5.18 Schedule of Events

24 24 24 24 24 24 25 26 26 27 28 28 29 29 29 30 30 30 30 31 31 31 32 33 33 33

6

STUDY PROCEDURES 6.1 Study Procedures

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Clinical Study Protocol SRT-2104-013 October 22, 2010

6.1.1 Visit 1 (Screening) 6.1.2 Visit 2 6.1.3 Visits 3, 5 and 7 6.1.4 Visits 4 and 6 6.1.5 Visit 8 6.1.6 Follow-Up Procedures Pharmacokinetic Sampling Laboratory Assessments Skin Biopsy Evaluation and Scoring Appropriateness of Measurements Data Quality Assurance

37 37 38 38 38 38 39 39 41 41 42

7

ADVERSE EVENTS 7.1 Definitions 7.1.1 Adverse Event Definition 7.1.2 Serious Adverse Event Definition 7.1.3 Suspected Unexpected Serious Adverse Reaction Definition 7.1.4 QTc Withdrawal Criteria 7.1.5 Liver Chemistry Stopping Rules and Follow-up 7.2 Procedures for Recording and Reporting AEs and SAEs 7.3 Monitoring of Adverse Events and Period of Observation 7.4 Pregnancy Reporting

43 43 43 43 45 45 45 49 52 53

8

STATISTICAL PROCEDURES 8.1 Randomization and Stratification 8.2 Sample Size 8.3 Populations for Analysis 8.4 Procedures for Handling Missing, Unused, and Spurious Data 8.5 Statistical Methods 8.5.1 Subject Disposition 8.5.2 Subjects Baseline Characteristics 8.5.3 Exposure to Investigational Product 8.5.4 Safety Analysis 8.5.5 Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 8.5.6 Activity Analysis 8.6 Procedures for Reporting Deviations to Original Statistical Analysis Plan

54 54 54 55 56 56 56 57 57 57 58 59 60

9

ADMINISTRATIVE REQUIREMENTS 9.1 Good Clinical Practice 9.2 Ethical Considerations 9.3 Subject Information and Informed Consent 9.4 Subject Confidentiality 9.5 Protocol Compliance 9.6 Study Monitoring 9.7 On-site Audits 9.8 Case Report Form Completion 9.9 Drug Accountability 9.10 Premature Closure of the Study

61 61 61 61 61 62 62 62 63 63 64

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Record Retention Sample Disposition Liability and Insurance

64 64 65

10

USE OF INFORMATION

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11

INVESTIGATOR AGREEMENT

67

12

REFERENCES

68

13

Appendix 1 List of Permitted Rescue Medications

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14

Appendix 2 Pharmacogenetic Research

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15

Appendix 3 Summary of Changes to Amendment 1

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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS AE

Adverse Event

ALT

Alanine Aminotransferase

ANCOVA

Analyses of Covariance

AUC

Area Under the Plasma Concentration Time Curve

◦

C

Degrees Celsius

CFR

Code of Federal Regulations

CL

Clearance

Cmax

Maximum (plasma) Concentration

CR

Calorie Restriction

CRP

C-reactive Protein

CRF

Case Report Form

CRO

Contract Research Organization

CTC

Common Toxicity Criteria

DIO

Diet-Induced Obesity

DNA

Deoxyribonucleic Acid

DSS

Dextran Sulphate Sodium

EAE

Experimental Autoimmune Encephalitis

ECG

Electrocardiogram

FAS

Full Analysis Set

FDA

Food and Drug Administration (U.S.)

FGF21

Fibroblast Growth Factor 21

FOXO

Forkhead Transcription Factors

GCP

Good Clinical Practice

GSK

GlaxoSmithKline

HADS

Hospital Anxiety and Depression Scale

HCV

Hepatitis C Virus

HIV

Human Immunodeficiency Virus

hr

Hour

hsCRP

High sensitivity C-reactive protein

ICH

International Conference on Harmonization

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IEC

Independent Ethics Committee

IL

Interleukin

IRB

Institutional Review Board

ISRC

Internal Safety Review Committee

IV

Intravenous

Km

Michaelis-Menten Constant

LOCF

Last Observation Carried Forward

LPS

Lipopolysaccharide

MedDRA

Medical Dictionary for Regulatory Activities

NCI

National Cancer Institute

NCoR

Nuclear Receptor Co-repressor

NFκβ

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells

NOAEL

No Observable Adverse Effect Level

ob/ob

Genetically Obese Mouse Model, Lepob/ob

PASI

Psoriasis Area and Severity Index

PD

Pharmacodynamics

PGA

Physician’s Global Assessment

PGC-1α

PPAR Gamma Coactivator-1α

PGx

Pharmacogenetics

PHQ-9

Patient Health Questionnaire

PINP

Procollagen-I-N-Terminal Propeptide

PK

Pharmacokinetics

PPS

Per-Protocol Analysis Set

PQOL-12

Koo-Menter Psoriasis Quality of Life Instrument

PUVA

Psoralen and Ultraviolet Light A

QOL

Quality of Life

SAE

Serious Adverse Event

SAF

Safety Analysis Set

SIRT

Silent Information Regulator Transcript; Sirtuin

SIRT1

Sirtuin Enzyme 1

SRT2104

A SIRT1 Activator

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SD

Standard Deviation

SUSAR

Suspected Unexpected Serious Adverse Reaction

t

Time

Tmax

Time of Maximum Concentration

t1/2

Terminal Elimination Half –Life

TGF

Transforming Growth Factor

TMF

Trial Master File

TNF

Tumor Necrosing Factor

ULN

Upper Limit of Normal

UVB

Ultraviolet light B

V

Volume of distribution

WBC

White Blood Cell

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Clinical Study Protocol SRT-2104-013 October 22, 2010

INTRODUCTION AND STUDY RATIONALE Disease Background

Psoriasis is a chronic inflammatory skin disorder that impacts approximately 2-3% of the world’s population. [Schon, 2005; Koo J, 1996]. It is typically characterized by sharply demarcated, raised, erythematous plaques covered by silvery white scales. Psoriasis impacts both the physical and emotional well-being of the patient. Its effect on quality of life is comparable to that of other chronic medical disorders [Rapp, 1999]. Significant unmet medical need remains for safe, effective, and convenient treatments. Psoriasis is a complex, immune-mediated disease in which T-lymphocytes, neutrophils, and dendritic cells play a major role. Numerous cytokines are over-expressed in psoriatic skin lesions including TNF-α, IL-17, and IL-23 [Krueger JG, 2007]. Several growth factors are also over-expressed including transforming growth factor type alpha (TGF-α). The result is an epidermis characterized by hyperproliferation, inflammatory cell infiltrates, and vascular changes. Current treatments are primarily geared at reducing the excessive cellular proliferation and/or blocking the inflammatory response. 2.2

Scientific Background

One novel therapeutic approach to treating psoriasis and other diseases of inflammation has come from the study of aging and calorie restriction (CR). CR is a dietary regimen in which 30%-40% fewer calories than those required to maintain ideal body weight are consumed. It has been demonstrated that CR extends lifespan in lower organisms and mammals and improves a number of metabolic and inflammatory parameters [Heilbronn, 2003; Roth, 2001, Fontana, 2009]. As such the molecular components of the aging pathways downstream of CR may provide relevant intervention points for the development of therapeutic drugs to treat inflammatory and metabolic disease [Weindruch, 2001; Ingram, 2006]. Sirtuin Enzyme 1 (SIRT1) is a member of the sirtuin family of NAD+-dependent deacetylases [Frye, 1999; Frye, 2000; Imai, 2000]. There are seven human sirtuins (SIRT1-7) with different subcellular compartmentalization and downstream targets [Blander, 2004]. SIRT1 is predominantly nuclear and is upregulated in tissues of calorically restricted animals [Cohen, 2004]. The precise biological pathway whereby SIRT1 promotes the beneficial effects of CR is an area of intense study, but it appears that the ability of SIRT1 to interact and deacetylate PGC-1α is an important component [Rodgers, 2005]. PGC1α controls energy metabolism and muscle function with an inhibitory role in pro-inflammatory cytokine production [Handschin, 2008] and has been implicated as a key mediator of the effects of CR [Corton, SRT-2104-013 Version 3.0

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2005]. Additionally, a number of other cellular substrates for SIRT1 have been identified including NCoR, p300, NFκβ, FOXO, and p53 [Bouras, 2005; Brunet, 2004; Luo, 2001; Motta, 2004; Nemoto, 2005; Picard, 2004; Rodgers, 2005; van der Horst, 2004; Vaziri, 2001; Yeung, 2004].

For example,

SIRT1 has been shown to physically interact with and deacetylate the RelA/p65 subunit of NFκβ, and thereby inhibit NFκβ-induced transcription [Yeung, 2004; Sirtris unpublished data] which is involved in up regulation of proinflammatory cytokines such as TNF-α and IL-6. Furthermore, SIRT1 activators have been shown to inhibit TNF-α secretion in both in vitro [Smith 2009; Yoshizaki 2009] and in vivo (Sirtris unpublished data) LPS-induced cellular and animal models. Through modulation of the activities of these proteins, SIRT1 regulates inflammation, cellular differentiation and survival, mitochondrial biogenesis, and glucose metabolism [Cohen, 2004; Heilbronn, 2005; Nisoli, 2005; Picard, 2004]. SRT2104 is a potent and selective small molecule activator of SIRT1. SRT2104 was identified as a SIRT1 activator in a high throughput screen of a diverse library of 290,000 compounds [Milne, 2007]. SIRT1 activity is increased by SRT2104 due to a lowering of the Km for its acetylated protein substrate, resulting in an approximately two-fold increase in activity. SRT2104 is selective for SIRT1 activation over the two most closely related sirtuin homologs, SIRT2 and SIRT3. 2.3

SRT2104 Non-Clinical Experience

The effect of once daily oral administration of SRT2104 on fasting blood glucose and fed insulin levels, body weight, triglyceride and plasma lipid levels was evaluated in a number of animal models of diabetes and obesity (DIO mice and ob/ob mice). In general, SRT2104 lowered fasting blood glucose and fed insulin and enhanced the response to a glucose tolerance test. No effect on body weight was observed with SRT2104. Activity in the diabetes models was seen following daily doses of 100-3000 mg/kg/day of SRT2104. SRT2104 has also shown efficacy following once daily oral administration in a number of in vivo inflammation models including LPS-induced TNF-α production, dextran sulphate sodium (DSS) and trinitrobenzesulphonic acid-induced colitis, cecal ligation and puncture-induced sepsis as well as in experimental autoimmune encephalomyelitis (EAE). The efficacy of SRT2104 in these inflammation studies was seen at doses of 10 – 300 mg/kg/day given orally once daily for five to twenty eight days depending on the model studied. In the DSS and EAE models SRT2104 was given therapeutically, that is after the diseases had been induced in the mice. SRT2104 was tested in vitro in counter-receptor binding studies and showed no significant inhibitory activity against 39 common receptors. SRT2104 was not an inhibitor of five major cytochrome P450 SRT-2104-013 Version 3.0

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isoforms tested (CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), and is not a significant inducer of cytochrome P450 isoforms CYP1A and CYP3A4 at the concentrations tested. The non-clinical safety of SRT2104 was investigated in the Ames and mouse micronucleus genetic toxicology models, and in safety pharmacology studies in rats and dogs. SRT2104 was not genotoxic at the doses investigated. No central nervous system (CNS), cardiovascular system (CVS), or pulmonary effects were observed in the safety pharmacology studies at the doses tested (300-2000 mg/kg). SRT2104 has been dosed up to 2000 mg/kg/day in two species (rat and dog) for 28 days. The compound was well tolerated at all doses in both species. Toxicity studies showed a no observable adverse effect level (NOAEL) of 2000 mg/kg/day in male rats and 1000 mg/kg/day in female rats and 1000 mg/kg/day in male and female dogs. In the male rat, the NOAEL was 2000 mg/kg/day, the highest dose tested. In the female rat, the NOAEL was considered to be 1000 mg/kg/day, due to a vacuolation of pancreatic acinar cells in 3 of 10 animals on Day 29 which was not seen after 4 weeks in the recovery animals. The physiological significance of this finding is unclear. Furthermore, this effect was not seen in the rat 90 day study or in the 28 or 90 day dog studies. The NOAEL in the female dog was determined to be 1000 mg/kg/day due to a mild increase in indirect bilirubin in the 2000 mg/kg/day group and microscopic bilirubin accumulation in the liver of one female dog at 2000 mg/kg/day. No adverse findings were seen in male dogs. SRT2104 has also been dosed in two species (rat and dog) for 90 days. In the 90 day studies no toxicologically relevant adverse events were seen at the highest doses tested in rats (2,000 mg/kg/day males, 1,000 mg/kg/day females) and in dogs (300 mg/kg/day in fed males and females). In the 90 day rat study there were reductions in mean body weights primarily due to a reduction in food consumption during the first week of the study. There were reversible increases in bilirubin in both male and female rats with no corresponding histopathological changes in the liver. Minor histopathology findings of increased acinar cell apoptosis in the pancreas and accumulation of amorphous material in the basal pits of the stomach were judged to be non-adverse since neither were associated with overt degenerative changes and/or were also seen in control rats. In the 90 day dog study there were mild, reversible increases in serum total/direct/indirect bilirubin in males and females at 300 mg/kg/day and reversible mild increases in serum alkaline phosphatase (males) or cholesterol (females) at 300 mg/kg/day. The increased serum bilirubin levels corresponded with pigment accumulation in the canaliculi of the liver on Day 91 for the 100 and 300 mg/kg/day males and SRT-2104-013 Version 3.0

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females. However, the pigment accumulation and increased serum bilirubin, suggestive of impaired excretion or stasis, were not associated with any microscopic effect (degeneration or necrosis) on bile duct epithelium or hepatocytes. Furthermore, the clinical pathology results were reversible and well within the normalized historical control ranges. The findings seen in the 90 day studies reflect what was seen in the 28 day studies with an increase in bilirubin being the most notable finding in both the dog and rat studies. The stasis finding at 2000 mg/kg/day in female dogs was judged to be adverse in the 28 day study but not adverse in the 90 day study due to the observation that there was no progression from 28 to 90 days and no evidence of necrosis, inflammation or any damage associated with the stasis. From a safety perspective, the 1000 mg/day dose, the highest dose to be tested in this SRT-2104-013 protocol, is supported by the pre-clinical safety toxicology package and by the cumulative human safety experience gathered to date. From the pre-clinical 90-day toxicology studies, the safety intervals are 1.33.6 based on Cmax and 1.9-6.8 based on AUC at the NOAELs. There were no adverse findings at the highest doses tested in the 90-day studies so these safety intervals may be an under-estimate of the true values. 2.4

SRT2104 Clinical Experience

As of December 31 2009, approximately 85 subjects have been dosed in completed clinical trials with SRT2104. Based on currently available clinical data, the investigational product appeared well tolerated and no safety concerns have been identified with the administration of SRT2104 in healthy volunteers at doses up to 3.0 g per day for 7 consecutive days in the fasted state and up to 2.0 g per day for 7 days in the fed state. Completed and Reported Trials The first administration of SRT2104 to humans was performed as part of clinical study SRT-2104-001, a randomized, placebo-controlled, single-blind, multiple-dose, dose-escalation study (EudraCT Number: 2007-007598-22). A total of 28 healthy male volunteers received SRT2104 in the form of a liquid suspension as both a single dose and during a separate multiple dose period (once per day for 7 days) at the following dose levels: 30, 100, 250, 500, 1000, 2000, and 3000 mg/day (4 volunteers at each dose level). SRT2104 was well-tolerated following both the single- and multiple-dose periods at all dose levels investigated and all adverse events (AEs) recorded were either mild or moderate in severity and were predominantly gastrointestinal in nature. Treatment-emergent AEs observed in more than one subject were flatulence, headache, nausea, and diarrhea. All AEs were short in duration and resolved SRT-2104-013 Version 3.0

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without sequelae. No dose-related AEs were identified. There were no serious adverse events. The pharmacokinetic parameters AUC(0-t) and Cmax exhibited dose proportionality over the dose range of 30 to 1000 mg/day in healthy volunteers. At doses greater than 1000 mg /day increases in AUC(0-t) and Cmax were less than proportional to the increase in dose. The terminal elimination half-life (t½) ranged from 8 to 24 hours and was not affected by dose. There was no evidence to suggest saturation of any elimination pathways over the dose range investigated (30 to 3000 mg /day). A second administration of SRT2104 to human volunteers was performed as part of a single-center, combined intravenous (IV) and oral dosing study to evaluate the PK and absolute bioavailability of SRT2104 (Clinical Protocol SRT-2104-002; EudraCT Number 2008-006283-10). SRT2104 was administered as a single dose of 250 mg administered as an oral suspension and an IV microdose of 100 µg 14C-SRT2104 to eight healthy male subjects. SRT2104 was well tolerated by all subjects. No serious adverse events (SAEs) were recorded. The AEs assessed as related to SRT2104 were aching at infusion site and paresthesia. All AEs were of mild severity and resolved without sequelae. The maximal drug concentrations generally occurred at the end of the 15-minute IV infusion. The terminal elimination half-life for total radioactivity after intravenous dosing was similar to that for the parent drug. The mean t½ for 14C-SRT2104 was 23.7 ± 9.37 hours following a 15-minute IV infusion of approximately 100 μg 14

C-SRT2104 and mean t½ for SRT2104 was 25.5 ± 6.45 hours following oral administration of 250 mg

SRT2104. Absolute bioavailability of SRT2104, when dosed as a 250 mg oral suspension in a fasted state, was approximately 14%. A third clinical study was conducted to assess the effect of food and gender on the PK of SRT2104 (Clinical Protocol SRT-2104-004; EudraCT Number: 2008-007364-41). This Phase I, randomized, openlabel study enrolled 10 male and 10 female healthy volunteers to characterize the PK profile of a single 500 mg dose of SRT2104 when administered as an oral suspension and as a capsule formulation in both the fed and fasted states. SRT2104 was well tolerated at the dose level tested. The absorption of SRT2104 administered as capsules and oral suspension was significantly increased when administered to subjects in the fed versus fasted state. There was a very slight decrease in absorption when SRT2104 was administered as a capsule. No gender effects were noted. Clinical Protocol SRT-2104-009 (EudraCT Number: 2009-010829-39) was a prospective, randomized study to assess the safety and PK of SRT2104 in healthy male volunteers. Ten male subjects were randomized to receive 2000 mg SRT2104 or placebo capsules under fed conditions on eight occasions SRT-2104-013 Version 3.0

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during the study, once as a single dose and once per day for seven consecutive days. SRT2104 was considered to be safe and well tolerated at the dose levels tested. The mean AUC(0-τ) following once daily dosing for seven days was found to be increased when compared with the mean AUC(0-∞) following single dose administration, providing evidence for accumulation of SRT2104 following once daily dosing at 2000 mg for seven days. Evaluation of the pre-dose plasma SRT2104 concentrations during the multiple dose period suggested that steady state had likely not been achieved by all subjects at the end of the 7-day dosing interval. However, review of the individual subject plasma concentrations over the multiple dose period indicated that some subjects appeared to have reached steady state plasma SRT2104 concentrations within seven days of daily dosing. Following 7 days of dosing of 2 g SRT2104 to fed volunteers the mean Cmax was 1,874 ng/ml and the mean AUC was 13,997 ng.h/mL. The safety intervals from the 90 day study are 0.50-1.37 ng/mL based on Cmax and 0.93-3.40 ng.hr/mL based on AUC. It should be pointed out that there were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals are likely to be an under-estimate of the true values. Clinical Protocol SRT-2104-008 (EudraCT Number 2009-010620-25) was conducted to assess the pharmacodynamic effect of single oral doses of SRT2104 and prednisolone as measured by levels of ex vivo LPS-induced TNF-α production in whole blood of healthy adult subjects. This was a prospective, single center, non-therapeutic, randomized, double-blind study. Twenty male subjects were enrolled in the study and randomized to receive single doses of SRT2104 (250, 500, 1000, and 2000 mg) and/or placebo on 5 separate occasions followed by a single 30 mg dose of prednisolone on the sixth dosing occasion. Although Cmax increased with SRT2104 dose, the relationship between dose and Cmax was less than proportional. Median Tmax did not appear to vary significantly according to dose. Ongoing Trials Clinical Protocol SRT-2104-005 (EudraCT Number: 2009-010720-26) is a randomized, placebocontrolled, double-blind, multiple-dose, inpatient/outpatient study to assess the safety and PK of SRT2104 in male and female subjects with type 2 diabetes on an existing, stable, background metformin therapy. Approximately 225 subjects will be enrolled in this study. Subjects will be evenly randomized to receive SRT2104 or placebo in one of five cohorts: placebo (A); 250 mg/day SRT2104 (B); 500 mg/day SRT2104 (C); 1000 mg/day SRT2104 (D); or 2000 mg/day SRT2104 (E). Subjects will be dosed once a day for 28 consecutive days, approximately 15 minutes following the consumption of a standardized SRT-2104-013 Version 3.0

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meal. Subjects will remain on a fixed dose of investigational product for all dosing days in the study. As of December 31, 2009, 51 subjects had been randomized into the study, 17 subjects had completed the study, 2 subjects had withdrawn (due to voluntary consent withdrawal), and 13 subjects had experienced treatment-emergent adverse events. A review of blinded safety data showed the most commonly reported adverse events were dyspepsia and hyperglycemia, each of which was reported twice and by different subjects. Two additional studies of SRT2104 are currently ongoing. Clinical Protocol SRT-2104-007 (EudraCT Number 2009-011918-21) is a randomized, placebo-controlled, double-blind, study to assess the safety, tolerability and pharmacokinetics of oral SRT2104 capsules administered to healthy elderly subjects for 28 days. Twenty-four subjects will be randomized to receive one of the following three treatments: SRT2104 500 mg/day, SRT2104 2000 mg/day or placebo. This study is currently enrolling as is Clinical Protocol SRT-2104-010 (EudraCT Number 2009-011918-21). Protocol SRT-2104-010 is being conducted to determine if single or multiple doses of SRT2104 attenuate the inflammatory response in normal healthy male subjects after exposure to low-dose endotoxin. Twenty-four healthy male subjects will be randomized to receive single or multiple doses of 2000 mg of SRT2104 and/or placebo for 7 days. Study endpoints include safety, PK and clinical signs and symptoms and laboratory parameters for inflammation.

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STUDY RATIONALE

A direct role for SIRT1 in promoting keratinocyte differentiation was elucidated [Blander, 2004] and is supportive of earlier findings that resveratrol, a natural plant-derived polyphenol that has been shown to activate SIRT1, inhibited the proliferation of human keratinocytes in vitro [Holian, 2001] and suppressed angiogenesis [Brakenhielm, 2001]. Taken together with the finding that SIRT1 activators are potent inhibitors of cytokine production, including TNF-α [Smith, 2009], the therapeutic potential for SIRT1 activators in the treatment of psoriasis will be explored as part of this clinical protocol. We hypothesize that SIRT1 activators may demonstrate anti-psoriatic action by promoting keratinocyte differentiation, reducing inflammation and/or inhibiting angiogenesis.

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4 4.1

Clinical Study Protocol SRT-2104-013 October 22, 2010

STUDY OBJECTIVES Primary 1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis

4.2

Secondary 1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician’s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg, and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaquetype psoriasis

4.3

Exploratory 1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of well-being in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the Koo-Menter Psoriasis Instrument, PQOL-12.

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INVESTIGATIONAL PLAN

5.1 Overall Study Design Three cohorts of ten subjects each will be enrolled. Subjects within each cohort will be randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. Each cohort of subjects will be dosed sequentially. Dosing in the second and third cohort will not commence until subjects in the previous cohort have completed at least 28 days of dosing, and a review of safety parameters (physical examination findings, vital signs, electrocardiograms, adverse events and laboratory values) has been completed by an Internal Safety Review Committee (ISRC). Subjects will receive either SRT2104 or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety will be assessed on an ongoing basis. The study consists of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Potential subjects will sign the IRB-approved informed consent form at the Screening Visit, and will undergo screening assessments to verify eligibility for the study. If eligible and willing to participate, subjects will return to the clinic within 21 days of the Screening Visit to participate in the dosing phase of the study. For the dosing phase of the study, starting on Day 1, subjects will be randomized on approximately Day -6 to receive either 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo once daily for 84 consecutive days. PK sampling will occur on Days 28, 56 and 84. 5.2 5.2.1

Selection of Study Population Number of Subjects

A sample size of 8 evaluable subjects per active treatment group and 6 evaluable subjects in the merged placebo group is based on feasibility. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2). 5.2.2

Replacement of Subjects

Subjects who withdraw from the study prior to completing 8 weeks of treatment may be replaced. 5.2.3

Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following Screening and baseline PASI criteria are met: 1. Able and willing to provide written informed consent to participate in the study SRT-2104-013 Version 3.0

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2. Be male or female aged 18 to 80 years (inclusive) 3. Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving >10% of body surface area 4. Have a baseline PASI of >10 5. Be a candidate for systemic psoriasis therapy, in the opinion of the investigator 6. If a female subject of child-bearing potential, be willing to use reliable contraception (see Section 5.15) for the duration of the study, through the 30 day safety follow up visit (a female of child-bearing potential is defined as any female, regardless of her age with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. Females with oligomenorrhea or who are perimenopausal, and young females who have begun to menstruate are considered to be of child-bearing potential) 7. Be willing and able to comply with the protocol for the duration of the study. 5.2.4

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria are met at Screening: 1. Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit 2. Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 3. Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study 4. Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however, the administration of proton pump inhibitors during the study dosing period is prohibited 5. Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit 6. Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 7. Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 8. Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation 9. Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit 10. Has a positive test for HIV antibody

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11. Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial 12. Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: •

QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period)

•

QTcB ≥480 msec in subjects with Bundle Branch Block

13. Has renal or liver impairment, defined as: •

Serum creatinine level of ≥ 1.4 mg/dL for females and ≥ 1.5 mg/dL for males

•

AST and ALT ≥ 2xULN or

•

Alkaline phosphatase and bilirubin > 1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)

14. Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) 15. Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 16. Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine 17. History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation 18. Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. 5.2.5

Definition of Treatment Failure

A subject who experiences a treatment failure is anyone who demonstrates a score of “no improvement” based on the Krueger criteria defined in Section 6.4, or any subject who is prematurely withdrawn from the study due to lack of efficacy as judged by the investigator. 5.2.6

Removal of Subjects from the Study

Subjects will be informed that they have the right to withdraw from the study at any time for any reason, without prejudice to their medical care. The investigator can withdraw subjects from the study for any of the following reasons: •

QT interval changes as defined in Section 7.1.4

•

Liver event (see Section 7.1.5)

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•

Treatment failure

•

Subject request

•

Failure to return for follow-up

•

Administrative reasons

•

General non-compliance with the protocol

•

Positive pregnancy test result

The investigator also reserves the right to withdraw subjects in the interest of subject safety and welfare. If a subject is withdrawn from the study, the subject must complete Day 84 assessments at the time of discontinuation and return to the clinic approximately 30 days after the last dose to conduct a safety and activity (PASI and PGA) evaluation. The sponsor reserves the right to terminate the study in the interest of subject safety as defined in Section 5.11. The sponsor also reserves the right to terminate the study at any time for administrative reasons. 5.3

Selection of Doses in the Study

Three different doses of SRT2104 were selected for study in this protocol, 250 mg/day, 500 mg/day, and 1000 mg/day. These doses should be distinct enough to give different systemic exposures. Comparing three different doses may allow establishment of a pharmacokinetic/pharmacodynamic relationship for SRT2104 and will assist in understanding whether a dose effect exists with regard to the psoriatic efficacy parameters being tested. This will provide valuable information in choosing doses for future trials. In prior human clinical trials, subjects have received doses of SRT2104 as high as 3000 mg/day with good tolerability. Pharmacokinetic data demonstrated dose-related increases in exposure up to 2000 mg/day, but not beyond. No in vivo pharmacodynamic parameters were collected in the normal volunteer studies, thus no human pharmacokinetic/pharmacodynamic relationship has been established to date. In preclinical testing, SRT2104 has been shown to positively impact a variety of animal models, including those of both metabolic and inflammatory disorders, at daily doses ranging from 10 - 300 mg/kg/day. The most consistent doses associated with good efficacy results in these models range from 100 - 200 mg/kg/day. Adjusting for body surface area between human and mouse, these equilibrate to potential pharmacologically active doses in man of 500 mg to 1000 mg, respectively.

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From a safety perspective, the 1000 mg/day dose, the highest dose to be tested, is supported by the preclinical safety toxicology package described in Section 2.3 and by the cumulative human safety experience gathered to date. From the pre-clinical 90 day toxicology studies, the safety intervals are 1.33.6 based on Cmax and 1.9-6.8 based on AUC. There were no adverse findings at the highest doses tested in the 90 day studies, so these safety intervals may be an under-estimate of the true values. The most notable finding in the rat and dog toxicity studies has been a small, reversible increase in serum bilirubin. Bilirubin levels will be closely monitored in the proposed clinical trial. The entry criteria are written to exclude subjects with elevated bilirubin levels. Subjects developing elevated bilirubin values that meet the criteria for stopping investigational product will be withdrawn from the study (see Section 7.1.5, Liver Chemistry Stopping Rules and Follow-Up). In the completed and ongoing clinical trials with SRT2104, there have been no serious adverse events reported to date. In addition, no specific safety signals have been identified at this time. 5.4

Identity of Investigational Product

SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule, packaged as one, two or four capsules in dosing bottles. For the matching placebo product, the SRT2104 drug substance will be replaced by microcrystalline cellulose (Avicel® PH 105) to match the SRT2104 investigational product. All subjects will be provided with one dosing bottle per day that contains one, two or four capsules for oral ingestion as described in Section 5.5. Prior to being dispensed, the investigational product should be stored at 15 – 25 oC and protected from light. Subjects will be instructed to store investigational product at room temperature away from direct light. 5.5

Treatments to be Administered

Investigational product will be dispensed only to eligible subjects under the supervision of the investigator or identified sub-investigator(s). A trained investigative site member will administer the investigational product to subjects when they are in the clinic, where applicable. As shown in study SRT-2104-004, the administration of SRT2104 with food increased exposure levels and reduced variability in exposure levels in humans. For this reason, subjects participating in this study SRT-2104-013 Version 3.0

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are required to take SRT2104 approximately 15 minutes following the consumption of food. Investigational product should be administered with approximately 250 to 500 cc of water at approximately the same time every dosing day. Subjects should refrain from eating or drinking anything other than water for 1 hour after dosing. Dietary recommendations for the meal that precedes dosing will be included in the study reference manual and provided to the study subjects by the clinical site staff. 5.6

Method of Assigning Subjects to Treatment Groups

Subjects will be randomized to receive 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo in a 4:1 fashion. Treatments will be administered as follows for the duration of the study:

5.7

•

Arm 1: 250 mg/day administered as one 250 mg capsule (active or placebo)

•

Arm 2: 500 mg/day administered as two 250 mg capsules (active or placebo)

•

Arm 3: 1000 mg/day administered as four 250 mg capsules (active or placebo)

Individuals Who Will Be Unblinded to Treatment Assignments

Designated individuals of Sirtris’ Pharmaceutics Research Department will be unblinded for purposes of assigning the treatment assignments according to a randomization schema that will be retained in a secure location with limited access. In addition, selected personnel at the bioanalytical laboratory will be unblinded to treatment assignments for purposes of data analysis. Members of the ISRC will be unblinded for purposes of conducting the cohort safety assessments. 5.8

Unblinding Procedures

Procedures for obtaining unblinded treatment information will be provided to the clinical sites in the study operations manual. If it is medically imperative to know the treatment that a subject is receiving, the investigator shall, prior to requesting the treatment information, make every attempt to contact the medical monitor for the study to discuss the rationale for breaking the blind. In situations where the investigator is unable to contact the medical monitor as described above (e.g., a medical emergency on the part of the subject), the investigator must contact the medical monitor within 24 hours after the code break to inform him/her of the rationale for the code break.

