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FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting May 27, 2021

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FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting May 27, 2021 FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting May 27, 2021 Teplizumab BLA 761183 The committee will discuss the safety and efficacy of the Biologics License Application (BLA) 761183, for PRV-031, or teplizumab (proposed trade name TZIELD), an intravenous infusion submitted by Provention Bio, Inc. The proposed indication is for the delay of clinical type 1 diabetes mellitus (T1D) in at-risk individuals. Date Prepared: April 30, 2021 Department of Health & Human Services Food & Drug Administration Center for Drug Evaluation & Research Office of New Drugs Office of Cardiology, Hematology, Endocrinology, and Nephrology Division of Diabetes, Lipid Disorders, and Obesity Silver Spring, MD 20993 BLA 761183 Teplizumab 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 this application for PRV-031 to this Advisory Committee in order to gain the Committee’s insights and opinions. The background package may not include all issues relevant to the final regulatory recommendation, but is instead 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 BLA 761183 Teplizumab Table of Contents Table of Tables............................................................................................................. 5 Tables of Figures .......................................................................................................... 6 Glossary ....................................................................................................................... 7 1. Division Director Memorandum ................................................................................ 9 2. Draft Discussion Points for the Committee .............................................................. 13 3. Overview of Clinical Studies Submitted to Support Efficacy and Safety ................... 14 4. Clinical Pharmacology Summary ............................................................................ 16 4.1. Clinical Pharmacology Assessment ................................................................... 16 4.1.1. Clinical Pharmacokinetics and Pharmacodynamics ...................................... 16 4.1.2. Bridging Between the To-Be-Marketed Commercial and Clinical Trial Drug Products ........................................................................................... 19 5. Statistical Summary of Efficacy .............................................................................. 20 5.1. Executive Summary.......................................................................................... 20 5.2. Statistical Evaluation ........................................................................................ 21 5.2.1. TN-10 ........................................................................................................ 21 5.2.2. Meta-Analysis of Stage 3 Studies - Supportive Evaluation of Efficacy on C-peptide Data...................................................................................... 34 6. Clinical Summary of Safety .................................................................................... 40 6.1. Methods ........................................................................................................... 40 6.1.1. Studies Reviewed for Safety and Pooling Strategy ....................................... 40 6.1.2. Capture and Categorization of Adverse Events............................................. 40 6.2. Safety Results................................................................................................... 41 6.2.1. Demographics ............................................................................................ 41 6.2.2. Total Exposure ........................................................................................... 41 6.2.3. Deaths........................................................................................................ 42 6.2.4. Serious Adverse Events (SAEs) .................................................................. 43 6.2.5. Adverse Events Leading to Withdrawal....................................................... 44 6.2.6. Common Treatment-Emergent Adverse Events ........................................... 47 6.2.7. Cytokine Release Syndrome ....................................................................... 48 6.2.8. Hypersensitivity/Skin Reactions/Rash ......................................................... 50 6.2.9. Lymphopenia ............................................................................................. 51 6.2.10. Hepatic Enzyme Elevations ...................................................................... 52 6.2.11. Infections and Infestations ........................................................................ 53 6.2.12. Malignancy .............................................................................................. 56 6.2.13. Safety By Subpopulation Analyses............................................................ 56 7. References.............................................................................................................. 57 3 BLA 761183 Teplizumab Appendix A................................................................................................................ 59 Appendix B ................................................................................................................ 60 4 BLA 761183 Teplizumab Table of Tables Table 1. Clinical Studies to Support Efficacy and Safety (Teplizumab Administered IV) ....................................................................................................................... 14 Table 2. TN-10 Efficacy Analysis Sets (All Screened Patients) .................................... 23 Table 3. TN-10: Patient Disposition (ITT Population) .................................................. 24 Table 4. TN-10: Patient Demographics (ITT Population) ............................................. 25 Table 5. TN-10: Baseline Characteristics (ITT Population) .......................................... 25 Table 6. TN-10: Primary Efficacy Endpoint Analysis Results (ITT Population) ............ 27 Table 7. ISE-MA: Study Disposition ........................................................................... 36 Table 8. ISE-MA: Pooled Demographics ..................................................................... 37 Table 9. ISE-MA: C-peptide Data Availability By Unified Visit Windows ................... 37 Table 10. Demographics - mISS.................................................................................. 41 Table 11. Total Exposure - TN-10 and mISS ............................................................... 42 Table 12. Serious Adverse Events Reported in the First Cycle of Treatment (14-Day Treatment Course and Follow Up), in At Least Two Patients in the Teplizumab Group with Risk Difference >0.1%, – Full ISS ...................................................... 43 Table 13. Prespecified Discontinuation Criteria for Studies Included in ISS.................. 45 Table 14. Adverse Events Leading To Treatment Discontinuation With Risk Difference At Least 1% - mISS ............................................................................. 47 Table 15. Adverse Events in the Full ISS (TN-10 + ISS), 14-Day Treatment Period, Reported By At Least 10% of Patients in the Teplizumab Group, Ordered By Risk Difference ............................................................................................................ 48 Table 16. CTCAE Version 3.0 CRS Grading System ................................................... 49 Table 17. Cytokine Release Syndrome Cases by CTCAE Grading Criteria and Treatment Group, All Studies - Full ISS ................................................................ 50 Table 18. Acute Mononucleosis-Like Illness – Full ISS ............................................... 54 Table 19. CTCAE v.3 Grading System for Cytokine Release ....................................... 59 Table 20. ISE-MA: Change From Baseline in Log (Mean C-peptide AUC +1) at the End of Year One – Imputed Data........................................................................... 61 Table 21. ISE-MA: Change From Baseline in Log (Mean C-peptide AUC +1) at the End of Year One – Observed Data......................................................................... 62 Table 22. ISE-MA: Change From Baseline in Log (Mean C-peptide AUC +1) at the End of Year Two – Imputed Data .......................................................................... 62 Table 23. ISE-MA: Change From Baseline in Log (Mean C-peptide AUC +1) at the End of Year Two – Observed Data ........................................................................ 63 5 BLA 761183 Teplizumab Tables of Figures Figure 1. Proposed Type 1 Diabetes Disease Model ....................................................
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