RBP-6000 Briefing Document: 31 October 2017 FDA Advisory Committee Meeting FDA ADVISORY COMMITTEE MEETING BRIEFING DOCUMENT RBP-6000 (extended-release buprenorphine) JOINT MEETING OF THE PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE AND THE DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE MEETING DATE: 31 October 2017 Available for Public Release RBP-6000 Briefing Document: 31 October 2017 FDA Advisory Committee Meeting TABLE OF CONTENTS Table of Contents ............................................................................................................................ 2 List of Tables .................................................................................................................................. 5 List of Figures ................................................................................................................................. 7 List of Abbreviations ...................................................................................................................... 9 1 Executive Summary .............................................................................................................. 11 Introduction .................................................................................................................... 11 Background on Opioid Use Disorder and Medication-Assisted Treatment ................... 11 Rationale for Product Development ............................................................................... 14 Pharmacokinetics and Dose Selection............................................................................ 14 Efficacy Findings ........................................................................................................... 16 Safety Findings ............................................................................................................... 20 Risk Evaluation and Management Strategy (REMS) ..................................................... 22 Conclusions .................................................................................................................... 22 2 Background on Opioid Use Disorder .................................................................................... 24 Opioid Use Disorder....................................................................................................... 24 Current Treatment Landscape ........................................................................................ 25 Unmet Patient Need ....................................................................................................... 27 3 RBP-6000 Product Description and Clinical Development.................................................. 29 Proposed Indication ........................................................................................................ 29 Treatment Administration and Dosing Regimen ........................................................... 29 Mechanism of Action ..................................................................................................... 31 Objectives of Clinical Development Program ............................................................... 31 Clinical Studies .............................................................................................................. 31 4 Clinical Pharmacology .......................................................................................................... 34 Background .................................................................................................................... 34 Overview of Clinical Pharmacology Program ............................................................... 35 Pharmacokinetic Characteristics .................................................................................... 36 Phase 1/2 SAD and MAD Studies .......................................................................... 36 Effect of Intrinsic Factors ....................................................................................... 36 Population PK Modeling......................................................................................... 37 Studies Supporting Dose Selection for Phase 3 Studies ................................................ 38 SAD and MAD Studies ........................................................................................... 38 Page 2 of 104 RBP-6000 Briefing Document: 31 October 2017 FDA Advisory Committee Meeting Opioid Blockade Study (Study 13-0002) ................................................................ 39 Rationale for Phase 3 Dosing Regimens ................................................................. 41 Pharmacokinetics of Phase 3 Dosing Regimens ............................................................ 41 5 Phase 3 Clinical Efficacy ...................................................................................................... 43 Pivotal Phase 3 Double-Blind Study (Study 13-0001)................................................... 43 Study Design ........................................................................................................... 43 Efficacy Endpoints .......................................................................................... 45 Statistical Analyses .......................................................................................... 47 Subject Disposition ................................................................................................. 48 Subject Demographic and Baseline Characteristics ............................................... 49 Primary Endpoint – Percentage Abstinence ........................................................... 50 Additional Analyses of Percentage Abstinence (UDS + Self-report) ............. 51 Abstinence at Week 24 and Total Weeks Abstinent ....................................... 53 Subgroup Analyses of Percentage Abstinence ................................................ 53 Key Secondary Endpoint ........................................................................................ 55 Other Secondary Endpoints .................................................................................... 56 Opioid Craving VAS ....................................................................................... 56 COWS .............................................................................................................. 58 SOWS .............................................................................................................. 58 Percentage Abstinence Based on UDS Only ................................................... 59 Percentage Abstinence Based on Self-Reports Only ....................................... 60 Employment Status ................................................................................................. 60 Exposure-Response Analyses ................................................................................. 61 Phase 3 Open-Label Study 13-0003 ............................................................................... 63 Study Design ........................................................................................................... 63 Maintenance of Efficacy ......................................................................................... 64 Efficacy Conclusions...................................................................................................... 65 6 Clinical Safety ....................................................................................................................... 66 Treatment Exposure ....................................................................................................... 66 Treatment-Emergent Adverse Events ............................................................................ 67 Serious Adverse Events .......................................................................................... 69 Deaths ..................................................................................................................... 70 Page 3 of 104 RBP-6000 Briefing Document: 31 October 2017 FDA Advisory Committee Meeting TEAEs Leading to Study Discontinuation .............................................................. 70 TEAEs Leading to Dose Reduction ........................................................................ 72 Injection Site Reactions .................................................................................................. 73 Injection Site TEAEs .............................................................................................. 73 Injection Site Tolerability Assessments .................................................................. 75 Local Injection Site Assessments .................................................................... 75 Subject-Reported Injection Site Pain (VAS) ................................................... 77 Depot Removal ............................................................................................................... 77 Electrocardiograms......................................................................................................... 77 Liver Chemistry.............................................................................................................. 79 Respiratory Depression and RBP-6000 Overdose ......................................................... 82 Overdose with Other Drugs............................................................................................ 82 Safety by Subgroup .......................................................................................................