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The investigator must provide a written narrative describing the event(s) that led to the code break to the medical monitor within 48 hours following the code break. In addition, the investigator must record the date of the code break and the reasons for breaking the blind in the CRF and in the subject’s medical records. 5.9

Duration of Treatment

All subjects enrolled in the study will receive SRT2104 or placebo once daily for up to 84 days during the study period. 5.10 Internal Safety Review Committee An ISRC will be utilized during the conduct of this study to assess safety and advise on dose escalation as described in Section 5.11. The membership of the ISRC and the plan for the safety data review are described in detail in the ISRC charter. A copy of the ISRC charter is available upon request. 5.11 Safety Review and Dose Escalation or Cessation Subject safety will be monitored on an ongoing basis. Dose escalation will be dependent upon the review of the unblinded safety data by the ISRC. All safety data generated for all subjects in the 250 mg and 500 mg cohorts who have completed at least 28 days of dosing will be reviewed by the ISRC. In the event of clinically significant adverse events deemed to be of sufficient severity to pause dosing (refer to criteria in Section 5.11.1), a full analysis of all safety data will be conducted before continuing with a given dose or with dose escalation. When the last subject in the applicable cohort has completed 28 days of dosing, the data for each subject will be manually entered into an electronic data capture system. The laboratory data will be transferred electronically into the database. The safety data will then be listed and presented to the ISRC for review. If the safety data is acceptable, any subjects still active in the current cohort will continue dosing, and the ISRC will authorize the initiation of dosing to the next cohort of subjects at the higher dose level. This will be repeated until the first 2 cohorts have completed at least 28 days of dosing. 5.11.1 Criteria for discontinuing dosing/dose escalation In the event that there are SAEs or severe AEs reported in a cohort in which a possible relationship to investigational product cannot be fully excluded, one of the following procedures will be applied: •

If one subject receiving SRT2104 in a cohort experiences a severe AE or an SAE, but the other subjects receiving that same dose are tolerant of that dose, the ISRC and Sponsor will determine

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whether the nature, severity, or the number of AEs permit continuing the dosing cohort, or if dosing and/or dose escalation will stop. •

If at least two subjects receiving SRT2104 in a cohort experience a severe AE or an SAE, but similar AEs are recorded for subjects on placebo, the ISRC and Sponsor will determine whether the nature, severity, or the number of AEs permit continuing the dosing cohort, or if dosing and/or dose escalation will stop.

•

If at least two subjects receiving SRT2104 in a cohort experience a severe AE or an SAE, and no severe AEs or SAEs are seen in placebo subjects, the dosing of new subjects and/or dose escalation will be halted pending full review by the GSK Global Safety Board.

5.12 Prior Treatments See the exclusion criteria (Section 5.2.4) for details regarding medications that are prohibited prior to entry into the study. 5.13 Proscribed Medications In addition to the restrictions described in Section 5.2.4, no other concomitant medications, dietary supplements, or herbal products are permitted for the duration of this trial except as described in Section 5.14. 5.14 Permitted Medications The following concomitant medications are permitted during the study: •

Non-prescription medications administered to treat an AE (e.g., acetaminophen, or non-steroidal anti-inflammatory agents taken for headache) NOTE: Over-the-counter antacids should not be taken within four hours of investigational product administration as they may interfere with the absorption of investigational product.

•

Topical Class 6 and/or 7 “rescue” corticosteroid treatment for psoriasis flares may be used, but use must be limited to the face, axillae and groin regions. See Section 13 for a list of permitted topical corticosteroid treatments. NOTE: Topical treatments should not be applied to other areas and in particular the plaque being assessed for efficacy, at or near the biopsy site

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•

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Any chronically prescribed non-psoriatic medication or herbal or dietary supplements administered at a stable dose for at least 6 weeks prior to enrollment with the exception of proton pump inhibitors. Potential subjects taking proton pump inhibitors at the time of the Screening Visit must be willing and able to discontinue these medications prior to taking investigational product and for the duration of the dosing period.

•

If the investigator desires to initiate therapy with a prescription medication (e.g., in the event of a newly diagnosed medical condition) during the dosing period, s/he should contact the Medical Monitor to discuss the new therapy prior to initiating it.

All medications administered during the study must be recorded in the subject’s CRF and in the source documents. 5.15 Contraceptive Use All female subjects of child-bearing potential must use an adequate form of contraception for the duration of the trial (from the Screening Visit through Day 114). Adequate forms of contraception are defined as: •

Abstinence

•

Oral Contraceptive, either combined or progestogen alone

•

Injectable progestogen

•

Implants of levonorgestrel

•

Estrogenic vaginal ring

•

Percutaneous contraceptive patches

•

Intrauterine device or intrauterine system

•

Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject (“documentation” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records)

•

Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

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5.16 Treatment Compliance Compliance with the investigational product dosing regimen will be assessed by trained study personnel. Subjects are required to bring all study medication (both empty and full containers) to study visits. Study medication containers will be reviewed by the site staff at each study visit to verify treatment compliance. Subjects who do not comply with the investigational product dosing regimen and who consequently miss either three consecutive doses or six individual doses of investigational product at any time point during the study may be withdrawn from the study. The Investigator must call the medical monitor to discuss the disposition of subjects who miss doses as described above. 5.17 Missed Doses of Investigational Product Subjects who inadvertently miss a dose of investigational product should skip that dose and recommence dosing on the next dosing day. 5.18 Schedule of Events A detailed visit-by-visit schedule of study procedures is provided in Section 1.1. Prior to engaging in any study procedure, each subject must sign and date an IRB-approved informed consent form.

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Clinical Study Protocol SRT-2104-013 October 22, 2010

STUDY PROCEDURES

The timepoints for all study procedures are reflected in the Schedule of Events (see Section 1.1). Visit windows are as follows: a plus/minus 4-day window will be applied to Visits 3 through 7; a 1-day plus/minus window will be applied to Visit 8 (Day 84).

The date of the visit will be recorded in the

CRF. Descriptions of the required study procedures are provided below: Physical Examination A complete physical examination should be performed at Screening. A symptom-driven, directed physical examination will be performed at other timepoints as defined in the schedule of events. Body systems that will be included are the following: general appearance, musculoskeletal, skin and mucosa, head and neck, lymphatic, respiratory, breast, gastrointestinal, cardiovascular, extremities, neurological, psychological, eyes, ears, nose and throat. Other body systems may be examined as needed, at the discretion of the investigator. Body Weight/Height Height is measured once at the Screening visit. Body weight will be measured at all other clinic visits. The clinical staff will be instructed to use calibrated scales to measure subjects’ body weight. Vital Signs Vital sign assessments will include measurements of resting pulse rate, blood pressure, respiration rate, and temperature. Electrocardiogram A 12-lead ECG will be performed in the rested state. The subject should be lying comfortably in the supine position with ECG leads on for at least 5 minutes prior to the ECG recording. The ECGs will be read locally by the clinical site. The ECG will include the assessment of PR (PQ), QRS, QT, and QTc intervals and heart rate. Identification of any conduction abnormalities will be recorded in the CRF. If a subject’s QTc intervals are prolonged, then the ECG should be done in triplicate with results reported as an average of the three ECGs. Copies of the ECG graphs and available reports will be collected by the study sponsor at the end of the study.

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Prolonged QTc intervals will be managed according to the QTc withdrawal criteria described in Section 7.1.4. Pregnancy Testing Serum pregnancy testing will be performed at the Screening Visit; urine pregnancy tests will be performed at all other visits where a pregnancy test is performed (see Section 1.1). Tuberculosis Test A tuberculosis test will be performed at the Screening Visit. A positive test result that cannot be attributed to a prior BCG inoculation will disqualify the subject. (see Section 5.2.4) Blood and Urine Sample Collection for Clinical Laboratory Testing Blood and urine samples will be collected as outlined in the Schedule of Events (see Section 1.1) for clinical laboratory safety testing, serology and biomarker analyses. See Section 6.3 for a complete listing of blood and urine parameters. Sample collection, processing, and shipping instructions for samples that will not be analyzed in the local laboratory at the clinical site will be provided in the study operations manual. Pharmacokinetics Approximately 20 mL of blood will be collected throughout the duration of the trial for PK analyses. Samples will be collected on Days 28, 56 and 84 using sparse sampling techniques as described in Section 6.2. Analyses may include metabolite profiling in a subset of samples. Collected samples will be transferred for analysis to Simbec Research Ltd., South Wales, United Kingdom. Additional sample collection, processing, and shipping instructions will be provided in the study operations manual. Pharmacodynamics Biomarkers of psoriatic disease activity and/or sirtuin pathway activation will be analyzed in blood samples collected for this purpose on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21. Pharmacogenetics

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A single blood sample will be obtained on Day 1 for potential pharmacogenetic analysis. The sample is labelled (or “coded”) with a study-specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers such as name or social security number. A full description of the pharmacogenetic assessment is included in Appendix 2. Subject participation in the pharmacogenetic portion of the study is voluntary and refusal to participate will not preclude participation in the clinical study. Photography Subjects who provide consent to photography procedures will have full body photographs taken from the neck down at timepoints outlined in the Schedule of Events (see Section 1.1).

Identifying marks such as

tattoos that might reveal the identity of a subject will be covered. Skin Biopsy A skin biopsy will be collected on Days 1 and 84 and transferred to the USA, for evaluation by a central reader. Biopsy tissue analyses are described in detail in Section 6.4. Skin biopsy collection, processing, and shipping instructions will be provided in the study operations manual. Quality of Life Assessments Some authors have noted that the psychosocial consequences of psoriasis can be as disruptive to the individual's life as the physical aspects of the illness itself [Fortune DG, 1997]. As part of an effort to explore whether improvements in the psychosocial consequences of psoriasis represent potential independent targets for treatment with SRT2104, the present study includes the three patient-reported outcome instruments described below. The Patient Health Questionnaire 9 (PHQ-9) is a 9-item, validated self-rating instrument that assesses eight core symptoms of depression in addition to an item that assesses functioning. The PHQ-9 has been validated as a diagnostic instrument for major depression, and it also provides an assessment of the severity of depression [Kroenke K, 2001]. The Hospital Anxiety and Depression Scale (HADS) is a 14-item, validated self-rating instrument of symptoms of anxiety and depression [Mykletun A, 2001]. It is intended to provide a cross-sectional assessment of anxiety and depressive symptoms whether or not subjects meet formal criteria for anxiety SRT-2104-013 Version 3.0

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and depressive disorders. As such, the HADS could provide a signal of efficacy in a broad-based population of psoriasis sufferers. The 12-item Psoriasis Quality of Life questionnaire (PQOL-12) is a brief, validated instrument derived from a 41-item instrument covering both psychosocial and physical domains [Feldman SR, 2005; Koo J, 2002]. The focus of the PQOL-12 on patient reports of psychosocial and physical effects specifically related to psoriasis reflects the growing emphasis among dermatologists on the major impact of the illness on patients' quality of life. Adverse Event Monitoring AE assessment (including SAEs) will be assessed on an ongoing basis throughout the study starting from the time of first dose. All SAEs/SUSARs should be monitored until they are resolved or clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Definitions, documentation, and reporting of AEs are described in detail in Section 7. Concomitant Medications Concomitant medication usage will be assessed throughout the study. See Section 5.13 for a description of permitted and restricted concomitant medications. 6.1 6.1.1

Study Procedures Visit 1 (Screening)

Potential subjects will be given an opportunity to have any questions about the study or their participation in it answered by the principal investigator or his designate. Prior to engaging in any study procedure, each potential subject must sign and date an IRB-approved informed consent form. When the consent form is signed, each subject will be assigned a unique screening number and screening procedures will be performed. 6.1.2

Visit 2

Those subjects meeting the study entry criteria who agree to participate in the study will return to the clinical site on Day 1. The investigator may, at his/her discretion choose to conduct a portion of the Day 1 visit procedures (exclusive of investigational product administration) on Day -1. Study procedures including safety, activity (PASI and PGA) and QOL assessments will be performed as outlined in the Schedule of Events (Section 1.1). Blood samples for biomarker analysis, pharmacogenetics and skin biopsies will be obtained. In addition, a photograph will be taken to document the body surface area SRT-2104-013 Version 3.0

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affected by psoriatic lesions. Subjects will be randomized to a treatment group approximately 6 days prior to this visit to allow sufficient time for delivery of investigational product. The first dose of study medication will be administered in the clinic following consumption of food. Prior to leaving the clinic, subjects will receive a kit containing study medication and will be instructed to continue once daily dosing after eating, and to store the study medication under ambient conditions (between 15 and 25 ºC), protected from direct light for the remainder of the dosing period. 6.1.3

Visits 3, 5 and 7

On Days 14, 42 and 70 subjects will return to the clinic for safety assessments as outlined in the Schedule of Events (Section 1.1). 6.1.4

Visits 4 and 6

On Days 28 and 56 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.5

Visit 8

On Day 84 subjects will return to the clinic for safety, activity, well-being and QOL assessments, PK sampling and pregnancy tests as outlined in the Schedule of Events (Section 1.1). A photograph will be taken to document the body surface area affected by psoriatic lesions. Skin biopsies and blood samples for biomarker analysis will be obtained. Wherever possible, based on scheduling of the subject visits, investigational product will be administered in the clinic to facilitate the accurate recording of dosing time and PK sampling times. Information regarding AEs and concomitant medications will be collected. 6.1.6

Follow-Up Procedures

On Day 114 subjects will return to the clinic for safety and activity assessments, and pregnancy testing as outlined in the Schedule of Events (Section 1.1).

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Clinical Study Protocol SRT-2104-013 October 22, 2010

Pharmacokinetic Sampling

PK measurements will be required for all subjects at all participating centers. Accurate recording of dosing and sample collection times is critical. The actual dosing and sample collection times must be recorded in the CRF. A total of five blood samples (6 mL each) will be obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. The following samples can be taken over the course of Visits 4, 6, and 8. Multiple PK samples can be taken during one visit provided the sampling windows as described below are observed and no 2 samples are separated by less than 1 hour. •

One pre-dose sample will be collected prior to taking investigational product (30 minutes or less before dosing). This sample must be collected on any ONE of the following: Visit 4, 6 or 8. It is recommended that the dose associated with this sample be administered in the clinic.

•

A single PK sample will be collected in the time interval of 0.5 to 2 hours post-dose. It is recommended that the dose associated with this sample be administered in the clinic. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

A single PK sample will be collected in the time interval of 3 to 6 hours post-dose. This sample must be collected on any ONE of the following: Visit 4, 6 or 8.

•

Two PK samples will be collected in the time interval of 6 to 22 hours post-dose. These 2 samples must be collected on any of the following: Visit 4, 6 or 8.

PK samples may be collected at any time during the defined sampling intervals. An effort should be made to ensure that samples are not consistently collected at the same time point within a defined collection interval. This study provides flexible options for scheduling of most PK samples. This flexibility is incorporated to improve subject convenience for sampling at later time points. 6.3

Laboratory Assessments

Safety (e.g., hematology, chemistry, and urinalysis) and screening (e.g., serum β-HCG and serology) samples will be analyzed by a central laboratory. A subset of samples (e.g., PK and FGF21 samples) may be transferred for analysis to Sirtris, GlaxoSmithKline (GSK), or other designated representative working with GSK and/or Sirtris. SRT-2104-013 Version 3.0

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The following clinical laboratory parameters will be evaluated at the time points specified in the Schedule of Events (see Section 1.1). Collected samples may be transferred for analysis to Sirtris, GSK, or other designated representatives working with GSK or Sirtris. Hematology White blood cell count (WBC)

Complete WBC differential

Hemoglobin

Platelets

Hematocrit

Mean corpuscular volume

Red blood cell count

Mean Corpuscular Hemoglobin Concentration

Red Cell Distribution Width

Mean Corpuscular Hemoglobin

Clinical Chemistry Sodium

Alanine aminotransferase

Potassium

Aspartate aminotransferase

Chloride

Total, direct, and indirect bilirubin

Blood Urea Nitrogen

Alkaline phosphatase

Serum creatinine

Lactate dehydrogenase

Plasma Glucose

Gamma-glutamyl transferase

Calcium

Amylase

Magnesium

Bicarbonate

Uric acid

Albumin

ProthrombinTime/International Normalized

Phosphate

Ratio

1

Activated Partial Thromboplastin Time 1

Creatine Kinase

Lipid Profile (Total Cholesterol, Low Density Lipoprotein, High Density Lipoprotein, Free Fatty Acids, Triglycerides)2 1

Coagulation studies will be performed at Screening and on Days 1, 42 and 84 only.

2

Lipid profiling will be performed in fasting samples at Screening, Days 1, 42 and 84 only.

Pregnancy Monitoring Serum β-HCG at Screening

Urine testing at other timepoints as defined in the Schedule of Events (Section 1.1)

Urinalysis Dipstick

Microscopic exam only if dipstick abnormal

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Serology HCV ab

HBsAg

HIV 1 & 2

Biomarkers* hsCRP

FGF21

*Biomarker analysis will be performed in fasting samples according to the timepoints displayed in the Schedule of Events (Section 1.1). Additional biomarkers thought to be associated with SIRT1 activation may be assessed.

6.4

Skin Biopsy Evaluation and Scoring

Skin biopsies will be obtained from the same designated plaque on Days 1 and 84. The central reader at (who will be blinded to treatment assignments) will evaluate the biopsy tissue for general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells). Keratinocyte expression of K-16 and ICAM-l will be measured. RT-PCR will be used to assess for expression of specific genes which may include, but not be limited to, K-16, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22, IL-23, INFγ, TNF-α, iNOS, IL-1R antagonist, PGC-1α, NCoR, NFĸβ, FOXO, p300, PPARα, PPAR-delta, and p53.

In addition, global changes in gene expression may be assessed using

gene micro-array techniques. Skin biopsies will be assigned an improvement score according to the Krueger criteria defined below: Improvement Score

Definition

No improvement

defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes

Good improvement

defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16

Excellent improvement

defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16.

6.5 Appropriateness of Measurements Per the U.S. Food and Drug Administration (FDA) guidance, “Collection of Race and Ethnicity Data in Clinical Trials, September 2005”, demographic data and complete subject medical histories will be

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documented for all subjects during screening. Investigational product administration data, including dose interruptions and modifications and the associated reason(s), also will be documented. AEs and SAEs will be monitored in this study in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines to ensure the safety of subjects. 6.6

Data Quality Assurance

Sirtris or its designated representative will conduct a clinical site visit to verify the qualifications of the investigator, inspect clinical site facilities, and inform the investigator of responsibilities and procedures for ensuring adequate and correct study documentation. The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. All information recorded on the CRFs for this study must be consistent with the subject’s source documentation. During the course of the study, the study monitor will conduct clinical site visits to review protocol compliance, compare CRFs and individual subject’s medical records (source documents), assess investigational product accountability, and ensure that the study is being conducted according to pertinent regulatory requirements. CRFs will be verified with source documentation. The review of medical records will be performed in a manner to ensure that subject confidentiality is maintained. A hardcopy of the final CRFs will be placed in the investigator’s study file and Sirtris’ Trial Master File (TMF). Instances of missing or uninterpretable data will be discussed with the investigator for resolution. Study data will be entered into a secure, validated data processing system and a backup will be maintained. Any changes to study data will be documented. A quality assurance audit will be performed on the database.

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ADVERSE EVENTS

The principal investigator and designated study staff are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE/SUSARs. 7.1 7.1.1

Definitions Adverse Event Definition

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can be any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational product, whether or not it is considered to be investigational product-related. This includes any newly occurring event or previous condition that has increased in severity or frequency since the administration of investigational product. 7.1.2

Serious Adverse Event Definition

A serious adverse event (SAE) is any AE, occurring at any dose and regardless of causality that: •

Results in death.

•

Is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.

•

Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry, are not considered AEs if the illness or disease existed before the subject was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the study (e.g., surgery performed earlier than planned).

•

Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person’s ability to conduct normal life functions.

•

Is a congenital anomaly/birth defect.

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Clinical Study Protocol SRT-2104-013 October 22, 2010

Is an important medical event. An important medical event is an event that may not result in death, be life-threatening, or require hospitalization but may be considered an SAE when, based upon appropriate medical judgment, it may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. See Section 7.1.5 for guidance on liver events that would be considered SAEs.

•

Is associated with liver injury and impaired liver function defined as: • ALT ≥ 3xULN, and • total bilirubin ≥ 2xULN or INR > 1.5. NOTES: (1) Bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury). (2) INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.

•

Pregnancy complications: spontaneous abortions in subjects exposed to investigational product must be reported as SAEs. NOTE: Any SAE occurring in association with a pregnancy that is brought to the investigator’s attention after the subject has completed the study and that is considered by the investigator as possibly related to the investigational product, must be promptly reported to Sirtris.

Clarification should be made between the terms “serious” and “severe” as they ARE NOT synonymous. The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as a severe headache). This is NOT the same as “serious,” which is based on subject/event outcome or action criteria described above, and is usually associated with events that pose a threat to a subject’s life or functioning. A severe AE does not necessarily need to be considered serious. For example, persistent nausea of several hours’ duration may be considered severe nausea but not an SRT-2104-013 Version 3.0

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SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild, but would be defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 7.1.3

Suspected Unexpected Serious Adverse Reaction Definition

A suspected unexpected serious adverse reaction (SUSAR) is any adverse drug reaction (i.e., any AE that is assessed by the Investigator as associated with [i.e., unlikely, possibly or probably related to] SRT2104, the specificity or severity of which is not consistent with those noted in the current protocol and/or Investigator’s Brochure (IB). This refers to any adverse reaction that has not been previously observed (e.g., included in the IB), rather than from the perspective of such an event not being anticipated from the pharmacological properties of the product. 7.1.4

QTc Withdrawal Criteria

A subject that meets the criteria below will be withdrawn from the study. •

QTcB > 500 msec (machine or manual overread). If the subject has bundle branch block then the criterion is QTcB > 530 msec

•

Prolongation of QTcB > 60 msec as compared to baseline

These criteria are based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, 2 additional ECGs are to be obtained over a brief period and the averaged QTc values of the 3 ECGs is used to determine whether the subject should be discontinued from the study. All ECGs with a machine-read QTcB value of > 500 msec collected during the study (including at Screening) will be manually over-read by a cardiologist to verify the QTcB value. 7.1.5

Liver Chemistry Stopping Rules and Follow-up

Liver Chemistry Stopping Rules Investigational product will be stopped if any of the following liver chemistry stopping criteria is met: 1.

ALT ≥ 3xULN and bilirubin ≥ 2xULN (or ALT ≥ 3xULN and INR > 1.5) NOTE: serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).

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2.

ALT ≥ 5xULN

3.

ALT ≥ 3xULN if associated with the appearance or worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia)

4.

ALT ≥ 3xULN persists for ≥ 4 weeks

5.

ALT ≥ 3xULN and cannot be monitored weekly for 4 weeks

6.

Alkaline phosphatase ≥ 3xULN and bilirubin ≥ 2xULN.

7.

Subjects with ALT ≥ 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash, can continue investigational product as long as they can be monitored weekly for 4 weeks. Liver Chemistry Follow-up If any of criteria 1 through 5 above are met, the following actions should be taken: •

Immediately withdraw investigational product

•

Report the event to Sirtris within 24 hours of learning its occurrence

•

Complete the SAE reporting form if the event also meets the criteria for an SAE. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT ≥ 3xULN and INR >1.5, if INR measured; INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE.

NOTE: if serum bilirubin fractionation is not immediately available, investigational product should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. •

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline values as described below

•

Withdraw the subject from the study (unless further safety follow up is required) after completion of the liver chemistry monitoring as described below

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Clinical Study Protocol SRT-2104-013 October 22, 2010

Do not re-challenge with investigational product.

In addition, for criterion 1: •

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

•

A specialist or hepatology consultation is recommended

•

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values

For criteria 2, 3, 4 and 5: •

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

•

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.

For criteria 6 and 7: •

Notify the Sirtris medical monitor within 24 hours of learning of the abnormality to discuss subject safety

•

Can continue investigational product

•

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilize or return to within baseline

•

If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

•

If, after 4 weeks of monitoring, ALT < 3xULN and alkaline phosphatase < 3xULN and bilirubin < 2xULN, monitor subjects twice monthly until liver chemistries normalize or return to within baseline values.

For criteria 1-5, make every attempt to carry out the assessments described below:

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Clinical Study Protocol SRT-2104-013 October 22, 2010

Viral hepatitis serology including: o Hepatitis A IgM antibody; o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); o Hepatitis C RNA; o Cytomegalovirus IgM antibody; o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); o Hepatitis E IgM antibody (if subject has travelled outside US in past 3 months);

•

Blood sample for PK analysis, obtained as soon as possible but no later than 5 days following last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for PK sample handling and shipping are in the study operations manual.

•

Serum creatine phosphokinase and lactate dehydrogenase

•

Fractionate bilirubin, if total bilirubin ≥ 2xULN

•

Obtain complete blood count with differential to assess eosinophilia

•

Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia as relevant on the AE report form

•

Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form

•

Record alcohol use on the liver event alcohol intake case report form

The following are required for subjects with ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) but are optional for other abnormal liver chemistries: SRT-2104-013 Version 3.0

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Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies

•

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.

7.2

Procedures for Recording and Reporting AEs and SAEs

All AEs spontaneously reported by the subject and/or in response to an open question from study personnel or revealed by observation, physical examination or other diagnostic procedures will be recorded on the appropriate page of the CRF. Any clinically relevant change in laboratory assessments or other clinical findings is considered an AE and must be recorded on the appropriate pages of the CRF. When possible, signs and symptoms indicating a common underlying pathology should be noted as one comprehensive event. All SAEs and SUSARs that occur during the course of the study, as defined by the protocol, must be reported by the investigator to Sirtris by faxing the SAE/SUSAR form within 1 working day from the point in time when the investigator becomes aware of the SAE/SUSAR. In addition, all SAEs/SUSARs, including all deaths, which occur up to and including 30 days after administration of the last dose of investigational product, must be reported to Sirtris within 1 working day. All SAEs/SUSARs and deaths must be reported whether or not considered causally related to the investigational product. The information collected using the SAE/SUSAR form will include a minimum of the following: subject number, a narrative description of the event and an assessment by the investigator as to the intensity of the event and relatedness to investigational product. A sample of the SAE/SUSAR form can be found in the study operations manual. Follow-up information on the SAE/SUSAR may be requested by Sirtris.

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Clinical Study Protocol SRT-2104-013 October 22, 2010

SAE/SUSAR Reporting Contact Information: Sirtris Pharmacovigilance Sirtris Pharmaceuticals 200 Technology Square Cambridge, MA 02139 USA Fax Line: or Email:

and to the Medical Monitor: MD Chief Medical Officer Sirtris Pharmaceuticals 200 Technology Square Cambridge, MA 02139 USA Direct Line: Extension If there are suspected, unexpected, serious adverse drug reactions (SUSARs) associated with the use of the investigational product, Sirtris or its designee will notify the appropriate regulatory agency(ies) and all participating investigators on an expedited basis (7 days for fatal or life-threatening suspected, unexpected, serious adverse drug reactions). Sirtris has delegated the responsibility to promptly notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all SUSARs involving risk to human subjects in accordance with the rules and regulations of the IRB/IEC to the principal investigator. An unexpected event is one that is not reported in the Investigator’s Brochure. Planned hospital admissions or surgical procedures for an illness or disease that was diagnosed before the subject was enrolled in the study or before investigational product was given, are not to be considered AEs. For both serious and non-serious AEs, the investigator must determine both the intensity and the relationship of the event to investigational product administration. Intensity for each AE will be determined by using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 4.0 as a guideline, wherever possible. Dose-limiting toxicities will be defined as those AEs of Grade 3 or greater that are seen to occur with an evident temporal relationship to SRT2104 SRT-2104-013 Version 3.0

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dosing. In those cases where the NCI CTC criteria do not apply, intensity should be defined according to the following criteria: Mild

Awareness of sign or symptom, but easily tolerated

Moderate

Discomfort enough to cause interference with normal daily activities

Severe

Inability to perform normal daily activities

Life Threatening or Disabling

Immediate risk of death from the reaction as it occurred

Death

The event resulted in death

Relationship to investigational product administration will be determined as follows: Not Related

No relationship between the experience and the administration of investigational product; related to other etiologies, such as concomitant medications or subject’s clinical state.

Unlikely Related

The current state of knowledge indicates that a relationship is unlikely.

Possibly Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product. The reaction might have been produced by the subject’s clinical state or other modes of therapy administered to the subject.

Related

A reaction that follows a plausible temporal sequence from administration of the investigational product and follows a known response pattern to the suspected investigational product and can be confirmed with a positive re-challenge test or supporting laboratory data.

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7.3

Clinical Study Protocol SRT-2104-013 October 22, 2010

Monitoring of Adverse Events and Period of Observation

AEs, both serious and non-serious, and deaths will be recorded on the CRFs throughout the study from the time of first dose until the final follow-up contact. However, any SAEs assessed as related to study participation (e.g., investigational product, protocol-mandated procedures, invasive tests, or change in existing therapy) will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs should be monitored until they are resolved or are clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Any SAE that occurs at any time after completion of the study including the designated follow-up period, which the investigator considers to be related to study medication, must be reported to Sirtris. AEs or SAEs requiring therapy must be treated by recognized standards of medical care to protect the health and well-being of the subject. Appropriate resuscitation equipment and medicines must be available to ensure the best possible treatment of an emergency situation. The outcome of AEs will be rated as: • Recovered/Resolved; • Recovering/Resolving; • Not Recovered/Not Resolved; • Recovered/Resolved with Sequelae; • Fatal; • Unknown. Any non-serious AE which occurs in the course of the study should be monitored and followed for up to 30 days following the last dose of investigational product.

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7.4

Clinical Study Protocol SRT-2104-013 October 22, 2010

Pregnancy Reporting

The investigator will attempt to collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to Sirtris within 2 weeks of learning of the pregnancy. The outcome of the pregnancy will also be followed. Any premature termination of the pregnancy will be reported. Information on the status of the mother and child will be forwarded to Sirtris at the time of birth, where applicable. Generally, follow-up of live births will occur at approximately 3-month intervals and will be no longer than 12 months following the estimated delivery date. Pregnancy complications, including spontaneous abortions, and the medical reason(s) for elective terminations must be reported as AEs or SAEs.

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8

Clinical Study Protocol SRT-2104-013 October 22, 2010

STATISTICAL PROCEDURES

The primary objectives are (1) to assess the effects of SRT2104 on clinical activity, based on the Krueger criteria, relative to a historical placebo response rate of 5% and (2) to assess safety and tolerability of SRT 2104. For the first objective the analysis will be based on an exposure-response analysis. Previous studies have indicated that the pharmacokinetic exposure is relatively variable. For this reason, the active treatments will be combined and then dichotomized into low and high drug exposure groups. The cut-off point will likely be the midpoint of exposure but the selection of the final cut-point will be dependent on the distribution of exposure. Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responders, defined as “good” or “excellent” Krueger improvement score, for each of the exposure groups and the historical null placebo response of 5%. No formal hypothesis testing will be performed. The second primary objective will be accomplished by review of individual subject data and descriptive summaries of the safety data. Safety displays will be summarized by treatment group (placebo, 250mg, 500mg, and 1000mg). Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity ( PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the differences between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. The clinical activity endpoints will also be summarized by treatment group, as a secondary analysis. All other pharmacodynamic endpoints will summarized by treatment group. Point estimates and corresponding 90% confidence intervals will be constructed for PK comparisons. 8.1

Randomization and Stratification

On entry into each of the three cohorts, the study subjects will be randomized to active SRT2104 (250mg, 500 mg, or 1000 mg) or placebo in a 4:1 fashion using a predetermined randomization schedule. All subjects will receive the assigned, double-blind study medication for 84 days. 8.2

Sample Size

A sample size of 8 evaluable subjects per active treatment group and 6 evaluable placebo subjects in a merged placebo group is based on feasibility. The following information is provided to estimate the precision of the estimates, assuming SRT2104 histology success rate (an improvement score of “good or excellent” based on the Krueger criteria [see Section 6.4] of .33%) and the exposure data is dichotomized at the midpoint (n=12 for each exposure SRT-2104-013 Version 3.0

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group). True Krueger response

Null

rate

Power

Cut-off value

Difference

placebo

for rejecting

between true and difference*

response

Ho

null response

rate

.33

.05

.33

.10

90% CI for the

rate

.8124

.5973

3

4

.28

(0.1229,0.6084)

.20

(0.0719, 0.5272)

.23

(0.1230,0.6090)

.15

(0.0720, 0.5272)

*90% CI is based on exact methods Note, if hypothesis testing was performed, instead of an estimation approach, based on the twelve subjects: a single sample exact binomial test with a nominal 0.05 one-sided significance level will have 82% power to detect the difference from the between a null placebo response success rate of 5%, given the and a true SRT2104 histology success response rate (an improvement score of “excellent improvement” based on the Krueger criteria [see Section 6.4]) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2). In addition, with a sample size of 8 for active dose groups, the probability of observing at least one adverse event of a given type will be 72.8% when the probability of such an adverse event is actually 15.0%. Based on the results of the second cohort (SRT2104 500 mg) the sample size of the last cohort (SRT2104 1000 mg) may be slightly increased. 8.3

Populations for Analysis

All subjects randomized will be included in the Randomized Set. The population for all safety analyses is the Safety Analysis Set (SAF). All subjects who receive at least one dose of any investigational product during the study will be included in the SAF population. Subjects will be analyzed according to the treatment received. SRT-2104-013 Version 3.0

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Subjects will be included in the Full Analysis Set (FAS) for the primary assessment of activity according to the intent-to-treat principle. The FAS will include all randomized subjects who take at least one dose of investigational product, have at least one activity measurement at baseline and at least one postbaseline study visit with post-baseline activity measurements, and have the presence of keratinocyte K16 expression on baseline biopsies indicative of psoriasis (note that absence of K16 expression at baseline would call into question the underlying diagnosis of psoriasis). Subjects will be analyzed according to the treatment received. The Per-Protocol Analysis Set (PPS) is defined as all subjects from the FAS set who complete the study and are deemed to be protocol-compliant. This analysis population will only be used if the difference between the FAS population and the PPS population is greater than 10%. To be protocol-compliant, a subject must not have any major protocol deviations during the study period. Protocol deviations will be identified prior to database lock and will be listed by treatment group in the clinical study report. The PPS will be used for a secondary assessment of activity endpoints. Pharmacokinetics Population is defined as all subjects who receive at least one dose of SRT2104 and have PK data available. 8.4

Procedures for Handling Missing, Unused, and Spurious Data

All available data will be included in data listings and tabulations. Missing values will be imputed using last-observation-carried-forward (LOCF) for the primary analysis of the clinical activity based on biopsy histopathology and for the analyses of PASI-50, PASI-75, and PGA, No other imputation of values for missing data will be performed. Data that are potentially spurious or erroneous will be examined under the auspices of standard data management operating procedures. 8.5 8.5.1

Statistical Methods Subject Disposition

The total number of subjects screened, randomized, completed, and prematurely discontinued from the study will be summarized by treatment group and overall. The reason for termination for all subjects who discontinued will be summarized by treatment group and overall. A listing of subjects who discontinued from the study by reason for termination will also be presented.

