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Mar 18, 2011 - Ribavirin in Treatment Naive Subjects Chronically Infected with Hepatitis C Virus. Genotypes 1, 2, or 3 .... Female subjects must not be nursing, or pregnant. Women of Child ..... 3.4.2 Other Restrictions and Precautions .

Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-21. DOI: 10.1056/NEJMoa1306218

For New England Journal of Medicine submission of 13-01989 - Daclatasvir plus Sofosbuvir for Chronic HCV Genotype 1, 2, or 3 Infection This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

Page: Protocol Number: IND Number: EUDRACT Number Date:

1 AI444040 79,599 and 106,739 N/A 18-Mar-2011

Clinical Protocol AI444040 Parallel, Open-Label, Randomized Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of PSI-7977 in Combination with BMS-790052 with or without Ribavirin in Treatment Naive Subjects Chronically Infected with Hepatitis C Virus Genotypes 1, 2, or 3 Study Director/Medical Monitor David Gardiner, MD Bristol-Myers Squibb Research and Development 311 Pennington-Rocky Hill Road Pennington, NJ 08534 Telephone (office): 1-609-818-5619 Fax: 1-609-818-3220 24-hr Emergency Telephone Number USA: 1-866-470-2267 International: +1-248-844-7390 Bristol-Myers Squibb Research and Development 311 Pennington-Rocky Hill Road Pennington, NJ 08534 This protocol contains information that is confidential and proprietary to Bristol-Myers Squibb This document is the confidential and proprietary information of Bristol-Myers Squibb Company and its global affiliates (BMS). By reviewing this document, you agree to keep it confidential and to use and disclose it solely for the purpose of assessing whether your organization will participate in and/or the performance of the proposed BMS-sponsored study. Any permitted disclosures will be made only on a confidential "need to know" basis within your organization or to your independent ethics committee(s). Any other use, copying, disclosure or dissemination of this information is strictly prohibited unless expressly authorized in writing by BMS. Any supplemental information (e.g., amendments) that may be added to this document is also confidential and proprietary to BMS and must be kept in confidence in the same manner as the contents of this document. Any person who receives this document without due authorization from BMS is requested to return it to BMS or promptly destroy it. All other rights reserved.

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DOCUMENT HISTORY Document Original Protocol

Date of Issue 18-Mar-2011

Summary of Change Not applicable.

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SYNOPSIS Clinical Protocol AI444040 Title of Study: Protocol AI444040: Parallel, Open-Label, Randomized Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of PSI-7977 in Combination with BMS-790052 with or without Ribavirin in Treatment Naive Subjects Chronically Infected with Hepatitis C Virus Genotypes 1, 2, or 3 Indication: Genotypes 1, 2, and 3 Chronic Hepatitis C (HCV) in patients who are treatment naive. Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational Product(s): BMS-790052 60 mg dose (2 x 30 mg) tablets orally daily for 23 or 24 Weeks. PSI-7977 400 mg dose (2 x 200 mg) tablets orally daily for 24 weeks. Ribavirin 200 mg tablets orally twice daily for 24 weeks (dose based upon recommendations for use with pegylated interferon by genotype.) Study Phase: 2a Research Hypothesis: A combination of PSI-7977 and BMS-790052 will be identified with or without ribavirin which provides potent antiviral activity and prevents emergence of resistance in multiple HCV genotypes. Primary Objective: To estimate the rate of sustained virologic response (SVR) SVR24 in each treatment group, where SVR24 is defined as undetectable HCV RNA ( 1000 IU/mL. Blood samples from all subjects will be obtained on Days -1 (baseline), 1 to 7, 14, 21 and every two weeks from Week 4 until EOT and at Week 4, 12, 24, 36, and 48 post-treatment in subjects

Primary Endpoint: −

The primary endpoint in the study is the proportion of subjects in each treatment group who reach SVR24

Statistical Methods: Sample Size Determination: With a target sample size of 12 subjects per treatment group, the probability of observing 50% or more subjects in a treatment group with SVR24 is 0.05, 0.61, or 0.99 if the true population rate is 25%, 50%, or 75%, respectively. Correspondingly, given the same sample size and the same true population rates, the probability of observing 25% or fewer subjects with SVR24 is 0.65, 0.07, or less than 0.01, respectively. In addition, a target sample size of 12 treated subjects can detect with 80% probability a safety event that occurs at an incident rate of 13%.

