Sofosbuvir For Treatment of Chronic Hepatitis C Infection Antiviral Drugs Advisory Committee Meeting Briefing Document 25 October 2013 NDA 204671 AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Applicant: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 USA Sofosbuvir Advisory Committee Briefing Document TABLE OF CONTENTS TABLE OF CONTENTS .......................................................................................................................................2 LIST OF IN-TEXT TABLES.................................................................................................................................5 LIST OF IN-TEXT FIGURES ...............................................................................................................................7 1. EXECUTIVE OVERVIEW...........................................................................................................................8 1.1. Unmet Medical Need ........................................................................................................................9 1.2. Development Program ......................................................................................................................9 1.3. Nonclinical Program .......................................................................................................................10 1.3.1. Mechanism of Action....................................................................................................10 1.3.2. In Vitro Anti-viral Activity, Resistance and Cross-resistance Characterization ............................................................................................................10 1.3.3. Pharmacokinetics and In Vitro Drug Interactions .........................................................11 1.3.4. Nonclinical Safety Pharmacology and Toxicology.......................................................11 1.4. Clinical Development Program.......................................................................................................12 1.4.1. Clinical Pharmacology ..................................................................................................12 1.5. Efficacy in Phase 2 Studies.............................................................................................................14 1.6. Efficacy in Phase 3 Studies.............................................................................................................14 1.6.1. Primary Efficacy Endpoint for the Phase 3 Studies ......................................................15 1.6.2. FISSION: Treatment-Naive Patients with Chronic Genotype 2 or 3 HCV Infection...............................................................................................................17 1.6.3. POSITRON: Patients with Chronic Genotype 2 or 3 HCV Infection who were Interferon Intolerant, Ineligible, or Unwilling ..............................................18 1.6.4. FUSION: Treatment-Experienced Patients with Chronic Genotype 2 or 3 HCV Infection........................................................................................................20 1.6.5. NEUTRINO: Treatment-Naive Patients with Chronic Genotype 1, 4, 5, or 6 HCV Infection....................................................................................................21 1.6.6. Resistance Surveillance in Patients who did not Achieve SVR ....................................22 1.6.7. Efficacy Conclusions and Proposed Treatment Recommendations ..............................22 1.7. Safety ..............................................................................................................................................24 1.7.1. Safety of SOF+RBV Treatment in Patients with Genotype 2 or 3 HCV Infection...............................................................................................................25 1.7.2. Safety of SOF+Peg-IFN+RBV Treatment in Patients with Genotype 1, 4, 5, or 6 HCV Infection............................................................................................27 1.8. SOF+RBV Treatment in Patients Awaiting Liver Transplantation ................................................28 1.9. Benefit/Risk Profile of Sofosbuvir..................................................................................................29 1.9.1. Benefits of Sofosbuvir Treatment .................................................................................29 1.9.2. Risks of Sofosbuvir Treatment......................................................................................30 1.9.3. Conclusions...................................................................................................................31 2. UNMET MEDICAL NEED ........................................................................................................................32 2.1. Hepatitis C Virus.............................................................................................................................32 2.2. Current Treatment Options for HCV Treatment .............................................................................33 2.2.1. Limitations with Current HCV Therapies.....................................................................34 2.2.2. Conclusions...................................................................................................................36 Page 2 Sofosbuvir Advisory Committee Briefing Document 2.3. Rationale for Development of Sofosbuvir ......................................................................................36 3. NONCLINICAL DEVELOPMENT PROGRAM .......................................................................................37 3.1. Nonclinical Pharmacology..............................................................................................................38 3.1.1. Mechanism of Action....................................................................................................38 3.1.2. In Vitro Activity............................................................................................................38 3.1.3. In Vitro Resistance and Cross-resistance Characterization...........................................38 3.1.4. Selectivity......................................................................................................................39 3.2. Safety Pharmacology ......................................................................................................................40 3.3. Pharmacokinetics and In Vitro Drug Interactions...........................................................................40 3.4. Nonclinical Toxicology...................................................................................................................41 4. CLINICAL DEVELOPMENT PROGRAM................................................................................................43 5. CLINICAL PHARMACOLOGY ................................................................................................................44 5.1. Clinical Pharmacokinetics...............................................................................................................45 5.2. Pharmacokinetic Profiles ................................................................................................................45 5.2.1. Absorption.....................................................................................................................45 5.2.2. Distribution ...................................................................................................................45 5.2.3. Metabolism and Elimination .........................................................................................46 5.2.4. Sofosbuvir Pharmacokinetics after Single- and Multiple-Dose Administration in Healthy Subjects ..............................................................................46 5.2.5. Sofosbuvir Pharmacokinetics in HCV-Infected Patients...............................................46 5.2.6. Comparison of Sofosbuvir and GS-331007 Exposures Between Healthy Subjects and HCV-Infected Patients................................................................47 5.2.7. Demographic Effects.....................................................................................................47 5.2.8. Renal Impairment..........................................................................................................47 5.2.9. Hepatic Impairment.......................................................................................................48 5.2.10. Established and Other Potentially Significant Drug Interactions..................................49 5.2.11. Clinically Important Drug Interactions .........................................................................51 5.3. Clinical Pharmacokinetics/Pharmacodynamics ..............................................................................52 5.3.1. Dose Response Relationship with Efficacy Evaluated as On- Treatment Suppression of HCV RNA...........................................................................52 5.3.2. Efficacy Pharmacokinetics/Pharmacodynamics............................................................54 5.3.3. Safety Pharmacokinetics/Pharmacodynamics...............................................................54 6. EFFICACY ..................................................................................................................................................56 6.1. Phase 2 Clinical Development