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A table summarizing the analysis sets will be presented, with the number of randomized subjects who satisfy the requirements for inclusion and frequencies of exclusion from the respective SAF, FAS, PPS, and PK analysis sets. A listing of subjects with major protocol deviations will also be presented. 8.5.2

Subjects Baseline Characteristics

Descriptive summaries of demographic and baseline characteristics will be presented by treatment group for all subjects randomized. Baseline characteristics will include a summary of the following: •

Subject demographics including age, gender, race;

•

Baseline disease characteristics, including duration since diagnosis;

•

Pre-existing medical conditions;

•

Prior therapies.

8.5.3

Exposure to Investigational Product

Exposure to SRT2104 will be tabulated by group by presenting number of days on study, defined as number of days from day of first dose to day of last dose taken. Total amount of investigational product taken using a similar calculation method will be presented by group. 8.5.4

Safety Analysis

Safety evaluations will be based on the incidence, severity, and type of AEs and clinically significant changes in the subject’s physical examination findings, vital signs, and clinical laboratory results. Safety variables will be tabulated and presented for all subjects who receive SRT2104 or placebo (the safety population). Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. AEs will be coded using the Medical Dictionary of Regulatory Activities (MedDRA) AE coding system for purposes of summarization. All AEs occurring on study will be listed in by-subject data listings. Treatment-emergent events will be tabulated, where treatment-emergent is defined as any AE that occurs after administration of the first dose of investigational product through 30 days after the last dose of SRT2104, any event that is considered causally drug-related regardless of the start date of the event, or SRT-2104-013 Version 3.0

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any event that is present at baseline but worsens in intensity or is subsequently considered drug-related by the investigator. Events that are considered related to treatment (unlikely related, possibly related, or related) will also be tabulated. Tabulation will also be provided that enumerates AEs by maximum severity. Deaths, other SAEs, and events resulting in study discontinuation will be tabulated. Change from baseline in clinical laboratory parameters will be summarized across time on study. Shift tables may be produced for selected laboratory parameters if implied by the data. Changes in vital sign parameters will be summarized over time in a similar fashion to laboratory parameters, and any abnormal values will be tabulated. Additional safety analyses may be determined at any time without prejudice, in order to most clearly enumerate rates of toxicities and to further define the safety profile of SRT2104. 8.5.5

Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses

The PK population includes all subjects for which SRT2104 concentration data are available. For the current study, plasma concentrations of SRT2104 for each subject will be listed on the basis of the dose level, time and day at which each sample was collected relative to the first dose. Relevant data from the current study, which may be combined with historical data, will be analyzed using a non-linear mixed effects modeling approach (population PK). Population PK parameters including clearance (CL), volume of distribution (V) and AUC will be estimated. Dependent on the final structural PK model additional PK parameters also may be estimated. Sources of variability in PK parameters will be investigated during population modeling. Demographic or clinical variables including, but not limited to, age, sex, race, and body weight will be evaluated as potential predictors of inter- and intra-subject variability for PK parameters. Results of the population PK model may be used in additional PK/PD analyses. Population modeling will be performed using the non-linear mixed effects modeling software (NONMEM, Globomax LLC; Ellicott City, MD). Further details of population PK analyses will be described under a separate analysis plan to be completed prior to database lock. Results of the population PK analysis will be included in a report separate from the clinical study report. Measures of individual exposure to SRT2104, such as AUC, may be correlated with selected efficacy endpoints, biomarkers, and measures of safety and tolerability as exploratory analyses of pharmacokinetic/pharmacodynamic relationships. Specific analyses that may be conducted are not specified a priori; they will be determined on the basis of study outcome. SRT-2104-013 Version 3.0

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8.5.6

Clinical Study Protocol SRT-2104-013 October 22, 2010

Activity Analysis

Activity analyses will be performed to examine the effect of daily doses of SRT2104 on clinical activity in subjects with moderate to severe plaque type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure. Analyses will also assess the effects of SRT2104 on the PASI in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure. The effects of SRT2104 on the PGA score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure will also be analyzed. Exploratory analyses may be performed to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity. Analyses will also be performed in order to assess the effects of SRT2104 on sense of wellbeing in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the PHQ-9 and the HADS. The potential effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the PQOL-12 will also be analyzed. Analyses of activity will be performed on the FAS. It may also be performed on the PPS population if the difference between the FAS population and the PPS population is greater than 10%. Summary statistics for activity variables will be presented for each planned assessment and, for continuous variables, change plus percent change will be presented at each assessment by treatment group. For all subject reported outcomes, appropriate calculations will be made to produce each factor or subscore for each instrument as well as the overall or total instrument score. For all assessments of activity, the placebo groups will be merged from the 3 cohorts prior to inferential comparisons against active treatments. In addition, the SRT2104 dose cohorts may be merged and serve as an additional group of treated subjects for all activity comparisons. The primary clinical activity outcome will be on histology (i.e., skin pathology) using the Krueger criteria (see Section 6.4). Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responders, defined as “good” or “excellent” Krueger improvement score, for each of the exposure groups and the historical null placebo response of 5%.

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In secondary efficacy assessments, “response” to treatment will be determined by PASI-50 and PASI-75 response rates. Response is defined as the proportion of subjects who achieve a PASI-50 or PASI-75. Comparisons will also be made for mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity ( PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the differences between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. The number and percentage of subjects who experience treatment failure as defined in Section 5.2.5 will be displayed by treatment group. Subjects experiencing treatment failure will be identified in the data listings. The number and percentage of subjects receiving at least one rescue medication (see Section 5.13), will be displayed by treatment group. All rescue medication administrations will be provided in the data listings. 8.6

Procedures for Reporting Deviations to Original Statistical Analysis Plan

A formal statistical analysis plan for the analysis and presentation of data from this study will be prepared before database lock. Deviations from the statistical analyses outlined in this protocol will be indicated in this plan; any further modifications will be noted in the final clinical study report.

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9 9.1

Clinical Study Protocol SRT-2104-013 October 22, 2010

ADMINISTRATIVE REQUIREMENTS Good Clinical Practice

The study will be conducted in accordance with the ICH for GCP and the appropriate regulatory requirement(s). The investigator will be thoroughly familiar with the appropriate use of the investigational product as described in the protocol and IB. Essential clinical documents will be maintained to demonstrate the validity of the study and the integrity of the data collected. The investigator site file and associated study documentation will be archived for up to 30 years. The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the sponsor delegates the set-up and maintenance of the sponsor TMF, the TMF will be returned to the sponsor at the end of the study and the sponsor will archive it for up to 30 years after initial marketing approval or termination of development. 9.2

Ethical Considerations

The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki (see Section 12) and the relevant regulations under 21 CFR parts 312, 50 and 56. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety, and well-being of the subjects. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written information given to the subjects, safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator. 9.3

Subject Information and Informed Consent

After the study has been fully explained, written informed consent will be obtained from either the subject or their guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s). 9.4

Subject Confidentiality

In order to maintain subject privacy, all CRFs, investigational product accountability records, study reports, and communications will identify the subject by initials and the assigned subject number. The investigator will grant monitor(s) and auditor(s) from Sirtris or its designee and regulatory authority(ies) access to the subject’s original medical records for verification of data gathered on the CRFs and to audit SRT-2104-013 Version 3.0

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the data collection process. The subject’s confidentiality will be maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations. 9.5

Protocol Compliance

The investigator will conduct the study in compliance with the protocol provided by Sirtris, and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies). Modifications to the protocol should not be made without agreement by both the investigator and Sirtris. Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to implementation, except when the modification is needed to eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC. Sirtris or its designee will submit all protocol modifications to the regulatory authority(ies) in accordance with the governing regulations. When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to subjects, the investigator will contact Sirtris, if circumstances permit, to discuss the planned course of action. Any departures from the protocol must be fully documented in the CRF and source documentation. 9.6

Study Monitoring

Monitoring and auditing procedures developed by Sirtris will be followed, in order to comply with GCP guidelines. On-site checking of the CRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative matters will be performed. The study will be monitored by Sirtris or its designee. Monitoring will be done by personal visits from a representative of the sponsor (site monitor) who will review the CRFs and source documents. The site monitor will ensure that the investigation is conducted according to protocol design and regulatory requirements by frequent communications (letter, telephone, and fax). All unused investigational product and other study materials are to be returned to Sirtris or its designee, or destroyed on site after the clinical phase of the study has been completed (see Section 9.9). 9.7

On-site Audits

Regulatory authorities, the IEC/IRB, and/or Sirtris’ clinical quality assurance group may request access to all source documents, CRFs, and other study documentation for on-site audit or inspection. Direct access SRT-2104-013 Version 3.0

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Clinical Study Protocol SRT-2104-013 October 22, 2010

to these documents must be guaranteed by the investigator, who must provide support at all times for these activities. 9.8

Case Report Form Completion

Case report forms will be completed for each study subject. It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported in the subject’s CRF. Source documentation supporting the CRF data should indicate the subject’s participation in the study and should document the dates and details of study procedures, AEs, and subject status. The investigator, or designated representative, should complete the CRF pages as soon as possible after information is collected, preferably on the same day that a study subject is seen for an examination, treatment, or any other study procedure. Any outstanding entries must be completed immediately after the final examination. An explanation should be given for all missing data. 9.9

Drug Accountability

Accountability for the investigational product at the study site and with the subject is the responsibility of the investigator. The investigator will ensure that the investigational product is used only in accordance with this protocol. Where allowed, the investigator may choose to assign some of the drug accountability responsibilities to a pharmacist or other appropriate individual. Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, use by each subject, and return to Sirtris (or destruction and disposal of the drug, if approved by Sirtris) will be maintained by the clinical site. These records will adequately document that the subjects were provided the doses as specified in the protocol and should reconcile all investigational product received from Sirtris. Accountability records will include dates, quantities, batch/serial numbers, expiration dates (if applicable), and subject numbers. The sponsor or its designee will assign a site monitor to review drug accountability at the site on an ongoing basis during monitoring visits. All unused and used investigational product will be retained at the site until they are inventoried by the site monitor. All used, unused or expired investigational product will be returned to Sirtris or its designee, or if authorized, disposed of at the study site and documented. All material containing SRT2104 will be treated and disposed of as hazardous waste in accordance with governing regulations.

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Clinical Study Protocol SRT-2104-013 October 22, 2010

9.10 Premature Closure of the Study This study may be prematurely terminated, if in the opinion of the investigator or Sirtris, there is sufficient reasonable cause. Written notification documenting the reason for study termination will be provided to the investigator or Sirtris by the terminating party. Circumstances that may warrant termination include, but are not limited to: • Determination of unexpected, significant, or unacceptable risk to subjects; • Failure to enter subjects at an acceptable rate; • Insufficient adherence to protocol requirements; • Insufficient complete and/or evaluable data; • Plans to modify, suspend or discontinue the development of the investigational product. Should the study be closed prematurely, all study materials must be returned to Sirtris. 9.11 Record Retention The investigator will maintain all study records according to ICH-GCP, applicable regulatory requirement(s) and Sirtris’ record retention policy. Records will be retained for 30 years after the last marketing application approval or 30 years after formal discontinuation of the clinical development of the investigational product or according to applicable regulatory requirement(s). The study documentation may be transferred to an offsite storage facility during this period but will remain under the control of the site. If the investigator withdraws from the responsibility of keeping the study records, custody must be transferred to a person willing to accept the responsibility. Sirtris must be notified in writing in advance of any change in disposition of the study records, including if a custodial change occurs. 9.12 Sample Disposition Samples collected for safety analyses will be destroyed by the central laboratory approximately 15 days after the analysis is completed. The PK samples will be stored at Simbec Research in Merthyr Tydfil in the United Kingdom for up to 2 years after the last subject completes the study. The skin biopsy tissue samples will be stored at the

in

for up to 2 years after the last

subject completes the study. At the end of the 2-year interval, the samples will, at the directive of Sirtris SRT-2104-013 Version 3.0

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Pharmaceuticals either be destroyed, or will be transferred to GSK where they will be stored for up to 15 years after the last subject completes the study. 9.13 Liability and Insurance Sirtris will be subscribed to an insurance policy covering, in its terms and provisions, its legal liability for injuries caused to participating persons and arising out of this research performed strictly in accordance with the scientific protocol as well as with applicable law and professional standards.

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10 USE OF INFORMATION All information regarding SRT2104 supplied by Sirtris to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Sirtris. It is understood that there is an obligation to provide Sirtris with complete data obtained during the study. The information obtained from the clinical study will be used towards the development of SRT2104 and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required. Publication of the results of the study, whether in whole or in part, shall be within the sole and absolute discretion of Sirtris. Investigators, sites, CROs and/or designees shall not be entitled to publish any of the data or information arising during or out of the provision of the services without the prior written consent of Sirtris. For the avoidance of doubt Sirtris reserves the unqualified right to reject any paper or article utilizing any data generated from this study before such paper or article is presented or submitted for publication.

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11 INVESTIGATOR AGREEMENT I have read the Protocol entitled, “A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe PlaqueType Psoriasis” I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good Clinical Practice and applicable regulatory requirements and to inform all who assist me in the conduct of this study of their responsibilities and obligations.

Principal Investigator (Printed Name)

Principal Investigator Signature

Date

Investigational site or name of institution and location (printed)

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12 REFERENCES Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004; 73:417435. Bouras T, Fu M, Sauve AA, et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem. 2005 Mar; 280:10264-76. Brunet A, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303:2011-2015. Brakenhielm, E, et al. Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. Faseb J. 2001 Aug, 15:1798-1800. Cohen H, Miller C, Bitterman K, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul; 305(5682):390-392. Corton JC, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci. 2005 Dec; 60:14941509. Feldman SR, et al. Decision points for the initiation of systemic treatment for psoriasis. Journal of the American Academy of Dermatology. 2005; 53:101 Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Experimental Gastroenterology. 2009; 44:41-45. Fortune DG, et al. Quality of life in patients with psoriasis: the contribution of clinical variables and psoriasis. British Journal of Dermatology. 1997; 137: 755-760 Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun. 1999; 260:273-279. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 2000; 273:793-798. Handschin C, Spiegelman, BM. The role of exercise and PGC1-α in inflammation and chronic disease. Nature. 2008; 454(7203):463-469 Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003 Sep; 78:361-369. Heilbronn LK, Ravussin E. Calorie restriction extends life span-but which calories? PLoS Med. 2005 Aug; 2:e231.

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Holian, O, Walter RJ. Resveratrol inhibits the proliferation of normal human keatinocytes in vitro. J Cell Biol. 2001; Supplement 36:55-62 Imai S, Armstrong CM, Kaeberlein M. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb; 403:795-800. Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006; 5:97-108. Koo J, Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996; 485-96) Koo J, et al. The Development of a Disease-Specific Questionnaire to Assess Quality of Life for Psoriasis Patients: An Analysis of the Reliability, Validity, and Responsiveness of the Psoriasis Quality of Life Questionnaire. Dermatol. Psychosom. 2002; 3:171–179. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a Brief Depression Severity Measure. J Gen Intern Med; 2001 16(9): 606–613. Krueger JG, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. NEJM. 2007; 356:580 Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001 Oct; 107:137-148. Mykletun A, et.al.. Hospital Anxiety and Depression (HAD) scale: factor structure, item analyses and internal consistency in a large population. British Journal of Psychiatry, 2001; 179: 540 Milne J, Lambert P, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov; 450:712-716. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb; 116:551-563. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem. 2005 Apr; 280:16456-16460. Nisoli E, Tonello C, Cardile A, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005 Oct; 310:314-317. Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun; 429:771-776. Rapp SR, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41:401-7 SRT-2104-013 Version 3.0

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Rodgers J, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through complex of PGC1α and SIRT1. Nature. 2005 Mar; 434(7029):113-118. Roth, G. S., Ingram, D. K. & Lane, M. A. Caloric restriction in primates and relevance to humans. Ann N Y Acad Sci. 2001; 928:305-315. Schon MP, Boehncke WH. Psoriasis. NEJM. 2005; 352:1899 Smith J, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Systems Biology. 2009; 3:31. van der Horst A, et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004; 279, 28873-28879. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001 Oct; 107:149-159. Weindruch R, Keenan KP, Carney JM et al. Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci. 2001 Mar; 56 Spec No 1:20-33. World Medical Association Declaration of Helsinki : Ehtical Principles for Medical Research Involving Human Subjects. October, 2008. http://www.wma.net/en/30publications/10policies/b3/index.html Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun; 23:2369-80. Yoshizaki T, et al. SIRT1 Inhibits Inflammatory Pathways in Macrophages and Modulates Insulin Sensitivity. Am J Physiol Endocrinol Metab. Dec, 2009.

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13 Appendix 1 List of Permitted Rescue Medications Class 6 steroids Alclometasone dipropionate 0.05% cream and 0.05% ointment Desonide 0.05% cream, 0.05% foam, 0.05% gel and 0.05% lotion Fluocinolone acetonide 0.01% shampoo and 0.01% solution Flurandrenolide 0.025% cream Triamcinolone acetonide 0.025% cream and 0.025% lotion Class 7 steroids Hydrocortisone 0.5% cream and 0.5% ointment Hydrocortisone 1% cream, 1% lotion and 1% ointment Hydrocortisone 2.5% cream, 2.5% lotion and 2.5% ointment

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14 Appendix 2 Pharmacogenetic Research Background Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, and elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include: Drug Abacavir

Tranilast

ABT-761

Disease HIV [Hetherington, 2002; Mallal, 2002] Restenosis prevention following coronary bypass [Roses, 2002] Asthma [Drazen, 1999]

Gene HLA (human leukocyte antigen)

Outcome Caucasian males with HLA B57 variant were at increased risk for experiencing hypersensitivity to abacavir

UGT1A1

Drug induced hyperbilirubinemia explained by high proportion of affected patients having 7/7 TA repeat genotype, consistent with clinically benign Gilbert’s Syndrome

ALOX5

ALOX5 Sp1 promoter genotype (x,x) associated with reduced response to 5-lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies. Collection of whole blood samples, even when no a priory hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to SRT2104. Pharmacogenetics Research Objectives The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to SRT2104. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with SRT2104 that may be attributable to genetic variations of subjects, the following objectives may be investigated: •

Relationship between genetic variants and the pharmacokinetics of investigational product

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•

Relationship between genetic variants and safety and/or tolerability of investigational product

•

Relationship between genetic variants and efficacy of investigational product.

Study Population Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research. Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled. Study Assessments and Procedures In addition to any blood samples taken for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labelled (or coded) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study. If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed. The need to conduct PGx analysis may be identified after a study (or set of studies) of SRT2104 has been completed and the study data reviewed. In some cases, the samples may not be studied e.g., no questions are raised about how people respond to SRT2104. Samples will be stored securely and may be kept for up to 30 years after the last subject completes the study or Sirtris may destroy the samples sooner. Sirtris or those working with Sirtris (for example, other SRT-2104-013 Version 3.0

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researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form. Subjects can request their sample to be destroyed at any time. Provision of Study Results and Confidentiality of Subject’s PGx Data Sirtris may summarize the cumulative PGx research results in the clinical study report. In general, Sirtris does not inform the investigator, subject or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of the PGx research results because the information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research, under any circumstance unless required by law. References Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

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15 Appendix 3 Summary of Changes to Amendment 1 Detailed description of changes Section Section 1.1, Schedule of Events

Section 5.15 Contraceptive Use

Section 5.2.1, Number of Subjects

Section 5.2.3, Inclusion Criteria

CHANGES (new text indicated in bold, removed text indicated as strikethrough): Tuberculosis (TB) test was added to Screening Visit. Original version of the protocol included an exclusion criterion of a positive TB test at the Screening visit, however the TB test was inadvertently omitted from the Schedule of Events in the original protocol. First sentence modified: All female subjects of child-bearing potential must use two an adequate forms of contraception for the duration of the trial (from the Screening Visit through Day 114). The text was modified: A sample size of 10 8 evaluable subjects per active treatment group and 6 evaluable subjects in the merged placebo group is based on feasibility. the following assumptions: an exact binomial test with a nominal 0.05 one-sided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (response of excellent) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2). The first sentence was modified:

A subject will be eligible for inclusion in this study only if all of the following Screening and baseline PASI criteria are met: Inclusion Criterion # 6 was modified: If a female subject of child-bearing potential, be willing to use reliable contraception (see Section 5.15) for the duration of the study, through the 30 day safety follow up telephone call visit (a female of child-bearing potential is defined as any female, regardless of her age with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. Females with oligomenorrhea or who are perimenopausal, and young females who have begun to menstruate are considered to be of child-bearing potential)

Section 5.11, Safety Review and Dose Escalation or Cessation

The second and third paragraph were modified: All safety data generated for all subjects in the 250 mg and 500 mg every cohorts who have completed at least 28 days of dosing will be reviewed by the ISRC. In the event of clinically significant adverse

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Detailed description of changes Section

CHANGES (new text indicated in bold, removed text indicated as strikethrough): events deemed to be of sufficient severity to pause dosing (refer to criteria in Section 5.11.1), a full analysis of all safety data will be conducted before continuing with a given dose or with dose escalation. When the last subject in the applicable a cohort has completed 28 days of dosing, the data for each subject will be manually entered into an electronic data capture system. The laboratory data will be transferred electronically into the database. The safety data will then be listed and presented to the ISRC for review. If the safety data is acceptable, any subjects still active in the current cohort will continue dosing, and the ISRC will authorize the initiation of dosing to the next cohort of subjects at the higher dose level. This will be repeated until the first 2 all three dosing cohorts have completed at least 28 days of dosing.

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Detailed description of changes Section Section 5.11.1, Criteria for discontinuing dosing/dose escalation

Section 5.14, Permitted Medications

CHANGES (new text indicated in bold, removed text indicated as strikethrough): Section modified: In the event that there are SAEs or severe AEs reported any serious adverse events or moderate to severe adverse event toxicities reported in a cohort in which a possible relationship to investigational product cannot be fully excluded , one of the following procedures will be applied: • If one subject receiving SRT2104 test material in a cohort experiences a severe AE or an SAE, is intolerant of the test material, but the other subjects receiving that same dose are tolerant of that dose, the ISRC and Sponsor will determine whether the nature, severity, or the number of AEs toxicities permit continuing the dosing cohort, or if dosing and/or dose escalation will stop. • If at least two subjects receiving are intolerant of a given dose of SRT2104 in a cohort experience a severe AE or an SAE, but similar AEs toxicities are recorded for subjects on placebo, the ISRC and Sponsor will determine whether the nature, severity, or the number of AEs toxicities permit continuing the dosing cohort, or if dosing and/or dose escalation will stop. If at least two subjects receiving SRT2104 in a cohort experience a severe AE or an SAE, are intolerant of SRT2104 at a given dose level, and no severe AEs or SAEs toxicities are seen in placebo subjects, the dosing of new subjects and/or dose escalation will be halted pending full review by the GSK Global Safety Board. stop. A fourth bullet has been added: If the investigator desires to initiate therapy with a prescription medication (e.g., in the event of a newly diagnosed medical condition) during the dosing period, s/he should contact the Medical Monitor to discuss the new therapy prior to initiating it.

Section 6, Study Procedures

The first paragraph has been modified: The timepoints for all study procedures are reflected in the Schedule of Events (see Section 1.1). All visits and telephone contacts will be scheduled to take place as near as possible to the scheduled day. Visit windows are as follows: a plus/minus 4-day window will be applied to Visits 3 through 7; a 1-day plus/minus window will be applied to Visit 8 (Day 84).

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Detailed description of changes Section

CHANGES (new text indicated in bold, removed text indicated as strikethrough): New section added: Tuberculosis Test A tuberculosis test will be performed at the Screening Visit. A positive test result that cannot be attributed to a prior BCG inoculation will disqualify the subject. (see Section 5.2.4)

Section 6.2, Pharmacokinetic Sampling

Section 7.1.5, Liver Chemistry Stopping Rules and Follow Up Section 7.2 Procedures for Recording and Reporting AEs and SAEs

The 4th sentence has been modified: A total of five blood samples (4 6 mL each) will be obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. References to reporting to Akos Limited have been deleted. SAE/SUSAR Reporting Contact Information modified: Akos Limited The Coach House, Pipers Lane Harpenden, Hertfordshire AL5 1AH United Kingdom SAE Reporting Line:

or

Telephone: Sirtris Pharmacovigilance Sirtris Pharmaceuticals 200 Technology Square Cambridge, MA 02139 USA Fax Line: Or Email: Section 7.4, Pregnancy Reporting

Text following 3rd sentence modified: The outcome of the pregnancy will also be followed. Any premature termination of the pregnancy will be reported. Information on the status of the mother and child will be forwarded to Sirtris at the time of birth, where applicable. Generally, followup of live births will occur at approximately 3-month intervals and

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Detailed description of changes Section

Section 8, Statistical Procedures

CHANGES (new text indicated in bold, removed text indicated as strikethrough): will be no longer than 12 months following the estimated delivery date. Any premature termination of the pregnancy will be reported. Text modified: The sample size has been chosen based on the probability of overall response to treatment and feasibility to allow preliminary characterization of safety, tolerability, and PK and to explore pharmacodynamic measures. Alphas will be two-tailed in nature and set at 0.05 for all analyses unless otherwise stated. As this is a proof of concept study, no adjustment for multiple analyses will be made. The primary objectives are (1) to assess the effects of SRT2104 on clinical activity, based on the Krueger criteria, relative to a historical placebo response rate of 5% and (2) to assess safety and tolerability of SRT 2104. For the first objective the analysis will be based on an exposure-response analysis. Previous studies have indicated that the pharmacokinetic exposure is relatively variable, for this reason, the active treatments will be combined and then dichotomized into a low and high drug exposure group. The cut-off point will likely be the midpoint of exposure but, the selection of the final cut-point will be dependent on the distribution of exposure. Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responders, defined as “good” or “excellent” Krueger improvement score, for each of the exposure groups and the historical null placebo response of 5%. No formal hypothesis testing will be performed. The second primary objective will be accomplished by review of individual subject data and descriptive summaries of the safety data. Safety displays will be summarized by treatment group (placebo, 250mg, 500mg, and 1000mg). Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity ( PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the differences between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. The clinical activity endpoints will also be summarized by treatment group, as a secondary analysis. All other pharmacodynamic endpoints will summarized by treatment group. Point estimates and corresponding 90% confidence intervals will be constructed for PK comparisons.

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Detailed description of changes Section Section 8.2, Sample Size

CHANGES (new text indicated in bold, removed text indicated as strikethrough): Text modified as follows: A sample size of 8 evaluable subjects per active treatment group and 6 evaluable placebo subjects in a the merged placebo group is based on feasibility. The following information is provided to estimate the precision of the estimates, assuming assumptions: an exact binomial test with a nominal 0.05 one-sided significance level will have 80% power to detect the difference between a null placebo success rate of 10.0% and a SRT2104 histology success rate (an improvement score of “good or excellent” improvement” based on the Krueger criteria [see Section 6.4]) of 33.0% and the exposure data is dichotomized at the midpoint (n=12 for each exposure group). Time Krueger response rate

Null placebo response rate

Power

Cut-off value for rejecting Ho

.33

.05

.8124

3

.33

.10

.5973

4

Difference between true and null response rate .28 .20 .23 .15

90% CI for the difference*

(0.1229,0.6084) (0.1230,0.6090)

*90% CI is based on exact methods

Note, hypothesis testing was performed, instead of an estimation approach, based on the twelve subjects: a single sample exact binomial test with a nominal 0.05 one-sided significance level will have 82% power to detect the difference from the between a null placebo response success rate of 5%, given the and a true SRT2104 histology success response rate (an improvement score of “excellent improvement” based on the Krueger criteria [see Section 6.4]) of 33.0%. Subjects who withdraw from the study prior to 8 weeks of treatment may or may not be replaced (see Section 5.2.2 ) In addition, with a sample size of 8 for active dose groups, the probability of observing at least one adverse event of a given type will be 72.8% when the probability of such an adverse event is actually 15.0%. Based on the results of the second cohort (SRT2104 500 mg) the sample size of the last cohort (SRT2104 1000 mg) may be slightly increased. SRT-2104-013 Version 3.0

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Detailed description of changes Section Section 8.3, Populations for Analysis

CHANGES (new text indicated in bold, removed text indicated as strikethrough): The 3rd and 4th paragraphs were modified: Subjects will be included in the Full Analysis Set (FAS) for the primary assessment of activity according to the intent-to-treat principle. The FAS will include all randomized subjects who take at least one dose of investigational product and have at least one activity measurement at baseline and at least one post-baseline randomization study visit with post-baseline activity measurements and have the presence of keratinocyte K16 expression on baseline biopsies indicative of psoriasis (note that absence of K16 expression at baseline would call into question the underlying diagnosis of psoriasis). . Subjects will be analyzed according to the treatment received. included in the treatment group to which they were randomized. The Per-Protocol Analysis Set (PPS) is defined as all subjects from the FAS set who complete the study and are deemed to be protocolcompliant. This analysis population will only be used if the difference between the FAS population and the PPS population is greater than 10%.

Section 8.4, Procedures for Handling Missing, Unused, and Spurious Data

The 2nd and 3rd paragraphs were modified: All available data will be included in data listings and tabulations. Missing values will be imputed using last-observation-carriedforward (LOCF). The primary analysis of the clinical activity based on biopsy histopathology and for the analyses of PASI-50, PASI-75, and PGA. No other imputation of values for missing data will be performed. Percentages of subjects with AEs or laboratory toxicities will be based on non-missing values.

Section 8.5.6, Activity Analysis

Modifications were made beginning with the 3rd paragraph: Analyses of activity will be performed on both the FAS. It may also be performed on the and PPS populations if the difference between the FAS population and the PPS population is greater than 10%. Summary statistics for activity variables will be presented for each planned assessment and, for continuous variables, change plus percent change will be presented at each assessment by treatment

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Detailed description of changes Section

CHANGES (new text indicated in bold, removed text indicated as strikethrough): group. For all subject reported outcomes, appropriate calculations will be made to produce each factor or subscore for each instrument as well as the overall or total instrument score. For all assessments of activity, the placebo groups will be merged from the 3 cohorts prior to inferential comparisons against active treatments. In addition, the two highest SRT2104 dose cohorts may be merged and serve as an additional group of treated subjects for all activity comparisons. The primary clinical activity outcome will be on histology (i.e., skin pathology) using the Krueger criteria (see Section 6.4). Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responders, defined as “good” or “excellent” Krueger improvement score, for each of the exposure groups and the historical null placebo response of 5%. The proportion of subjects with an improvement score of “excellent improvement” will be compared against the null placebo response of 10% using single-sided, one sample binomial tests. In secondary efficacy assessments, “response” to treatment will be determined by PASI-50 and PASI-75 response rates. Response is defined as the proportion of subjects who achieve a PASI-50 or PASI-75. Comparisons will also be made for mean change in PASI score, proportion of subjects who achieve “clear” or ”almost clear” on the PGA assessment, and proportion of subjects who achieve improvement in PGA by one or more levels. Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity ( PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the differences between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. Response rates for the active treatment groups will be compared against the null placebo response of 10% using single sided, one sample binomial tests. For all other activity assessments, analysis of baseline to each assessment differences will be performed employing analyses of covariance (ANCOVA) on values, changes, and percent changes. Baseline values will be used as the covariate for these analyses. If distributions are found to deviate significantly from normal, nonparametric analyses will be substituted for ANCOVA. For variables where change from baseline and percent change from baseline are not appropriate, t-tests will be performed to assess difference

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Detailed description of changes Section

CHANGES (new text indicated in bold, removed text indicated as strikethrough): between groups. The number and percentage of subjects who experience treatment failure as defined in Section 5.2.5 will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between groups. Subjects experiencing treatment failure will be identified in the data listings. The number and percentage of subjects receiving at least one rescue medication (see Section 5.13), will be displayed by treatment group. The proportion of subjects who experience treatment failure will be inferentially assessed by employing Fisher’s Exact tests for potential differences between groups. All rescue medication administrations will be provided in the data listings.

