CRDAC Briefing Document – Vernakalant injection VERNAKALANT INJECTION FOR CONVERSION OF RECENT ONSET ATRIAL FIBRILLATION BRIEFING DOCUMENT FOR THE CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE Correvio International Sàrl MEETING DATE: 10 December 2019 Advisory Committee Briefing Materials: Available for Public Release Correvio International Sàrl 04 November 2019 Page 1 of 166 CRDAC Briefing Document – Vernakalant injection TABLE OF CONTENTS TABLE OF CONTENTS ....................................................................................................................... 2 LIST OF TABLES ................................................................................................................................. 6 LIST OF FIGURES................................................................................................................................ 8 LIST OF ABBREVIATIONS AND TERMS ....................................................................................... 9 1 EXECUTIVE SUMMARY .......................................................................................................... 12 2 INTRODUCTION ........................................................................................................................ 26 2.1 Proposed Indication and Contraindications for Use ....................................................... 27 2.2 Regulatory History ............................................................................................................. 27 3 DISEASE BACKGROUND AND MEDICAL NEED ............................................................... 29 3.1 Epidemiology ...................................................................................................................... 29 3.2 Impact on Patients .............................................................................................................. 30 3.3 Guidelines for Treating AF ............................................................................................... 30 3.4 Current Treatment Strategies ........................................................................................... 31 3.4.1 Pharmacological Cardioversion ............................................................................... 31 3.4.2 Electrical Cardioversion .......................................................................................... 34 3.4.2.1 Limitations of Electrical Cardioversion ................................................... 35 3.4.2.2 Review of Risks Associated with Electrical Cardioversion ..................... 35 3.4.2.3 ECV Safety Data from Vernakalant Clinical Program ............................ 36 3.4.3 Watchful Waiting for Spontaneous Conversion ...................................................... 36 3.5 Vernakalant to Address Medical Need ............................................................................. 36 4 NONCLINICAL ........................................................................................................................... 38 4.1 Nonclinical Overview ......................................................................................................... 38 4.2 Nonclinical Pharmacokinetics/Pharmacodynamics ........................................................ 38 4.2.1 Pharmacodynamics .................................................................................................. 38 4.2.1.1 Primary Pharmacodynamics and Efficacy ............................................... 38 4.2.1.2 Mechanism of Action for Vernakalant-Induced Hypotension ................. 39 4.3 Nonclinical Safety and Toxicology .................................................................................... 41 4.3.1 Safety Pharmacology ............................................................................................... 41 4.3.2 Toxicology Studies .................................................................................................. 41 5 CLINICAL PHARMACOLOGY ................................................................................................ 42 5.1 Overview ............................................................................................................................. 42 5.2 Pharmacokinetics ............................................................................................................... 42 5.3 Influence of Intrinsic and Extrinsic Factors on Vernakalant Injection ........................ 44 5.4 Pharmacodynamics ............................................................................................................ 45 5.4.1 Electrophysiological Study ...................................................................................... 45 5.4.2 Pharmacokinetic/Pharmacodynamic Modelling ...................................................... 45 5.4.2.1 QTcF PK/PD Model ................................................................................. 45 5.4.2.2 Systolic Blood Pressure PK/PD Model .................................................... 46 6 CLINICAL DEVELOPMENT PROGRAM .............................................................................. 47 Correvio International Sàrl 04 November 2019 Page 2 of 166 CRDAC Briefing Document – Vernakalant injection 6.1 Original NDA Submission ................................................................................................. 47 6.1.1 Efficacy Endpoints and Safety Monitoring ............................................................. 48 6.2 NDA Resubmission ............................................................................................................. 50 6.2.1 Overview of New Clinical Studies .......................................................................... 50 6.2.2 Study Oversight ....................................................................................................... 53 6.2.3 Analysis Populations, Demographics, and Exposure .............................................. 53 6.2.3.1 Efficacy Analyses .................................................................................... 54 6.2.3.2 Safety Analyses ........................................................................................ 54 6.3 Post-Authorization Safety Study (SPECTRUM) ............................................................. 56 6.3.1 Endpoint Selection and Assessments ...................................................................... 57 6.3.2 Patient Selection ...................................................................................................... 58 6.3.2.1 Baseline Characteristics ........................................................................... 58 6.3.2.2 Patient Disposition ................................................................................... 60 6.3.3 Study Oversight and Data Reporting ....................................................................... 61 6.4 Other Post-marketing Data ............................................................................................... 61 7 EFFICACY RESULTS ................................................................................................................ 62 7.1 Original NDA Submission ................................................................................................. 62 7.1.1 Disposition ............................................................................................................... 63 7.1.2 Primary Efficacy ...................................................................................................... 63 7.1.3 Secondary and Exploratory Efficacy Endpoints ...................................................... 64 7.1.4 Comparison of Efficacy Results in Subpopulations (ACT I/III) ............................. 65 7.2 NDA Resubmission ............................................................................................................. 67 7.2.1 Conversion to Sinus Rhythm ................................................................................... 67 7.2.2 Secondary and Exploratory Efficacy Endpoints in All Phase 2 and 3 Trials .......... 67 7.2.3 Target Patient Population ........................................................................................ 70 7.3 Post-Authorization Safety Study (SPECTRUM) ............................................................. 70 7.3.1 Study Results ........................................................................................................... 70 7.4 Other Post-marketing Efficacy Data ................................................................................ 70 7.5 Efficacy Conclusions .......................................................................................................... 71 8 SAFETY ........................................................................................................................................ 72 8.1 FDA Approvable Letter ..................................................................................................... 73 8.2 NDA Resubmission ............................................................................................................. 74 8.3 Eight Cases of Interest ....................................................................................................... 74 8.4 Death Resulting in Clinical Hold ...................................................................................... 78 8.5 Overview of Adverse Events .............................................................................................. 79 8.6 Adverse Events of