CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208464Orig1s000 MEDICAL REVIEW(S) Clinical Review Tanvir Bell, MD NDA 208464 Vemlidy (Tenofovir Alafenamide) CLINICAL REVIEW Application Type New Drug Application (NDA) Application Number(s) 208464 Priority or Standard Standard Submit Date(s) 1/11/2016 Received Date(s) 1/11/2016 PDUFA Goal Date November 11, 2016 Division/Office DAVP/OAP Reviewer Name(s) Tanvir Bell, MD Review Completion Date October 7, 2016 Established Name Tenofovir Alafenamide (Proposed) Trade Name VemlidyTM Applicant Gilead Formulation(s) Tablet Dosing Regimen 25 mg tablet orally (po) once daily Applicant Proposed Treatment of chronic hepatitis B in adults Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Treatment of chronic hepatitis B in adults with compensated Indication(s)/Population(s) liver disease (if applicable) CDER Clinical Review Template 2015 Edition 1 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3996126 Clinical Review Tanvir Bell, MD NDA 208464 Vemlidy (Tenofovir Alafenamide) Table of Contents Glossary ........................................................................................................................................... 9 1 Executive Summary ............................................................................................................... 11 1.1. Product Introduction ...................................................................................................... 11 1.2. Conclusions on the Substantial Evidence of Effectiveness ............................................ 11 1.3. Benefit-Risk Assessment ................................................................................................ 11 2 Therapeutic Context .............................................................................................................. 16 2.1. Analysis of Condition ...................................................................................................... 16 2.2. Analysis of Current Treatment Options ......................................................................... 17 3 Regulatory Background ......................................................................................................... 18 3.1. U.S. Regulatory Actions and Marketing History ............................................................. 18 3.2. Summary of Presubmission/Submission Regulatory Activity ........................................ 19 3.3. Foreign Regulatory Actions and Marketing History ....................................................... 19 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 19 4.1. Office of Scientific Investigations (OSI) .......................................................................... 19 4.2. Product Quality .............................................................................................................. 20 4.3. Clinical Microbiology ...................................................................................................... 20 4.4. Nonclinical Pharmacology/Toxicology ........................................................................... 21 4.5. Clinical Pharmacology .................................................................................................... 22 4.5.1. Mechanism of Action .............................................................................................. 22 4.5.2. Pharmacodynamics ................................................................................................. 22 4.5.3. Pharmacokinetics .................................................................................................... 23 4.6. Devices and Companion Diagnostic Issues .................................................................... 25 4.7. Consumer Study Reviews ............................................................................................... 25 5 Sources of Clinical Data and Review Strategy ....................................................................... 25 5.1. Table of Clinical Studies .................................................................................................. 25 5.2. Review Strategy .............................................................................................................. 27 6 Review of Relevant Individual Trials Used to Support Efficacy ............................................. 28 CDER Clinical Review Template 2015 Edition 2 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3996126 Clinical Review Tanvir Bell, MD NDA 208464 Vemlidy (Tenofovir Alafenamide) 6.1. Study 108 ........................................................................................................................ 28 6.1.1. Study Design............................................................................................................ 28 6.1.2. Study Results ........................................................................................................... 35 6.2. Study 110 ........................................................................................................................ 45 6.2.1. Study Design............................................................................................................ 45 6.2.2. Study Results ........................................................................................................... 49 7 Integrated Review of Effectiveness ....................................................................................... 60 7.1. Assessment of Efficacy Across Trials .............................................................................. 60 7.1.1. Primary Endpoints ................................................................................................... 61 7.1.2. Secondary and Other Endpoints ............................................................................. 61 7.1.3. Subpopulations ....................................................................................................... 62 7.1.4. Dose and Dose-Response........................................................................................ 62 7.1.5. Onset, Duration, and Durability of Efficacy Effects ................................................ 62 7.2. Additional Efficacy Considerations ................................................................................. 63 7.2.1. Considerations on Benefit in the Postmarket Setting ............................................ 63 7.3. Integrated Assessment of Effectiveness ........................................................................ 63 8 Review of Safety .................................................................................................................... 64 8.1. Safety Review Approach ................................................................................................ 64 8.2. Review of the Safety Database ...................................................................................... 65 8.2.1. Overall Exposure ..................................................................................................... 65 8.2.2. Relevant characteristics of the safety population: ................................................. 66 8.2.3. Adequacy of the safety database ........................................................................... 66 8.3. Adequacy of Applicant’s Clinical Safety Assessments .................................................... 67 8.3.1. Issues Regarding Data Integrity and Submission Quality ....................................... 67 8.3.2. Categorization of Adverse Events ........................................................................... 67 8.3.3. Routine Clinical Tests .............................................................................................. 67 8.4. Safety Results ................................................................................................................. 68 8.4.1. Deaths ..................................................................................................................... 68 8.4.2. Dropouts and/or Discontinuations Due to Adverse Effects ................................... 69 8.4.3. Significant Adverse Event........................................................................................ 71 CDER Clinical Review Template 2015 Edition 3 Version date: November 5, 2015 for initial rollout (NME/original BLA reviews) Reference ID: 3996126 Clinical Review Tanvir Bell, MD NDA 208464 Vemlidy (Tenofovir Alafenamide) 8.4.4. Treatment Emergent Adverse Events and Adverse Reactions ............................... 72 8.4.5. Laboratory Findings ................................................................................................ 73 8.4.6. Vital Signs ................................................................................................................ 73 8.4.7. Electrocardiograms (ECGs) ...................................................................................... 73 8.4.8. QT ............................................................................................................................ 74 8.4.9. Immunogenicity ...................................................................................................... 74 8.5. Analysis of Submission-Specific Safety