Section 9.12, Sample Disposition

New section added. Subsequent sections are re-numbered. Samples collected for safety analyses will be destroyed by the central laboratory approximately 15 days after the analysis is completed. The PK samples will be stored at Simbec Research in Merthyr Tydfil in the United Kingdom for up to 2 years after the last subject completes the study. The skin biopsy tissue samples will be stored at the in for up to 2 years after the last subject completes the study. At the end of the 2-year interval, the samples will, at the directive of Sirtris Pharmaceuticals either be destroyed, or will be transferred to GSK where they will be stored for up to 15 years after the last subject completes the study.

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Screening Number (last 3 digits): Randomizati on Number (last 4 digits): Subject Initials Screening ID (auto-populat ed):

2 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Demographics Generated On: 23 Nov 2010 15:40:59 Date of Informed Consent (dd MMM yyyy) Date of Birth (dd MMM yyyy) Age (Calculated) Sex Race Other, Specify Ethnicity

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5 6 7

3 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Demographics Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 ICDT

dd MMM yyyy

2 BRTHDAT

dd MMM yyyy

3 z_AGE

3

4 SEX 5 RACE 6 RACEOTH

1 2 $50

7 ETHNIC

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Date of Informed Consent (dd MMM yyyy) Date of Birth (dd MMM yyyy) Age (Calculated) Sex Race Other, Specify Ethnicity

Units

Values

Pre-Filled Values

Sex_EG Race_EG

Ethnicity_EG

4 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Urine Pregnancy Generated On: 23 Nov 2010 15:40:59 Was urine pregnancy test completed? Date completed (dd MMM yyyy) Result If positive, was a serum pregnancy test performed? Result of serum pregnancy test

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5

5 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Urine Pregnancy Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 PGUYN

2

2 PGUDAT

dd MMM yyyy

3 PGURES 4 PGUYPGS

2 2

5 PGSRES

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Was urine pregnancy test completed? Date completed (dd MMM yyyy) Result If positive, was a serum pregnancy test performed? Result of serum pregnancy test

Units

Values

Pre-Filled Values

Yes / No

Pos/Neg Yes / No

Pos/Neg

6 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 A subject will be eligible for inclusion in this study only if all of the following Screening and baseline PASI criteria are met: Protocol Version Number Inclusion Criteria: Did the subject meet the criterion? 1. - Able and willing to provide written informed consent to participate in the study 2. - Be male or female aged 18 to 80 years (inclusive) 3. - Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving ≥10% of body surface area 4. - Have a baseline PASI of ≥10 5. - Be a candidate for systemic psoriasis therapy, in the opinion of the investigator 6 - If a female subject of child-bearing potential, be willing to use reliable contraception (see Section 5.15) for the duration of the study, through the 30 day safety follow up visit (a female of child-bearing potential is defined as any female, regardless of her age with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. Females with oligomenorrhea or who are perimenopausal, and young females who have begun to menstruate are considered to be of child-bearing potential) 7. - Be willing and able to comply with the protocol for the duration of the study. Exclusion Criteria: 1. - Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit 2. - Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104 3. - Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study 4. - Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however the administration of proton pump inhibitors during the study dosing period is prohibited. V1.016 Draft3 QC 23NOV2010 (252)

2 4 5 6

7 8 9

10

12

13

14

15

7 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 5. - Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit 6. - Has received any investigational drug or experimental procedure within 30 days prior to the first dose of SRT2104 7. - Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104 8. - Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation 9. - Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit 10. - Has a positive test for HIV antibody 11. - Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial 12. - Has a 12-lead electrocardiogram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period) QTcB ≥480 msec in subjects with Bundle Branch Block 13. - Has renal or liver impairment, defined as: Serum creatinine level of ≥1.4 mg/dL for females and ≥1.5 mg/dL for males AST and ALT ≥2xULN or Alkaline phosphatase and bilirubin >1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) 14. - Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) 15. - Is pregnant or breast-feeding. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1 16. - Has a significant history of alcoholism or drug/chemical abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine V1.016 Draft3 QC 23NOV2010 (252)

16

17 18

19

20

21 22

23

24

25

26

27

8 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 17. - History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation 18. - Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. Did the subject meet all Eligibility Criteria? Was Protocol Exemption granted?

V1.016 Draft3 QC 23NOV2010 (252)

28

29 30 31

9 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 2 IEAMD

1

4 IEIN01

1

5 IEIN02

1

6 IEIN03

1

7 IEIN04

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Protocol Version Number Able and willing to provide written informed consent to participate in the study Be male or female aged 18 to 80 years (inclusive) Have a diagnosis of clinically confirmed, stable (without recent documented flare within 30 days prior to the Screening Visit), plaque-type psoriasis for at least 6 months involving ≥10% of body surface area Have a baseline PASI of ≥10

Units

Values

Pre-Filled Values

IEAMD

Yes / No

Yes / No

Yes / No

Yes / No

10 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 8 IEIN05

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Be a candidate for systemic psoriasis therapy, in the opinion of the investigator

Units

Values

Pre-Filled Values

Yes / No

11 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 9 IEIN06_3

1

Field Label

If a female subject of child-bearing potential, be willing to use reliable contraceptio n (see Section 5.15) for the duration of the study, through the 30 day safety follow up visit (a female of child-bearing potential is defined as any female, regardless of her age with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. Females with oligomenorrh ea or who are perimenopau sal, and young females who have begun to menstruate are V1.016 Draft3 QC 23NOV2010 considered to be of (252) child-bearing potential)

Units

Values

Pre-Filled Values

Y/N/NA

12 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 10 IEIN07

1

12 IEEX01

1

13 IEEX02

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Be willing and able to comply with the protocol for the duration of the study. Has received systemic non-biologic psoriasis therapy or PUVA phototherapy within 4 weeks prior to the Screening Visit, or had topical psoriasis treatment or UVB phototherapy within 2 weeks prior to the Screening Visit Has received previous treatment with biologic agents within 5 drug half-lives (or within 3 months if half-life is unknown) prior to the first dose of SRT2104

Units

Values

Pre-Filled Values

Yes / No

Yes / No

Yes / No

13 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 14 IEEX03

1

15 IEEX04

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has received a live vaccination within 4 weeks prior to the Screening Visit or intends to have a live vaccination during the course of the study Use of any other non-psoriatic prescription drug therapy, with the exception of any prescription medication administered at a stable dose for at least 6 weeks prior to the Screening Visit; however the administratio n of proton pump inhibitors during the study dosing period is prohibited.

Units

Values

Pre-Filled Values

Yes / No

Yes / No

14 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 16 IEEX05

1

17 IEEX06

1

18 IEEX07

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Use of any dietary or herbal supplements, with the exception of those administered at a stable dose for at least 6 weeks prior to the Screening Visit Has received any investigation al drug or experimental procedure within 30 days prior to the first dose of SRT2104 Has an active infection (e.g., sepsis, pneumonia, abscess, etc.) or be at high risk of developing an infection, in the opinion of the investigator, prior to the first dose of SRT2104

Units

Values

Pre-Filled Values

Yes / No

Yes / No

Yes / No

15 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 19 IEEX08

1

20 IEEX09

1

21 IEEX10

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has a history of a positive tuberculosis test or a positive tuberculosis test at the Screening Visit that cannot be attributed to a prior BCG inoculation Has a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of the Screening Visit Has a positive test for HIV antibody

Units

Values

Pre-Filled Values

Yes / No

Yes / No

Yes / No

16 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 22 IEEX11

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has an abnormal chest x-ray at the Screening Visit which, in the opinion of the investigator, would preclude entry into the trial

Units

Values

Pre-Filled Values

Yes / No

17 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 23 IEEX12

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has a 12-lead electrocardio gram (ECG) with changes considered to be clinically significant on medical review including prolonged QTc intervals as defined below: QTcB ≥450 msec (based on single or average QTc value of triplicate ECGs obtained over a brief period) QTcB ≥480 msec in subjects with Bundle Branch Block

Units

Values

Pre-Filled Values

Yes / No

18 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 24 IEEX13

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has renal or liver impairment, defined as: Serum creatinine level of ≥1.4 mg/dL for females and ≥1.5 mg/dL for males AST and ALT ≥2xULN or Alkaline phosphatase and bilirubin >1.5xULN (an isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)

Units

Values

Pre-Filled Values

Yes / No

19 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 25 IEEX14

1

26 IEEX15

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has active neoplastic disease or history of neoplastic disease within 5 years of study entry (except for basal or squamous cell carcinoma of the skin, or carcinoma in situ which have been definitively treated with standard of care approaches) Is pregnant or breast-feedin g. Confirmation that a female subject is not pregnant must be established by negative pregnancy tests at Screening and Day 1

Units

Values

Pre-Filled Values

Yes / No

Y/N/NA

20 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 27 IEEX16

1

28 IEEX17

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has a significant history of alcoholism or drug/chemic al abuse, or consumes more than 3 standard units/day of alcohol. A standard unit of alcohol is defined as 250 mL of beer, 25 mL of spirit, or 125 mL of wine History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicat es their participation

Units

Values

Pre-Filled Values

Yes / No

Yes / No

21 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Inclusion/Exclusion Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 29 IEEX18

1

30 IEELCR

1

31 IEPEXYN

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Has an acute or chronic illness which, in the opinion of the investigator, could pose a threat or harm to the subject. Did the subject meet all Eligibility Criteria? Was Protocol Exemption granted?

Units

Values

Pre-Filled Values

Yes / No

Yes / No

Yes / No

22 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Medical and Surgical History Generated On: 23 Nov 2010 15:40:59 Did the subject have any other major relevant medical/surgical history? If Yes, complete below Event Description Currently being treated with Concomitant Medication? Is condition ongoing at Screening? Date Diagnosed/Performed (dd MMM yyyy) Stop Date (dd MMM yyyy)

V1.016 Draft3 QC 23NOV2010 (252)

1

3 4 5 6 7

23 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Medical and Surgical History Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 MHSTAT

1

3 MHTERM

$80

4 MHCM

1

5 MHONG

1

6 MHSTDAT

dd- MMMyyyy

7 MHENDAT

dd- MMMyyyy

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Did the subject have any other major relevant medical/surgi cal history? Event Description Currently being treated with Concomitant Medication? Is condition ongoing at Screening? Date Diagnosed/P erformed (dd MMM yyyy) Stop Date (dd MMM yyyy)

Units

Values

Pre-Filled Values

Yes / No

Yes / No

Yes / No

24 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Physical Examination Generated On: 23 Nov 2010 15:40:59 Was a Physical Examination completed at this visit? Date of Assessment (dd MMM yyyy) Check Normal or Abnormal for any significant Abnormal physical exam findings at Screening visit should not be recorded as AEs. Abnormal findings that are associated with a pre-dosing event should be captured on the pre-dosing event CRF. Clinical Assessment If other, specify Result Specify Abnormal Conditions Check if abnormality is an Adverse Event

V1.016 Draft3 QC 23NOV2010 (252)

25 of 80

1 2

4 5 6 7 8

V1.016 Draft3 QC 23NOV2010: Online Review Form: Physical Examination Generated On: 23 Nov 2010 15:40:59 Field Name Data Type

Field Label

1 PESTAT

1

2 PEDTC

dd MMM yyyy

4 PETEST

2

5 PEOTH

$25

If other, specify

6 PEORRES

2

Result

V1.016 Draft3 QC 23NOV2010 (252)

Was a Physical Examination completed at this visit? Date of Assessment (dd MMM yyyy) Clinical Assessment

Units

Values

Pre-Filled Values

Yes / No

PETEST

1: General Appearance 2: Musculoskel etal 3: Skin and Mucosa 4: Head and Neck 5: Lymphatic 6: Respiratory 7: Gastrointesti nal 8: Cardiovascul ar 9: Extremities 10: Neurological 11: Genitourinar y 12: Eyes, ears, nose & throat 13: Other (specify)

PE Result 26 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Physical Examination Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 7 PESPY

$200

8 PEAE

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label

Units

Values

Pre-Filled Values

Specify Abnormal Conditions Check if abnormality is an Adverse Event

27 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Vital Signs Generated On: 23 Nov 2010 15:40:59 Were vital signs assessed? Date of Assessment: (dd MMM yyyy) Time of Assessment (24-hour clock) Weight:

kg

1 2 3 4

lb Height:

cm

5

in Position: Respiratory Rate: Heart Rate:

6 Fixed Unit: breaths/min 7 Fixed Unit: bpm 8

Systolic Blood Pressure:

Fixed Unit: mmHg 9

Diastolic Blood Pressure:

Fixed Unit: mmHg 10

Temperature:

Celsius

11

Fahrenheit Method Other Method

V1.016 Draft3 QC 23NOV2010 (252)

12 13

28 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Vital Signs Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 VSSTAT

1

2 VSDAT

dd MMM yyyy

3 VSTIM

HH:nn

4 5 6 7

VSWGHT VSHGHT VSPOS VSRR

4.1 4.1 1 3

8 VSHR 9 VSSYSBP

3 3

10 VSDIABP

3

11 VSTEMP

4.1

12 VSMTHD 13 VSOTHMD

2 $20

V1.016 Draft3 QC 23NOV2010 (252)

Field Label

Units

Values

Pre-Filled Values

Were vital Yes / No signs assessed? Date of Assessment: (dd MMM yyyy) Time of Assessment (24-hour clock) Weight: Weightunits Height: Heightunits Position: VSPOS Respiratory Rate: Heart Rate: Systolic Blood Pressure: Diastolic Blood Pressure: Temperature Temperature : units Method VSMTHD Other Method

29 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: 12 Lead Electrocardiogram Generated On: 23 Nov 2010 15:40:59 Was a 12 Lead Electrocardiogram performed? If yes, complete below Date of Assessment:(dd MMM yyyy) Time of Assessment (24 hour clock) Position: Ventricular Rate:

1 3 4 5 Fixed Unit: bpm 6

PR:

Fixed Unit: msec 7

QRS:

Fixed Unit: msec 8

QT:

Fixed Unit: msec 9

QTc:

Fixed Unit: msec 10

Method Overall Impression: If abnormal, specify

V1.016 Draft3 QC 23NOV2010 (252)

11 12 13

30 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: 12 Lead Electrocardiogram Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 EGSTAT

1

3 EGDAT

dd MMM yyyy

4 EGTIM

HH:nn

5 EGPOS 6 EGVR

1 3

7 8 9 10 11 12

EGPR EGQRS EGQT EGQTC EGQTCMD EGRES

13 EGCOM

3 3 3 3 1 1 $250

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Was a 12 Lead Electrocardio gram performed? Date of Assessment: (dd MMM yyyy) Time of Assessment (24 hour clock) Position: Ventricular Rate: PR: QRS: QT: QTc: Method Overall Impression: If abnormal, specify

Units

Values

Pre-Filled Values

Yes / No

EGPOS

EGQTCMD EGRES

31 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Concomitant Medication YN? Generated On: 23 Nov 2010 15:40:59 Were any concomitant medications taken while on study?

V1.016 Draft3 QC 23NOV2010 (252)

1

32 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Concomitant Medication YN? Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 CMYN

$1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were any concomitant medications taken while on study?

Units

Values

Pre-Filled Values

Yes / No

33 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Concomitant Medication Generated On: 23 Nov 2010 15:40:59 Record all prescription and non-prescription medications, including vitamins, herbal, and nutritional supplements, administered from 6 weeks prior to the screening visit through follow-up visit. Also include any biologics administered within 3 months of screening visit. Study drug should not be included. Medication (Generic or Trade Name) Indication Dose Unit If other unit, specify Frequency If other frequency, specify Route If other route, specify Ongoing Start Date (dd MMM yyyy) Stop Date (dd MMM yyyy)

V1.016 Draft3 QC 23NOV2010 (252)

34 of 80

2 3 4 5 6 7 8 9 10 11 12 13

V1.016 Draft3 QC 23NOV2010: Online Review Form: Concomitant Medication Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 2 CMTRT

3 4 5 6

CMINDC CMDOSE CMDOSU CMDOSUO

$100

$100 6.3 $30 $25

7 CMDOSFRQ 2 8 CMFRQOTH $25 9 CMROUTE 2 10 CMROUTEO $25 11 CMONGO 12 CMSTDAT

1 dd- MMMyyyy

13 CMENDAT

dd- MMMyyyy

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Medication (Generic or Trade Name) Indication Dose Unit If other unit, specify Frequency If other frequency, specify Route If other route, specify Ongoing Start Date (dd MMM yyyy) Stop Date (dd MMM yyyy)

Units

Values

Pre-Filled Values

CM Units

CM Freq Units

CM Route

35 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Adverse Events YN? Generated On: 23 Nov 2010 15:40:59 Were there any adverse events for this subject?

V1.016 Draft3 QC 23NOV2010 (252)

1

36 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Adverse Events YN? Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 AEYN

$1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were there any adverse events for this subject?

Units

Values

Pre-Filled Values

Yes / No

37 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Adverse Events Generated On: 23 Nov 2010 15:40:59 List all treatment-emergent AEs (AEs that are new in onset or aggravated in severity or frequency from the first dose of study medication to 30 days following the last dose.) Report all serious adverse events, regardless of relationship to study drug, via telephone or fax within 24 hours of discovery. Adverse Event Is AE Serious? Date of Onset (dd MMM yyyy) Time of Onset (HH:mm 24-hour clock) Intensity Frequency Relationship to SRT2104 Action Taken with Study Treatment Other Action Taken Specify Outcome Date Resolved (dd MMM yyyy) Time Resolved (HH:mm 24-hour clock)

V1.016 Draft3 QC 23NOV2010 (252)

38 of 80

2 3 4 5 6 7 8 9 10 11 12 13 14

V1.016 Draft3 QC 23NOV2010: Online Review Form: Adverse Events Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 2 AETERM

$50

3 AESER

$1

4 AESTDAT

dd MMM yyyy

5 AESTTIM

HH:nn

6 AESEV 7 AEPATT

1 1

8 AEREL

1

9 AEACN

2

10 AECONTRT 2 11 AEACNOTH $200 2 12 AEOUT 13 AEENDAT dd MMM yyyy 14 AEENTIM

HH:nn

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Adverse Event Is AE Serious? Date of Onset (dd MMM yyyy) Time of Onset (HH:mm 24-hour clock) Intensity Frequency Relationship to SRT2104 Action Taken with Study Treatment Other Action Taken Specify Outcome Date Resolved (dd MMM yyyy) Time Resolved (HH:mm 24-hour clock)

Units

Values

Pre-Filled Values

Yes / No

AE Severity AE Frequency AE Relationship AE Action Taken AE Other Action Outcome

39 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pre-Dosing Events Associated with Study Procedure YN? Generated On: 23 Nov 2010 15:40:59 Were there any events associated with study procedures for this subject?

V1.016 Draft3 QC 23NOV2010 (252)

1

40 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pre-Dosing Events Associated with Study Procedure YN? Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 AESPYN

$1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were there any events associated with study procedures for this subject?

Units

Values

Pre-Filled Values

Yes / No

41 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pre-Dosing Events Associated with Study Procedure Generated On: 23 Nov 2010 15:40:59 List all pre-dosing events associated with study procedures for this subject that occurred prior to first dose. Event Is Event Serious? Date of Onset (dd MMM yyyy) Time of Onset (HH:mm 24-hour clock) Intensity Frequency Action Taken Specify Outcome Date Resolved (dd MMM yyyy) Time Resolved (HH:mm 24-hour clock)

V1.016 Draft3 QC 23NOV2010 (252)

42 of 80

2 3 4 5 6 7 8 9 10 11 12

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pre-Dosing Events Associated with Study Procedure Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 2 AETERM 3 AESER

$50 $1

4 AESTDTC

dd MMM yyyy

5 AESTTIM

HH:nn

6 AESEV 7 AEPATT

1 1

Field Label Event Is Event Serious? Date of Onset (dd MMM yyyy) Time of Onset (HH:mm 24-hour clock) Intensity Frequency

8 AECONTRT 2

Action Taken

9 AEACNOTH $200 2 10 AEOUT 11 AEENDTC dd MMM yyyy

Specify Outcome Date Resolved (dd MMM yyyy) Time Resolved (HH:mm 24-hour clock)

12 AEENTIM

HH:nn

V1.016 Draft3 QC 23NOV2010 (252)

Units

Values

Pre-Filled Values

Yes / No

AE Severity AE Frequency AE Other Action Outcome

43 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Hematology Generated On: 23 Nov 2010 15:40:59 Were Hematology results obtained at this visit?

V1.016 Draft3 QC 23NOV2010 (252)

1

44 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Hematology Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 LBSTAT

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were Hematology results obtained at this visit?

Units

Values

Pre-Filled Values

Yes / No

45 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Chemistry, Electrolytes, Lipid Profile, and Coagulation Generated On: 23 Nov 2010 15:40:59 Were Chemistry, Electrolytes, Lipid Profile, and Coagulation results obtained at this visit?

V1.016 Draft3 QC 23NOV2010 (252)

1

46 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Chemistry, Electrolytes, Lipid Profile, and Coagulation Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 LBSTAT

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were Chemistry, Electrolytes, Lipid Profile, and Coagulation results obtained at this visit?

Units

Values

Pre-Filled Values

Yes / No

47 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Urinalysis Generated On: 23 Nov 2010 15:40:59 Were Urinalysis results obtained at this visit?

V1.016 Draft3 QC 23NOV2010 (252)

1

48 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Laboratory Data - Urinalysis Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 LBSTAT

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were Urinalysis results obtained at this visit?

Units

Values

Pre-Filled Values

Yes / No

49 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: End of Study Generated On: 23 Nov 2010 15:40:59 Date off study (dd MMM yyyy) Disposition at End of Study (if treatment was not completed per protocol criteria, specify the primary reason): Specify Date of final dose (dd mmm yyyy) Time of final dose (24 hour clock) If this subject’s treatment was unblinded during the study record date of unblinding and reason for unblinding. Date of Unblinding (dd mmm yyyy) Reason for Unblinding

V1.016 Draft3 QC 23NOV2010 (252)

50 of 80

1 2 3 4 5

7 8

V1.016 Draft3 QC 23NOV2010: Online Review Form: End of Study Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 DSSTDAT

dd MMM yyyy

2 DSTERM

2

3 DSSPY 4 EXENDAT

$50 dd MMM yyyy

5 EXENTIM

HH:nn

7 DSBLNDAT dd MMM yyyy

8 DSBLNRSN $250

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Date off study (dd MMM yyyy) Disposition at End of Study (if treatment was not completed per protocol criteria, specify the primary reason): Specify Date of final dose (dd mmm yyyy) Time of final dose (24 hour clock) Date of Unblinding (dd mmm yyyy) Reason for Unblinding

Units

Values

Pre-Filled Values

DSTERM

51 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Drug Administration Generated On: 23 Nov 2010 15:40:59 Date of initial dose (dd MMM yyyy) Time of initial dose (24 hour clock) Kit # Lot # Date Dispensed (dd MMM yyyy)

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5

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V1.016 Draft3 QC 23NOV2010: Online Review Form: Drug Administration Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 EXSTDAT

dd MMM yyyy

2 EXSTTIM

HH:nn

3 DAKIT 4 DALOT 5 DADDAT

6 5 dd MMM yyyy

V1.016 Draft3 QC 23NOV2010 (252)

Field Label

Units

Values

Pre-Filled Values

Date of initial dose (dd MMM yyyy) Time of initial dose (24 hour clock) Kit # Lot # Date Dispensed (dd MMM yyyy)

53 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Dosing Compliance Generated On: 23 Nov 2010 15:40:59 Did subject miss any doses while on study (do not record any doses missed due to early withdrawal)? Number of capsules missed Date Missed (dd MMM yyyy) Missed between visit And

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5

54 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Dosing Compliance Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 DAYN

2

2 DANUM

3

3 DADAT

dd MMM yyyy

4 DATPT1

2

5 DATPT2

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Did subject miss any doses while on study (do not record any doses missed due to early withdrawal)? Number of capsules missed Date Missed (dd MMM yyyy) Missed between visit And

Units

Values

Pre-Filled Values

Yes / No

DA_DAY1 DA_DAY2

55 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pharmacokinetics YN? Generated On: 23 Nov 2010 15:40:59 Were PK samples collected at this visit?

V1.016 Draft3 QC 23NOV2010 (252)

1

56 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pharmacokinetics YN? Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 PK_YN

2

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were PK samples collected at this visit?

Units

Values

Pre-Filled Values

Yes / No

57 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pharmacokinetics Generated On: 23 Nov 2010 15:40:59 Were pharmacokinetic samples collected? Date of dose at this visit (dd mmm yyyy) Time of dose at this visit (24 hour clock) Planned collection time Date of collection (dd MMM yyyy) Time of Collection (24 hour clock)

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5 6

58 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Pharmacokinetics Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 PKSTAT

2

2 EXDAT

dd MMM yyyy

3 EXTIM

HH:nn

4 PKTPT

2

5 PKDAT

dd MMM yyyy

6 PKTIM

HH:nn

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Were pharmacokin etic samples collected? Date of dose at this visit (dd mmm yyyy) Time of dose at this visit (24 hour clock) Planned collection time

Units

Values

Pre-Filled Values

Yes / No

PK TPT

1: Pre-dose 2: 0.5 - 2 hr post-dose 3: 3 - 6 hr post-dose 4: 6 - 22 hr post-dose 5: 6 - 22 hr post-dose

Date of collection (dd MMM yyyy) Time of Collection (24 hour clock)

59 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: hsCRP/FGF21 Sample Collection Generated On: 23 Nov 2010 15:40:59 Was hsCRP sample drawn? Date of collection (dd MMM yyyy) Time of collection (24 hour clock) Was FGF21 sample collected? Date of collection (dd MMM yyyy) Time of collection (24 hour clock)

V1.016 Draft3 QC 23NOV2010 (252)

1 2 3 4 5 6

60 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: hsCRP/FGF21 Sample Collection Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 PBYN

2

2 PBDAT

dd MMM yyyy

3 PBTIM

HH:nn

4 PBYNFG

2

5 PBDATFG

dd MMM yyyy

6 PBTIMFG

HH:nn

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Was hsCRP sample drawn? Date of collection (dd MMM yyyy) Time of collection (24 hour clock) Was FGF21 sample collected? Date of collection (dd MMM yyyy) Time of collection (24 hour clock)

Units

Values

Pre-Filled Values

Yes / No

Yes / No

61 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Hospital Anxiety and Depression Scale (HADS) Generated On: 23 Nov 2010 15:40:59 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

V1.016 Draft3 QC 23NOV2010 (252)

62 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Patient Health Questionnaire (PHQ-9) Generated On: 23 Nov 2010 15:40:59 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

V1.016 Draft3 QC 23NOV2010 (252)

65 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: 12-item Psoriasis Quality of Life Questionnaire (PQOL-12) Generated On: 23 Nov 2010 15:40:59 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

V1.016 Draft3 QC 23NOV2010 (252)

69 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Psoriasis Area and Severity Index Generated On: 23 Nov 2010 15:40:59 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

V1.016 Draft3 QC 23NOV2010 (252)

72 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Physician Global Assessment (PGA) Generated On: 23 Nov 2010 15:40:59 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

V1.016 Draft3 QC 23NOV2010 (252)

74 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Skin Biopsy Generated On: 23 Nov 2010 15:40:59 Was biopsy performed at this visit? Date of collection

V1.016 Draft3 QC 23NOV2010 (252)

1 2

76 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Skin Biopsy Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 BXYN

2

2 BXDAT

dd MMM yyyy

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Was biopsy performed at this visit? Date of collection

Units

Values

Pre-Filled Values

Yes / No

77 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Unscheduled Event Generated On: 23 Nov 2010 15:40:59 Date (dd MMM yyyy) Visit Select all assessments performed at this visit Urine Pregnancy Test Physical Examination Vital Signs 12 Lead Electrocardiogram Hematology Chemistry, Electrolytes and Lipid Profile Urinalysis Coagulation Serology Pharmacokinetics hsCRP/FGF21 Sample Collection Hospital Anxiety and Depression Scale (HADS) Patient Health Questionnaire (PHQ-9) 12-item Psoriasis Quality of Life Questionnaire (PQOL-12) Psoriasis Area and Severity Index Physician's Global Assessment (PGA) Skin Biopsy

V1.016 Draft3 QC 23NOV2010 (252)

1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

78 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Unscheduled Event Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 1 UNSDAT 2 UNSVISIT 4 UNSPG_U

dd MMM yyyy 2 1

5 UNSPE

1

6 UNSVS 7 UNSEG

1 1

1 8 UNSHEM 9 UNSCHEM 1

10 11 12 13

UNSURINE UNSCOAG UNSSERO UNSPK

1 1 1 1

14 UNSPB

1

15 UNSHADS

1

16 UNSPHQ

1

17 UNSPQOL

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label Date (dd MMM yyyy) Visit Urine Pregnancy Test Physical Examination Vital Signs 12 Lead Electrocardio gram Hematology Chemistry, Electrolytes and Lipid Profile Urinalysis Coagulation Serology Pharmacokin etics hsCRP/FGF 21 Sample Collection Hospital Anxiety and Depression Scale (HADS) Patient Health Questionnair e (PHQ-9) 12-item Psoriasis Quality of Life Questionnair e (PQOL-12)

Units

Values

Pre-Filled Values

EX STDY

79 of 80

V1.016 Draft3 QC 23NOV2010: Online Review Form: Unscheduled Event Generated On: 23 Nov 2010 15:40:59 Field Name Data Type 18 UNSPASI

1

19 UNSPGA

1

20 UNSBX

1

V1.016 Draft3 QC 23NOV2010 (252)

Field Label

Units

Values

Pre-Filled Values

Psoriasis Area and Severity Index Physician's Global Assessment (PGA) Skin Biopsy

80 of 80

List and Description of Investigators and Other Important Participants in the Study

Name

Role

Dr.

Principal Investigator

Dr.

Principal Investigator

Dr.

Principal Investigator

(SIV - 5/16/11) (5/16/11 - COV) Dr.

Study Site(s)

Principal Investigator

Dr. Dr. Dr.

Site #

Principal Investigator Principal Investigator Principal Investigator

Dr.

Dr.

Dr.

Principal Investigator      

Local IRB Chairperson Local IRB Chairperson

Dr.

Dr.

Dr.

Dr.

Local IRB Chairperson

(

Central IRB Chairperson CRO Monitoring Principal

N/A

Dyad Systems, LLC 222 Third Street, Suite 3211 Cambridge, MA 02142

RAVE Electronic Data Capture Data Manager

N/A

Eliassen Group 603 West Street, Mansfield MA 02048

PK/FGF-21 Analysis Bioanalytical Unit Manager

N/A

Central Laboratory Senior Project Manager

N/A

Skin Biopsy Laboratory Supervisor

N/A

Simbec Research Limited Merthyr Tydfil Ind. Park Cardiff Road, Merthyr Tydfil South Wales, CF48 4DR, UK Quest Diagnostics Clinical Trials 26081 Avenue Hall #150 Valencia, CA 91325, USA

(

This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

SRT-2104-013 Subjects Receiving Study Drug

Site

Subject

Number

Number

Cohort

Dose

Kit 1 or 2

Kit 1 or 2

Kit 3

Lot Number

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.

Page 1 of 2

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 1 of 2 Clinical Study Report SRT-2104-013

Listing 16.2.5.1 Listing of Planned and Actual Treatment Schedule Randomized Set Population Subj.

Randomization Number Cohort Randomized Treatment Actual Treatment -----------------------------------------------------------------------------------Cohort 1 Placebo Placebo Cohort 2 Placebo Placebo Cohort 1 Placebo Placebo Cohort 3 Placebo Placebo Cohort 2 Placebo Placebo Cohort 2 Placebo Placebo Cohort 3 Placebo Placebo Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort

1 1 1 1 1 1 1 1 1 1

SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104

0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25

Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort Cohort

2 2 2 2 2 2 2 2 2 2 2 2

SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

g g g g g g g g g g g g g g g g g g g g g g

SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 SRT2104 0.25 No Treatment SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104 SRT2104

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

g g g g g g g g g g g g g g g g g g g g g

SRT2104 Sirtris Pharmaceuticals, Inc.

Page 2 of 2 Clinical Study Report SRT-2104-013

Listing 16.2.5.1 Listing of Planned and Actual Treatment Schedule Randomized Set Population Subj.

Randomization Number Cohort Randomized Treatment Actual Treatment -----------------------------------------------------------------------------------Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g Cohort 3 SRT2104 1.0 g SRT2104 1.0 g

CONFIDENTIAL The GlaxoSmithKline group of companies

SRT-2104-013

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Reporting and Analysis Plan

Title:

Clinical Pharmacology Reporting and Analysis Plan for A Randomized, Double-Blind, Placebo-Controlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2014 in Subjects with Moderate to Severe Plaque-Type Psoriasis

Compound Number: SRT2104 Effective Date:

11 November 2011

Description: The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol SRT2104-013. This RAP is intended to describe the safety, tolerability, clinical activity, pharmacodynamics and health outcomes analyses required for the study. Identifier/Version Number: [RM2010//00] Subject: SRT2104, psoriasis, patients, Phase IIa, placebo-controlled, parallel group, safety, tolerability, clinical activity, health outcomes

Author’s Name and Functional Area:

Discovery Biometrics

1

CONFIDENTIAL

TABLE OF CONTENTS PAGE 1.

