ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS ADVISORY COMMITTEE 25 April 2016 ETEPLIRSEN BRIEFING DOCUMENT NDA 206488 Sarepta Therapeutics, Inc. 215 First Street Cambridge, MA 02142 USA AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION Sarepta Therapeutics, Inc. Eteplirsen (NDA 206488) PCNSD Advisory Committee Meeting Briefing Document TABLE OF CONTENTS LIST OF ABBREVIATIONS ........................................................................................................12 1. EXECUTIVE SUMMARY ........................................................................................15 2. OVERVIEW OF DUCHENNE MUSCULAR DYSTROPHY (DMD) .....................28 2.1. Onset and Progression ................................................................................................28 2.2. Diagnosis and Determination of Mutation .................................................................29 2.3. Current Treatments for DMD and Unmet Medical Need ...........................................29 2.4. Epidemiology ..............................................................................................................29 2.5. Pathophysiology and Role of Dystrophin ...................................................................30 2.5.1. Dystrophin in Normal Muscle ....................................................................................30 2.5.2. Dystrophin Protein in DMD and BMD ......................................................................31 2.5.3. Relationship of Dystrophin to DMD and BMD Severity ...........................................32 3. ETEPLIRSEN DEVELOPMENT ..............................................................................34 3.1. Background Information on Eteplirsen Injection .......................................................34 3.2. Rationale for Development and Mechanism of Action ..............................................35 3.3. Proposed Indication, Dosing and Administration .......................................................37 3.4. Regulatory History and Framework ...........................................................................37 3.4.1. Regulatory Framework ...............................................................................................38 3.4.2. Eteplirsen Regulatory History ....................................................................................39 4. NONCLINICAL STUDIES........................................................................................43 4.1. Exon Skipping Increases Dystrophin and Improves Function in Dystrophic Animals .......................................................................................................................43 4.2. Nonclinical Development of Eteplirsen......................................................................43 4.2.1. Nonclinical Pharmacokinetics ....................................................................................43 4.2.2. Renal Toxicity of Eteplirsen in Animals ....................................................................44 4.2.3. Other Nonclinical Findings for Eteplirsen ..................................................................44 5. CLINICAL PHARMACOLOGY ...............................................................................46 5.1. Pharmacokinetics ........................................................................................................46 5.2. Pharmacodynamic Effects ..........................................................................................47 5.3. Drug-Drug Interactions ...............................................................................................47 6. ETEPLIRSEN CLINICAL STUDIES CONTRIBUTING TO EVALUATION OF EFFICACY ................................................................................48 2 Sarepta Therapeutics, Inc. Eteplirsen (NDA 206488) PCNSD Advisory Committee Meeting Briefing Document 6.1. Clinical Studies Contributing to Pharmacodynamic Endpoints and Clinical Efficacy .......................................................................................................................48 6.2. Pivotal Studies 201/202 ..............................................................................................51 6.2.1. Study Design ...............................................................................................................51 6.2.2. Inclusion and Exclusion Criteria ................................................................................52 6.2.3. Study 201/202 Pre-specified Endpoint Results ..........................................................52 6.2.3.1. Primary Endpoint of Study 201 ..................................................................................52 6.2.3.2. Primary Endpoint of Study 202 ..................................................................................53 6.3. External Control Cohort Used For Comparison of Long Term Efficacy Data ...........54 6.3.1. Selection of External Registries for Long Term Clinical Outcome Data ...................54 6.3.2. Registry Characteristics Similar to Eteplirsen Studies 201/202 .................................54 6.3.3. Criteria for Identification of Patients for External Control Cohort was Based on Study 201 Inclusion Criteria ..................................................................................55 6.3.4. Schematic for Identification of External Control Groups ...........................................55 6.4. Comparability of Baseline Characteristics of Eteplirsen Treated Patients and the External Control Groups .......................................................................................57 6.4.1. Comparability of Glucocorticoid Use for Eteplirsen-Treated and External Control Group (N = 13) ..............................................................................................59 6.4.2. Physical Therapy and Use of Orthotic Devices Eteplirsen-Treated (N = 12) vs External Control (N = 13) ......................................................................................60 6.5. Approaches or Analyses to Address Potential Limitations of Use of an External Control Group Per ICH E10 .........................................................................61 6.6. Clinical Endpoints ......................................................................................................62 6.6.1. Six-Minute Walk Test (6MWT) .................................................................................62 6.6.1.1. Results for 6MWT of Eteplirsen (N = 12) vs External Control Amenable to Exon 51 (N = 13) ........................................................................................................63 6.6.1.2. Sensitivity Analyses of the Primary Functional Efficacy Endpoint: 6MWT .............65 6.6.1.3. 6MWT of Eteplirsen (N = 12) vs External Controls Amenable to Any Exon Skipping (N = 50) .......................................................................................................66 6.6.1.4. Decline of 6MWT for External Control (N = 13) Compared to Published Literature .....................................................................................................................68 6.6.2. Loss of Ambulation (LOA) ........................................................................................69 6.6.2.1. Kaplan-Meier Analysis of Loss of Ambulation ..........................................................69 6.6.2.2. Loss of Ambulation of External Control Group Compared to Published Literature .....................................................................................................................70 6.6.3. North Star Ambulatory Assessment (NSAA) .............................................................71 3 Sarepta Therapeutics, Inc. Eteplirsen (NDA 206488) PCNSD Advisory Committee Meeting Briefing Document 6.6.3.1. Eteplirsen Patients with NSAA Scores ≤9 by Year 3, Ambulant at Year 4 ...............72 6.6.4. Ability to Rise .............................................................................................................73 6.6.4.1. Eteplirsen Patients Unable to Rise Independently by Year 3, Ambulant at Year 4 ..........................................................................................................................74 6.6.5. Pulmonary Function Tests ..........................................................................................75 7. PHARMACODYNAMIC RESULTS ........................................................................77 7.1. Methods for Assessing Pharmacodynamic Endpoints ................................................77 7.2. Pharmacodynamic/Biological Endpoints ....................................................................78 7.2.1. RT-PCR Demonstrates Exon 51 Skipping in Studies 201/202, 28 and 33 .................78 7.2.2. Dystrophin Protein Expression – Percent Dystrophin Positive Fibers .......................79 7.2.2.1. Study 201/202 .............................................................................................................79 7.2.2.2. Dose selection of 30 mg/kg based on Week 48 analysis of Studies 201/202 .............81 7.2.2.3. Independent Verification of Percent Dystrophin Positive Fibers ...............................82 7.2.2.4. Independent Verification of Study 201/202 Percent Positive Dystrophin Fibers ..........................................................................................................................82 7.2.2.5. Study 28