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To allow for dropouts, an adequate number of subjects will need to meet the enrollment criteria at screening so that 14 subjects per treatment group will be dosed on Day 1. Statistical Analysis: Analyses will be based on treated subjects. In the main analysis for the antiviral activity endpoints, the numerator will be based on the number of subjects meeting the response criteria, classifying rescued subjects requiring therapeutic rescue (subjects who added on IFN/RBV or IFN before the endpoint assessment) as failures; the denominator will be based on all treated subjects. In addition, an analysis where the numerator is based on treated subjects meeting the response criteria (regardless of therapeutic rescue) will be used. Response rates and 80% exact binomial CIs will be presented by treatment group. Selected antiviral activity endpoints will also be summarized by HCV subtype (1a, 1b, 2, and 3 as well as combined genotype 1). No adjustments will be made for multiplicity. Safety analysis: All recorded adverse events will be listed and tabulated by system organ class, preferred term and treatment , treatment regimen (combining data from treatment groups A and B, C and D, and E and F, respectively). Vital signs, ECGs, and clinical laboratory tests will be listed and summarized by treatment regimen. Any abnormal physical exam findings, clinical laboratory results, and vital sign measurements will be listed. ECG readings will be evaluated by the investigator and abnormalities, if present, will be listed. Pharmacokinetic analysis: The pharmacokinetics of PSI-7977, PSI-6206, and BMS-790052 will be described by summary statistics by analyte, treatment regimen (combining data from treatment groups A and B, C and D, and E and F, respectively), and, when appropriate, by study day. The effect of BMS-790052 on the pharmacokinetic parameters for PSI-7977 and PSI-6206 will be estimated by ratios of geometric means, and 90% confidence intervals, using data from treatment groups A and B (Day 14 versus Day 7). The effect of RBV on the pharmacokinetic parameters for PSI-7977, PSI6206, and BMS-790052 will be explored by estimating ratios of geometric means, and 90% confidence intervals, using data from treatment groups C, D, E, and F. To explore any difference in BMS-790052 exposure that might occur from co-administering PSI-7977 and BMS-790052, pharmacokinetic parameters for BMS-790052 when co-administered will be compared with descriptive statistics for the same parameters reported in study AI444-004 where BMS-790052 was administered alone. Pharmacodynamic analysis: The following antiviral activity endpoints will be summarized by treatment groups: proportions of subjects with SVR24, SVR12, RVR, cEVR, eRVR, and undetectable at EOT; and frequency of genotypic substitutions associated with virologic failure. SVR endpoints will also be summarized by the duration subjects stay on PSI-7977, BMS-790052, and, for treatment groups E and F, RBV. Cumulative rates of viral breakthrough and relapse will be estimated by treatment group and time point. In addition, the change from baseline (Day -1) in log10 HCV RNA will be summarized by study day and treatment group. Each individual’s maximum decrease from baseline in log10 HCV RNA, as well as the day of maximum observed decrease, will be summarized by treatment group, and frequency distributions for maximum decrease in log10 HCV RNA will be provided. For subjects who experience viral breakthrough, HCV RNA at the time of therapeutic rescue for all rebounding subjects will be listed and summarized by treatment group, including only subjects who start therapeutic rescue. The time from first dose to viral breakthrough may be described using Kaplan-Meier graphs and time from first undetectable HCV RNA to breakthrough will be listed, where applicable. Relationship between baseline HCV RNA and the incidence of viral breakthrough will be explored. The trajectory of HCV RNA change from the level at the time of rescue may also be explored by descriptive statistics and graphic methods.

