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Janssen Research & Development, LLC Advisory Committee Briefing Janssen Research & Development, LLC Advisory Committee Briefing Document Esketamine Nasal Spray for Patients with Treatment-resistant Depression JNJ-54135419 (esketamine) Status: Approved Date: 16 January 2019 Prepared by: Janssen Research & Development, LLC EDMS number: EDMS-ERI-171521650, 1.0 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE 1 Status: Approved, Date: 16 January 2019 JNJ-54135419 (esketamine) Treatment-resistant Depression Advisory Committee Briefing Document GUIDE FOR REVIEWERS This briefing document provides 3 levels of review with increasing levels of detail: The Executive Overview (Section 1, starting on page 11) provides a narrative summarizing the disease, need for novel treatments, key development program characteristics for esketamine nasal spray, study results, and conclusions. References are made to the respective supporting sections in the core document. The core document (Section 2 to Section 11, starting on page 30) includes detailed summaries and discussion in support of the Executive Overview. The appendices (starting on page 180) provide additional or more detailed information to complement brief descriptions provided in sections of the core document (e.g., demographic and baseline characteristics of the study populations, additional efficacy analyses in the Phase 3 studies, statistical methods). These appendices are referenced in the core document when relevant. This review structure allows review at varying levels of detail; however, reviewers who read at multiple levels will necessarily encounter repetition of key material across the levels. 2 Status: Approved, Date: 16 January 2019 JNJ-54135419 (esketamine) Treatment-resistant Depression Advisory Committee Briefing Document TABLE OF CONTENTS GUIDE FOR REVIEWERS............................................................................................................................ 2 TABLE OF CONTENTS ............................................................................................................................... 3 LIST OF IN-TEXT TABLES.......................................................................................................................... 6 LIST OF IN-TEXT FIGURES ........................................................................................................................ 7 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................................... 10 1. EXECUTIVE OVERVIEW .................................................................................................................. 11 1.1. Introduction .................................................................................................................................... 11 1.2. Overview of Nonclinical Assessment............................................................................................. 15 1.3. Overview of Clinical Pharmacology ............................................................................................... 15 1.4. Overview of Phase 2 Clinical Studies ............................................................................................ 16 1.5. Overview of Phase 3 Study Design and Population ...................................................................... 17 1.6. Overview of Clinical Efficacy.......................................................................................................... 19 1.7. Overview of Clinical Safety ............................................................................................................ 23 1.8. Overview of Abuse Potential.......................................................................................................... 27 1.9. Overview of Risk Mitigation Strategies .......................................................................................... 28 1.10. Benefit-risk Conclusions................................................................................................................. 29 2. INTRODUCTION................................................................................................................................ 30 2.1. Unmet Medical Need...................................................................................................................... 31 2.2. Mechanism of Action...................................................................................................................... 32 2.3. Development Program for Esketamine Nasal Spray ..................................................................... 34 2.3.1. Regulatory History ...................................................................................................................... 35 2.3.2. Features of the Development Program ...................................................................................... 36 3. NONCLINICAL ASSESSMENT ........................................................................................................ 38 3.1. Safety Pharmacology..................................................................................................................... 38 3.2. Toxicology ...................................................................................................................................... 39 3.3. Pharmacokinetics in Animals and Product Metabolism................................................................. 41 4. CLINICAL PHARMACOLOGY.......................................................................................................... 41 4.1. Pharmacokinetic Characteristics of Esketamine Nasal Spray....................................................... 42 4.2. Pharmacokinetics of Esketamine Nasal Spray in Subpopulations ................................................ 44 4.3. Effect of Other Drugs on the Pharmacokinetics of Esketamine Nasal Spray................................ 44 4.3.1. Effect of Esketamine Nasal Spray on Other Drugs .................................................................... 45 5. PHASE 2 CLINICAL STUDIES ......................................................................................................... 45 5.1. Phase 2 Studies with IV Esketamine and Ketamine in Patients with TRD.................................... 46 5.2. Phase 2 Studies with Esketamine Nasal Spray............................................................................. 47 5.2.1. Phase 2 Dose-response Study with Esketamine Nasal Spray in Patients with TRD (SYNAPSE) ................................................................................................................................ 47 5.2.2. Phase 2 Study with Esketamine Nasal Spray in Patients with MDD at Imminent Risk for Suicide (PERSEVERE)............................................................................................................... 52 6. PHASE 3 STUDY DESIGN AND POPULATION .............................................................................. 55 6.1. Phase 3 TRD Clinical Development Program................................................................................ 55 6.1.1. Selection of Patients with Treatment-resistant Depression........................................................ 57 6.1.2. Study Treatments and Dose Selection....................................................................................... 57 6.1.3. Blinding ....................................................................................................................................... 59 6.1.4. Challenges of Placebo Response in Clinical Studies with Antidepressant Medications............ 59 6.2. Short-term Double-blind Studies.................................................................................................... 60 6.3. Maintenance of Effect Study .......................................................................................................... 66 6.4. Long-term, Open-label Safety Study.............................................................................................. 68 3 Status: Approved, Date: 16 January 2019 JNJ-54135419 (esketamine) Treatment-resistant Depression Advisory Committee Briefing Document 7. CLINICAL EFFICACY IN THE PHASE 3 STUDIES ......................................................................... 70 7.1. Efficacy Measures and Endpoints for Phase 3 TRD Studies......................................................... 70 7.2. Key Features of Statistical Methods for Phase 3 TRD Studies ..................................................... 72 7.3. Key Efficacy Results in the Phase 3 Program ............................................................................... 74 7.3.1. Key Efficacy Results in the Short-term Phase 3 Studies (TRANSFORM-1, 2, and 3)............... 75 7.3.1.1. Primary Efficacy Endpoint: Change in MADRS Total Score from Baseline to Day 28............ 76 7.3.1.2. Key Secondary Efficacy Endpoints: Onset of Clinical Response and Changes from Baseline in SDS and PHQ-9 Total Scores .............................................................................. 87 7.3.2. Efficacy Results from the Phase 3 Maintenance of Effect Study SUSTAIN-1 ........................... 90 7.3.2.1. Primary Efficacy Endpoint: Time to Relapse in Patients Achieving Stable Remission on Esketamine + Oral AD........................................................................................................ 91 7.3.2.2. Secondary Efficacy Endpoint: Time to Relapse in Patients Achieving Stable Response on Esketamine + Oral AD......................................................................................
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