SIGNATURE PAGE ................................................................................................... 2

2.

INTRODUCTION ...................................................................................................... 7

3.

STUDY OBJECTIVE(S) AND ENDPOINT(S) ........................................................... 7 3.1. Study Objective(s) ........................................................................................ 7 3.1.1. Primary Objective(s) ...................................................................... 7 3.1.2. Secondary Objectives .................................................................... 7 3.1.3. Exploratory Objectives ................................................................... 7 3.2. Study Endpoint(s) ......................................................................................... 8 3.2.1. Primary Endpoint(s) ....................................................................... 8 3.2.2. Secondary Endpoints(s)................................................................. 8 3.2.3. Exploratory Endpoints .................................................................... 8

4.

STUDY DESIGN ...................................................................................................... 9

5.

PLANNED ANALYSES ............................................................................................ 9 5.1. Interim Analyses ........................................................................................... 9 5.2. Final Analyses ............................................................................................ 10

6.

ANALYSIS POPULATIONS ................................................................................... 10 6.1. Randomized Set (RS) ................................................................................. 10 6.2. Safety Analysis Set (SAF) ........................................................................... 10 6.3. Efficacy Analysis Set (EAS) ........................................................................ 10 6.4. Per-Protocol Analysis Set (PPS) ................................................................. 10 6.5. Pharmacokinetic (PK) Population ............................................................... 11

7.

HYPOTHESES AND TREATMENT COMPARISONS ............................................ 11

8.

TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS.............................................................................................................. 11

9.

GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ........... 12 9.1. Reporting Conventions ............................................................................... 12 9.2. Data Management ...................................................................................... 13 9.3. Premature Withdrawal and Missing Data .................................................... 13 9.4. Baseline Definition ...................................................................................... 13 9.5. Assessment Windows ................................................................................. 14 9.6. Derived and Transformed Data ................................................................... 15 9.6.1. Change from Baseline ................................................................. 15 9.6.2. Pharmacokinetic Parameters ....................................................... 15 9.6.3. Multiple Measurements at One Time point ................................... 15 9.6.4. Imputation Strategy ...................................................................... 15 9.6.5. Demography ................................................................................ 16 9.6.6. Health Outcomes Measures......................................................... 16 9.7. Values of Potential Clinical Importance ....................................................... 16

10. STUDY POPULATION ........................................................................................... 18 10.1. Disposition of Subjects................................................................................ 18 3

CONFIDENTIAL

10.2. 10.3.

Protocol Deviations ..................................................................................... 18 Demographic and Baseline Characteristics................................................. 19 10.3.1. Medical and Surgical History........................................................ 19 10.3.2. Concomitant medication .............................................................. 19

11. SAFETY ANALYSES ............................................................................................. 19 11.1. Extent of Exposure ..................................................................................... 19 11.2. Adverse Events........................................................................................... 20 11.2.1. Deaths and Serious Adverse Events............................................ 20 11.2.2. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events .......................................... 21 11.3. Physical Examination .................................................................................. 21 11.4. Clinical Laboratory Evaluations ................................................................... 21 11.5. Vitals Signs and Body Weight ..................................................................... 22 11.6. ECG............................................................................................................ 22 11.7. Urine Pregnancy Test ................................................................................. 23 12. PHARMACOKINETIC ANALYSES ......................................................................... 23 13. PHARMACODYNAMIC .......................................................................................... 23 13.1. Clinical Activity analyses ............................................................................. 23 13.1.1. Histological Assessments of Skin Biopsies of Psoriatic Lesions ........................................................................................ 24 13.1.2. Estimation of the Improvement Score Based on the Krueger Criteria ........................................................................... 24 13.1.3. Psoriasis Area and Severity Index (PASI) .................................... 25 13.1.4. Statistical Analyses of PASI Scores ............................................. 26 13.1.4.1. Estimation of Improvement based on PASI-50 and PASI-75 Proportions ............................................ 26 13.1.4.2. Repeated Measures Analyses of PASI Scores .............. 26 13.1.5. Physicians Global Assessment (PGA) ......................................... 27 13.1.5.1. Estimation of Improvement based PGA Scores .......... 27 13.1.6. Use of Rescue Medications ......................................................... 28 13.1.7. Biomarkers: hsCRP and FGF21 .................................................. 28 14. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ................................... 29 15. PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES ............................................................................................................ 29 16. HEALTH OUTCOMES ANALYSES ........................................................................ 29 16.1. Hospital Anxiety and Depression Scale (HADS) ......................................... 29 16.2. Patient Health Questionnaire (PHQ-9) ........................................................ 30 16.3. Psoriasis Quality of Life Questionnaire (PQOL-12) ..................................... 30 17. REFERENCES ....................................................................................................... 31 18. ATTACHMENTS .................................................................................................... 32 18.1. Schedule of Events ..................................................................................... 33 18.2. Data Displays for Safety Reviews of Cohorts .............................................. 34 18.3. Psoriasis Area and Severity Index .............................................................. 35

4

CONFIDENTIAL

LIST OF ABBREVIATIONS AE ALT ANOVA AST ATC AUC BMI CI Cm CPSSO CRO CSR CSSO CSV CV DMPK

Adverse Event Alanine aminotransferase (SGPT) Analysis of variance Aspartate aminotransferase (SGOT) Anatomical, Therapeutic, and Chemical Area under concentration-time curve Body mass index Confidence interval centimeter Clinical Pharmacology Study Operations Contract Resource Organization Clinical Study Report Clinical Science and Study Operations Comma-separated values Coefficient of variance Discovery Medicine Pharmacokinetics

DSM-IV EAS ECG eCRF FAS FGF21 GLS GSK HADS hsCRP IDSL IRB ISRC K16 Kg LLN LSLV M MedDRA NF

Diagnostic and Statistical Manual of Mental Disorders Efficacy Analysis Set Electrocardiogram Electronic Case Report Form Full Analysis Set Fibroblast Growth Factor 21 Geometric Least-Squares GlaxoSmithKline Hospital Anxiety and Depression Scale High-Sensitive C-Reactive Protein Integrated Data Standards Library Internal Review Board Internal Safety Review Committee Keratin 16 Kilogram Lower Limit of Normal Last Subject Last Visit Meter Medical Dictionary for Regulatory Activities QTc method calculated on the Nihon Kohden products. QTc = QT +(1000-RR)/7

PASI PASI-50 PASI-75

[msec]

Psoriasis Area and Severity Index The proportion of subjects who achieve a ≥ 50% reduction in PASI score from baseline The proportion of subjects who achieve a ≥ 75% reduction in PASI score from baseline

5

CONFIDENTIAL

PCI PE PGA PHQ-9 PQOL-12 PK PD PPS PT QOL QTc QTcB QTcF RS SAF SAP SAS SD SOC ULN WBC WHODrug

Potential Clinical Importance Physical Exam Physician Global Assessment Patient Health Questionnaire-9 Koo-Menter Psoriasis Instrument to assess Quality of Life Pharmacokinetic Pharmacodynamics Per Protocol Set Preferred Term Quality of Life QT corrected for heart rate QT interval corrected for heart rate using Bazett‟s formula QT interval corrected for heart rate using Fridericia‟s formula Randomized Set Safety Analysis Set Statistical and Analysis Plan Statistical Analysis Software Standard Deviation System Organ Class Upper Limit of Normal White Blood Cell World Health Organization Drug Dictionary

Trademark Information Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies SAS

6

CONFIDENTIAL

2.

INTRODUCTION

The purpose of this statistical analysis plan (SAP) is to describe the analyses to be included in the Clinical Study Report for Protocol SRT-2104-013. Revision Chronology: Original Document 2009-FEB-12 Number: Version 1.0

Original

Revised Document 2010-MAR-19 Number: Version 2.0

Explanation of reason for revision

All decisions regarding final analysis, as defined in this SAP document, have been made prior to Database Freeze (unblinding) of the study data. Interim analyses are detailed within Section 5.1.

3.

STUDY OBJECTIVE(S) AND ENDPOINT(S)

3.1.

Study Objective(s)

3.1.1.

Primary Objective(s)

1. To assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity in subjects with moderate to severe plaque-type psoriasis based on histological assessment of skin biopsies after 12 weeks of exposure 2. To assess the safety and tolerability of multiple doses of SRT2104 in subjects with moderate to severe plaque-type psoriasis 3.1.2.

Secondary Objectives

1. To assess the effects of SRT2104 on the Psoriasis Area and Severity Index (PASI) in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 2. To assess the effects of SRT2104 on the Physician‟s Global Assessment (PGA) score in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure 3. To determine the pharmacokinetics of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects with moderate to severe plaque-type psoriasis 4. To assess the pharmacodynamic effects of SRT2104 in subjects with moderate to severe plaque type psoriasis 3.1.3.

Exploratory Objectives

1. To characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the

7

CONFIDENTIAL

relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity 2. To assess the effects of SRT2104 on sense of depression and anxiety in subjects with moderate to severe plaque-type psoriasis after 4, 8, and 12 weeks of exposure using the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) 3. To assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure using the KooMentor Psoriasis Instrument, PQOL-12.

3.2.

Study Endpoint(s)

3.2.1.

Primary Endpoint(s)

Clinical Activity: The primary clinical activity outcome will be an Improvement Score using the Krueger criteria which are based on histological assessment of skin biopsies after 12 weeks of exposure Safety and tolerability parameters following multiple doses of SRT2104 including adverse events, physical examination, clinical laboratory results, ECGs and vital signs assessments 3.2.2.

Secondary Endpoints(s)

Psoriasis Area and Severity Index (PASI) after 4, 8, and 12 weeks of exposure Physician‟s Global Assessment (PGA) score after 4, 8, and 12 weeks of exposure Pharmacokinetics of 84 days of dosing with 250 mg, 500 mg and 1000 mg SRT2104 in the fed state in subjects Pharmacodynamic effects of SRT2104 as measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation in blood samples collected on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21. 3.2.3.

Exploratory Endpoints

Genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) to assess the effects of SRT2104 on sense of depression and anxiety after 4, 8, and 12 weeks of exposure Koo-Mentor Psoriasis Instrument, PQOL-12 to assess the effects of SRT2104 on health-related quality of life in subjects with moderate to severe plaque-type psoriasis after 12 weeks of exposure

8

CONFIDENTIAL

4.

STUDY DESIGN

Three cohorts of ten subjects each will be enrolled. Subjects within each cohort will be randomized 4:1 to receive SRT2104 at one of three escalating doses (250, 500, or 1000 mg/day) or placebo. The study will be a double blind study. Each cohort of subjects will be dosed sequentially. Dosing in the second and third cohort will not commence until subjects in the previous cohort have completed at least 28 days of dosing, and a review of safety parameters (physical examination findings, vital signs, electrocardiograms, adverse events and laboratory values) has been completed by an Internal Safety Review Committee (ISRC). Subjects will receive either SRT2104 or matching placebo once daily for 84 days with activity assessments at baseline and after 28, 56 and 84 days of dosing. Safety will be assessed on an ongoing basis. The study consists of a Screening Visit, 7 clinic visits during the dosing period and a follow-up visit. Potential subjects will sign the IRB-approved informed consent form at the Screening Visit, and will undergo screening assessments to verify eligibility for the study. If eligible and willing to participate, subjects will return to the clinic within 21 days of the Screening Visit to participate in the dosing phase of the study. For the dosing phase of the study, starting on Day 1, subjects will be randomized on approximately Day -6 to receive either 250 mg, 500 mg, or 1000 mg of SRT2104 or placebo once daily for 84 consecutive days. PK sampling will occur on Days 28, 56 and 84.

5.

PLANNED ANALYSES

5.1.

Interim Analyses

Dose escalation will be dependent upon the review of un-blinded safety data by an Internal Safety Review Committee (ISRC). Safety data generated for all subjects in every cohort who have completed at least 28 days of dosing will be reviewed by the ISRC. The following data will be reviewed: Demography, Study termination, ECG values, Vital signs, Physical Examination, Adverse Events and Clinical laboratory values. In the event of clinically significant adverse events deemed to be of sufficient severity to pause dosing, a full analysis of all safety data will be conducted before continuing with a given dose or with dose escalation. When the last subject in a cohort has completed 28 days of dosing, the data for each subject will be manually entered into an electronic data capture system. The laboratory data will be transferred electronically into the database. The required data for the safety review will be transferred from the CRO, Eliassen, to GSK Discovery Biometrics, Metabolic for programming and review of displays. The safety data displays will then be sent to the ISRC for review. If the safety data are acceptable, any subjects still active in the current cohort will continue dosing, and the ISRC will authorize the initiation of dosing to the next cohort of subjects at the higher dose level. This will be repeated until all three dosing cohorts have completed at least 28 days of dosing.

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An ISRC will be utilized during the conduct of this study to assess safety and to advise on dose escalation. The membership of the ISRC and the plan for the safety data review are described in detail in the ISRC charter. The data displays to be created are listed in Attachment 18.2.

5.2.

Final Analyses

The final planned analyses will be performed after all subjects have completed the study and after database freeze/unblinding.

6.

ANALYSIS POPULATIONS

6.1.

Randomized Set (RS)

All subjects randomized will be included in the Randomized Set. This is compatible with an ITT population.

6.2.

Safety Analysis Set (SAF)

The population for all safety analyses is the Safety Analysis Set (SAF). It includes all subjects who receive at least one dose of study medication.

6.3.

Efficacy Analysis Set (EAS)

The Efficacy Analysis Set will include all randomized subjects who take at least one dose of investigational product, have at least one activity measurement at baseline, at least one post-baseline study visit, and have the presence of keratincyte K16 expression on baseline biopsies indicative of psoriasis. The Efficacy Analysis Set is equivalent to the Full Analysis Set (FAS) in the protocol.

6.4.

Per-Protocol Analysis Set (PPS)

The Per-Protocol Analysis Population is defined as all subjects from the Efficacy Analysis Set who complete the study and are deemed to be protocol compliant. To be protocol compliant, a subject must not have any major protocol deviations, which impact the clinical activity endpoints, during the study period. Protocol deviations will be identified prior to unblinding and database lock. This analysis population will only be used if the difference between the EAS and the PPS is greater than 10%. The PPS Population will be used for a secondary assessment of activity endpoints. The protocol deviations, may include, but are not limited to: -

Failure to satisfy inclusion/exclusion

-

Subjects who developed withdrawal criteria during the study but were not withdrawn

-

Subjects who received an excluded concomitant treatment

-

Drug is not administered per protocol

-

Procedure not performed per protocol

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6.5.

Pharmacokinetic (PK) Population

The PK population is defined as all subjects who receive at least one dose of SRT2104 for whom a pharmacokinetic sample was obtained and analysed.

7.

HYPOTHESES AND TREATMENT COMPARISONS

The primary objectives is to assess the effects of 250 mg, 500 mg, and 1000 mg SRT2104 on clinical activity, based on the Krueger criteria, relative to a historical placebo response rate of 5% in subjects with moderate to severe plaque type psoriasis. Since previous studies have indicated that the pharmacokinetic exposure is relatively variable, the primary objective will be accomplished based on an exposure-response analysis. Using the Efficacy Analysis Set population, the treatments will be combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs will be natural log transformed prior to selecting the mid-point. Point estimates and 90% confidence intervals will be constructed for differences between the proportion of responses, defined as “good” or “excellent” Krueger improvements score, for each of the exposure groups and the historical null placebo response. No formal hypothesis testing will be performed. Point estimates and 90% confidence intervals will also be constructed for the secondary endpoints of clinical activity (PASI-50, PASI-75, and PGA of “almost clear” or “clear”) for the difference between the proportion of responders for each of the exposure groups and the historical null placebo response of 5%. The clinical activity endpoints will also be summarized by treatment group, as a secondary analysis. PASI scores at each time point will be assessed using an estimation approach to estimate the effect of SRT2104 active treatments relative to placebo. Point estimates and corresponding 90% confidence intervals will be constructed as appropriate for comparisons (difference between the mean of each active treatment and the mean of the placebo treatment). For other subject reported outcome endpoints and safety and tolerability endpoints, descriptive statistics by treatment group will be presented. No formal hypotheses will be tested for these endpoints.

8.

TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS

The following treatment groups will be used: Treatment Description Placebo SRT2104 0.25 g

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SRT2104 0.5 g SRT2104 1.0g If a subject is randomized and discontinues prior to dosing then a “No Treatment” group will be used for any of the displays using the Randomized Set Population.

9.

GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING

9.1.

Reporting Conventions

SAS® System, Version 9 or higher will be used for reporting the data. Cohort will not be displayed on any listings or summaries except in the Listing of Subject Disposition. Listings will be sorted by treatment, subject, and then visit. Data will be reported and analyzed according to the actual treatment the subject received. In general, summaries will be present data by treatment and assessment time unless specified otherwise. The placebo subjects from the three cohorts will be merged to create the placebo group for summaries. All data collected will be presented in data listings. Unscheduled assessments will be listed but not summarized. There will be no adjustments for multiplicity. The same color, symbol and line types will be used to differentiate treatment groups across all graphs. Unless otherwise specified, categorical variables will be presented with frequency and percentage, with percentage based on number of subjects in each treatment group in the relevant population with a row indicating the number of subjects with missing data; and continuous variables will be summarized using descriptive statistics, including n, mean, standard deviation (SD), median, minimum, and maximum values. In some cases, 25% and 75% percentiles will be presented. If there are no data to report for a planned display, the display should have a title and state „No Data to Report‟.

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9.2.

Data Management

Data Type

Source

Random Code Biomarkers

Sirtris Pharmaceutics Research External (hsCRP from central lab, FGF21 from Simbec) External - Dr. lab

Histology Improvement Score & Skin Biopsy Cell marker and gene expression data

9.3.

External – Dr. lab

Format of Data Excel

Planned Date of Final File1 at DBF date

Responsibility

Excel or SAS dataset

at DBR date

CPSSO

Excel

at DBR date

Clinical Statistics

Excel

Post DBF

CPSSO

CPSSO

Premature Withdrawal and Missing Data

All subjects who withdraw prematurely from the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Study Report (CSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 6. In the event that the study is prematurely discontinued, all available data will be listed and a review carried out by the study team to assess which statistical analyses are still considered appropriate.

9.4.

Baseline Definition

The following table indicates the baseline day to be used in the analysis:

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Parameter

Baseline (Predose) Days Collected Day Day -1 Day 1 (-21 to -6)

Safety : Laboratory Vital Signs ECG Physical Examination

X X X X

PD : PASI PGA QOL Biomarkers Skin Biopsy results 1. 2.

Baseline (Predose) Day Used in Analysis

X

Day -21 to Day 1 Day -21 to Day 1 Day -21 to Day 1 Day 1

X X X X X

Day 1 Day 1 Day 1 Day 1 Day 1

The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1, in which case, the baseline designated for Day 1 would be Day -1. Use the mean of replicate assessments at any given time point as the value for that time point in all summaries, figures and statistical analyses.

The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 prior to Day 1. In general, baseline is defined as the last non-missing value before administration of the SRT104/placebo dose.

9.5.

Assessment Windows

Deviations from planned time will be examined for scheduled assessments. If there are substantial deviations from the planned time, adjustments for assessment windows may be done. The following assessment windows may be used for the activity assessments (Krueger score, PASI and PGA). Day 1 is considered to be the date of first dose of randomized study medication. Table

Visit Window* Day -21 to Day1 Days 14 to 44 Days 45 to 70 Days 71 to 98

Visit Slotting During the Treatment Phase

Target Day* 1 28 56 84

Visit Slot/Week Randomisation 4/Week 4 6/Week 8 8/Week 12

* Relative to the first dose date of randomised study medication

All tables, listings and figures for Krueger score, PGA and PASI should present the slotted visit, unless otherwise indicated. If two or more assessments are in the same visit interval, the data recorded closest to the target day will be used for the summary tables and analyses.

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9.6.

Derived and Transformed Data

9.6.1.

Change from Baseline

The change from baseline will be calculated by subtracting the baseline values from the individual post-randomisation values. If either the baseline or post-randomisation value is missing, the change from baseline is set to missing as well. 9.6.2.

Pharmacokinetic Parameters

For the purposes of calculating summary statistics, the PK parameter AUC will be loge transformed. Geometric mean for the transformed data will be calculated according to the following method: Geometric mean = exp(mean on loge scale) Between-subject coefficient of variation (%CVb) will be calculated according to the following methods: Untransformed Data

: 100 * (SD/Mean),

where SD and Mean are the standard deviation and mean of the untransformed data. Transformed Data

: 100 * (sqrt(exp(SD2)-1)),

where SD is the standard deviation of the loge-transformed data 9.6.3.

Multiple Measurements at One Time point

Where planned multiple measurements are recorded for a particular time point, the mean of the measurements will be calculated and used in any derivation of summary statistics. However all available data will be listed. Where more than the specified number of measurements has been taken, the most recently recorded values will be used in the derivation of the appropriate summary measure (i.e. mean or maximum). 9.6.4.

Imputation Strategy

For the clinical activity binomial endpoints, if the subject withdrew from the study due to treatment failure (coded as “Disease Progression”) then any missing assessments since the date of withdraw will be imputed as a non-responder with a value of zero. If the subject withdrew from the study due to reasons other than treatment failure they will be excluded from the analysis with the value for the binomial response set to missing. Missing values will be imputed using last-observation-carried forward (LOCF) for the primary analysis of the clinical activity based on PASI-50, PASI-75, and PGA.

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The displays that use this imputation strategy will be clearly footnoted. 9.6.5.

Demography

Body Mass Index (BMI) will be calculated as: BMI = Weight (kg) / (Height (m) x Height (m)) 9.6.6.

Health Outcomes Measures

Missing data for any of the questions in the outcomes measures will not be imputed.

9.7.

Values of Potential Clinical Importance

Laboratory Values of Potential Clinical Importance Hematology Analyte

Effect

Lymphocytes

Low High Low High – Male High – Female High – Male High – Female Low High Low

Chemistry Analyte

Effect

Albumin

Low Low High High High Low High Low High Low High Low High Low High Low High

White Blood Cell Count (WBC) Neutrophil Count Hemoglobin Hematocrit Platelet Count

Calcium Creatinine Glucose Magnesium Phosphorus Potassium Sodium Bicarbonate

Potential Clinical Importance (PCI) Range < 0.67 x LLN > 1.82 x ULN < 0.83 x LLN > 1.03 x ULN > 1.13 x ULN > 1.02 x ULN > 1.17 x ULN < 0.67 x LLN > 1.57 x ULN < 0.81 x LLN Potential Clinical Importance (PCI) Range/Value < 0.86 x LLN < 0.91 x LLN > 1.06 x ULN > 1.3 x ULN > 44.2 change from baseline < 0.71 x LLN > 1.41 x ULN < 0.63 x LLN > 1.03 x ULN < 0.80 x LLN > 1.14 x ULN < 0.86 x LLN > 1.10 x ULN < 0.96 x LLN > 1.03 x ULN < 0.86 x LLN > 1.14 x ULN

16

Unit x109/ L x109/ L x109/ L g/L g/L Ratio of 1 Ratio of 1 x109/ L x109/ L x109/ L Unit g/L mmol/L mmol/L mol/L mol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L mmol/L

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Liver Function Test Analyte ALT/SGPT AST/SGOT AlkPhos T Bilirubin

Effect High High High High

T. Bilirubin + ALT

High

Potential Clinical Importance (PCI) Range 2x ULN 2x ULN 2x ULN 1.5xULN 1.5xULN T. Bilirubin + 2x ULN ALT

Unit U/L U/L U/L µmol/L µmol/L U/L

ECG Values of Potential Clinical Importance ECG Parameter Absolute QTc interval Increase from baseline QTc PR interval QRS interval

Potential Clinical Importance Range (PCI) >450 >60 <110 and >220 <75 and >110

Unit msec msec msec msec

The following further subdivision will be used to summarize the absolute and increase from baseline QTc interval data by category. ECG Parameter Absolute QTc interval Absolute QTc interval Absolute QTc interval Increase from baseline QTc Increase from baseline QTc

Potential Clinical Importance Range (PCI) > 450 to 480 > 480 to 500 > 500 > 30 to 60 > 60

Unit msec msec msec msec msec

Vital Sign Values of Potential Clinical Importance Vital Sign Parameter Systolic Blood Pressure Diastolic Blood Pressure Heart Rate

Potential Clinical Importance Range (PCI) < 85 and > 160 < 45 and > 100 < 40 and > 110

Unit mmHg mmHg bpm

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The following further subdivision will be used to summarize the increase from baseline vital signs data by category. Vital Sign Parameter

Potential Clinical Importance Range (PCI)

Systolic Blood Pressure (Change from Baseline) Diastolic Blood Pressure (Change from Baseline) Heart Rate (Change from Baseline)

10.

Increase ≥ 20 and ≥ 40

Unit mmHg

Decrease ≥ 20 and ≥ 40 Increase ≥ 10 and ≥ 20

mmHg

Decrease ≥ 10 and ≥ 20 Increase ≥ 15 and ≥ 30

bpm

Decrease ≥ 15 and ≥ 30

STUDY POPULATION

Summaries will use the Randomized Set Population and will present the data by treatment.

10.1.

Disposition of Subjects

The total number of subjects randomized and the total number of subjects in each of the analysis populations will be summarized by treatment group and overall. The number and percentage of subjects who completed the study as well as subjects who withdrew from the study will be summarized by subject status and reason for withdrawal. Listing of Planned and Actual Treatment Schedule Summary of Analysis Populations Listing of Analysis Populations Summary of Subject Disposition The reason for withdrawal will be listed for subjects who prematurely discontinue the study. If a subject‟s treatment blind was broken during study, it would be listed on the the date and reason for unblinding will be listed for subjects for whom the blind was broken during the study. Listing of Reasons for Withdrawal Listing of Subjects for whom the Treatment Blind was Broken During the Study

10.2.

Protocol Deviations

Subjects who do not meet all inclusion and exclusion criteria will be listed along with the corresponding violated criteria. Protocol Exemptions will be listed. Listing of Subjects with Inclusion/Exclusion Criteria Deviations

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Listing of Protocol Exemptions

10.3.

Demographic and Baseline Characteristics

Demographic and racial characteristics will be listed and summarized. Demographic variables to be summarized will include age, sex, race, ethnicity, height, weight and body mass index (BMI). Summary of Demographic Characteristics Listing of Demographic Characteristics 10.3.1.

Medical and Surgical History

Medical and Surgical History is collected at Screening; it will be summarized and listed. Summary of Medical and Surgery History Listing of Medical and Surgery History 10.3.2.

Concomitant medication

Concomitant medications will be will be summarized ATC level II level and a subject listing will be provided. The verbatim text from the medications will be coded using the World Health Organization Drug Dictionary (WHODrug) version December 08 B2. Summary of Concomitant Medications Listing of Concomitant Medications

11.

SAFETY ANALYSES

Summaries will use the Safety Population and will present the data by treatment.

11.1.

Extent of Exposure

The Listing of Drug Administration will include the date and time of first dose, the kit and lot numbers. The Listing of Dosing Compliance will include whether the subject missed any doses while on study, number of capsules missed, and when the doses were missed. Exposure to SRT2104 will be tabulated by treatment group. The table will present number of days on study, defined as number of days from date of first dose to date of last dose taken. For number of days, calculation is last dose – first dose +1. Listing of Drug Administration and Accountability Summary of SRT2104 Exposure

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Listing of Exposure Data

11.2.

Adverse Events

All adverse events (AEs) will be coded and classified according to System Organ Class (SOC) and preferred term using the current version of MedDRA 12.0. A summary by treatment of the number and percentage of subjects with all relevant adverse events will be displayed. Adverse events will be sorted by MedDRA System Organ Classes (SOCs), in descending order from the SOC with the highest total incidence (i.e., summed across all treatment groups) for any adverse event within the class to the SOC with the lowest total incidence. In the same manner, adverse events will be grouped by the MedDRA hierarchy level, Preferred Term (PT). A summary of adverse events by severity and highest relationship will be summarized. The hierarchical relationship between MedDR SOCs, PTs, and verbatim text will be displayed for relevant adverse events. Stop date will not be imputed, but the partial or complete missing start dates for AEs will be imputed as follows: - Month and year known and study medication start during that month then set start equal to study medication start date - Month and year known and study medication started prior to or after that month then set start date equal to the 1st day of the month - If only year is known, and it is the same as first dose date year, assume it is the first dose date. If it is different from the first dose year, assume it is the first day of the year. - Complete AE start date (i.e., day, month and year are missing) is unknown impute start dates as the study medication start date. Relationship between System Organ Class, Preferred Term and Verbatim Text Summary of All Adverse Events Listing of All Adverse Events Summary of Adverse Events by Highest Relationship to Study Drug Summary of Adverse Events by Maximum Intensity Listing of Subject Numbers for Individual Adverse Events 11.2.1.

Deaths and Serious Adverse Events

Deaths and serious AEs, if they occur, will also be listed and summarized separately. Death is defined as a subject having an AE outcome of “fatal”. Summary of Serious Adverse Events 20

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Listing of Serious Adverse Events Listing of Adverse Events Leading to Death 11.2.2.

Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events

AEs leading to discontinuation of investigational product and/or withdrawal from the study, if they occur, will also be listed and summarized separately. Summary of Adverse Events Leading to Permanent Discontinuation from Treatment Listing of Adverse Events Leading to Permanent Discontinuation from Treatment

11.3.

Physical Examination

Results of physical examinations (PE) conducted at each visit will be presented in listings and summarized based on PE status of normal, abnormal and not done. The assessments are collected at baseline, day 28, day 56, day 84, and follow up by treatment group. A footnote will be included on the displays to indicate that Breast evaluations will be included in the Musculoskeletal Body System and Psychological evaluations will be included in the Neurological Body System. Summary of Abnormal Physical Examinations Listing of Physical Examination

11.4.

Clinical Laboratory Evaluations

All haematology, coagulation, and clinical chemistry values will be listed for each subject who has any values of potential clinical importance (PCI) and flagged relative to the normal range and relative to the potential clinical importance as described in Section 8.7, where applicable. For laboratory tests, that do not have criteria for potential clinical importance, a listing of values flagged relative to the normal range will be produced. All laboratory data will by summarized by System International (SI) units for the analysis. Parameter values and change from baseline will be summarized separately. A listing of the reference ranges for the clinical laboratory tests will also be provided. Listing of Reference Ranges for Clinical Laboratory Tests Summary of Hematology and Coagulation Data Summary of Change from Baseline in Hematology and Coagulation Data Listing of Hematology and Coagulation Abnormalities of Potential Clinical Importance

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Listing of Hematology and Coagulation Data for Subjects with Abnormalities of Potential Clinical Importance Summary of Clinical Chemistry Data Summary of Change from Baseline in Clinical Chemistry Data Listing of Clinical Chemistry Data of Potential Clinical Importance Listing of Clinical Chemistry Data for Subjects with Abnormalities of Potential Clinical Importance Listing of Clinical Chemistry Abnormalities Outside of the Normal Range Listing of Hematology and Coagulation Abnormalities Outside of the Normal Range Mean (+/- SE) Change from Baseline of Hematology and Coagulation Data Mean (+/- SE) Change from Baseline of Clinical Chemistry Data This display of urinalysis data will summarise the dipstick test results at each assessed time point. If more detailed test results are collected (e.g., blood, protein), then these will be summarized. The urinalysis data will also be listed. Summary of Urinalysis Results Listing of Urinalysis Data

11.5.

Vitals Signs and Body Weight

All vital sign data will be listed for each subject who has any values of potential clinical importance and flagged relative to the potential clinical importance as described in Section 8.7 (as High or Low). A descriptive summary of the interval data including change from baseline will be presented. Summary of Vital Signs and Body Weight Summary of Change from Baseline for Vital Signs Listing of Vital Signs of Potential Clinical Importance Listing of All Vital Signs for Subjects with any Values of Potential Clinical Importance

11.6.

ECG

A summary of ECG overall impressions (Normal, Abnormal – not clinically significant, Abnormal – clinically significant) will be generated. A summary of ECG parameters (heart rate, PR, QRS, QT and QTc) will be provided by treatment and visit, where QTc is expressed as QTcB or QTcF. If a site used another method for calculating QTc, such as NF, the QTc value will be used to evaluate Potential Clinical Importance values but it

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will not be included in the Summary of ECG values. A listing of ECG values will be listed for each subject who has any value of potential clinical importance and flagged relative to the potential clinical importance as described in Section 8.7. In the event that replicate assessments are performed, they will be averaged prior to summarization and prior to evaluating against the PCI criteria. Summary of ECG Overall Impressions Summary of ECG Values Summary of Change from Baseline in ECG Values Listing of ECG Values of Potential Clinical Importance Listing of All ECG Intervals for Subjects with Values in the Potential Clinical Importance Summary of Category of QTc interval Data by Treatment and Time Summary of Category of Increase from Baseline QTc Interval Data by Treatment and Time

11.7.