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Pharmacokinetic-Pharmacodynamic analysis: Associations between steady state exposure to PSI-7977, PSI-6206 and BMS-790052 and safety endpoints will be explored graphically. Associations between steady state exposure to PSI-7977, PSI-6206, and BMS-790052 and antiviral activity endpoints (eg RVR, cEVR, eRVR, SVR12, SVR24, as well as the magnitude and day of maximum change in HCV RNA levels from baseline) will be explored graphically. Exploratory biomarker analysis: Results from the exploratory biomarkers will be explored through graphical and/or by summary statistics and listings. Observed associations will if appropriate be estimated. Interim analyses: To ensure the safety of study subjects, interim analyses may be conducted during the study to monitor the emerging safety and viral activity profiles of the study treatments. Interim analyses will be conducted after all subjects complete Week 4, Week 12, Week 24 (end of treatment), 12 Weeks post treatment (SVR12, all subjects not receiving rescue therapy), and 24 weeks post treatment (SVR24, all subjects not receiving rescue therapy). An interim analysis may be conducted 4 weeks post treatment (SVR4, all subjects not receiving rescue therapy). Interim analyses will include HCV RNA and clinical safety data including but not limited to SAEs, AEs and clinical laboratory tests as defined in the statistical analysis plan. In event of emergence of clinically significant safety issues which may require study design change beyond individual stopping rules, interim analyses may be conducted on an ad hoc basis after consultation between the study director and Global Biometric Sciences (GBS).

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TABLE OF CONTENTS

TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 DOCUMENT HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1 INTRODUCTION AND STUDY RATIONALE . . . . . . . . . . . 16 1.1 Study Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.1.1 HCV Disease and Standard of Care . . . . . . . . . . . . . . . . . . 16 1.1.2 Development of BMS-790052. . . . . . . . . . . . . . . . . . . . . . . 17 1.1.3 Development of PSI-7977. . . . . . . . . . . . . . . . . . . . . . . . . . 17 1.1.4 Development of direct-acting antiviral combination treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

1.2 Research Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.3 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.4 Product Development Background . . . . . . . . . . . . . . . . 22 1.4.1 BMS-790052 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.4.1.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.4.1.2 Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.4.1.3 Preclinical Metabolism and Pharmacokinetics . . . . . . 23 1.4.1.4 Clinical Pharmacology and Safety . . . . . . . . . . . . . . . 23 1.4.1.5 Summary of Clinical Investigational Program for BMS-790052 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 1.4.2 Pharmasset PSI-7977. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

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1.4.2.1 Pharmacology of PSI-7977 . . . . . . . . . . . . . . . . . . . . . 28 1.4.2.2 Toxicity of PSI-7977 . . . . . . . . . . . . . . . . . . . . . . . . . . 29 1.4.2.3 Preclinical Metabolism and Pharmacokinetics of PSI-7977 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 1.4.2.4 Clinical Pharmacology and Safety of PSI-7977 . . . . . 30 1.4.2.5 Summary of Clinical Investigational Program for PSI-7977 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 1.4.3 Rationale for Combination of BMS-790052 and PSI-7977 . 35 1.4.3.1 Dose Selection of BMS-790052 . . . . . . . . . . . . . . . . . 35 1.4.3.2 Dose Selection of PSI-7977 . . . . . . . . . . . . . . . . . . . . 35 1.4.3.3 Anticipated safety of BMS-790052 and PSI-7977 in combination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 1.4.3.4 Anticipated Pharmacokinetic Interactions . . . . . . . . . . 36 1.4.3.5 Rationale for Duration of Therapy. . . . . . . . . . . . . . . . 37 1.4.3.6 Approaches to Reduce Drug Resistance . . . . . . . . . . 37 1.4.3.7 Rationale for the Addition of Ribavirin to BMS-790052 and PSI-7977 . . . . . . . . . . . . . . . . . . . . . . . . 38 1.4.3.8 Rationale for “lead-in” phase. . . . . . . . . . . . . . . . . . . . 39 1.4.3.9 Rationale for Testing Different Genotypes . . . . . . . . . 39

