FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting January 17, 2019 1 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought New Drug Application (NDA) 210934 for sotagliflozin to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 Table of Contents Table of Figures............................................................................................................................. 5 Table of Tables .............................................................................................................................. 7 Division Director Memorandum ................................................................................................. 9 Clinical Pharmacology Summary .............................................................................................. 13 Exposure-Response Relationships ............................................................................................ 16 Safety and Efficacy: Executive Summary and Conclusions .................................................. 24 Summary of Efficacy .................................................................................................................. 26 Study Designs and Endpoints ............................................................................................... 26 Patient Disposition ................................................................................................................ 28 Patient Demographics ........................................................................................................... 29 Statistical Efficacy .................................................................................................................... 32 Statistical Methodologies ...................................................................................................... 32 Efficacy Results .................................................................................................................... 35 Subgroup efficacy analysis ................................................................................................... 50 Summary of Safety ...................................................................................................................... 65 Studies Reviewed for Safety ..................................................................................................... 65 Categorization of Adverse Events ........................................................................................ 65 Safety Findings ......................................................................................................................... 66 Serious Adverse Events ........................................................................................................ 66 Diabetic Ketoacidosis ........................................................................................................... 69 Statistical Analysis of DKA (CEC-adjudicated Events) ....................................................... 76 Hypoglycemia ....................................................................................................................... 82 Statistical Analysis of Hypoglycemia Results ...................................................................... 85 Additional Safety Findings ....................................................................................................... 89 Genital Mycotic Infections ................................................................................................... 89 Renal Events ......................................................................................................................... 92 Volume Depletion Events ..................................................................................................... 94 Urinary Tract Infections ........................................................................................................ 96 Amputations .......................................................................................................................... 97 Gastrointestinal Events ......................................................................................................... 98 MACE (Major Adverse Cardiovascular Events) ................................................................ 100 Malignancies ....................................................................................................................... 102 Fractures .............................................................................................................................. 104 Postmarketing Experience: SGLT2 inhibitors and DKA in patients with T1DM, Office of Surveillance and Epidemiology ............................................................................................... 106 3 Analysis of FAERS Cases of Diabetic Ketoacidosis in Type 1 Diabetes Mellitus Patients Using a Sodium-Glucose Co-Transporter 2 Inhibitor ............................................................. 106 Sentinel analysis of SGLT-2 inhibitor use in patients with type-1 diabetes mellitus and rates of diabetic ketoacidosis ............................................................................................................... 114 Appendices ................................................................................................................................. 126 Appendix A: Supplemental Clinical Pharmacology Information ........................................... 126 Appendix B: Insulin Dose Adjustment Guidelines ................................................................. 134 Appendix C: Demographics Table for EFF-1 ......................................................................... 137 Appendix D: Demographics for Study 312 ............................................................................ 141 Appendix E: Baseline Demographics of Subjects with DKA versus no DKA in SAF-1 ....... 144 Appendix F: Kidney Function Tables ..................................................................................... 147 Appendix G. FDA ADVERSE EVENT REPORTING SYSTEM (FAERS) ........................ 150 4 Table of Figures Figure 1. Potential mechanisms related to efficacy and safety profile of SGLT2 inhibitors........ 15 Figure 2. LS mean change from baseline in urinary glucose excretion (g/day) and 2-hour postprandial glucose (mg/dL) at Week 12 .................................................................................... 16 Figure 3. Distribution of Average Plasma Concentrations, Separated by Dose ........................... 16 Figure 4. Exposure-Response for HbA1c In Studies 309 and 310 ............................................... 18 Figure 5. Changes in Insulin Dose versus Time, Separated by Sotagliflozin Dose (Studies 309 and 310) ........................................................................................................................................ 19 Figure 6. Exposure-Response Relationship for Total Insulin Dose Reduction, with Model Fit Overlay (Studies 309 and 310) ..................................................................................................... 20 Figure 7. Exposure-Response Relationship for Urinary Glucose Excretion (Studies 309 and 310) ....................................................................................................................................................... 21 Figure 8. Kaplan-Meier Curves for CEC Adjudicated Time-to-DKA Event Stratified by Quartiles of Sotagliflozin Exposure (Studies 309 and 310).......................................................... 22 Figure 9. Study Design for Study 309 and 310 ............................................................................. 27 Figure 10. Study Design for Study 312 ........................................................................................ 28 Figure 11. Subgroup Analysis 200 mg vs. Placebo- Study 309 ................................................... 51 Figure 12. Subgroup Analysis 400 mg vs. Placebo- Study 309 ................................................... 52 Figure 13. Subgroup Analysis 200 mg vs. Placebo- Study 310 ................................................... 53 Figure 14. Subgroup Analysis 400 mg vs. Placebo- Study 310 ................................................... 54 Figure 15. Subgroup Analysis 200 mg vs. Placebo- Studies 309 and 310 ................................... 55 Figure 16. Subgroup Analysis 400mg vs. Placebo- Studies 309 and 310 .................................... 56 Figure 17. Subgroup Analysis 400mg vs. Placebo- Study