Spark Therapeutics Briefing Document: October 12, 2017 FDA Advisory Committee Meeting FDA ADVISORY COMMITTEE BRIEFING DOCUMENT Spark Therapeutics, Inc LUXTURNATM (voretigene neparvovec) MEETING OF THE CELLULAR, TISSUE, AND GENE THERAPIES ADVISORY COMMITTEE MEETING DATE: October 12, 2017 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Page 1 of 149 Spark Therapeutics Briefing Document: October 12, 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 1.1 Background and Unmet Need .....................................................................................11 1.2 Product Development Overview .................................................................................13 1.3 Natural History Study .................................................................................................14 1.4 Efficacy .......................................................................................................................16 1.4.1 Phase 1 .................................................................................................................16 1.4.2 Phase 3 .................................................................................................................20 1.5 Safety ..........................................................................................................................29 1.6 Conclusions.................................................................................................................33 2 Background on Biallelic RPE65 Mutation-Associated Retinal Dystrophy .........35 2.1 Overview of Biallelic RPE65 Mutation-Associated Retinal Dystrophy ....................35 2.1.1 Diagnosis .............................................................................................................38 2.1.2 Epidemiology ......................................................................................................38 2.2 Current Treatment Options .........................................................................................38 2.3 Unmet Medical Need ..................................................................................................38 3 Product Description ..................................................................................................39 3.1 Overview of Voretigene Neparvovec .........................................................................39 3.2 Mechanism of Action .................................................................................................40 3.3 Manufacturing .............................................................................................................40 3.4 Non-clinical Findings .................................................................................................42 3.5 Biodistribution and Viral Shedding ............................................................................43 3.5.1 Biodistribution in Non-Clinical Studies ..............................................................43 3.5.2 Viral Shedding in Clinical Studies ......................................................................44 3.6 Proposed Indication ....................................................................................................44 3.7 Regulatory History ......................................................................................................45 3.8 Dosing and Administration .........................................................................................45 4 Development History ................................................................................................47 Page 2 of 149 Spark Therapeutics Briefing Document: October 12, 2017 FDA Advisory Committee Meeting 4.1 Clinical Development Program ..................................................................................47 4.1.1 Genetic Diagnoses ...............................................................................................47 4.1.2 Injection Procedure ..............................................................................................48 4.1.3 Clinical Evaluation Methods ...............................................................................49 5 Multi-Luminance Mobility Test Endpoint .............................................................50 5.1 Multi-Luminance Mobility Test .................................................................................50 5.2 Clinically Meaningful Change on MLMT ..................................................................52 5.3 Evolution of Mobility Testing from Phase 1 to Phase 3 .............................................53 5.3.1 Standardization ....................................................................................................53 5.4 Mobility Test Validation Study (MTVS) ...................................................................54 5.4.1 Study Design .......................................................................................................55 5.4.2 Validation Study Results .....................................................................................55 6 Measurements of Visual Function ...........................................................................60 6.1 Visual Function vs Functional Vision ........................................................................60 6.2 Full-field Light Sensitivity Threshold Testing ...........................................................60 6.3 Visual Acuity ..............................................................................................................61 6.4 Visual Field .................................................................................................................62 6.5 Endpoint Selection for Phase 3 Study ........................................................................63 7 RPE65 Mutation-Associated Retinal Dystrophy Natural History Study ............65 7.1 Methodology ...............................................................................................................65 7.2 Sources ........................................................................................................................65 7.3 Demographics .............................................................................................................66 7.4 Diagnosis ....................................................................................................................66 7.5 Results.........................................................................................................................66 8 Efficacy in the Phase 1 and Phase 3 Studies ...........................................................70 8.1 Phase 1 Studies 101 and 102 ......................................................................................70 8.1.1 Clinical Design ....................................................................................................70 8.1.2 Study Population .................................................................................................72 8.1.3 Efficacy Results ...................................................................................................72 8.2 Phase 3 Study 301 .......................................................................................................74 8.2.1 Clinical Design ....................................................................................................74 8.2.2 Demographics ......................................................................................................78 8.2.3 Efficacy Results ...................................................................................................80 8.3 Efficacy Conclusions ..................................................................................................97 Page 3 of 149 Spark Therapeutics Briefing Document: October 12, 2017 FDA Advisory Committee Meeting 9 Clinical Safety ...........................................................................................................98 9.1 Extent of Exposure .....................................................................................................98 9.2 Overall Adverse Events ............................................................................................100 9.2.1 Severe Adverse Events ......................................................................................102 9.3 Serious Adverse Events ............................................................................................102 9.4 Deaths .......................................................................................................................103 9.5 Adverse Events of Special Interest ...........................................................................104 9.6 Other Safety Topics of Interest .................................................................................105