Gepirone Hydrochloride Extended-Release Tablets NDA #21-164 Psychopharmacologic Drugs Advisory Committee Meeting Briefing Materials December 1, 2015 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE WITHOUT REDACTION Fabre-Kramer Pharmaceuticals, Inc. Page ii 10/27/2015 TABLE OF CONTENTS Contents Table of Contents ............................................................................................................................ ii I. List of Tables In text .............................................................................................................. iv II. List of Figures in text ............................................................................................................. vi III. List of Abbreviations ........................................................................................................ vii 1. EXECUTIVE SUMMARY .................................................................................................... 1 2. Introduction ............................................................................................................................. 3 2.1 Medical Need for New Anti-Depressant Treatments ....................................................... 3 2.1.1 Unique Sexual Functioning Profile ........................................................................... 4 2.2 Clinical Study Challenges in Antidepressant Development ............................................ 5 2.3 Gepirone ER Formulation Characteristics ....................................................................... 6 2.4 The Unique Mechanism of Action of Gepirone ER ......................................................... 7 2.5 Gepirone ER Clinical Development and Regulatory History .......................................... 8 3. Efficacy ................................................................................................................................. 10 3.1 Overview of Clinical Studies ......................................................................................... 10 3.2 Selection of Studies for Assessment of Efficacy ........................................................... 11 3.3 Summary of Individual Interpretable Gepirone ER Studies .......................................... 13 3.3.1 Study 134001 .......................................................................................................... 13 3.3.2 Study 134002 .......................................................................................................... 13 3.3.3 Study 134023 .......................................................................................................... 13 3.3.4 Study FKGBE007 ................................................................................................... 14 3.3.5 Study FKGBE008 ................................................................................................... 14 3.3.6 Summary of Efficacy Data from Interpretable Gepirone ER Studies ..................... 14 3.4 Summary of Individual Uninterpretable Gepirone ER Studies ...................................... 15 3.4.1 Studies CN105-078 and CN105-083 ...................................................................... 15 3.4.2 Studies CN105-052 and CN105-053 ...................................................................... 15 3.4.3 Studies 134004 and 134006 .................................................................................... 16 3.4.4 Study 134017 .......................................................................................................... 16 3.4.5 Summary of Uninterpretable Gepirone ER Studies ................................................ 16 3.5 Impact of Dropouts on Demonstration of Efficacy ........................................................ 18 3.6 Meta-Analysis of Gepirone ER Studies ......................................................................... 18 3.6.1 Methodology ........................................................................................................... 19 3.6.2 Results ..................................................................................................................... 20 Fabre-Kramer Pharmaceuticals, Inc. Page iii 10/27/2015 3.6.3 Conclusions from Meta-Analyses ........................................................................... 25 3.7 Additional Efficacy Data ................................................................................................ 26 3.8 Overall Efficacy Summary and Conclusions ................................................................. 27 4. Safety .................................................................................................................................... 28 4.1 Safety Profile .................................................................................................................. 28 4.1.1 Gepirone ER - Overall Safety Assessment ............................................................. 28 4.1.2 Sexual Adverse Events ........................................................................................... 30 5. Risk/Benefit Profile in the Treatment of MDD .................................................................... 32 5.1.1 Additional Clinical Utility of Gepirone ER - Sexual Functioning ......................... 32 5.1.2 Conclusions on Sexual Functioning with Gepirone ER ......................................... 33 5.2 Further Support for Sexual Functioning Benefits .......................................................... 34 5.3 Risk/Benefit Profile ........................................................................................................ 34 6. Discussion and Conclusions ................................................................................................. 36 7. References ............................................................................................................................. 38 8. Appendix 1 – Summaries of 5 Interpretable Studies ............................................................ 42 8.1.1 134001..................................................................................................................... 43 8.1.2 FKGBE007 ............................................................................................................. 48 8.1.3 134002..................................................................................................................... 54 8.1.4 FKGBE008 ............................................................................................................. 60 8.1.5 134023..................................................................................................................... 64 9. Appendix 2 – Summaries of 7 Uninterpretable Studies ........................................................ 68 9.1.1 CN105-078 .............................................................................................................. 69 9.1.2 CN105-083 .............................................................................................................. 75 9.1.3 CN105-052 .............................................................................................................. 81 9.1.4 CN105-053 .............................................................................................................. 85 9.1.5 134004..................................................................................................................... 94 9.1.6 ORG134006 .......................................................................................................... 100 9.1.7 134017................................................................................................................... 106 10. Appendix 3 - Summary of Relapse Prevention Study (28709) ....................................... 113 11. Appendix 4 – Gepirone ER Statistical Review (January 2011) ...................................... 119 Fabre-Kramer Pharmaceuticals, Inc. Page iv 10/27/2015 I. LIST OF TABLES IN TEXT Table 1: Three Recent FDA Approved NCE Antidepressants - Characterization of All Short- Term 3 Arm Comparator Trials ...................................................................................................... 6 Table 2: Gepirone ER – Summary of Short-term Clinical Studies ............................................... 10 Table 3: Summary of Gepirone ER Short-Term Studies – Comparison of Factors Influencing Study Validity ............................................................................................................................... 12 Table 4: Primary Reasons for Characterizing Seven Studies as Uninterpretable ......................... 17 Table 5: Number (%) of Subjects with AEs Regardless of Relationship to Study Drug by Preferred Term and Treatment for AEs Reported by ≥5% of Subjects in any Treatment Group (All Subjects Treated in Gepirone ER Controlled Phase II/III Studies in Depression) ................ 29 Table 6: Incidence of Antidepressant-Related AEs in All Subjects Treated in Gepirone ER Controlled Phase II/III Studies in Depression by Relationship to Study Drug and Treatment .... 30 Table 7: Incidence of Sexual Dysfunction Adverse Events: All Gepirone ER Phase II/III Studies in Depression ................................................................................................................................ 31 Table 8: Flexible Dosing Schedule in Study 134001.................................................................... 43 Table 9: Subjects Discontinued