1.5 Overall Risk/Benefit Assessment . . . . . . . . . . . . . . . . . 41 1.5.1 BMS-790052 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 1.5.2 PSI-7977 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 1.5.3 Additional Risks in Study AI444040 . . . . . . . . . . . . . . . . . . 43 1.5.4 Overall risk-benefit for study AI444040. . . . . . . . . . . . . . . . 44

2 ETHICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . 44 2.1 Good Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . 44

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2.2 Institutional Review Board/Independent Ethics Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.3 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3 INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . 46 3.1 Study Design and Duration. . . . . . . . . . . . . . . . . . . . . . 46 3.1.1 Individual Subject Decision Rules for Therapeutic Rescue

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3.1.2 Group Decision Rules for Interruption of a Dose Cohort . . 50

3.2 Post Study Access to Therapy . . . . . . . . . . . . . . . . . . . 50 3.3 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.3.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.3.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3.3.3 Women of Childbearing Potential . . . . . . . . . . . . . . . . . . . . 55

3.4 Concomitant Treatments . . . . . . . . . . . . . . . . . . . . . . . 56 3.4.1 Prohibited and/or Restricted Treatments . . . . . . . . . . . . . . 56 3.4.2 Other Restrictions and Precautions . . . . . . . . . . . . . . . . . . 58

3.5 Discontinuation of Subjects from Treatment. . . . . . . . . 58 4 TREATMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 4.1 Study Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 4.1.1 Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.1.2 Noninvestigational Product . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.1.3 Handling and Dispensing . . . . . . . . . . . . . . . . . . . . . . . . . . 63

4.2 Method of Assigning Subject Identification . . . . . . . . . . 63 4.3 Selection and Timing of Dose for Each Subject . . . . . . 64

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4.3.1 Dose Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 4.3.1.1 BMS-790052 and PSI-7977 . . . . . . . . . . . . . . . . . . . . 66

4.4 Blinding/Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 4.5 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . 67 4.6 Destruction and Return of Study Drug . . . . . . . . . . . . . 67 4.6.1 Destruction of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . 67 4.6.2 Return of Study Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

5 STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . 69 5.1 Flow Chart/Time and Events Schedule . . . . . . . . . . . . 69 5.2 Study Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.3 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 5.3.1 Laboratory Test Assessments . . . . . . . . . . . . . . . . . . . . . . 83

5.4 Efficacy Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . 85 5.4.1 Primary Efficacy Assessment . . . . . . . . . . . . . . . . . . . . . . . 85 5.4.2 Secondary Efficacy Assessments. . . . . . . . . . . . . . . . . . . . 85

5.5 Pharmacokinetic Assessments. . . . . . . . . . . . . . . . . . . 85 5.5.1 Pharmacokinetics: Collection and Processing . . . . . . . . . . 85 5.5.2 Pharmacokinetic Sample Analyses. . . . . . . . . . . . . . . . . . . 88 5.5.3 Labeling and Shipping of Biological Samples . . . . . . . . . . . 88

5.6 Biomarker Assessments . . . . . . . . . . . . . . . . . . . . . . . . 89 5.7 Exploratory Biomarker Assessments . . . . . . . . . . . . . . 89 5.8 Outcomes Research Assessments . . . . . . . . . . . . . . . 91 5.9 Other Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

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6 ADVERSE EVENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 6.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 92 6.1.1 Serious Adverse Event Collection and Reporting . . . . . . . . 93

6.2 Nonserious Adverse Events . . . . . . . . . . . . . . . . . . . . . 95 6.2.1 Nonserious Adverse Event Collection and Reporting . . . . . 95

