SECTION 2.5 CLINICAL OVERVIEW EMTRICITABINE/RILPIVIRINE/ TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION Gilead Sciences International Limited 18 August 2010 CONFIDENTIAL AND PROPRIETARY INFORMATION Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.5 Clinical Overview Final TABLE OF CONTENTS SECTION 2.5 CLINICAL OVERVIEW ...............................................................................................................1 TABLE OF CONTENTS .......................................................................................................................................2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................7 2.5. CLINICAL OVERVIEW.............................................................................................................................12 2.5.1. Product Development Rationale .....................................................................................................12 2.5.1.1. Introduction and Background........................................................................................12 2.5.1.2. HIV-1 Infection and Current Approaches to Treatment................................................14 2.5.1.3. Rationale for Development of the FTC/RPV/TDF FDC Tablet....................................15 2.5.1.4. Overview of Clinical Development Program................................................................16 2.5.2. Overview of Biopharmaceutics.......................................................................................................18 2.5.2.1. Details of Formulation ..................................................................................................18 2.5.2.2. Results of Bioequivalence Study GS-US-264-0103......................................................20 2.5.2.3. Effect of Food ...............................................................................................................22 2.5.2.3.1. Emtriva ....................................................................................................22 2.5.2.3.2. Rilpivirine................................................................................................23 2.5.2.3.3. Viread ......................................................................................................24 2.5.2.3.4. Truvada FDC tablet .................................................................................24 2.5.2.3.5. FTC/RPV/TDF FDC tablet......................................................................24 2.5.3. Overview of Clinical Pharmacology...............................................................................................25 2.5.3.1. Pharmacology/Virology ................................................................................................25 2.5.3.1.1. Mechanism of Action ..............................................................................25 2.5.3.2. Clinical Pharmacodynamics..........................................................................................27 2.5.3.3. Clinical Pharmacokinetics.............................................................................................28 2.5.3.3.1. Pharmacokinetic Profiles .........................................................................28 2.5.3.3.2. Demographic Effects ...............................................................................32 2.5.3.3.3. Renal Impairment ....................................................................................35 2.5.3.3.4. Hepatic Impairment .................................................................................36 2.5.3.4. Potential for Drug Interactions......................................................................................37 2.5.3.4.1. Emtricitabine and Tenofovir DF..............................................................37 2.5.3.4.2. Rilpivirine................................................................................................38 2.5.3.4.3. Clinically Important Drug Interactions....................................................42 2.5.3.5. Summary of Clinical Pharmacology .............................................................................46 2.5.4. Overview of Efficacy......................................................................................................................47 2.5.4.1. Efficacy of Emtricitabine ..............................................................................................48 2.5.4.2. Efficacy of Rilpivirine...................................................................................................48 2.5.4.3. Efficacy of Tenofovir DF..............................................................................................48 2.5.4.4. Efficacy of the Truvada FDC Tablet.............................................................................48 2.5.4.4.1. Efficacy in Study GS-01-934...................................................................52 2.5.4.4.2. Efficacy in Study GS-99-903...................................................................55 2.5.4.4.3. Efficacy in Study M02-418......................................................................57 2.5.4.5. Efficacy of the FTC/RPV/TDF FDC Tablet .................................................................58 2.5.4.5.1. Subanalysis of the Virologic Outcomes using Pooled Data for Subjects Receiving RPV or EFV in Combination with FTC/TDF ...................................................................62 2.5.4.5.2. Baseline Genotype and Phenotype Characteristics..................................63 2.5.4.5.3. Efficacy in Studies C209 and C215.........................................................65 2.5.4.6. Summary of Clinical Resistance Findings ....................................................................77 2.5.4.6.2. Clinical Resistance Findings for C209 and C215 ....................................81 2.5.4.7. Conclusions on Resistance Determination ....................................................................91 CONFIDENTIAL Page 2 18AUG2010 Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.5 Clinical Overview Final 2.5.4.7.1. Conclusions on Resistance Determination for Emtricitabine ...........................................................................................91 2.5.4.7.2. Conclusions on Resistance Determination for Rilpivirine................................................................................................92 2.5.4.7.3. Conclusions on Resistance Determination for Tenofovir DF ............................................................................................................93 2.5.4.7.4. Conclusions on Resistance Determination for the FTC/RPV/TDF FDC Tablet.....................................................................93 2.5.4.8. Efficacy Against HBV in HIV/HBV Coinfected Subjects............................................93 2.5.4.9. Efficacy Discussion and Conclusions ...........................................................................94 2.5.5. Overview of Safety .........................................................................................................................97 2.5.5.1. Introduction...................................................................................................................97 2.5.5.2. Summary of Clinical Trial Safety Experience...............................................................99 2.5.5.2.1. Safety in Study GS-01-934......................................................................99 2.5.5.2.2. Safety in Study GS-99-903....................................................................101 2.5.5.2.3. Safety in Trials C209 and C215.............................................................103 2.5.5.2.4. AE Data to Support the FTC/RPV/TDF FDC Tablet ............................121 2.5.5.3. Renal Adverse Events .................................................................................................125 2.5.5.3.1. Renal Safety in Clinical Studies ............................................................125 2.5.5.3.2. Experience in Postmarketing Surveillance ............................................128 2.5.5.3.3. Mechanisms of Renal Toxicity..............................................................129 2.5.5.3.4. Risk Factors ...........................................................................................130 2.5.5.3.5. Conclusions on Renal Safety .................................................................131 2.5.5.4. Effects on the Skin ......................................................................................................132 2.5.5.4.1. Emtricitabine .........................................................................................132 2.5.5.4.2. Rilpivirine..............................................................................................132 2.5.5.4.3. Tenofovir DF .........................................................................................134 2.5.5.4.4. FTC/RPV/TDF FDC Tablet...................................................................134 2.5.5.5. Effects on the Bone .....................................................................................................134 2.5.5.5.1. Emtricitabine .........................................................................................134 2.5.5.5.2. Rilpivirine..............................................................................................134 2.5.5.5.3. Tenofovir DF .........................................................................................134