Urine Pregnancy Test

Pregnancy tests are performed at Screening and Days 1, 28, 56 and follow-up. A listing of female subjects who became pregnant during the study will be listed. Listing of Female Subjects who Became Pregnant during the Study

12.

PHARMACOKINETIC ANALYSES

The estimated AUCs, using a Population PK approach will performed by, or under the direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline and the details will be described in a separate analysis plan. Since previous studies have indicated that the pharmacokinetic exposure is relatively variable, the imputed AUCs from the active treatment will be combined and then dichotomized at the median into low and high drug exposure groups. The imputed AUCs will be natural log transformed prior to selecting the mid-point. Summary of AUC by Exposure Group

13.

PHARMACODYNAMIC

13.1.

Clinical Activity analyses

Analyses of clinical activity will be performed on the Efficacy Analysis Set Population. If the “Per Protocol” analysis population is warranted then it will also be summarized for this population as well. The primary analysis will be summarized by both the low vs. high exposure groups and by the SRT2104 Treatment Groups. In addition, the two highest SRT2104 dose cohorts

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may be merged and serve as an additional group of treated subjects for all activity comparisons. See Section 9.6.4 for the imputation strategy for missing data for the clinical activity binomial endpoints. 13.1.1.

Histological Assessments of Skin Biopsies of Psoriatic Lesions

Skin biopsies will be obtained from the same designated plaque on Days 1 and 84. Planned analyses for skin biopsy samples will be the following: general appearance, epidermal thickness, total inflammatory infiltrate, specific cell numbers (including but not limited to CD163+ monocytes, CD11c+ dendritic cells, CD83+and/or CD206+ cells, and CD3+ T-cells), and keratinocyte expression of K-16 and ICAM-l. The primary clinical activity endpoint is change in histologic assessments of skin biopsies of psoriatic lesions from baseline to 12 weeks as measured by an Improvement Score according to the Krueger criteria: Improvement Score Definition No improvement

defined as no improvement in epidermal thickness keratinocyte differentiation or K16 expression on keratinocytes

Good improvement

defined as reduction in epidermal thickness by at least 30% normalized keratinocyte differentiation but most keratinocytes still express K16

Excellent improvement

defined as reduction in epidermal thickness to normal or almost normal normalized keratinocyte differentiation and absent keratinocyte expression of K16.

Listing of Improvement Scores according to the Krueger Criteria and Skin Biopsy Data Summary of Dermal and Epidermal PBMC Counts Summary of Dermal and Epidermal PBMC Counts Change from Baseline Proportion of Subjects Expressing Abnormal Cellular Proteins by Visit Shift Table of Proportion of Subjects Expressing Abnormal Cellular Proteins by Visit 13.1.2.

Estimation of the Improvement Score Based on the Krueger Criteria

A binomial response will be defined for each subject according to whether the subject has an improvement score of “good or excellent improvement” (response=1) or not (response=0).

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Point estimates and 90% confidence intervals will be constructed for the differences between the proportion of responder, defined as “good” or “excellent” Krueger improvement score, for each of the exposure group and all SRT2104-treated relative to placebo. No formal hypothesis testing will be performed. The proportion of subjects with improvement of good or excellent in each exposure group and for all SRT2104-treated will be compared against a null placebo response rate of 5% using one-sided, one sample binomial tests. Summary of Histological Improvement on Day 84 Difference (90% CI) in Proportion of Histological Improvement between Exposure Groups or SRT2104 Treatment Groups and Placebo – Day 84 Summary of the Histological Improvement Compared to Historical 5% Placebo Rate Listing of Supportive SAS Output for Statistical Analysis of Two Sample Binomial Proportions of Histological Improvement Listing of Supportive SAS Output for Statistical Analysis of Single-Sample Binomial Proportions of Histological Improvement 13.1.3.

Psoriasis Area and Severity Index (PASI)

Disease assessments using the PASI score will be conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. The PASI score quantifies the extent of psoriasis and the degree of plaque erythema, scaling and thickness on the four body areas: head, trunk, upper limbs, and lower limb (see Attachment 18.3). Possible scores range from 0 (no disease) to 72 (maximal disease). The following proportions will be derived for each time point: PASI-50: defined as the proportion of subjects who achieve a ≥ 50% reduction in PASI score from baseline PASI-75: defined as the proportion of subjects who achieve a ≥ 75% reduction in PASI score from baseline The listing will include change from baseline and percent change from baseline in the PASI score. Listing of Psoriasis Area Severity Index (PASI) Score Summary of Psoriasis Area Severity Index (Total Score) Plot of mean (+/-SE) PASI vs. Time Plot of individual PASI scores vs. Time Scatter Plot of Day 84 Percent Change from baseline in PASI vs. AUC

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13.1.4.

Statistical Analyses of PASI Scores

13.1.4.1.

Estimation of Improvement based on PASI-50 and PASI-75 Proportions

The PASI-50 (PASI-75) proportion is the proportion of subjects who have a greater than or equal to 50% (75%) reduction from baseline in the PASI score. A binomial response will be defined for each subject at each visit in which PASI is collected according to whether the subject achieved a greater than or equal to 50% (75%) reduction from baseline at week 12 in the PASI score (response=1) or not (response=0). Point estimates and 90% confidence intervals will be constructed for the differences each of the exposure groups and placebo, for both PASI-50 and PASI75. Difference (90% CI) in Proportion of Improvement based on >= PASI 50 between Exposure Groups or SRT2104 Treatment Groups and Placebo - Day Difference (90% CI) in Proportion of Improvement based on >= PASI 75 between Exposure Groups or SRT2104 Treatment Groups and Placebo - Day Proportion of Subjects with Clinical Activity in the PASI score (≥ PASI-75, ≥PASI-50)

Proportion of Subjects with Clinical Activity in the PASI score ≥PASI-50) - LOCF 13.1.4.2.

-75,

Repeated Measures Analyses of PASI Scores

A repeated measures analysis of the PASI score will be performed using a mixed effects model with baseline PASI score, treatment group and time as fixed effects and subject as a random effect. Time will be the repeated measures term. Point estimates and their associated 90% confidence intervals will be constructed for the differences between each active treatment and placebo at each time point. An appropriate variance–covariance structure will be identified for the mixed model. Distributional assumptions underlying the analysis will be assessed by examining residual plots. Normality will be examined by normal probability plots and variance homogeneity will be assessed by plotting the studentized residuals against the predicted values from the model. If assumptions are seriously violated then alternative statistical methods ( a non-parametric approach-i.e, Hodges Lehmann estimate) will be considered. Example SAS code for the repeat measures ANCOVA Proc Mixed data=pd_data; class treat subject time; model pd_var = baselinepd treat time treat*time / outp=pred; random subject; lsmeans treat; *make sure placebo is the first level of the treatment code*/ estimate „0.25 g vs Placebo‟ treat -1 1 0 0/ cl alpha=0.1; estimate „0.50 g vs Placebo‟ treat -1 0 1 0/ cl alpha=0.1; 26

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estimate „1.0 g vs Placebo‟ treat -1 0 0 1/ cl alpha=0.1; run; The following SAS code will be run to generate output to assess the assumptions underlying the model. proc sort data=pred; by treat * residual plots *; proc plot data=pred; plot resid*pred=treat; by treat; * additional distributional assessment*; proc univariate data=pred plot normal; var resid; by treat; Summary of Results of Repeated Measure Analysis of Psoriasis Area Severity Index Score Plot of PASI Least Squares (LS) Mean Difference (90% CI) between SRT 2104 Treatment Groups and Placebo by Day

13.1.5.

Physicians Global Assessment (PGA)

Disease assessments using a PGA score will be conducted on Days 1, 28, 56, 84 and 114 to quantify the effects of SRT2104 on psoriasis activity. Two versions of the PGA were distributed to the sites: a 6-point grading scale and an older version based on a seven-point grading scale. Only the PGA from the 6-point grading scaled is databased and thus will be summarized. The PGA data will be listed by treatment and assessment time. The listing will indicate if the subject improved in PGA by one or more levels Listing of the PGA score Summary of Physician Global Assessment (Overall Score) by Visit 13.1.5.1.

Estimation of Improvement based PGA Scores

Three binomial response variables will be defined: 1.)

2.)

for each subject for each visit that PGA was collected according to whether the subject achieved a PGA score of “minimal” or “clear” (response=1) or not (response=0), for post baseline assessment of PGA according to whether the subject achieved an improvement of one or more levels of the PGA (response=1) or not (response=0),

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3.)

if either #2 or # 3 were achieved (response=1) or not (response =0)

Point estimates and 90% confidence intervals will be constructed for the difference between the proportion of responders for each of the exposure groups and all SRT2104treated relative to placebo. A binomial response will be defined for each subject at week 12 according to whether the subject achieved improvement in the PGA score by one or more levels (response=1) or not (response=0). Proportion of Subjects with Clinical Activity in PGA Score (Score of Clear or Minimal or an Improved PGA Score by One or More Levels) Proportion of Subjects with Clinical Activity in PGA Score (Score of Clear or Minimal or an Improved PGA Score by One or More Levels) – LOCF Difference (90% CI) in Proportion of improvement based on PGA Score (Score of Clear or Minimal) between Exposure Groups or SRT2104 Treatment Groups and Placebo Day

13.1.6.

Use of Rescue Medications

The following is the permitted list of rescue medications allowed per protocol (Appendix 1): Class 6 steroids Alclometasone dipropionate 0.05% cream and 0.05% ointment Desonide 0.05% cream, 0.05% foam, 0.05% gel and 0.05% lotion Fluocinolone acetonide 0.01% shampoo and 0.01% solution Flurandrenolide 0.025% cream Triamcinolone acetonide 0.025% cream and 0.025% lotion Class 7 steroids Hydrocortisone 0.5% cream and 0.5% ointment Hydrocortisone 1% cream, 1% lotion and 1% ointment Hydrocortisone 2.5% cream, 2.5% lotion and 2.5% ointment The number and percentage of subjects receiving at least one rescue medication (as indicated on the concomitant medications form) will be summarized by treatment group. Proportion of Subjects Using Rescue Medications Listing of Subjects Using Rescue Medications 13.1.7.

Biomarkers: hsCRP and FGF21

Pharmacodynamic effects of SRT2104 as measured by biomarkers of psoriatic disease activity and/or sirtuin pathway activation in blood samples will be collected on Days 1, 28, 56 and 84 and may include, but may not be limited to, hsCRP and FGF21.

28

CONFIDENTIAL

Summary of FGF21 and hsCRP Summary of FGF21 and hsCRP- Change from Baseline Listing of FGF21 data

14.

PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES

Measures of individual exposure to SRT2104, such as AUC, may be correlated with selected biomarkers and measures of safety and tolerability as exploratory analyses of pharmacokinetic/pharmacodynamic relationships. Summary of SRT2104 Pharmacokinetic Parameters by Treatment

15.

PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES

Exploratory analyses may be performed to characterize expression patterns of select genes and proteins hypothesized to be involved in psoriasis pathophysiology and sirtuin pathways and to evaluate the relationship between these biomarkers and investigational product pharmacokinetics and/or clinical activity.

16.

HEALTH OUTCOMES ANALYSES

Exploratory clinical activity endpoints include assessments of the subject‟s sense of wellbeing (PHQ-9 and HADS) and health-related quality of life (PQOL-12)

16.1.

Hospital Anxiety and Depression Scale (HADS)

The assessments are collected at baseline, day 28, day 56, and day 84. The HADS scale is a 14-item, validated self-rating instrument of symptoms of anxiety and depression. The HADS could provide a signal of efficacy in a broad-based population of psoriasis sufferers. Anxiety and Depression subscales, along with the total score will be listed and summarized by treatment and time. Summary Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score by Visit Summary Change from Baseline Statistics of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score by Visit Listing of Hospital Anxiety and Depression Scale (HADS) Total Score, Anxiety Score and Depression Score by Visit Listing of Hospital Anxiety and Depression Scale (HADS) Questionnaire Values

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16.2.

Patient Health Questionnaire (PHQ-9)

The assessments are collected at baseline, day 28, day 56, and day 84. PHQ-9, is a 9-item scale that assesses the 9 Diagnostic and Statistical Manual of Mental Disorders (DSMIV) depression symptom criteria for frequency of occurrence during the previous 2 weeks. The total score ranges from 0 (no depressive symptoms) to 27 (all symptoms occurring daily). Summary Statistics of the Patient Health Questionnaire by Visit Summary of Change from Baseline Statistics of the Patient Health Questionnaire by Visit This table will display summary statistics for PHQ-9 scores by treatment and Visit/Week. The table will include the total score for part 1 and part 2. Listing of Patient Health Questionnaire (PHQ-9) Results

16.3.

Psoriasis Quality of Life Questionnaire (PQOL-12)

The assessments are collected at baseline, day 28, day 56, and day 84. The PQOL-12 is an instrument to assess the severity of psoriasis and its effect on quality of life. Patients complete Part 1 of a validated measure of their quality of life (the PQOL-12). Summary Statistics of Psoriasis Quality of Life-12 Instrument by Visit Summary of Change from Baseline Psoriasis Quality of Life-12 Instrument by Visit Listing of Psoriasis Quality of Life Questionnaire (PQOL-12) Results

30

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17.

REFERENCES

Blyth C, Still H (1983). Binomial Confidence Intervals. Journal of American Statistical Association 78:108-116. Casella G (1986). Refining Binomial Confidence Intervals. Canadian Journal of Statistics 14:113-129.

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18.

ATTACHMENTS

32

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18.1.

Schedule of Events

A full description of the study procedures is provided in Section Error! Reference ource not found. of the protocol. Study Period

Screening

Visit Number

1

2

3

4

5

6

7

8

Study Day(s)

-21 to -6

18

14

28

42

56

70

8410

114

X X X X

X

X

X

X

X

X

X

X

Clinic Visit Informed Consent Medical History1 Viral Serology Photographs (total body surface area involvement) 2 Randomization Investigational Product Dispensed Physical Examination3 (including heightSigns at Screening and weight at all Vital subsequent visits) Chest X-Ray 12-lead ECG 4

Clinical Chemistry/Hematology Urinalysis Pregnancy Test5 Adverse Event/Concomitant 6 Medication Assessment PK Sampling

X X X X X X X X

Dosing Period

X

X

X

X X X

X X X

X X X

X X X X X

PASI & PGA QOL assessments (PHQ-9, HADS, PQOL-127) Biomarkers

X X X X

Skin Biopsy (Immunohistochemistry and Gene Footnotes: Expression Profiling)

X

Pharmacogenetics Sample9

X

X

X X X X

X X X X X X X X

Follow Up

X

X

X X X X

X X X X X X X X

X X X

X X X

X X X X X X X X X

1.

Medical events occurring prior to the first dose will be collected on the medical history case report form (CRF). AEs occurring after the first dose will be recorded on the AE CRF. AEs and concomitant medications will be followed for 30 days after the last dose of study medication. 2. Subjects will be randomized to a treatment on approximately Day – 6 to allow sufficient time for delivery of investigational product. 3. A complete physical examination (PE) will be conducted at the Screening Visit. A symptom-driven, directed PE will be performed as needed at all other timepoints. 4. See Section Error! Reference source not found. of the protocol for a complete listing of safety lab parameters to e measured/analyzed. Lipid profiling and coagulation studies will be performed in fasting samples at Screening, and on Days 1, 42 and 84 only. 5. Serum pregnancy test to be performed at Screening; urine screen for pregnancy at all other timepoints. 6. PK sampling will be performed according to the schedule described in Section Error! Reference source not ound. of the protocol. 7. PQOL-12 to be performed on Days 1 and 84 only 8. The investigator may at his/her discretion conduct a portion of the assessments scheduled for Day 1 on Day -1. 9. See Appendix 2 of the protocol for a description of the pharmacogenetic assessment. 10. Subjects withdrawing from the study prior to the study assessments on Day 84 will undergo all Day 84 assessments and return for a follow-up visit 30 days following the last dose of investigational product.

33

X X

X X X X X

CONFIDENTIAL

18.2.

Data Displays for Safety Reviews of Cohorts

Data

Demography Study Termination ECG values, Vital signs

Listings Tables Use Excel Provided by GSK Discovery files from Biometrics Eliassen Description X Summary by dose. X Summary by dose. X

Summary of absolute values and change from baseline by dose.

Clinial laboratory values

X

Summary of absolute values and change from baseline by dose.

Adverse Events

X

Physical Examination

X

Summary, by dose, of all Adverse Events and Serious Adverse Events. NA

Plots Provided by GSK Discovery Biometrics Description

NA NA

Plot individual profiles over time (Screening, Day 1, 14, 28 for vitals, Screening, Day 1, 28 for ECGs) For cohort 3 review, plot median profiles for each dose group Plot individual profiles over time (Screening, Day 1, 14, 28) For cohort 3 review, plot median profiles for each dose group NA NA

Notes: 1. 2. 3. 4.

Summaries will only be created for Cohort 3 review Data from previous cohorts will be included for each cohort review. Data from all placebo subjects will be combined for summaries. The format for the summary tables will follow GSK IDSL standards

34

CONFIDENTIAL

18.3.

Psoriasis Area and Severity Index

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

35

Sirtris Pharmaceuticals, A GSK Company Study ID: 7RM

Protocol Number: SRT-2104-013 A Randomized, Double-Blind, PlaceboControlled, Phase IIa Study of the Clinical Activity, Safety, and Tolerability of SRT2104 in Subjects with Moderate to Severe Plaque-Type Psoriasis

Investigator Manual

13 April, 2010

ENGLISH

Final 1.0

TABLE OF CONTENTS PHARMACOGENETIC STUDY ............................................................................................................................... 1 REQUISITION FORM: PHARMACOGENETICS (ROOM TEMPERATURE).................................................. 2 LABORATORY REQUISITION FORM EXAMPLE(S) ........................................................................................ 3 REQUISITION FORM: ROUTINE REQUISITION ............................................................................................. 4 REQUISITION FORM: UNSCHEDULED/RETEST REQUISITION.................................................................. 5 REQUISITION FORM: PHARMACOKINETICS ................................................................................................ 6 REQUISITION FORM: FGF-21 BIOMARKER ................................................................................................... 7 LIVER EVENT ASSESSMENT ................................................................................................................................. 8 WHEN A LIVER EVENT OCCURS ..................................................................................................................... 8 FOR PK (PHARMACOKINETICS) COLLECTION (INITIAL LIVER EVENT ASSESSMENT VISIT).............................................................................................................................................................. 8 REQUISITION FORM: LIVER EVENT ASSESSMENT ..................................................................................... 9 REQUISITION FORM: PHARMACOKINETICS (LIVER EVENT ASSESSMENT)....................................... 10 ORDER OF BLOOD DRAW AND AVOIDING COMMON PROBLEMS......................................................... 11 RECOMMENDED ORDER OF BLOOD DRAW FOR ROUTINE CENTRAL LABORATORY TESTING....................................................................................................................................................... 11 AVOIDING COMMON PROBLEMS – CHEMISTRY PANEL.......................................................................... 12 AVOIDING COMMON PROBLEMS – HEMATOLOGY (CBC: COMPLETE BLOOD COUNT) ........................... 13 AVOIDING COMMON PROBLEMS – URINALYSIS AND DIPSTICK........................................................... 14 AVOIDING COMMON PROBLEMS – COAGULATION TESTS: PT, APTT, FIBRINOGEN ......................... 15 AVOIDING COMMON PROBLEMS – PHARMACOGENETICS (BLOOD SAMPLE)......................................... 16 SPECIMEN COLLECTION AND PREPARATION ............................................................................................. 17 VISIT: SCREENING ........................................................................................................................................... 17 VISIT: VISIT 2 (DAY 1)...................................................................................................................................... 19 VISITS: 3 (DAY 14), 7 (DAY 70) AND FOLLOW-UP (DAY 114) .................................................................... 21 VISITS: 4 (DAY 28) AND 6 (DAY 56)................................................................................................................ 22 VISIT: 5 (DAY 42)............................................................................................................................................... 24 VISIT: 8 (DAY 84) AND EARLY TERMINATION ........................................................................................... 26 VISIT: PHARMACOKINETICS AND (FGF-21) BIOMARKER ....................................................................... 28 VISIT: INITIAL LIVER EVENT ASSESSMENT............................................................................................... 29 VISIT: INITIAL LIVER EVENT ASSESSMENT – PHARMACOKINETICS .................................................. 32 VISIT: LIVER EVENT ASSESSMENT – FOLLOW-UP VISITS (WEEKLY, TWICE WEEKLY, AND TWICE MONTHLY)..................................................................................................................................... 33 SUMMARY: SPECIMENS TO BE RETURNED ............................................................................................... 34 SPECIAL PROCEDURES ........................................................................................................................................ 37 CONVERSION OF RCF (G) TO RPM.................................................................................................................. 37 SPECIMEN LABELING ...................................................................................................................................... 38 BLOOD SMEAR (BLOOD FILM) PROCEDURE .............................................................................................. 39

TO REORDER SUPPLIES ....................................................................................................................................... 40 EXPIRY DATE NOTIFICATION FOR KITS/SUPPLIES ................................................................................... 41 RESULTS REPORTING .......................................................................................................................................... 42 LABORATORY REPORTS .......................................................................................................................... 42 INSTRUCTIONS FOR OBTAINING RESULTS BY PHONE ...................................................................... 42 WHAT KIND OF INFORMATION DO YOU FIND ON YOUR REPORT? ....................................................... 43 QUEST DIAGNOSTICS CLINICAL TRIALS REFERENCE RANGES............................................................ 45 U.S. COLLEGE OF AMERICAN PATHOLOGISTS CERTIFICATE ............................................................... 53 U.S. COLLEGE OF AMERICAN PATHOLOGISTS CERTIFICATE, NICHOLS INSTITUTE ................... 54

PHARMACOGENETIC STUDY Pharmacogenetics is part of this study. Please find below information regarding Pharmacogenetics supplies:

Account Number: Quest Diagnostics Clinical Trials assigns each investigator a unique account number. Each investigator participating in this study will have two investigator account numbers, one for the main portion of the study and another for the Pharmacogenetics portion. Pharmacogenetic Supplies Include: Pharmacogenetic Requisition: To be used when sending the Pharmacogenetic specimen back to the central laboratory. This document will be printed with your Pharmacogenetics account number. Pharmacogenetic Specimen Collection: The specimen collection supplies required to collect Pharmacogenetics samples will be included in one of the visit specific kits provided in your starterpack from Quest Diagnostics Clinical Trials. The Pharmacogenetics sample should be collected at the visit specified in the protocol and on the Specimen Collection pages in this investigator manual. Unless otherwise instructed please collect a sample for PGx only once per participant. Please ensure that the appropriate regulatory and ethics approval and participant’s informed consent is obtained before the Pharmacogenetics sample is drawn. Destruction of PGx Samples: If you require destruction of a PGx sample that has been shipped to Quest Diagnostics Clinical Trials, please fax or email a completed form F-GRD-001 to GlaxoSmithKline's PGx Sample Management: FAX: Email: Please place a copy of the form in the study file. Test Not Performed: If a PGx sample is received at Quest Diagnostics Clinical Trials and is unsuitable for testing, a notification will be sent to indicate that the Test has Not been Performed (TNP). If this occurs, please collect and submit another PGx sample to Quest Diagnostics Clinical Trials if possible. Study Closure: At the end of the study please ensure any Quest Diagnostics Clinical Trials PGx supplies and documents are destroyed. Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: PHARMACOGENETICS (ROOM TEMPERATURE) The TOP copy of this requisition form goes with the room temperature specimens to the central laboratory. The remaining copies are to be retained at your site for your files.

Your account number, name, address, and investigator number will be pre-printed here.

At all visits: complete this box with subject number*, sex, and collection date. * For PGx only. Please use the 3 digits site number, and the last 3 digits of the subject’s number. Please indicate the temperature the samples are stored at site.

Put a label on the tube sent back to the central laboratory. Please fill out the subject number on the label. Discard ALL unused labels. Your protocol number will be printed here. Ensure the requisition for the correct protocol is selected.

The sample type that needs to be sent for this study will be indicated here.

Quest Diagnostics Clinical Trials, 7RM

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LABORATORY REQUISITION FORM EXAMPLE(S)

The requisition form provides very important information for the laboratory. Please send this form to the central laboratory together with the specimens from one subject's visit. This will allow us to identify the specimens upon arrival and perform the relevant study specific tests.

On this form you will find your account number and the requisition number: Account Number: This number is unique, and identifies the principal investigator for this protocol. You can find it in the left top corner on all our documents. Please use this number when contacting us regarding results and services. Requisition Number: Each requisition form and its attached labels have corresponding requisition numbers. These numbers can be found next to your account number. Therefore the labels must be used only for the specimens accompanying that specific requisition form. Discard ALL unused labels. Subject Information: Accurate subject and collection information is important for accurate results assignment and delivery. Please be sure to confirm and record this information at the time of specimen collection.

* Note: the requisition forms illustrated in the manual are EXAMPLES used for illustration only.

Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: ROUTINE REQUISITION The TOP copy of this requisition form goes with the room temperature specimens to the central laboratory. The middle copy goes with the frozen specimens. The remaining copy is to be retained at your site for your files.

Your account number, name, address, and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, collection date and time, and fasting status. Fasting at Visits Screening, 2, 4, 5, 6, 8 and ET is required for the Lipid Profile and HsCRP tests.

All labels are test specific. Put a label on every tube sent to the central laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label.

243415

Indicate the subject visit here. Early termination: specimen collected for patients leaving the study before completion of all visits.

Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: UNSCHEDULED/RETEST REQUISITION The TOP copy of this requisition form goes with the room temperature specimens to the central laboratory. The SECOND BLUE copy goes with the frozen specimens. The remaining copy is to be retained at your site for your files.

Your account number, name, address, and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, collection date and time, and fasting status. Subject needs to be fasting only if submitting samples for Lipid Profiling or HsCRP.

All labels are test specific. Put a label on every tube sent to the central laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label. Discard ALL unused labels.

243715

Unscheduled Visits: Indicate visit type, previous visit, and test(s) requested. Retest: redraw of specimen for a prior visit, to be used in case of tests not performed at a prior visit (e.g. clotted specimen) or to check abnormal results from a prior visit. Early termination: specimen collected for patients leaving the study before completion of all visits. Unscheduled: specimens collected between regular scheduled visits. Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: PHARMACOKINETICS The TOP copy of this requisition form goes with the frozen primary aliquot(s) to the central laboratory. The SECOND BLUE copy goes with the frozen back-up aliquot(s). The remaining copy is to be retained at your site for your files.

Your account number, name, address, and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, and collection date.

Labels are visit specific. All labels are test specific. PK labels are also timepoint specific. Put a label on every tube sent to the central laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label. Discard ALL unused labels.

243714

Indicate the time of the sample collection here. If collecting for more than one timepoint, please fill in the times for all ***Please use only one requisition per visit.*** Indicate the subject visit here. Do not forget to indicate if no sample is sent for a specific PK timepoint.

Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: FGF-21 BIOMARKER The TOP copy of this requisition form goes with the frozen primary aliquot(s) to the central laboratory. The SECOND BLUE copy goes with the frozen back-up aliquot(s). The remaining copy is to be retained at your site for your files.

Your account number, name, address, and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, collection date and time, and fasting status. Fasting status is required at Visits 2, 4, 6 and 8.

Labels are visit specific. All labels are test specific. Put a label on every tube sent to the central laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label. Discard ALL unused labels.

247553

Indicate the subject visit here.

Quest Diagnostics Clinical Trials, 7RM

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LIVER EVENT ASSESSMENT You will receive separate visit specific kits and requisitions for the Liver Event Assessment and required follow-up testing.

WHEN A LIVER EVENT OCCURS A laboratory Client Response Center representative will contact the Study Coordinator/Study Nurse and Principal Investigator, and fax the Alert Report. If a liver event occurs, an initial Liver Event Assessment is required. Please refer to the protocol for specific follow-up instructions. Additional Liver Event specific supplies (one initial assessment visit and two follow-up visits) will automatically be ordered and sent to the site.

FOR PK (PHARMACOKINETICS) COLLECTION (INITIAL LIVER EVENT ASSESSMENT VISIT) Use the visit-specific PK kit supplied for the main study.

Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: LIVER EVENT ASSESSMENT The TOP copy of this requisition form goes with the room temperature specimens to the central laboratory. The BLUE copy goes with the frozen specimens. The remaining copy is to be retained at your site for your files.

Your account number, name, address and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, and collection date and time.

Put a label on every specimen sent back to laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label. Discard ALL unused labels.

243716

Do not forget to indicate if subject resides or has traveled outside the U.S./Canada in the past three months, or if additional testing is needed.

*****SEE PROTOCOL FOR SPECIFIC FOLLOW-UP TESTING INSTRUCTIONS***** ***USE SUPPLIED LIVER EVENT VISIT SPECIFIC KITS. REORDER IF NECESSARY***

Quest Diagnostics Clinical Trials, 7RM

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REQUISITION FORM: PHARMACOKINETICS (LIVER EVENT ASSESSMENT) The BLUE copy of this requisition form goes with the frozen specimens to the central laboratory. The remaining copy is to be retained at your site for your files.

Your account number, name, address and center number will be pre-printed here.

At all visits: complete this box with screening number, subject number, birthdate, sex, and collection date.

Put a label on every specimen sent back to laboratory. Please fill out the screening number and the subject number (V2 and thereafter) on every label. Discard ALL unused labels.

243717

Fill in collection time.

Subject visit is pre-marked.

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ORDER OF BLOOD DRAW AND AVOIDING COMMON PROBLEMS RECOMMENDED ORDER OF BLOOD DRAW FOR ROUTINE CENTRAL LABORATORY TESTING Unless sponsor requirements have indicated otherwise, the following order of blood draw is recommended when drawing blood specimens from a single venipuncture for the most commonly used laboratory testing performed in the central lab for clinical trials. If a tube listed below is not required for the protocol or visit, then disregard the tube(s) and move further down the list to the required tubes. This order of draw can be used for glass tubes, for plastic tubes, or for a mixture of glass and plastic tubes. 1. Blood culture tube 2. Light-blue-top tube (e.g. plasma from coagulation tube, 3.2% sodium citrate tube) 3. Serum tube with rubber stopper in red, speckled red/black or gray/yellow, or with plastic hemogard closures in red, gold, or orange (serum tube with or without gel serum separator) 4. Green-top heparin plasma tubes with or without gel plasma separator 5. Purple/lavender-top EDTA plasma or EDTA CBC/hematology tube 6. Gray-top glycolysis inhibitor tube, sodium fluoride/potassium oxalate tube 7. PAXgene tube for blood RNA or blood DNA Please note: Appropriate safety measures should be taken, including the use of adequate protective equipment, when handling and preparing specimens. Some items referred to below may not be provided by Quest Diagnostics Clinical Trials. Winged collection sets: When using a butterfly (winged) collection set and when a coagulation tube will be the first tube drawn, a small discard tube should be drawn first. This discard tube is used to fill the blood collection set tubing dead space with blood to ensure that the proper ratio of blood to anticoagulant is present in the blue top coagulation tube. The discard tube should be a non-additive tube or another coagulation tube that will then be discarded at the site. Vascular access devices (VAD): Devices such as intravenous lines, heparin or saline lock devices, or indwelling lines or catheters may have fluid in them or fluid flowing through them into the venous system. These devices may be using heparin or saline lock catheters or infusion devices to keep the VAD open or to periodically flush the VAD in order to keep the system non-obstructed and keep the blood from clotting. When these VADs are used for drawing blood for the central laboratory testing, it is recommended that the line be flushed with saline to clear any heparin, if present, from the line, and then an adequate amount of blood be drawn through the VAD and discarded in order to clear it of the fluid or saline. The samples for lab testing must not be diluted with any fluids or contaminated with heparin. The amount of blood drawn through the VAD to clear the fluid or heparin will depend on the nature of the testing that will be performed on the first tube that is subsequently drawn through the VAD. If the testing from the first specimen will be coagulation testing, then the amount of blood drawn and discarded should be 5 mL or a total of 6 times the actual volume of the VAD. If the testing from the first specimen will be non-coagulation testing, then the amount of blood drawn and discarded should be 2 times the volume of the VAD. Arterial blood collection: BD Vacutainer tubes and other tubes that use vacuum in the tube to draw blood from the venous system should not be used to obtain blood directly from the arterial system. Arterial blood must be obtained using an appropriate syringe with or without a needle prior to then placing the blood in any vacuum tube designed for the venous system. Reference: Clinical Laboratory Standards Institute (CLSI) H3-A6 Ed. 2007

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AVOIDING COMMON PROBLEMS – CHEMISTRY PANEL TOPIC

DON’T

DO

Patient preparation e.g. fasting

Ensure that the blood specimen is taken under the correct conditions.