6.3 Laboratory Test Abnormalities . . . . . . . . . . . . . . . . . . . 95 6.4 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 6.5 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 6.6 Potential Drug Induced Liver Injury (DILI) . . . . . . . . . . 96 6.7 Other Safety Considerations . . . . . . . . . . . . . . . . . . . . 97 7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES . . . . . . . . . . . . . . . . . . . . . . . . 97 8 STATISTICAL CONSIDERATIONS. . . . . . . . . . . . . . . . . . . 97 8.1 Sample Size Determination . . . . . . . . . . . . . . . . . . . . . 97 8.2 Populations for Analyses . . . . . . . . . . . . . . . . . . . . . . . 98 8.3 Endpoint Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 8.3.1 Safety Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 8.3.2 Efficacy Endpoints (s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 8.3.3 Pharmacokinetic Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . 99 8.3.4 Biomarker Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 8.3.5 Exploratory Biomarker Endpoint(s) . . . . . . . . . . . . . . . . . . . 101

8.4 Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 8.4.1 Demographics and Baseline Characteristics . . . . . . . . . . . 102

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8.4.2 Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 8.4.3 Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 8.4.4 Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . 102 8.4.5 Biomarker Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 8.4.6 Exploratory Biomarker Analyses. . . . . . . . . . . . . . . . . . . . . 104 8.4.7 Outcomes Research Analyses . . . . . . . . . . . . . . . . . . . . . . 105 8.4.8 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 8.4.8.1 Exposure Response Analyses . . . . . . . . . . . . . . . . . . 105 8.4.8.2 HCV Viral Variant Analyses . . . . . . . . . . . . . . . . . . . . 105

8.5 Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 9 STUDY MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 9.1 Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 9.1.1 Compliance with the Protocol and Protocol Revisions . . . . 108 9.1.2 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 9.1.3 Investigational Site Training . . . . . . . . . . . . . . . . . . . . . . . . 110

9.2 Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 9.2.1 Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 9.2.2 Study Drug Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 9.2.3 Case Report Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

9.3 Clinical Study Reports and Publications . . . . . . . . . . . . 112 10 GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . 113 11 LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . 114 12 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

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APPENDIX 1 DIAGNOSTIC CRITERIA FOR DRUG AND ALCOHOL ABUSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 APPENDIX 2 DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS , VERSION 1.0, DECEMBER 2004; CLARIFICATION AUGUST 2009 . . . . . . . . . . . . . . . . . . . . 126

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1

INTRODUCTION AND STUDY RATIONALE

1.1

Study Rationale

1.1.1

HCV Disease and Standard of Care

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Approximately 170 million people worldwide are chronically infected with Hepatitis C 1

virus (HCV), including approximately 4 million in the United States. The majority of infected individuals progress to chronic hepatitis, which can lead to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Currently, 10,000 to 12,000 deaths annually 1

in the United States are due to HCV infection.

There are 6 major HCV genotypes with many subtypes based on sequence heterogeneity 2

of the genome. Genotypes 1-3 have a worldwide distribution (with genotype 1 being the major genotype in the United States, Europe, and Japan), genotypes 4 and 5 are found principally in Africa, and genotype 6 is distributed primarily in Asia. Although genotype does not predict the outcome of infection, different genotypes are associated with differential responses to treatment, and allow dosage of current interferon-based 3,4,5

treatment to be tailored to the genotype being treated.

The current SOC for treating most patients with chronic HCV infection is a regimen of pegIFNα and RBV. In two (2) pivotal clinical trials in treatment-naive patients receiving pegIFNα-2b or pegIFNα-2a combined with ribavirin, treatment failure, defined as persistent HCV replication up to 24 weeks after the end of treatment (EOT), occurred in 18% and 24% of patients infected by genotype 2 or 3 and in 58% and 54% of patients 4,5

infected by genotype 1, respectively.

