Sloan Pharma, US WorldMeds ZELNORM™ (tegaserod maleate) FDA GIDAC and DSaRM Advisory Committee Briefing Document ZELNORM™ (tegaserod maleate) For the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) FDA Joint Meeting of the Gastrointestinal Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Briefing Document Sloan Pharma, US WorldMeds October 17th, 2018 US WorldMeds, LLC, US agent for NDA applicant, Sloan Pharma. ADVISORY COMMITTEE BRIEFING MATERIALS AVAILABLE FOR PUBLIC RELEASE. Page 1 of 99 Sloan Pharma, US WorldMeds ZELNORM™ (tegaserod maleate) FDA GIDAC and DSaRM Advisory Committee Briefing Document APPEARS THIS WAY ON ORIGINAL Page 2 of 99 Sloan Pharma, US WorldMeds ZELNORM™ (tegaserod maleate) FDA GIDAC and DSaRM Advisory Committee Briefing Document TABLE OF CONTENTS 1. EXECUTIVE SUMMARY ...................................................................................................8 2. REGULATORY HISTORY OF TEGASEROD ................................................................12 3. OVERVIEW OF CARDIOVASCULAR RISK ASSESSMENT .......................................14 3.1. Adjudication History ............................................................................................... 14 3.1.1. Long Term Open Label Studies ........................................................................ 17 3.1.2. Summary of Clinical Data Adjudications ......................................................... 18 3.2. Epidemiologic Data ................................................................................................ 18 3.2.1. Loughlin, 2010 .................................................................................................. 18 3.2.2. Anderson, 2009 ................................................................................................. 20 3.3. Overview of Mechanistic Evaluations .................................................................... 21 3.3.1. Receptor Based Studies..................................................................................... 21 3.3.2. Toxicology and Safety Pharmacology Studies ................................................. 22 3.3.3. Arterial Contractility ......................................................................................... 22 3.3.4. Platelet Aggregation.......................................................................................... 23 3.3.5. Summary of Mechanistic Evaluations .............................................................. 23 3.3.6. ECG, Blood Pressure, Heart Rate ..................................................................... 24 3.4. Cardiovascular Safety Conclusions ........................................................................ 27 4. MEDICAL LANDSCAPE ..................................................................................................28 4.1. Disease Background................................................................................................ 28 4.2. Current Available Therapies and the Unmet Medical Need ................................... 29 4.2.1. Efficacy and Safety Profile of Current Available Therapies ............................ 30 5. SUMMARY OF CLINICAL EFFICACY ..........................................................................33 5.1. Mechanism of Action .............................................................................................. 33 5.2. Clinical Efficacy Overview..................................................................................... 35 5.2.1. Original Approval ............................................................................................. 36 5.2.2. Exploratory Analyses for Reintroduction ......................................................... 41 5.2.3. Post Approval Studies ....................................................................................... 47 5.2.4. Efficacy Conclusions ........................................................................................ 50 6. SUMMARY OF CLINICAL SAFETY ..............................................................................51 6.1. Databases Used for Safety Analyses....................................................................... 51 Page 3 of 99 Sloan Pharma, US WorldMeds ZELNORM™ (tegaserod maleate) FDA GIDAC and DSaRM Advisory Committee Briefing Document 6.2. DB15 General Summary of Safety ......................................................................... 53 6.3. IBS-C Studies General Summary of Safety ............................................................ 54 6.4. DB14 General Summary of Safety ......................................................................... 54 6.5. Postmarketing Data ................................................................................................. 54 6.5.1. tIND .................................................................................................................. 54 6.5.2. eIND/spIND ...................................................................................................... 54 6.5.3. US Market ......................................................................................................... 55 6.5.4. Ex-US Markets.................................................................................................. 55 6.5.5. FAERs Reporting Ratios................................................................................... 55 6.5.6. Other Medical Conditions ................................................................................. 56 6.6. Safety Conclusions.................................................................................................. 57 7. BENEFIT-RISK ..................................................................................................................58 7.1. Benefit/Risk Overview............................................................................................ 58 7.2. Benefit/Risk Assessment ........................................................................................ 59 7.3. Regulatory Implications to Ensure Safe and Effective Use .................................... 61 8. CONCLUSION ...................................................................................................................62 9. APPENDICES ....................................................................................................................63 Appendix 1. Exploratory Analyses ..................................................................................... 63 Appendix 2. Summary of Clinical Pharmacology and Vascular Studies ........................... 68 Appendix 3. Summary of Tegaserod Binding Affinity for Other 5-HT Receptors and Possible Functional Cardiovascular Significance ............................................................... 72 Appendix 4. Patient Demographics of Safety Databases.................................................... 75 Appendix 5. Second External Adjudication of CV Events (Duke Adjudication) – Executive Summary ............................................................................................................................. 77 Appendix 6. Characteristics of Subjects with Adjudicated CV Ischemic or MACE Events in DB15 and DB14 .................................................................................................................. 78 Appendix 7. Subjects with CV Events in the First Adjudication Of DB15 Who Weren’t Confirmed in the Second Adjudication............................................................................... 80 Appendix 8. ECG Analyses ................................................................................................ 81 Appendix 9. Additional Safety Considerations .................................................................. 89 Appendix 10. Postmarketing Data ...................................................................................... 93 10. REFERENCES ............................................................................................................96 Page 4 of 99 Sloan Pharma, US WorldMeds ZELNORM™ (tegaserod maleate) FDA GIDAC and DSaRM Advisory Committee Briefing Document LIST OF TABLES Table 1: Body of Data Supporting Zelnorm U.S. Reintroduction ........................................9 Table 2: CV Ischemic Events from First External Adjudication ........................................15 Table 3: Summary of External Adjudications ....................................................................16 Table 4: CV Ischemic Events from Duke Adjudication .....................................................17 Table 5: Number of Adjudicated Ischemic CV Events and MACE Events in DB14 .........18 Table 6: Summary Statistics for Confirmed Cases .............................................................19 Table 7: Summary of Potential Clinical Arrhythmias (ICH E14) Occurrence ...................26 Table 8: Summary of Current Products Approved in US for IBS-C ..................................31 Table 9: Zelnorm IBS-C Efficacy Trials ............................................................................36 Table 10: Variations of Endpoints Utilized in Sensitivity Analyses ....................................43 Table 11: Indications and Number of Patients Contributing to Safety Database 15 ............51 Table 12: Indications and Number of Patients Contributing to Long Term Safety Database 14 ...........................................................................................................52 Table 13: Exposure in Clinical