Venipuncture using the BD Vacutainer system

Use the BD Vacutainer blood collection system for consistency and ease of use. Observe sharps and blood borne pathogen precautions.

Correct tube

Don’t use plasma. Plasma comes from an EDTA, citrate fluoride oxalate tube or other plasma tubes and is not the correct specimen type for the serum chemistry panel testing.

Use the correct tube: an SST (Serum Separator Tube) or a plain red top tube can be used depending on what is needed or required in the study.

Syringe and needle

Don’t use a syringe and needle, unless you have to.

Use a safety transfer device such as the BD blood transfer device to transfer the blood. If a syringe with a needle is required to draw the specimen, please refer to your Health and Safety Officer to meet safety precautions for needle, sharps use, and disposal.

Don’t transfer blood from a syringe through the needle into the tube as it may cause hemolysis and is not an accepted safety practice. Drip arm and intravenous fluid drip

Don’t take blood from the arm where fluids are being administered.

Use the other arm if clinically appropriate. Centrifuge after 30 minutes and within 60 minutes of draw for 15 minutes using the following formula to determine the centrifuge RPM required for the 1600 RCF (g). See the “Conversion of RCF to RPM” section for further guidance.

Centrifugation

n = √ [ 1600 / ( 0.00001118 * r ) ] where the n is the RPM to which to set the centrifuge, √ is the square root of the formula within the brackets [ ], and r is the radius distance in cm that is measured from the bottom of the tube when the rotor is spinning, to the center of the rotor.

Sufficient specimen

Provide sufficient specimen: check “Investigator Manual” for volume requirement.

Shipping

Send the specimens to the laboratory promptly as instructed.

Quest Diagnostics Clinical Trials, 7RM

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AVOIDING COMMON PROBLEMS – HEMATOLOGY (CBC: Complete Blood Count) TOPIC

DON’T

DO Use a lavender top EDTA tube for a CBC. No other tube is acceptable.

Correct tube

Syringe and needle

Clotting/clumping

Don’t use a syringe and needle, unless you have to. A slow flow of blood through a fine needle is a cause of partial clotting or fibrin strands.

Transfer the correct volume of blood to the tube. Too much blood may cause clotting due to insufficient anticoagulant. If a syringe with a needle is required to draw specimen, please refer to your Health and Safety Officer to meet established safety precautions. Use the BD Vacutainer system. This ensures correct negative pressure (vacuum) to draw the blood and ensures the correct volume is drawn into each tube. Mix the specimen gently but thoroughly (invert 8-10 times) to mix in the anticoagulant – otherwise you will get partial clotting.

Don’t shake the tube vigorously, as this will cause hemolysis. Don’t leave the specimens at refrigerated temperature overnight until the courier arrives – this may cause platelet clumping.

Don’t allow the specimens to Do keep the specimens at Cellular degradation – ambient room temperatures avoid high/low temperatures be overheated, e.g., left in a car in hot weather or near a while at the investigator site. window in direct sunlight. Don’t put the specimens in the freezer. This will cause hemolysis. Centrifuging CBC specimens

Don’t centrifuge CBC specimens and/or remove some of the plasma. CBC results are whole blood results and specimens must not be centrifuged. Ship the specimens promptly at ambient temperature – they must be analyzed within three days.

Analyze within three days

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AVOIDING COMMON PROBLEMS – URINALYSIS AND DIPSTICK TOPIC Menstrual bleeding

DON’T

DO

It is not recommended to collect a urine specimen during menstruation. Advise the patient how to collect a midstream specimen to avoid contamination with pus or debris from around the urethra.

Mid stream urine (Note: this applies to a noncatheterized subject)

Correct tube – antibacterial preservative tablet

Quest Diagnostics Clinical Trials, 7RM

Don’t discard the preservative tablet in the tube.

Page 14 Final 1.0

Use the correct urinalysis tube. The lab will not accept any other tube.

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

AVOIDING COMMON PROBLEMS – COAGULATION TESTS: PT, aPTT, FIBRINOGEN TOPIC

DON’T

Use the correct tube – light blue top with 3.2% sodium citrate anticoagulant.

Correct tube Syringe and needle

DO

Don’t use a syringe and needle, unless you have to. Don’t transfer blood from a syringe through the needle into the tube as it may cause hemolysis and is not an accepted safety practice.

Remove the needle/transfer the blood gently. If a syringe with a needle is required to draw the specimen, please refer to your Health and Safety Officer to meet established safety precautions. Ensure that the venipuncture is carried out efficiently by an experienced phlebotomist. A messy venipuncture may activate the clotting process and use up clotting factors.

Clean venipuncture

Mix specimen/anticoagulant

Don’t shake the tube vigorously since this will cause hemolysis.

Mix the specimen and anticoagulant gently but thoroughly.

Centrifuge

Don’t transfer the bottom layer of plasma as this contains platelets.

Centrifuge the specimen; remove the plasma without going too near to the cells or you will pick up some of the buffy coat (platelets and white cells). Centrifuge the plasma a second time and do the same as above.

If you are experiencing problems with your PT or aPTT results, here is a recommendation to try. Plasma

Freeze plasma in a non frost-free freezer or on dry ice as soon as possible and send to lab as instructed.

Mistaking serum for plasma

Ensure the coagulation plasma specimen is clearly identified. No other specimen type is acceptable.

Mixing serum/plasma

Quest Diagnostics Clinical Trials, 7RM

Don’t mix serum or any other specimen with the citrate plasma – only citrate plasma is acceptable.

Page 15 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

AVOIDING COMMON PROBLEMS – PHARMACOGENETICS (blood sample) TOPIC

DON’T

DO

Correct tube, volume, and labeling

Use a lavender top EDTA tube for Pharmacogenetics. No other tube is acceptable. Fill the tube completely. Label the tube with the subject number.

Correct requisition form

Use only the correct pharmacogenetic requisition form. Ensure the form selected is printed with the correct protocol number. Use the BD Vacutainer system. This ensures correct negative pressure (vacuum) to draw the blood and ensures the correct volume is drawn into each tube. Immediately after filling the tube, mix the specimen gently but thoroughly (invert 8-10 times) to mix in the anticoagulant – otherwise you will get partial clotting.

Clotting/clumping

Don’t shake the tube vigorously, as this will cause hemolysis.

Cellular degradation – avoid high/low temperatures

Don’t allow the specimens to be overheated, e.g., left in a car in hot weather or near a window in direct sunlight.

Do keep the specimens at ambient room temperatures while at the investigator site, unless authorized by the sponsor to store at -70ºC or colder.

Centrifugation

Don’t centrifuge Pharmacogenetics specimens and/or remove some of the plasma.

Ship the specimen as whole blood.

Unable to collect sample due to subject with a collapsed or poor veins or dehydration

Collect sample at the next scheduled visit. Use the PGx tube from a previous visit’s kit.

Shipping

Ship the specimens promptly at ambient temperature. If storing frozen at site, specimens must be stored at -70ºC or colder and shipped on dry ice.

Quest Diagnostics Clinical Trials, 7RM

Page 16 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

SPECIMEN COLLECTION AND PREPARATION VISIT: SCREENING COLLECT:

(Red/Gray)

(Sky Blue)

(Red/Gray)

Vacutainer Vacutainer

(Gold)

SST SST W ARD

W AR D

A DDR ES S

FO REN AME

AD D RESS

FO RENA ME

W ARD

A DD RESS

9NC 0.105M

FO RE N AME

Vacutainer

TI ME

TI ME

Vacutain er SST

WA R D

AD D RESS

FO RENA ME

WA R D

AD D RESS

FO RENA ME

SEX M/ F

DO B

AM D ATE PM

S EX M/F

DAT E

D OB

DAT E

D OB

TIME AM PM

AM PM

SE X M/ F

AM TI ME PM

AM TI ME PM

SST 3.5 mL

SEX M/ F

SST 8.5 mL

10x

DAT E

SEX M/ F

SST 8.5 mL

D OB

DAT E

D OB

Na CITRATE 4.5 mL

PREPARE:

(Gold) Vacutain er SST

(For women only)

SST 3.5 mL

10x COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES

COAGULATE MIN. 30'/MAX. 60'

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS. TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

(3.5 mL Sarstedt Vial)

PLASMA

(Green)

(Green)

(Green)

(Green)

(Green)

(12x75 Push Cap Tube)

SERUM

SERUM

SERUM

SERUM

SERUM

SERUM

1.5 mL

2 mL

2 mL

1 mL

1 mL

1 mL

1 mL

ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME WITH INR Do not fill tube completely as liquid will expand when frozen

CHEMISTRY WITH LIPIDS

HIV

HBV

HCV

SERUM PREGNANCY (For all females)

FREE-FATTY ACID

Do not fill tube completely as liquid will expand when frozen

FROZEN

ROOM TEMPERATURE

FROZEN

STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 17 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: SCREENING (cont’d) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME AM DA TE PM SEX M/F

SEE SPECIAL PROCEDURE SECTION

TTM M

BD BD Vacutainer Vacutainer

D OB

2 BLOOD SMEARS / AIR -DRY

(Lavender) K3E 7.5%

FLUORIDE OXALATE 2 mL

0.040

10x

2mL

URINE CONTAINER

EDTA 2.0 mL

PREPARE:

COMPLETELY AND GENTLY INVERT 10 TIMES

10x

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

COMPLETELY AND GENTLY INVERT 10 TIMES CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

(Lavender) K3E 7.5% 0.040

URINALYSIS

BD BD Vacutainer Vacutainer TTMM

(Yellow)

(Green) AIR-DRY NON-STER ILE

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

2mL

WHOLE BLOOD

SLIDE MAILER

PLASMA

2 mL

1 mL HEMATOLOGY

NON-FASTING PLASMA GLUCOSE

URINE VIAL WITH PRESERVATIVE TABLET

10 mL

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 18 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: VISIT 2 (DAY 1) COLLECT:

(Red/Gray)

(Sky Blue) Vacutainer

W ARD

A DD RESS

FO RE N AME

9NC 0.105M

2 BLOOD SMEARS / AIR -DRY

(Lavender)

(Gold)

SST

Vacutainer W AR D

A DD RES S

FO R EN AME

SEE SPECIAL PROCEDURE SECTION

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

TI ME

Vacutain er SST W AR D

A DD RESS

FO RE N AME

DAT E

D OB

S EX M/F

TIME AM PM

AM DATE PM

D OB

SEX M/F AM TI ME PM DAT E

D OB

2mL

S EX M/F

Na CITRATE 4.5 mL

SST 8.5 mL

10x

SST 3.5 mL

EDTA 2.0 mL

10x

10x

PREPARE:

RETURN:

COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES

COAGULATE MIN. 30'/MAX. 60'

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

(3.5 mL Sarstedt Vial)

(Green)

(Green)

(Lavender)

(Green)

AIR-DRY

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

2mL

PLASMA

SERUM

SERUM

SERUM

1.5 mL

2 mL

1 mL

1 mL

ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME WITH INR

CHEMISTRY WITH LIPIDS

C-REACTIVE PROTEIN

FREE-FATTY ACID

Do not fill tube completely as liquid will expand when frozen

FROZEN STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

WHOLE BLOOD

2 mL

SLIDE MAILER

HEMATOLOGY

Do not fill tube completely as liquid will expand when frozen

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

FROZEN

ROOM TEMPERATURE

STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting FGF-21 sample. Quest Diagnostics Clinical Trials, 7RM

Page 19 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: VISIT 2 (DAY 1) (cont’d) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME AM DA TE PM

D OB

(Lavender)

SEX M/F

BD Vacutainer

FLUORIDE OXALATE 2 mL

TM

K2E 18mg

10x

10 m l

URINE CONTAINER

PLASTIC K2 EDTA 10 mL

PREPARE:

Please protect samples from bright light and ship within 24 hours.

10x

COMPLETELY AND GENTLY INVERT 10 TIMES

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

(Lavender)

URINALYSIS

BD Vacutainer

(Yellow)

(Green)

TM

K2E 18mg

NON-STER ILE

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

10 m l

PLASMA

WHOLE BLOOD

10 mL

1 mL

PHARMACOGENETICS

NON-FASTING PLASMA GLUCOSE

URINE VIAL WITH PRESERVATIVE TABLET

10 mL

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting FGF-21 sample. Quest Diagnostics Clinical Trials, 7RM

Page 20 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISITS: 3 (DAY 14), 7 (DAY 70) AND FOLLOW-UP (DAY 114) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME

(Gold)

2 BLOOD SMEARS / AIR -DRY

AM DA TE PM SEX M/F

SST WA RD

ADD RE SS

FO R ENAME

TIME

FLUORIDE OXALATE 2 mL

SEE SPECIAL PROCEDURE SECTION

TTM M

BBD D Vacutainer Vacutainer

D OB

(Lavender)

Vacutainer

K3E 7.5%

AM DA TE PM

D OB

0.040

SEX M/F

10x

2mL

SST 5.0 mL

PREPARE:

10x

EDTA 2.0 mL

10x

COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES COAGULATE MIN. 30'/MAX. 60'

URINE CONTAINER

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

COMPLETELY AND GENTLY INVERT 10 TIMES CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

BBD D Vacutainer VacutainerTTMM

K3E 7.5% 0.040

(Yellow)

(Green)

URINALYSIS

(Green)

(Lavender) AIR-DRY

NON-STER IL E

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

2mL

SERUM

1.5 mL CHEMISTRY

WHOLE BLOOD

SLIDE MAILER

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

2 mL

1 mL HEMATOLOGY

10 mL

NON-FASTING PLASMA GLUCOSE

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 21 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISITS: 4 (DAY 28) AND 6 (DAY 56) COLLECT:

(Red/Gray)

(Lavender)

2 BLOOD SMEARS / AIR -DRY SEE SPECIAL PROCEDURE SECTION

Vacutainer SST WA RD

AD D RESS

FO RENA ME

TTM M

BD BD Va Vacuta cutainer i ner

K3E 7.5% 0.040

TI ME D ATE

DO B

SEX M/ F

AM PM

2mL

EDTA 2.0 mL

SST 8.5 mL

10x

PREPARE:

10x

COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES

COAGULATE MIN. 30'/MAX. 60'

NO FURTHER PREPARATION

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS. TRANSFER WITH A PIPETTE

RETURN:

(Lavender) (Green)

(Green)

BD BD Va Vacuta cutainer i ner TTMM

K3E 7.5% 0.040

AIR-DRY

2mL

SERUM

WHOLE BLOOD

SERUM

1.5 mL

1 mL

CHEMISTRY

C-REACTIVE PROTEIN

SLIDE MAILER

2 mL HEMATOLOGY

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting PK and FGF-21 samples.

Quest Diagnostics Clinical Trials, 7RM

Page 22 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISITS: 4 (DAY 28) AND 6 (DAY 56) (cont’d) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME AM DA TE PM

D OB

SEX M/F

FLUORIDE OXALATE 2 mL

10x

PREPARE:

URINE CONTAINER

COMPLETELY AND GENTLY INVERT 10 TIMES

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

TRANSFER WITH A PIPETTE (Yellow) URINALYSIS

(Green) NON-STER ILE

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

1 mL

10 mL

NON-FASTING PLASMA GLUCOSE

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting PK and FGF-21 samples. Quest Diagnostics Clinical Trials, 7RM

Page 23 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: 5 (DAY 42) COLLECT:

(Red/Gray)

(Sky Blue)

2 BLOOD SMEARS / AIR -DRY

(Lavender)

Vacutainer SST WA RD

AD D RESS

9NC 0.105M W AR D

FO REN AME

A DDR ES S

SEE SPECIAL PROCEDURE SECTION

FO RENA ME

Vacutainer

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

TI ME D ATE

DO B

DO B

AM D ATE PM

SEX M/ F

TIME AM PM

SE X M/ F

2mL

Na CITRATE 4.5 mL

SST 8.5 mL

10x

EDTA 2.0 mL

10x

10x

PREPARE:

COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

(3.5 mL Sarstedt Vial)

COAGULATE MIN. 30'/MAX. 60'

(Green)

(Lavender)

(Green)

AIR-DRY

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

2mL

PLASMA

SERUM

2 mL

1 mL

ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME WITH INR

CHEMISTRY WITH LIPIDS

FREE-FATTY ACID

1.5 mL Do not fill tube completely as liquid will expand when frozen

FROZEN STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

SERUM

WHOLE BLOOD

2 mL

SLIDE MAILER

HEMATOLOGY

Do not fill tube completely as liquid will expand when frozen

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

FROZEN

ROOM TEMPERATURE

STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Page 24 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: 5 (DAY 42) (cont’d) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME AM DA TE PM

D OB

SEX M/F

FLUORIDE OXALATE 2 mL

10x

PREPARE:

URINE CONTAINER

COMPLETELY AND GENTLY INVERT 10 TIMES

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

TRANSFER WITH A PIPETTE (Yellow) URINALYSIS

(Green) NON-STER IL E

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

1 mL

10 mL

NON-FASTING PLASMA GLUCOSE

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 25 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: 8 (DAY 84) AND EARLY TERMINATION COLLECT:

(Red/Gray)

(Sky Blue) Vacutainer

W ARD

A DD RESS

FO RE N AME

9NC 0.105M

2 BLOOD SMEARS / AIR -DRY

(Lavender)

(Gold)

SST

Vacutainer W AR D

A DD RES S

FO R EN AME

SEE SPECIAL PROCEDURE SECTION

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

TI ME

Vacutain er SST W AR D

A DD RESS

FO RE N AME

DAT E

D OB

S EX M/F

TIME AM PM

AM DATE PM

D OB

SEX M/F AM TI ME PM DAT E

D OB

2mL

S EX M/F

Na CITRATE 4.5 mL

SST 8.5 mL

10x

SST 3.5 mL

EDTA 2.0 mL

10x

10x

PREPARE:

RETURN:

COMPLETELY AND GENTLY INVERT 10 TIMES

COMPLETELY AND GENTLY INVERT 10 TIMES

COAGULATE MIN. 30'/MAX. 60'

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

NO FURTHER PREPARATION

TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

(3.5 mL Sarstedt Vial)

(Green)

(Green)

(Lavender)

(Green)

AIR-DRY

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

2mL

PLASMA

SERUM

SERUM

SERUM

1.5 mL

2 mL

1 mL

1 mL

ACTIVATED PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME WITH INR

CHEMISTRY WITH LIPIDS

C-REACTIVE PROTEIN

FREE-FATTY ACID

Do not fill tube completely as liquid will expand when frozen

FROZEN STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

WHOLE BLOOD

SLIDE MAILER

2 mL

HEMATOLOGY

Do not fill tube completely as liquid will expand when frozen

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

FROZEN

ROOM TEMPERATURE

STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting PK and FGF-21 samples. Quest Diagnostics Clinical Trials, 7RM

Page 26 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISITS: 8 (DAY 84) AND EARLY TERMINATION (cont’d) (Grey)

COLLECT: Vacutainer FX 12.5mg 10mg W AR D

A DD RE SS

FO R EN AME

TIME AM DA TE PM

D OB

SEX M/F

FLUORIDE OXALATE 2 mL

10x

PREPARE:

URINE CONTAINER

COMPLETELY AND GENTLY INVERT 10 TIMES

TRANSFER 10 mL MIDSTREAM URINE FRESHLY VOIDED WITH A PIPETTE

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

TRANSFER WITH A PIPETTE (Yellow) URINALYSIS

(Green) NON-STER ILE

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINSURINE PRESERVA-TIVE TABLET (mercuic

acid) .

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

1 mL

10 mL

NON-FASTING PLASMA GLUCOSE

URINALYSIS (Optional; submit only if dipstick is positive for any analyte)

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

NOTE: Please see the Pharmacokinetics and (FGF-21) Biomarker section for instructions for collecting PK and FGF-21 samples. Quest Diagnostics Clinical Trials, 7RM

Page 27 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: PHARMACOKINETICS AND (FGF-21) BIOMARKER NOTE:

A total of five blood samples (6 mL each) will be obtained from each subject over the course of the study for determination of SRT2104 plasma concentrations. The samples can be taken at Visits 4, 6, and 8. Multiple PK samples can be taken during one visit provided the sampling timepoint windows as described below are observed and no 2 samples are separated by less than 1 hour. (Green)

(Green)

Vacutainer

Vacutainer

LH 1 45 I.U.

LH 145 I.U . WAR D

ADD RESS

F OR ENAM E

WAR D

ADD RESS

F OR ENAM E

COLLECT:

T IM E

T IM E

DAT E

D OB

DAT E

D OB

AM PM

SEX M /F

AM PM

SEX M /F

(Subjects must be fasting)

LITHIUM HEPARIN 6.0 mL

LITHIUM HEPARIN 6.0 mL

10x

10x

Timepoints: COMPLETELY AND GENTLY INVERT 10 TIMES AND PLACE IMMEDIATELY IN AN ICE BATH

PREPARE:

CENTRIFUGE AT 1500 RCF (g) FOR 15 MINS. AT 4°C WITHIN 30 MINS. OF COLLECTION

Visits:

 Pre-dose  0.5-2.0 Hr Post-dose  3.0-6.0 Hr Post-dose  6-22 Hr Post-dose* *2 samples must be collected; please draw 2 lithium heparin tubes

(1.8 Nunc Cryovial)

PLASMA

1 mL

PHARMACOKINETICS

Visit 2, Day 1 Visit 4, Day 28 Visit 6, Day 56 Visit 8, Day 84

CENTRIFUGE AT 1500 RCF (g) FOR 15 MINS. AT 4°C WITHIN 30 MINS. OF COLLECTION

(1.8 Nunc Cryovial)

(1.8 Nunc Cryovial)

PLASMA

PLASMA

1 mL

PHARMACOKINETICS BACKUP

   

TRANSFER WITH A PIPETTE

TRANSFER WITH A PIPETTE

RETURN:

COMPLETELY AND GENTLY INVERT 10 TIMES AND PLACE IMMEDIATELY IN AN ICE BATH

1 mL

FGF-21 BIOMARKER

Do not fill tube completely as liquid will expand when frozen

(1.8 Nunc Cryovial)

PLASMA

1 mL

FGF-21 BIOMARKER BACKUP

FROZEN PLEASE DOCUMENT IN THE SAMPLE INVENTORY IF A REFRIGERATED CENTRIFUGE IS NOT AVAILABLE AND HANDLE THE SAMPLES THE SAME WAY AS DESCRIBED ABOVE. STORE IN AN UPRIGHT POSITION AT -20°C ON SITE AND SEND ON DRY ICE, AT THE END OF THE STUDY. PLEASE SEND THE BACKUP SAMPLES IN A DIFFERENT SHIPMENT.

Quest Diagnostics Clinical Trials, 7RM

Page 28 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: INITIAL LIVER EVENT ASSESSMENT (Red/Gray)

COLLECT:

(Red/Gray)

(Red/Gray)

Vacutainer

Vacutai ner

Vacutainer

SST

SST

SST WAR D

A DD RES S

FOR E N AM E

WAR D

A DD RES S

FOR E N AM E

WAR D

A DD RES S

FOR E N AM E

TI M E

TI M E

TI M E

DA T E

D OB

DA T E

D OB

DA T E

D OB

SEX M /F

SEX M /F

SEX M /F

AM PM

AM PM

AM PM

SST 8.5 mL

SST 8.5 mL

SST 8.5 mL

Only needed if subject resides or has traveled outside of U.S./Canada in the past three months.

10x PREPARE:

COMPLETELY AND GENTLY INVERT 10 TIMES COAGULATE MIN. 30'/MAX. 60'

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS. TRANSFER WITH A PIPETTE

RETURN: (Green)

SERUM

(Green)

SERUM

(Green)

SERUM

(12x75 Push Cap Tube)

SERUM

(12x75 Push Cap Tube)

SERUM

(Green)

(12x75 Push Cap Tube)

SERUM

SERUM

(12x75 Push Cap Tube)

SERUM

1.0 mL

1.0 mL

0.5 mL

1.0 mL

0.5 mL

0.5 mL

2.5 mL

0.5 mL

CHEMISTRY

HEPATITIS B SURF Ag

HEPATITIS B CORE Ab IgM

HEPATITIS A IgM Ab

CMV IgM Ab

EBV IgM Ab

HEPATITIS C VIRUS RNA

HEPATITIS E IgM

Do not fill tube completely as liquid will expand when frozen

ROOM TEMPERATURE

FROZEN STORE IN AN UPRIGHT POSITION AT –20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 29 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: INITIAL LIVER EVENT ASSESSMENT (cont'd) (Red/Gray)

COLLECT: Vacutainer SST WA RD

A D DR E SS

FO REN A ME

TIME D ATE

D OB

SE X M/F

AM PM

SST 8.5 mL

10x PREPARE:

COMPLETELY AND GENTLY INVERT 10 TIMES COAGULATE MIN. 30'/MAX. 60'

Only needed when ALT > or = 3X ULN AND Total Bilirubin > or = 2X ULN (> 35% Direct).

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS.

RETURN:

TRANSFER WITH A PIPETTE (12x75 Push Cap Tube)

SERUM

(12x75 Push Cap Tube)

SERUM

(12x75 Push Cap Tube)

SERUM

0.5 mL

0.5 mL

1.0 mL

ANA SCREEN WITH REFLEX TO TITER AND PATTERN

ACTIN (ANTI-SMOOTH MUSCLE Ab)

TYPE 1 ANTI-LIVER KIDNEY MICROSOMAL Ab

Do not fill tube completely as liquid will expand when frozen

FROZEN STORE IN AN UPRIGHT POSITION AT –20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 30 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: INITIAL LIVER EVENT ASSESSMENT (cont'd) COLLECT:

2 BLOOD SMEARS / AIR -DRY

(Lavender)

SEE SPECIAL PROCEDURE SECTION

TTM M

BD BD Vacutainer Vacutainer

K3E 7.5% 0.040

2mL

EDTA 2.0 mL

10x

PREPARE: COMPLETELY AND GENTLY INVERT 10 TIMES

NO FURTHER PREPARATION

RETURN:

(Lavender) AIR-DRY

BD BD Vacutainer Vacutainer TTMM

K3E 7.5% 0.040

2mL

WHOLE BLOOD

SLIDE MAILER

2 mL HEMATOLOGY

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 31 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: INITIAL LIVER EVENT ASSESSMENT – PHARMACOKINETICS (Green)

COLLECT:

Vacutaine LH 145 r I. U. FO RENAME

ADD RESS

WA RD AM T IME PM DAT E

DOB

SEX M/F

LITHIUM HEPARIN 4.0 mL

10x PREPARE:

COMPLETELY AND GENTLY INVERT 10 TIMES

CENTRIFUGE AT 1500 RCF (g) FOR 10 MINS.

RETURN:

TRANSFER WITH A PIPETTE

NUNC

(1.8 mL Nunc Cryovial)

PLASMA

1.0 mL PK

Do not fill tube completely as liquid will expand when frozen

FROZEN STORE IN AN UPRIGHT POSITION AT –20°C ON SITE AND SEND ON DRY ICE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 32 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT: LIVER EVENT ASSESSMENT – FOLLOW-UP VISITS (WEEKLY, TWICE WEEKLY, AND TWICE MONTHLY) (Gold)

COLLECT:

Vacutainer SST WARD

ADD RE SS

FORE NAM E

TI ME AM DAT E PM

DOB

S EX M/ F

SST 3.5 mL

10x

PREPARE:

See Protocol for Specific Follow-Up Testing Instructions.

COMPLETELY AND GENTLY INVERT 10 TIMES COAGULATE MIN. 30'/MAX. 60'

RETURN:

CENTRIFUGE AT 1600 RCF (g) FOR 15 MINS. TRANSFER WITH A PIPETTE (Green)

SERUM

1.0 mL CHEMISTRY

ROOM TEMPERATURE SEND AT ROOM TEMPERATURE ON THE DAY OF COLLECTION

Quest Diagnostics Clinical Trials, 7RM

Page 33 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

SUMMARY: SPECIMENS TO BE RETURNED VISIT(S)

FROZEN

ROOM TEMPERATURE (Green)

(Green) (12x75 Push Cap Tube)

K3E 15% 0.054 WA RD

AD DRE SS

FO RENA ME

TI ME

x3

(Lavender) Vacutainer

DO B

ADMATE PM SEX M/F

SCREENING

SERUM

SERUM

SERUM

(For all females)

WHOLE BLOOD

(3.5 mL Sarstedt Vial)

(Yellow)

(Green)

(Green)

SLIDE MAILER

URINALYSIS STABILIZED SAMPLE FOR URINALYSIS ONLY . CONTAINS URINE PRESERV A-TIVE TABLET (mercuic

acid).

NON-STERILE

PLASMA

SERUM

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

Optional; submit only if dipstick is positive for any analyte

(Green)

(Lavender)

(Lavender)

Vacutainer

Vacutainer

K3E 15%

K3E 15%

0.054

WAR D TIM E

DO B

DO B SEX M/ F

SEX M/ F

VISIT 2 (DAY 1)

ADD R ES S

TIM E

SERUM

FO R ENAME

WAR D

ADD R ES S

FO R ENAME

x2

0.054

WHOLE BLOOD

SLIDE MAILER

WHOLE BLOOD

(Yellow)

(Green)

Please protect samples from bright light and ship within 24 hours. (Green) (3.5 mL Sarstedt Vial)

URINALYSIS NON-STERILE

acid).

STABILIZED S AMP LE FOR URINALYSIS ONLY. CONTAINS URINE PRESE RVA-TIVE TABLET (mercuic

PLASMA

PLASMA

SERUM

URINE VIAL WITH PRESERVATIVE TABLET Optional; submit only if dipstick is positive for any analyte

Quest Diagnostics Clinical Trials, 7RM

Page 34 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT(S)

FROZEN

ROOM TEMPERATURE (Green)

(Yellow)

(Green) URINALYSIS

(Lavender) Vacutainer K3E 15% 0.054 W ARD

A DDR ESS

FO RE N AME

S EX M/ F

WHOLE BLOOD

SLIDE MAILER

acid).

NON-STERILE

AM DAT E PM

D OB

SERUM

STABILIZED S AMPLE FOR URINALYSIS ONLY. CO NTAINS URINE PRESERV A- TIVE TABLET (mercuic

TIM E

3 (DAY 14), 7 (DAY 70) AND FOLLOW-UP (DAY 114)

NOT APPLICABLE

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

Optional; submit only if dipstick is positive for any analyte

(Green)

(Yellow)

(Green) URINALYSIS

(Lavender) Vacutainer K3E 15% 0.054 W ARD

A DDR ESS

FO RE N AME

acid).

NON-STERILE

AM DAT E PM

D OB

SEX M/F

SERUM

WHOLE BLOOD

SLIDE MAILER

STABILIZED S AMP LE FOR URINALYSIS ONLY. CONTAINS URINE PRESE RVA- TIVE TABLE T (mercuic

TIME

x2

4 (DAY 28) AND 6 (DAY 56)

NOT APPLICABLE

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

Optional; submit only if dipstick is positive for any analyte

(Green)

(Yellow)

(Green)

(Green)

URINALYSIS

(Lavender) Vacutainer K3E 15%

(3.5 mL Sarstedt Vial)

0.054 WAR D

ADD R ES S

FO R ENAME

acid).

NO N-STERILE

DO B

STABILIZED SAMPLE FOR URINALYS IS ONLY. CONTAINS URINE PRE SERVA-TIVE TABLET ( mercuic

TIM E

5 (DAY 42)

SEX M/ F

SERUM

WHOLE BLOOD

SLIDE MAILER

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

Optional; submit only if dipstick is positive for any analyte

(Green) K3E 15% W AR D

A DDR ES S

FO RE N AME

S EX M/ F

WHOLE BLOOD

SLIDE MAILER

acid).

NON-STERILE

DO B

SERUM

STABILIZED SAMPLE FOR URINALYSIS ONLY. CONTAINS URI NE PRESE RVA-TIVE TABLET (mercuic

TIM E

x2

URINE VIAL WITH PRESERVATIVE TABLET

PLASMA

Optional; submit only if dipstick is positive for any analyte

Quest Diagnostics Clinical Trials, 7RM

(Green)

URINALYSIS

Vacutainer 0.054

8 (DAY 84) AND EARLY TERMINATION

Page 35 Final 1.0

SERUM

(Yellow)

(Green)

(Lavender)

PLASMA

(3.5 mL Sarstedt Vial)

PLASMA

SERUM

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

VISIT(S)

FROZEN

ROOM TEMPERATURE (1.8 Nunc Cryovial)

PHARMACOKINETICS AND (FGF-21) BIOMARKER

NOT APPLICABLE

(1.8 Nunc Cryovial)

(1.8 Nunc Cryovial)

x5 PLASMA (Pharmacokinetic)

(1.8 Nunc Cryovial)

x5 PLASMA (FGF-21 Biomarker)

PLASMA (Pharmacokinetic)

PLASMA (FGF-21 Biomarker)

(BACK-UPS) (Green) (Green)

(Lavender)

x3

x3

K3E 15% 0.054 W AR D

A D DRESS

F ORE N A ME

SERUM (12x75 Push Cap Tube)

TI ME D OB

S EX M/ F

SERUM

WHOLE BLOOD

SLIDE MAILER

x3 SERUM

NOT APPLICABLE

NUNC

INITIAL LIVER EVENT ASSESSMENT – PHARMACOKINETICS

Quest Diagnostics Clinical Trials, 7RM

(12x75 Push Cap Tube)

Vacutainer

INITIAL LIVER EVENT ASSESSMENT

LIVER EVENT ASSESSMENT – FOLLOW-UP VISITS (WEEKLY, TWICE WEEKLY, AND TWICE MONTHLY)

(12x75 Push Cap Tube)

SERUM Hepatitis E IgM only needed if subject resides or has traveled outside of the U.S./Canada in the past three months.