Treatment failure is more frequent for some

groups, including African Americans and individuals coinfected with human immunodeficiency virus (HIV).

6,7,8,9,10,11

In addition, current therapies are unpleasant to

administer and are associated with significant side effects resulting in high rates of noncompliance and apprehension about starting treatment. This highlights the unmet medical need for new therapeutic regimens that are more effective (especially in patients infected by genotype 1), better tolerated and easier to administer.

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Development of BMS-790052

HCV contains a single-stranded ribonucleic acid (RNA) genome of positive polarity which is translated into a precursor polyprotein and cleaved secondarily into individual proteins. Based on their functions in the viral life cycle, these individual proteins can be divided into 2 groups: structural proteins (C, E1, and E2) and non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). BMS-790052 is a first-in-class inhibitor of HCV NS5A. BMS-790052 is being developed for use in combination with pegylatedinterferon alpha (pegIFNα) and ribavirin (RBV) and for pegIFNα/RBV-sparing combinations studies with other direct acting antivirals (DAA). The precise mechanism of action of NS5A inhibitors has not been fully elucidated, but the function of NS5A proteins is well described. HCV NS5A is a multifunctional protein with key functions in HCV replication, modulation of cellular signaling pathways and the IFN response. It contains a putative IFN sensitivity-determining region and may play a role in resistance to IFNα. The essential nature of NS5A has been demonstrated in vitro in the cell-based replicon assay and in vivo in the chimpanzee model of infection. As a multifunctional protein required for in vivo and in vitro replication with no known human homologues, NS5A represents an attractive target for therapeutic intervention. Monotherapy studies have demonstrated mean reductions in HCV RNA of > 3.5 log10 after a single dose of 100 mg of BMS-790052. AI444014 is an ongoing Phase 2a study of BMS-790052 combined with pegIFNα-2a/RBV for 48 weeks in HCV genotype 1 infected subjects. AI444014 SVR12 interim analysis results have demonstrated improvement in Extended Rapid Virologic Response (eRVR) rates over placebo, indicating that BMS 790052 plus pegIFNα-2a/RBV can rapidly suppress HCV RNA. 1.1.3

Development of PSI-7977

Novel anti-hepatitis C treatments under study such as PSI-7977 are directed against a variety of molecular targets, which include the virally encoded RNA-dependent RNA polymerase (RDRP, NS5B) and proteases (NS2 and NS3). Some of the most consistently effective antiviral therapies have been nucleoside/nucleotide analogs. These compounds share characteristics with the natural nucleoside substrates found in the cell, and once

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phosphorylated to the nucleoside-triphosphate, cause termination of the newly encoded HCV genome. PSI-7977 is one of the diastereomers present in the PSI-7851 drug substance which has been evaluated in a single dose escalation study in healthy subjects and a multiple dose escalation study conducted in HCV-infected patients. PSI-7851 is a mixture of two diastereoisomers, PSI-7977 and PSI-7976, in a ratio of approximately 50:50. Both PSI7977 and PSI-7976 proceed through the same metabolic pathway and are ultimately converted into the same active form, PSI-7409. To comply with the strong regulatory and clinical preference to develop single isomeric compounds, the decision was made to develop an isomerically enriched mixture favoring the single isomer, PSI-7977, in a ratio of approximately 98:2. All subsequent clinical studies have been conducted with PSI7977. PSI-7977 is a prodrug of PSI-6206, which was found to be inactive in the replicon assay when administered in its unmodified form. However, it has recently been shown that the 5’-triphosphate of PSI-6206 (PSI-7409) is a potent inhibitor of the HCV RNA polymerase. To circumvent the block in phosphorylation responsible for the lack of activity of PSI-6206, a phosphoramidate analog of PSI-6206 5’-monophosphate, PSI7977, was synthesized. A complete summary of the preclinical data supporting PSI-7977 can be found in the PSI-7977 Clinical Investigators’ Brochure. 1.1.4

