FDA Briefing Document Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Meeting October 9, 2020 Topic: New Drug Application 213378 ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and bipolar I disorder 1 The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committees. The FDA background package contains assessments or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final positions of the individual reviewers, review Divisions, or Office. FDA has brought New Drug Application 213378, ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and bipolar I disorder, to these Advisory Committees in order to gain the Committees’ insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation and, instead, is intended to focus on issues identified by FDA for discussion by the Advisory Committees. 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 CONTENTS .....................................................................................................3 TABLE OF TABLES ..........................................................................................................4 TABLE OF FIGURES .........................................................................................................5 GLOSSARY ........................................................................................................................6 1. DIVISION DIRECTOR MEMORANDUM....................................................................7 2. OBJECTIVE OF MEETING AND OVERVIEW OF DEVELOPMENT PROGRAM ..................................................................................................................10 2.1. PURPOSE ...............................................................................................................10 2.2. PRODUCT UNDER REVIEW ...............................................................................10 2.3. ANTIPSYCHOTIC METABOLIC CONSIDERATIONS .....................................10 2.4. REGULATORY BACKGROUND.........................................................................13 3. SUMMARY OF CLINICAL DATA .............................................................................14 3.1. EFFECTIVENESS OF ALKS 3831 .......................................................................14 3.1.1. Study ALK3831-302 ........................................................................................16 3.1.2. Study ALK3831-A303 .....................................................................................21 3.1.3. Study ALK3831-A305 .....................................................................................38 3.1.4. Studies ALK3831-A304 and ALK3831-A306 .................................................40 3.2. SAFETY OF ALKS 3831 .......................................................................................45 3.2.1. Adverse Events and Investigations ...................................................................45 3.2.2. Safety Concerns Regarding Precipitated Opioid Withdrawal, Inadequate Analgesia, and Opioid Overdose ..................................................46 4. REFERENCES ..............................................................................................................51 5. APPENDICES ...............................................................................................................54 5.1. STUDY ASSESSMENT SCHEDULES .................................................................54 5.2. WEIGHT GAIN TRAJECTORIES BY DROPOUT REASON (STUDY A303) .....................................................................................................................56 3 TABLE OF TABLES Table 1. Olanzapine Weight Gain in Clinical Trials as Described in Labeling .................11 Table 2. Relevant Clinical Studies .....................................................................................14 Table 3. Percent Change in Body Weight at Week 12 (Study 302, Part A; FAS 1 and FAS 2 Populations) ......................................................................................................18 Table 4. Categorical Weight Gain Assessment at Week 12 (Proportion of Completers Meeting Criteria; Study 302) .......................................................................................20 Table 5. Primary Analysis Results for First Coprimary Endpoint (Study A303) ..............23 Table 6. Primary Analysis for Second Coprimary Endpoint (Study A303) ......................25 Table 7. Primary Analysis Results for Key Secondary Endpoint (Study A303) ...............25 Table 8. Sensitivity Analysis of Percent Change from Baseline in Body Weight at Week 24 – Delta Adjusted Pattern Mixture Model (Study A303) ...............................27 Table 9. Sensitivity Analyses by Including Both On- and Off-Treatment Weight Assessments after Premature Discontinuation of Study Drug (Study A303) ..............30 Table 10. Additional Analyses for Proportion of Subjects With ≥10% Weight Gain from Baseline at Week 24 by Imputation Method (Study A303) ................................31 Table 11. Other Secondary Metabolic Endpoints, Week 24 (Study A303) .......................31 Table 12. Categorical Increases in Glucose and HbA1c (Study A3030) ...........................33 Table 13. Blood Pressure (Study A303) ............................................................................36 Table 14. Change from Baseline in PANSS Total Score at Week 4 (Study A305) ..........40 Table 15. Weight and Metabolic Laboratory Parameters (Studies A304 and A306) ........44 Table 16. Assessment Schedule for A303 .........................................................................54 Table 17. Assessment Schedule for A305 .........................................................................55 4 TABLE OF FIGURES Figure 1. Mean Weight Change at Each Visit by Treatment Cohort, European SOHO Observational Study .....................................................................................................12 Figure 2. Schematic of Study 302 ......................................................................................17 Figure 3. Percent Change in Body Weight by Treatment Group (Study 302, Part A, FAS 1) ..........................................................................................................................19 Figure 4. Percent Change in Body Weight by Treatment Group (Study 302, Part A, FAS 2) ..........................................................................................................................20 Figure 5. Schematic of Study A303 ...................................................................................21 Figure 6. LS Mean Percent Change Weight Gain from Baseline by Treatment During 24-Week Double-Blind Period (Study A303) ..............................................................24 Figure 7. Cumulative Frequency Distribution of Percent Change from Baseline in Body Weight at Week 24 (Completers; Study A303) .................................................26 Figure 8. Mean Weight Trajectories of Subjects in Various Cohorts (Study A303) .........29 Figure 9. Change from Baseline in Fasting Glucose by Visit (Study A303) .....................33 Figure 10. Proportion of Subjects with Baseline Fasting Glucose < 126 mg/dL and a Subsequent Fasting Glucose ≥ 126 mg/dL (Study A303) ...........................................34 Figure 11. Proportion of Subjects with Fasting Glucose Increase from Baseline of ≥ 10 mg/dL (Study A303) ...............................................................................................35 Figure 12. Proportion of Subjects with Baseline Triglycerides <200 and a Subsequent Triglyceride Measurement of ≥ 200 mg/dL (A303) ....................................................36 Figure 13. Change from Baseline in Blood Pressure by Visit (Study A303) ....................37 Figure 14. Schematic of Study A305 .................................................................................38 Figure 15. Mean Percent Change from Baseline in Body Weight by Visit and Treatment Sequence Through Week 12 of the Extension Study .................................42 Figure 16. Side-by-Side View of Historical Weight Results in Long-Term OLZ Studies and Long-Term Weight Results for ALKS 3831 ............................................43 Figure 17: Weight Gain Trajectories of Individual Dropouts with Top Three Discontinuation Reasons (Study A303) .......................................................................56 5 GLOSSARY AE adverse event BMI body mass index BP blood pressure CI confidence interval DDLO Division of Diabetes, Lipids, and Obesity DP Division of Psychiatry (the primary review division) DSaRM Drug Safety and Risk Management FAS full-analysis set FDA Food and Drug Administration LS least squares NDA new drug application NI non-inferiority OL open-label PANSS Positive and Negative Syndrome Scale PDAC Psychopharmacologic Drugs Advisory Committee 6 1. DIVISION DIRECTOR MEMORANDUM M E M O R A N D U M DEPARTMENT OF HEALTH