SERUM Only needed when ALT > or = 3X ULN AND Total Bilirubin > or = 2X ULN (> 35% Direct)

(1.8 mL Nunc Cryovial)

PLASMA

(Green)

NOT APPLICABLE SERUM

Page 36 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

SPECIAL PROCEDURES CONVERSION OF RCF (g) TO RPM Fixed bucket centrifuge Consult the manufacturer’s instructions that were received with the fixed bucket centrifuge or that are available on the manufacturer’s website to determine how the RPM or speed settings of the centrifuge are related to the RCF (g) produced during centrifugation. Swinging bucket centrifuge Use the following formula to determine the centrifuge RPM for the 1600 RCF (g) that is recommended:

RCF (g)= 0.00001118 x r x N2 N = square root of [ RCF (g) / ( 0.00001118 x r ) ] RCF (g) = r = N

=

Relative Centrifugal Force (g) Rotating radius in centimeters (radius distance in cm that is measured from the bottom of the swing bucket in the horizontal position to the center of the rotor) Rotating speed in revolutions per minute (RPM)

Centrifuge Rotor Radius Measurement: Using a ruler determine your centrifuge’s radius of rotation (cm) by measuring the distance from the center of the centrifuge rotor to the bottom of the swing bucket when the bucket is in the horizontal position. See illustration.

Centrifuge RPMs required given rotor length and the RCF (g) required Rotor radius RCF (g) In mm ↓ In cm ↓ 1000 RCF(g) 1200 RCF(g) 1400 RCF(g) 1500 RCF(g) 1600 RCF(g) 1800 RCF(g) 2000 RCF(g) RPMs ↓ --> 3790 100 10 3000 3280 3540 3670 4020 4230 3460 120 12 2740 3000 3240 3350 3670 3870 3200 140 14 2530 2770 3000 3100 3400 3580 3000 160 16 2370 2600 2800 2900 3180 3350 2820 180 18 2230 2450 2640 2740 3000 3160 2680 200 20 2120 2320 2510 2600 2840 3000 2560 220 22 2020 2210 2390 2470 2710 2860 2450 240 24 1940 2120 2290 2370 2600 2740 2350 260 26 1860 2040 2200 2280 2490 2630 2270 280 28 1790 1960 2120 2190 2400 2530 2190 300 30 1730 1900 2050 2120 2320 2450 2030 350 35 1600 1760 1900 1960 2150 2270 1900 400 40 1500 1640 1770 1840 2010 2120 1790 450 45 1410 1550 1670 1730 1900 2000 1700 500 50 1340 1470 1590 1640 1800 1900 Quest Diagnostics Clinical Trials, 7RM

Page 37 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

SPECIMEN LABELING 1.

Fill out the required information on the requisition label.

2.

Label the tubes at the time of collection and confirm that subject identification and other required information is correct.

3.

When applying the label, place the label in a vertical position. Do not wrap the label around the tube horizontally.

4.

Do not adhere the label on the cap of the tube. Do not cover any written information with the label.

5.

Adhere the label to the tube as shown below:

Acct ########

Req ######

LABEL

WRONG

Requisition Label (Apply to Vial) Acct ########

Req ######

Wrap vertically around upper portion of vial

Quest Diagnostics Clinical Trials, 7RM

LABEL

Acct ########

Req ######

LABEL

Page 38 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

BLOOD SMEAR (BLOOD FILM) PROCEDURE Using a lead pencil, write the subject identification and collection date on the frosted end of the slide. Always wear appropriate gloves for handling of the tube, Diff-Safe, and slides. The Diff-Safe dispenser is to be inserted through the stopper of an EDTA tube held in the upright position. After mixing the blood, turn the tube upside down and press moderately on the slide within one centimeter of the frosted end. The instant the drop appears, discontinue pressure. If the drop fails to appear, check specimen for clots. E ID SL R PE UP

Blood

Blood

Using another slide as the upper slide, place the upper slide at a 30 degree angle halfway down the slide from the drop of blood.

Drag the upper slide into the drop of blood and allow the blood to disperse along the edge of the upper slide.

Push the upper slide forward towards the non-frosted end to smear the blood smoothly over the bottom slide. The smear should cover approximately half the slide with a gradual transition from thick to thin. No ridges or streaks should be present and the end (called the "feather edge") should be smooth and even. The smear should be labelled on the frosted end of the slide with the patient's identification and collection date. AIR-DRY

Quest Diagnostics Clinical Trials, 7RM

Proceed the same way for the second slide. Allow both of the slides to air-dry. Carefully remove Diff-Safe dispenser from EDTA tube and discard the Diff-Safe in a proper sharps container. Attach the requisition labels to the slide mailers.

Page 39 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

TO REORDER SUPPLIES Your account number, name and address will be pre-printed here. In order to reduce the number of resupply shipments to your site, where possible, please order additional material for 3 months at a time! Indicate your name, the date of ordering, and the date the supplies are needed. We will ship resupplies within five working days of receiving the request. Please note this does not include transport time, which will vary by country of destination. Upon successful receipt and processing of your reorder, our system will automatically generate a fax confirmation to your site with your order number.

Fill out the quantity of the items you require in this column. HOW TO PLACE YOUR ORDER: Fax the completed form to our dedicated fax for client reorders as indicated in the “Contact & Shipping Information” Appendix. OR Call the central laboratory by using the phone numbers available in the “Contact & Shipping Information” Appendix. Quest Diagnostics Clinical Trials, 7RM

Page 40 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

EXPIRY DATE NOTIFICATION FOR KITS/SUPPLIES You will receive Expiry Date Notifications via fax. Please review your stock immediately and reorder as needed.

ATTN: EXPIRY NOTICE!

!

Urgent Action Required Supplies Approaching Expiration

FROM:

TO:

Tel: Fax:

Tel: Fax:

To: Study: Protocol: Sponsor:

!

Investigator Name Study Code Protocol # Company Name

Our records indicate that the following kits/supplies have expired or are approaching their expiry date. Please destroy these kits/supplies on or after the dates given below. If replacement kits are required, complete and return a reorder form (using the procedure explained in the investigator manual) either to the address or fax number noted above. Faxing the form will enable us to provide the most expeditious response to your request. Please allow 10 days for delivery of replacement kits.

Kit Number/Supply Number

Description

Lot Number

Expiry Date

If this study has batched or frozen samples, please ensure that they have been returned to Quest Diagnostics Clinical Trials as per instructions.

This box will describe supplies that have expired or are approaching expiration. Please use the reorder form to order more supplies.

► Expired kits should not be returned to Quest Diagnostics but should be disposed of on site.

Laboratory maintains a dedicated fax number to expedite your reorder. Please fax your reorder to U.S.: E.U.:

Quest Diagnostics Clinical Trials, 7RM

Page 41 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

RESULTS REPORTING

LABORATORY REPORTS Copies of reports will be faxed. Fax equipment should be left “on” as reports are faxed 24 hours a day. For combination voice and fax equipment, the fax option should be left “on” when the voice option is not in use. INSTRUCTIONS FOR OBTAINING RESULTS BY PHONE Results for safety tests are available in our system within 24-48 hrs of receipt of specimens. To obtain a particular result, please call our Client Response Centre (CRC) using the numbers available in the “Contact & Shipping Information” Appendix. In order to help our CRC staff assist you more effectively, please have the following information ready when you call: a) Your 8-digit ACCOUNT NUMBER

All this information can be obtained from your copy of the requisition form

b) The 6-digit REQUISITION NUMBER c) Subject number d) Date of collection

! INFORM THE CENTRAL LABORATORY OF ANY CHANGE IN YOUR ADDRESS, PHONE AND FAX NUMBERS !

Quest Diagnostics Clinical Trials, 7RM

Page 42 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

WHAT KIND OF INFORMATION DO YOU FIND ON YOUR REPORT? 1st line: screening number, age, gender 2nd line: page number, requisition number, collection date/time, log-in date, reporting date/time

Your name, address and account number Demographic block including protocol number, Quest Diagnostics Clinical Trials study ID, center number, screening number, subject number, birthdate, visit number, visit type, and fasting status Green column: values in range Pink column: values out of range Units of the results and reference ranges (determined by Quest Diagnostics Clinical Trials). Note: should either the birthdate or the gender be missing, generic reference ranges will be reported. Report status:  Partial: generated when first part of results is available  Temporary: generated when all results available but at least one item of information is missing or incorrect (demographics or specimen information)  Final: generated when all results are available and all demographics and specimen information is complete and correct  Amended: generated when information has been changed or corrected

Quest Diagnostics Clinical Trials, 7RM

Page 43 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

WHAT KIND OF INFORMATION DO YOU FIND ON YOUR REPORT?

E

Exclusion: exclusion criteria as defined in the protocol.

Sponsor-Defined Alerts: S = Check Protocol for Exclusion Criteria or Withdrawal F = Check Protocol for Exclusion Criteria

Specimen Retained: storage specimen received and stored.

Clinical Significance Summary: tabulation of all laboratory values that fall outside the reference ranges, exclusion criteria, telephone alerts, and F and S flags. ** Telephone Alert: life threatening values as defined by Quest Diagnostics Clinical Trials or sponsor-defined alerts will be called and/or faxed to the investigator. Quick Trend: summary of test results. Baseline results appear in the left column, followed by consecutive visits.

Quest Diagnostics Clinical Trials, 7RM

Page 44 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

QUEST DIAGNOSTICS CLINICAL TRIALS REFERENCE RANGES CHEMISTRY PANEL – CONVENTIONAL UNITS

ANALYTE

UNITS

REFERENCE RANGES

E

EXCLUSION CRITERIA

F,S

ALERT RANGE

** PHONE ALERT RANGE

SODIUM

MEQ/L

135-146 (0+y)

< 120 or > 160

POTASSIUM

MEQ/L

3.5-5.3 (13+y)

< 2.8 or > 6.5

CHLORIDE

MEQ/L

95-108 (0+y)

UREA NITROGEN

MG/DL

7-25 (13-64y) 7-30 (65+y)

CREATININE

MG/DL

0.5-1.4 (13+y)

CALCIUM

MG/DL

8.5-10.3 (3+y)

< 6.0 or > 13.0

MAGNESIUM

MEQ/L

1.2-2.0 (0+y)

< 0.7 or > 5.0

URIC ACID

MG/DL

M : 4.0-8.5 (13+y) F : 2.5-7.5 (13+y)

ALT (SGPT)

U/L

0-48 (13+y)

F: > 96

AST (SGOT)

U/L

0-42 (3-64y) 0-55 (65+y)

F: > 84 F: > 110

BILIRUBIN, TOTAL

MG/DL

0.0-1.3 (1+y)

S: > 1.95

BILIRUBIN, DIRECT

MG/DL

0.0-0.4 (0+y)

BILIRUBIN, INDIRECT

MG/DL

0.0-1.3 (1+y)

ALKALINE PHOS.

U/L

M: 30-225 (16-19y) ■ F: 30-165 (16-19y) ■ 20-125 (20+y)

LACTATE DEHYDROGENASE

U/L

0-250 (3-64y) 0-270 (65+y)

GGT

U/L

M : 0-65 (13-64y) F : 0-45 (13-64y) 0-75 (65+y)

†

LIVER EVENT FLAG

M: > 1.4 F: > 1.3

> 143 (and Total † Bilirubin > 2.5) > 239

> 2.5 (and ALT † > 143)

S: > 337.5 S: > 247.5 S: > 187.5

y = years ■

In individuals between 12-18 years of age, alkaline phosphatase levels vary according to period of maximum bone growth.

Quest Diagnostics Clinical Trials, 7RM

Page 45 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

CHEMISTRY PANEL – CONVENTIONAL UNITS (cont’d)

ANALYTE

REFERENCE RANGES

UNITS

CO2 CONTENT

MEQ/L

20-32 (13+y)

ALBUMIN

G/DL

3.2-5.0 (3+y)

PHOSPHORUS, INORG

MG/DL

2.5-4.5 (13-64y) 2.1-4.3 (65+y)

CPK, TOTAL

U/L

M : 0-235 (0+y) F : 0-190 (0+y)

CHOLESTEROL, TOTAL

MG/DL

< 170 (3-19y) < 200 (20+y)

CHOLESTEROL, LDL, CALCULATION

MG/DL

0-110 (3-19y) 0-130 (20+y)

CHOLESTEROL, HDL, DIRECT

MG/DL

> 34 (3+y)

TRIGLYCERIDES MG/DL

E

EXCLUSION CRITERIA

F,S

ALERT RANGE

** PHONE ALERT RANGE

†

LIVER EVENT FLAG

< 1.0

< 200 (0+y)

y = years

†

LE, L1, L2, L3, LQ, LR, LP EVENT OCCURRENCE ALT >3X ULN and Bilirubin >2X ULN (>35% Direct Bilirubin) All Phases ALT >3X ULN Phase I ALT >5X ULN Phase II ALT >8X ULN Phase III/IV ALT >3X ULN and <5X ULN and Bilirubin <2X ULN Phase II ALT >5X ULN and <8X ULN Bilirubin <2X ULN Phase III-IV ALT >3X ULN Phases II-IV

Quest Diagnostics Clinical Trials, 7RM

REPORT FLAG LE L1 L2 L3 LQ LR LP

GUIDANCE COMMENTS ON REPORT AND IN WEB RESULT\VIEW Call subject; stop study drug immediately. Request specialist or hepatologist consult. Follow up clinic and lab evaluation within 24 hours Call subject; Prompt clinic evaluation required, as per protocol Call subject; Prompt clinic evaluation required, as per protocol Call subject; Prompt clinic evaluation required, as per protocol Call subject; Prompt clinic evaluation required, as per protocol (Review ALT and Bilirubin in Quick Trend) Call subject; Prompt clinic evaluation required, as per protocol (Review ALT and Bilirubin in Quick Trend) Call subject; Prompt clinic evaluation required, as per protocol (Review ALT in Quick Trend)

Page 46 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

HEMATOLOGY – CONVENTIONAL UNITS ANALYTE

UNITS

REFERENCE RANGES

** PHONE ALERT RANGE

WHITE CELL COUNT

THOU/MCL

3.8-10.8 (18+y)

< 1.1

HEMOGLOBIN

G/DL

M : 13.8-17.2 (18-64y) M : 11.8-16.8 (65+y) F : 12.0-15.6 (18-64y) F : 11.1-15.5 (65+y)

< 7.1 or > 19.9

HEMATOCRIT

%

M : 41.0-50.0 (18-64y) M : 36.0-49.0 (65+y) F : 35.0-46.0 (18-64y) F : 33.0-46.0 (65+y)

< 20.1 or > 59.9

RED CELL COUNT

MILL/MCL

M : 4.4-5.8 (18-64y) M : 3.7-5.5 (65+y) F : 3.9-5.2 (18-64y) F : 3.6-5.1 (65+y)

RDW

%

9.0-15.0 (0+y)

NEUTROPHILS, BANDS, ABS.■

THOU/MCL

0.00-0.86 (18+y)

NEUTROPHILS, SEGS. ABS.

THOU/MCL

1.80-8.00 (1+y)

TOTAL NEUTROPHILS, ABS.

THOU/MCL

1.80-8.00 (1+y)

LYMPHOCYTES, ABS.

THOU/MCL

0.85-4.10 (1+y)

MONOCYTES, ABS.

THOU/MCL

0.20-1.10 (1+y)

EOSINOPHILS, ABS.

THOU/MCL

0.05-0.55 (0+y)

THOU/MCL

0.00-0.20 (1+y)

%

0.0-8.0 (18+y)

NEUTROPHILS, SEGS.

%

40.0-75.0 (18+y)

TOTAL NEUTROPHILS

%

40.0-75.0 (18+y)

LYMPHOCYTES

%

16.0-46.0 (18+y)

MONOCYTES

%

0.0-12.0 (18+y)

EOSINOPHILS

%

0.0-7.0 (18+y)

BASOPHILS

%

0.0-2.0 (0+y)

PLATELET COUNT

PER CUMM

130,000-400,000 (1+y)

MCV

FL

80-100 (18-64y) 82-103 (65+y)

MCHC

%

32.0-36.0 (18+y)

MCH

PG

27.0-33.0 (18-64y) 27.0-35.0 (65+y)

BASOPHILS, ABS. NEUTROPHILS, BANDS

■

< 31,000 or > 1,499,000

y = years ■

Neutrophil, Bands are reported only if seen on a manual differential.

Quest Diagnostics Clinical Trials, 7RM

Page 47 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

URINALYSIS ANALYTE

UNITS

REFERENCE RANGES

COLOR

YELLOW

APPEARANCE

CLEAR

SPECIFIC GRAVITY

1.001-1.035

URINE REACTION pH

4.6-8.0

GLUCOSE

NEGATIVE

PROTEIN QUAL.

NEGATIVE

KETONE

NEGATIVE

OCCULT BLOOD

NEGATIVE

BILIRUBIN

NEGATIVE

NITRITE

NEGATIVE

LEUKOCYTES

NEGATIVE

MICROSCOPIC: RBC

PER HPF

M: 0-3 F: 0-3

WBC

M: 0-5

PER HPF

F: 0-10

OTHER FINDINGS WILL BE REPORTED ONLY IF OBSERVED UNDER MICROSCOPIC EXAMINATION

Quest Diagnostics Clinical Trials, 7RM

Page 48 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

OTHER TESTS – CONVENTIONAL UNITS E

ANALYTE

UNITS

REFERENCE RANGES

AMYLASE, TOTAL, SERUM

U/L

29-103 (1+y)

C-REACTIVE PROTEIN (CRP) HIGHLY SENSITIVE

MG/L

< 3.1 (18+y)

EXCLUSION CRITERIA

HIV 1/2 ANTIBODIES

NON REACTIVE

REACTIVE

HEPATITIS Bs Ag

NON REACTIVE

REACTIVE

HEPATITIS C ANTIBODY

NON REACTIVE

REACTIVE

PREGNANCY TEST SERUM

Males and Non-Pregnant Females = NEGATIVE

POSITIVE/ BORDERLINE

** PHONE ALERT RANGE

Pregnant = POSITIVE FATTY ACID SERIES (NEFA)

MEQ/L

< 0.9

APTT, PTT

SECONDS

22-34 (18+y)

PT

SECONDS

9.0-11.5 (18+y)

INR

0.9-1.1 (18+y)

> 60

> 4.9

GLUCOSE, PLASMA y = years

Quest Diagnostics Clinical Trials, 7RM

Page 49 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

CHEMISTRY PANEL – LIVER EVENT ASSESSMENT - CONVENTIONAL

ANALYTE

UNITS

REFERENCE RANGES

ALT (SGPT)

U/L

0-48 (13+y)

AST (SGOT)

U/L

0-42 (3-64y) 0-55 (65+y)

ALKALINE PHOS.

U/L

M: 30-225 (16-19y) F: 30-165 (16-19y) 20-125 (20+y)

BILIRUBIN, TOTAL

MG/DL

0.0-1.3 (1+y)

MG/DL

0.0-0.4 (0+y)

CPK, TOTAL

U/L

M : 0-235 (0+y) F : 0-190 (0+y)

LACTATE DEHYDROGENASE

U/L

0-250 (3-64y) 0-270 (65+y)

BILIRUBIN, DIRECT

♦

** PHONE ALERT RANGE

y = years ♦

If Total Bilirubin is > 2.5 mg/dl, Direct Bilirubin will be reported.

Quest Diagnostics Clinical Trials, 7RM

Page 50 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

HEMATOLOGY – LIVER EVENT ASSESSMENT – CONVENTIONAL ANALYTE

UNITS

REFERENCE RANGES

** PHONE ALERT RANGE

WHITE CELL COUNT

THOU/MCL

3.8-10.8 (18+y)

< 1.1

HEMOGLOBIN

G/DL

M : 13.8-17.2 (18-64y) M : 11.8-16.8 (65+y) F : 12.0-15.6 (18-64y) F : 11.1-15.5 (65+y)

< 7.1 or > 19.9

HEMATOCRIT

%

M : 41.0-50.0 (18-64y) M : 36.0-49.0 (65+y) F : 35.0-46.0 (18-64y) F : 33.0-46.0 (65+y)

< 20.1 or > 59.9

RED CELL COUNT

MILL/MCL

M : 4.4-5.8 (18-64y) M : 3.7-5.5 (65+y) F : 3.9-5.2 (18-64y) F : 3.6-5.1 (65+y)

RDW

%

9.0-15.0 (0+y)

NEUTROPHILS, BANDS, ABS.■

THOU/MCL

0.00-0.86 (18+y)

NEUTROPHILS, SEGS. ABS.

THOU/MCL

1.80-8.00 (1+y)

TOTAL NEUTROPHILS, ABS.

THOU/MCL

1.80-8.00 (1+y)

LYMPHOCYTES, ABS.

THOU/MCL

0.85-4.10 (1+y)

MONOCYTES, ABS.

THOU/MCL

0.20-1.10 (1+y)

EOSINOPHILS, ABS.

THOU/MCL

0.05-0.55 (0+y)

THOU/MCL

0.00-0.20 (1+y)

%

0.0-8.0 (18+y)

NEUTROPHILS, SEGS.

%

40.0-75.0 (18+y)

TOTAL NEUTROPHILS

%

40.0-75.0 (18+y)

LYMPHOCYTES

%

16.0-46.0 (18+y)

MONOCYTES

%

0.0-12.0 (18+y)

EOSINOPHILS

%

0.0-7.0 (18+y)

BASOPHILS

%

0.0-2.0 (0+y)

PLATELET COUNT

PER CUMM

130,000-400,000 (1+y)

MCV

FL

80-100 (18-64y) 82-103 (65+y)

MCHC

%

32.0-36.0 (18+y)

MCH

PG

27.0-33.0 (18-64y) 27.0-35.0 (65+y)

BASOPHILS, ABS. NEUTROPHILS, BANDS

■

< 31,000 or > 1,499,000

y = years ■

Neutrophil, Bands are reported only if seen on a manual differential.

Quest Diagnostics Clinical Trials, 7RM

Page 51 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

LIVER EVENT ASSESSMENT

ANALYTE

REFERENCE RANGES

UNITS

HEPATITIS Bs Ag

NON REACTIVE

HEPATITIS B CORE Ab IgM

NON REACTIVE

HEPATITIS A IgM

NON REACTIVE

HEPATITIS C VIRUS RNA

IU/ML LOG IU/ML

HEPATITIS E IgM CMV IgM Ab EBV IgM Ab

** PHONE ALERT RANGE

< 50 < 1.7 NON REACTIVE

INDEX

< 0.90

ISR

NEGATIVE ≤ 0.90 (Strength of Signal)

ANA SCREEN W/ REFLEX TO TITER AND PATTERN

TITER

NEGATIVE (Screen) < 40 (IFA Titer)

ACTIN

UNITS

< 20

TYPE 1 ANTI-LIVER KIDNEY MICROSOMAL Ab

UNITS

 20

y = years

Quest Diagnostics Clinical Trials, 7RM

Page 52 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

U.S. COLLEGE OF AMERICAN PATHOLOGISTS CERTIFICATE

For more information and future updates of these certificates and accreditation, please visit www.questcentrallab.com/accreditation.html

Quest Diagnostics Clinical Trials, 7RM

Page 53 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

U.S. COLLEGE OF AMERICAN PATHOLOGISTS CERTIFICATE, NICHOLS INSTITUTE

Quest Diagnostics Clinical Trials, 7RM

Page 54 Final 1.0

Sirtris Pharmaceuticals – Protocol SRT-2104-013 13 April, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment A. SUPPLIES Methanol Dry Ice Saline 6 mm punch Scalpel Cryomold (24x24 mm) 50 mL conical tube 1.25 mL cryovial Petri dish 2x2 gauze pads OCT compound Sharpies Permanent Fine Point Markers Liquid Nitrogen B. LOCATION Biopsy should be taken from a target lesion initially and always taken from the same lesion or comparable lesion thereafter C. PUNCH BIOPSY PROCEDURE A 6 mm punch biopsy specimen will be divided into two halves; one half will be frozen in OCT compound and the other half flash frozen in liquid nitrogen. Both samples will be stored at –70 C. The following procedures MUST be followed for all the biopsy sampling. OBTAINING THE BIOPSY SPECIMENS 1) Ensure that all supplies are available and the subject informed consent is signed. 2) Label both the 50 ml conical tube and the 1.25 ml cryovial with the following subject information a. Protocol Number b. Subject ID c. Date of collection of specimen d. Time Point (e.g., Day 1 or 84). BIOPSY COLLECTION PROCEDURE: 1) Cleanse the biopsy sites with Betadine. 2) Give anesthesia as per protocol at your site. 3) Place a 6mm biopsy punch on the skin and orient it perpendicularly to the skin surface in a clockwise rotation, applying light pressure. 4) Insert the punch into the skin to the level of the hilt, then withdraw. 5) Gently lift the skin biopsy out with narrow forceps. If necessary, use iris scissors to clip the base of the specimen so it can be removed with forceps. Place the biopsy in the petri dish that contains gauze moistened with saline. Page 1 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment

WOUND CARE 1) After completing the biopsy, suture the site, as necessary. 2) Instruct the subject to gently cleanse the surgical site with peroxide, and apply an antibiotic ointment and band-aid daily. 3) Remove sutures in one or two weeks FREEZING THE BIOPSY SPECIMEN IN OCT 1) Cut the 6mm biopsy in half with the scalpel (see the Attachments section for a diagram of the biopsy bisection procedure). 2) Place a handful of small dry ice pieces into a shallow dish (break up the ice). Pour a small amount of methanol over the dry ice. 3) Obtain the cryomold, write an E (for epidermis) on the fatter edge of the cryomold. 4) Using forceps, place ONE of the biopsy specimen halves in the MIDDLE of the cryomold. The epidermis should face the E (see the Attachments section for a diagram of the biopsy orientation on the cryomold). 5) Gently squeeze OCT compound around and on top of the specimen in clockwise motion until the specimen is completely covered. Burst any large bubbles with forceps. 6) Place the cryomold over the dry ice and methanol slurry until completely frozen. AVOID ANY METHANOL SPLASHING ONTO THE CRYOMOLD DURING THE FREEZING PROCESS. OTHERWISE THE MOLD WILL NOT FREEZE THOUROUGHLY. 7) Allow the specimen to stand until completely frozen. Once completely frozen, the contents of the cryomold will turn white. QUICKLY pop the frozen biopsy out from the cryomold. You can now mark an “E” on the surface of the frozen sample to indicate the epidermal side. 8) Put the sample into the pre-labeled 50 ml conical tube and store immediately at –70 C until ready to be shipped. PROCEDURE FOR THE FLASH FROZEN SPECIMEN Note: THIS SAMPLE SHOULD BE PROCESSED FIRST AS RNA DEGRADES VERY FAST. 1) The second half of the biopsy specimen should be placed in the 1.25 ml pre-labeled cryovial and flash frozen in liquid nitrogen for 1 minute. 2) The second specimen should be stored at –70 C IMMEDIATELY AFTER FLASH FREEZING until ready to be shipped. IF THERE ARE ANY QUESTIONS OR PROBLEMS REGARDING THE BIOPSY PROCEDURE, COLLECTION, OR STORAGE, PLEASE DO NOT HESITATE TO CONTACT ANY ONE OF THE FOLLOWING PEOPLE.

Page 2 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment Dr. SHIPMENT OF BIOPSY SPECIMENS 1) Biopsy specimens will be batched and shipped from each site after all Day 84 biopsies for all subjects in each dosing cohort have been obtained. 2) Shipments of all frozen samples must be sent on dry ice (at least 5 pounds) and sent MONDAY through WEDNESDAY ONLY using priority overnight service. SPECIMENS SHOULD NOT BE SHIPPED THE DAY BEFORE ANY HOLIDAYS. 3) For each shipment, please include the BIOPSY INVENTORY LOG in a plastic bag inside the shipping box. Multiple subjects can be included on the log sheet. (See Attachments Section for a sample of the log sheet.) CRYOMOLD and CRYOVIAL specimens could be placed together in the 50 ml conical tube. 4) Prior to shipment, please alert of an incoming shipment by faxing the NOTIFICATION OF BIOPSY SPECIMEN SHIPMENT form to using the number on the form. (See Attachments Section for a sample of the shipment form). 5) Marken Ltd will provide courier services for purposes of shipping biopsy specimens. Marken can provide your site with packaging and dry ice for shipment of biopsy specimens, if needed. When calling in a pick-up, please let Marken Customer Support know if you require packaging or dry ice. Please give Marken at least 24 hours advance notice to place the packaging at your site. Dry ice will be brought at the time of pick-up. 6) An initial supply of pre-printed airway bills is included in the Skin Biopsy section of the Investigator Site File. Additional airway bills can be obtained by contacting Marken Customer Support Center using the contact information provided below. 7) To arrange for a pick up, please call or email the Marken Customer Support Center. Please reference the 12-digit number provided on the pre-printed airway bills. This will assist Customer Support in arranging your shipment. Customer Service will gather the necessary information about your pick-up including ready date & time. The airway bill should be secured to the outside of the box. 8) Marken maintains a 24/7 Customer Support Center. please call or email:

For questions regarding shipments

Marken Customer Support Center Fax: Email:

Page 3 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment ATTACHMENTS

Page 4 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment

Page 5 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment

Sirtris Protocol SRT-2104-013 Notification of Biopsy Specimen Shipment Form Date Sent______________________ Investigator name______________________________ Address________________________________________ ________________________________________________ Site contact’s name__________________________________ Site contact phone number____________________________ Site fax number_______________________________ Study name__________________________________ Site number__________________________ Number of specimens sent_____________ Number of boxes sent______________ Courier airbill number ____________________

PLEASE FAX TO

Page 6 of 7 Version Date: May 19, 2010

SRT-2104-013 PUNCH BIOPSY PROCEDURES: Collection, Storage, Shipment

Sirtris Protocol SRT-2104-013 BIOPSY INVENTORY LOG Investigator:

Study Protocol: SRT-2104-013

Address:

Contact Name: ________________________ Tel #:

________________________

Fax #:

________________________

Site #:

________________________

Number of samples included in shipment: __________ Date samples shipped to Pt. ID

Pt. Initials

Visit Name [Circle Day(s)]

_______________

Visit date

Frozen OCT

Liquid Nitrogen Lesional

Biopsy Location

Lesional Day 1 ____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84 Day 1

____-_______

Day 84

Please alert of incoming shipments by faxing the “Notification of biopsy specimen shipment” form to her prior to shipment using the number on the form. DO NOT SHIP PRIOR TO A HOLIDAY OR ON THURSDAYS OR FRIDAYS! Should you have any questions, you may contact the following persons at The *

* Page __ of __

Page 7 of 7 Version Date: May 19, 2010

* Dr.

16.1 Clinical Study Report Appendices SRT-2104-013

CSR Appendix 16.1.11 Publications based on the study

Not applicable.

This section contained journal publication(s), which are protected by copyright laws and therefore have been excluded.

16.1 Clinical Study Report Appendices SRT-2104-013

CSR Appendix 16.1.12 Important Publications Referenced in the Report

Not applicable.

Psoriasis Area and Severity Index (PASI) This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

Protocol SRT-2104-013 Study Day (Circle One):

Subject ID Day 1

Day 28

-_____-________ Subject Initials ________ Day 56

Day 84

PHQ9P PATIENT HEALTH QUESTIONNAIRE-9 This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

Copyright © 2005 Pfizer, Inc. All rights reserved. Reproduced with permission.

2783

Hospital Anxiety and Depression Scale (HADS) Name:

SRT-2104-013

Date:

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

A This form is printed in green. Any other colour is an unauthorized photocopy. TOTAL HADS copyright © R.P. Snaith and A.S. Zigmond, 1983, 1992, 1994. Record form items originally published in Acta Psychiatrica Scandinavica 67, 361–70, copyright © Munksgaard International Publishers Ltd, Copenhagen, 1983. This edition first published in 1994 by nferNelson Publishing Company Ltd, 414 Chiswick High Road, London W4 5TF GL Assessment is part of the Granada Group Code 0090002511 Printed in Great Britain 9(1.08)

D

SRT-2104-013 Patient Self-Assessment

Koo-Menter Psoriasis Instrument N

Date:

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.

Recommendations for Meals

Population PK Modeling