Development of direct-acting antiviral combination treatments

An important goal of HCV therapy is the establishment of more effective, better-tolerated treatments as compared to the current standard of care, PEG-IFN-α and RBV. In particular, validation of such improvements in all oral regimens composed entirely of direct-acting HCV antivirals (DAA) would be a welcome therapeutic advance. Since drug-resistant substitutions rapidly emerge against HCV-specific antivirals when given in monotherapy, combinations of 2 or more DAA agents are believed to be required in order to achieve therapeutic success and such approaches are under examination by several companies. In November 2008, Roche initiated the INFORM-1 trial, a ground-breaking study to investigate the activity of a combination of two oral antiviral molecules in the

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12

absence of interferon. The study investigated the combination of Pharmasset's R7128, a nucleotide polymerase inhibitor, with InterMune's R7227, an HCV specific protease inhibitor in combination for 14 days followed by administration of pegIFN/RBV. The results demonstrated robust, multi-log declines in HCV RNA over the 14 day observation period and over a variety of dose combinations. Combination DAA studies reported since then have met with varying degrees of success. Such studies include the Vertex study of Telaprevir and VX-222 (NCT01080222), Gilead’s study of GS-9190 and 9256 (NCT01225380), the Boehringer Ingelheim (BI) study of BI 207127 and BI 201335 (NCT01132313), and the Bristol-Myers Squibb studies AI447011 (NCT01012895) and AI447017 (NCT01051414) which combine the HCV protease inhibitor BMS-650032 with the HCV NS5A inhibitor BMS-790052. Data presented by Gilead and BI at the 10th annual American Liver Meeting in Boston, 2010, demonstrated variable degrees of early viral breakthrough with the DAA combination employed. Similar observations lead to cancelation of specific DAA only arms in the Vertex study named above. Thus far, BMS study AI447011 which combined BMS-650032 and BMS-790052 in combination alone for 24 weeks has provided the following observations: 1) viral breakthrough occurred within the first 12 weeks of treatment; 2) viral breakthrough occurred only in GT1a, a subtype with a lower barrier to generation of resistance to both the NS3 protease inhibitor and the NS5A inhibitor; and 3) several subjects from study AI447011, both GT1a and GT1b, have now achieved varying durations of SVR. We interpret these data to imply 1) DAA only regimen can cure HCV infection in the absence of immunomodulatory treatment, but 2) that a successful combination DAAs will require a combination of molecules with both adequate antiviral potency and a high barrier to antiviral resistance. This study will build on the results described above by combining the NS5A inhibitor BMS-790052, a molecule with picomolar in vitro potency, together with PSI-7977, a potent nucleotide HCV polymerase inhibitor which appears to confer a significant barrier to generation of resistance. If successful, this combination would present the potential for all oral, once daily, 24 week therapy for subjects infected with most genotypes of HCV. The rationale supporting different aspects of the design of this study will be discussed below.

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Research Hypothesis

A regimen of PSI-7977 and BMS-790052 will be identified with or without ribavirin which provides potent antiviral activity and prevents emergence of resistance in multiple HCV genotypes.

1.3

Objectives

Primary Objective: To estimate the rate of sustained virologic response (SVR) SVR24 in each treatment group, where SVR24 is defined as undetectable HCV RNA ( 90%) and has a molecular weight of > 500, dialysis is unlikely to significantly reduce plasma concentrations of the drug. 1.4.1.3

Preclinical Metabolism and Pharmacokinetics

The nonclinical safety evaluations demonstrated that BMS-790052 was safe for use in clinical testing. Based on nonclinical safety evaluations, events of interest were the possible risks of hematologic toxicity (i.e., bone marrow suppression), hepatic toxicity, and cortical hypertrophy/hyperplasia of the adrenal glands. Hepatic and hematologic monitoring will be assessed in the routine hematology and chemistry laboratory monitoring in this study. A full description of Preclinical Metabolism and Pharmacokinetics is available in the BMS-790052 Investigator’s brochure Section 4. 1.4.1.4

Clinical Pharmacology and Safety

A full description of Clinical Pharmacology and Safety is available in the Investigator’s brochure Section 5.

