VOLANESORSEN FDA ADVISORY COMMITTEE MEETING BRIEFING DOCUMENT ENDOCRINE AND METABOLIC DRUGS ADVISORY COMMITTEE MEETING DATE: 10 MAY 2018 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Volanesorsen (ISIS 304801) Akcea Therapeutics Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................2 TABLE OF TABLES ......................................................................................................................6 TABLE OF FIGURES .....................................................................................................................9 LIST OF ABBREVIATIONS ........................................................................................................10 1. EXECUTIVE SUMMARY ........................................................................................11 1.1 Familial Chylomicronemia Syndrome ........................................................................12 1.1.1 Overview of the Disease and Impact of Elevated Triglyceride Levels ......................12 1.1.2 Current Treatment Options .........................................................................................14 1.2 Volanesorsen Clinical Development Program ............................................................15 1.3 Efficacy and Safety of Volanesorsen ..........................................................................15 1.3.1 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 .......................16 1.3.2 Phase 3 Open-label Extension Study ISIS 304801-CS7.............................................24 1.3.3 Phase 3 Study ISIS 304801-CS16 ..............................................................................27 1.3.4 Safety of Volanesorsen Treatment ..............................................................................28 1.4 Risk Mitigation ...........................................................................................................30 1.5 Benefit and Risks Conclusions ...................................................................................31 2. BACKGROUND ON FAMILIAL CHYLOMICRONEMIA SYNDROME .............33 2.1 Overview of Familial Chylomicronemia Syndrome ...................................................33 2.2 Clinical Features of FCS .............................................................................................33 2.2.1 FCS Disease Complications .......................................................................................34 2.2.2 Platelet Variability in FCS ..........................................................................................37 2.3 FCS Unmet Medical Need ..........................................................................................37 3. PRODUCT DESCRIPTION .......................................................................................39 3.1 Proposed Indication and Dosing Regimen .................................................................39 3.2 Mechanism of Action .................................................................................................39 4. REGULATORY AND DEVELOPMENT HISTORY ...............................................41 4.1 Regulatory Milestones ................................................................................................41 4.2 Clinical Development Program ..................................................................................41 5. NONCLINICAL SUMMARY ...................................................................................47 06 April 2018 Page 2 of 144 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Volanesorsen (ISIS 304801) Akcea Therapeutics Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting 6. CLINICAL PHARMACOLOGY ...............................................................................49 6.1 Pharmacokinetics ........................................................................................................49 6.1.1 Absorption, Distribution, Clearance, Metabolism, and Elimination ..........................50 6.1.2 Dose-Proportionality of Pharmacokinetics .................................................................50 6.1.3 Effect of Intrinsic Factors on Pharmacokinetics .........................................................50 6.1.4 Effect of Extrinsic Factors on Pharmacokinetics ........................................................52 6.2 Anti-Drug Antibodies .................................................................................................52 6.3 Pharmacodynamics .....................................................................................................52 6.3.1 Concentration-Effect Relationships ............................................................................52 6.3.2 Pharmacodynamic Drug-Drug Interactions ................................................................53 7. OVERVIEW OF THE PIVOTAL AND SUPPORTIVE STUDIES ..........................54 7.1 Key Design Features of the Pivotal Phase 3 Study ISIS 304801-CS6 .......................54 7.1.1 Overview .....................................................................................................................54 7.1.2 Key Inclusion/Exclusion Criteria ...............................................................................56 7.1.3 Endpoints, Analysis Sets, and Statistical Methods .....................................................57 7.1.4 Discussion of Key Design Features ............................................................................60 7.2 Key Design Features of Study ISIS 304801-CS7 .......................................................60 7.3 Key Design Features of Study ISIS 304801-CS16 .....................................................61 8. CLINICAL EFFICACY .............................................................................................62 8.1 Phase 2 Study ISIS 304801-CS2 ................................................................................63 8.2 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 .......................64 8.2.1 Study Enrollment and Disposition ..............................................................................64 8.2.2 Discontinuations .........................................................................................................65 8.2.3 Dose Frequency Changes/Dose Pauses ......................................................................66 8.2.4 Medication Exposure and Treatment Duration ...........................................................67 8.2.5 Demographics and Baseline Disease Characteristics .................................................67 8.2.6 Primary Endpoint – Percent Change in Fasting Triglycerides from Baseline to Month 3...................................................................................................................69 8.2.7 Secondary Endpoints ..................................................................................................70 8.2.8 Exploratory Endpoints: Remaining Secondary Endpoints .........................................72 8.2.9 Exploratory Endpoints: Post-hoc Analyses ................................................................76 06 April 2018 Page 3 of 144 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Volanesorsen (ISIS 304801) Akcea Therapeutics Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting 8.2.10 Efficacy Following Dose Adjustments .......................................................................82 8.2.11 Comparison of Results in Subpopulations ..................................................................84 8.3 Phase 3 Open-label Extension Study ISIS 304801-CS7.............................................85 8.3.1 Study Enrollment and Disposition ..............................................................................85 8.3.2 Dose Adjustments and Dose Pauses ...........................................................................86 8.3.3 Demographics and Baseline Characteristics ...............................................................86 8.3.4 Efficacy Results ..........................................................................................................86 8.4 Study ISIS 304801-CS16 ............................................................................................88 8.4.1 Study Enrollment and Disposition ..............................................................................88 8.4.2 Demographics and Baseline Disease Characteristics .................................................88 8.4.3 Efficacy Results ..........................................................................................................88 8.4.4 Effect on Triglycerides ...............................................................................................88 8.4.5 Acute Pancreatitis .......................................................................................................90 8.5 Quality of Life – ReFOCUS .......................................................................................90 9. SAFETY .....................................................................................................................92 9.1 Safety Monitoring in Clinical Studies ........................................................................92 9.2 Treatment