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Summary of Clinical Investigational Program for BMS-790052

Twenty-two (22) clinical studies with BMS-790052 in healthy volunteers, HCV-infected subjects, and hepatic impaired subjects have been completed or are ongoing. 1.4.1.5.1

Human Pharmacokinetic Results for BMS-790052

BMS-790052 was initially evaluated in phase 1 multiple-dose studies as a capsule formulation. BMS-790052 was readily absorbed following multiple oral doses of the capsule formulation in HV and HCV-infected subjects at doses ranging from 1 to 100 mg daily for 14 days. Steady state was achieved in approximately 4 days of daily dosing with a terminal half-life of ~12 to 15 h supporting once-daily dosing. Tmax was achieved ~1-2 hr post-dose. Overall, BMS 790052 exposures (Cmax, Cmin, AUC(TAU)) increased in a largely dose-dependent manner for the once daily regimen. At steady state, BMS 790052 was ~99% bound to human plasma proteins at both pre-dose and 2h post-dose in subjects infected with HCV. The current formulation being administered in phase I and phase II studies is a dry granulated tablet. Biotransformation data indicated that there is minimal metabolism of BMS 790052. Of the total dose administered, ~ 87% was recovered in feces, primarily as parent drug, and some as BMS-805215 (M2); ~ 6.7% was recovered in urine predominantly as parent drug. In addition, minimal metabolites were present in plasma (< 5%). The major metabolic pathway of BMS-790052 is CYP3A4. Additional details and studies summaries are available in the Investigators Brochure. 1.4.1.5.2

Studies of Clinical Safety and Antiviral Activity of BMS-790052

BMS-790052 was generally well-tolerated in humans in Phase I trials of single oral doses (up to 200 mg) and multiple oral doses (up to 100 mg once daily for 14 days). There were no clinically relevant trends in AEs, vital sign changes, ECG changes, physical examinations or laboratory values. In the first multiple dose study in HCV-infected subjects, the mean decline in HCV RNA ranged from 2.13 log10 IU/mL (1 mg once daily) to 3.56 log10 IU/mL (100 mg once daily) at Day 7 compared to baseline. Following 14 days of monotherapy (range 1-100 mg once

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daily or 30 mg twice daily) in HCV-infected subjects, the most common AE was headache which was reported in 21% BMS-790052-treated subjects and 33% in placebo treated subjects. AI444014 is an ongoing randomized, double-blind 4-arm, placebo-controlled Phase IIa study of BMS-790052 combined with pegIFNα-2a/RBV, administered as triple therapy to treatment naive, genotype 1 HCV infected subjects for 48 weeks. Forty-eight subjects were randomized to 3, 10, or 60 mg BMS-790052 (N = 12 per group) once daily or placebo (N = 12). All subjects have completed treatment. By Week 2, the mean decrease from baseline in HCV RNA in the 3, 10 and 60 mg BMS 790052 dose groups was 4.3, 4.7 and 4.9 (log10 IU/mL), respectively, compared with 1.7 for placebo. By modified ITT, the primary endpoint of eRVR (HCV RNA < limit of detection at week 4 and week 12) was 42%, 83%, 75%, and 8% for BMS-790052 3 mg, 10 mg, 60 mg and placebo, respectively. SVR12 rates of 42%, 92%, 83% and 25% were observed for 3, 10, 60 mg, and placebo, respectively. BMS-790052 was well-tolerated at all doses studied. There were no deaths. Events reported as SAEs or AEs leading to discontinuation were comparable across treatment and control arms, and consistent with those reported in historical P/R studies. Only two subjects (3 mg and 60 mg BMS-790052) experienced HgB