CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 125509Orig1s000 STATISTICAL REVIEW(S) U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Office of Translational Sciences Office of Biostatistics S TATISTICAL R EVIEW AND E VA LU ATI O N ANIMAL EFFICACY STUDIES NDA/BLA #: BLA 125509 Drug Name: Anthim®(obiltoxaximab) 16 mg/kg IV Indication(s): Treatment and Prophylaxis of Inhalational Anthrax due to Bacillus anthracis Applicant: Elusys Therapeutics, Inc. Date(s): Submission date: 3/20/2015. PDUFA due date: 3/18/2016 Review Priority: Standard Biometrics Division: Division of Biometrics IV Statistical Reviewer: Xianbin Li, PhD Concurring Reviewers: Karen Higgins, ScD Daphne Lin, PhD Medical Division: Division of Anti-Infective Products (DAIP) Clinical Team: Elizabeth O'Shaughnessy, MD, Medical Reviewer John Alexander, MD, Medical Team Leader Sumathi Nambiar, MD, Medical Director Project Manager: Jane Dean, RN MSN Keywords: Animal efficacy studies Reference ID: 3859664 Table of Contents 1 EXECUTIVE SUMMARY .................................................................................................. 11 2 INTRODUCTION ................................................................................................................ 12 2.1 OVERVIEW ........................................................................................................................ 12 2.2 DATA SOURCES ................................................................................................................ 13 3 STATISTICAL EVALUATION ......................................................................................... 13 3.1 DATA AND ANALYSIS QUALITY ........................................................................................ 13 3.2 EVALUATION OF EFFICACY ............................................................................................... 14 3.2.1 Introduction............................................................................................................... 14 3.2.2 IV Treatment Studies ................................................................................................. 14 3.2.3 Post-exposure Prophylaxis Studies ........................................................................... 27 3.2.4 Pre-exposure Prophylaxis Studies ............................................................................ 33 3.2.5 Re-challenge Study .................................................................................................... 35 3.3 EVALUATION OF SAFETY .................................................................................................. 36 4 FINDINGS IN SPEAL/SUBGROUP POPULATIONS .................................................... 38 4.1 GENDER, RACE, AGE, AND GEOGRAPHIC REGION ............................................................ 38 4.2 OTHER SPECIAL/SUBGROUP POPULATIONS ....................................................................... 38 5 SUMMARY AND CONCLUSIONS................................................................................... 39 5.1 STATISTICAL ISSUES ......................................................................................................... 39 5.2 COLLECTIVE EVIDENCE .................................................................................................... 39 5.2.1 Meta-analysis of monkey and rabbits monotherapy studies ........................................ 40 5.2.2 Meta-analysis of PEP studies in monkeys and rabbits ............................................. 40 5.2.3 Efficacy of Lonza ETI-204 ........................................................................................ 42 5.2.4 Summary of collective evidence ................................................................................ 43 5.3 CONCLUSIONS AND RECOMMENDATIONS ......................................................................... 45 5.4 LABELING RECOMMENDATIONS ....................................................................................... 45 6 APPENDICES ...................................................................................................................... 47 6.1 OVERVIEW ........................................................................................................................... 47 6.2 IV MONKEY TREATMENT STUDIES ................................................................................... 47 6.2.1 Summary of IV monkey treatment studies ................................................................. 47 6.2.2 AP201 ........................................................................................................................ 49 6.2.3 AP204 ........................................................................................................................ 58 6.2.4 AP203 ........................................................................................................................ 67 6.2.5 AP202 ........................................................................................................................ 77 6.2.6 NIAID1056 ................................................................................................................ 89 6.3 IV RABBIT TREATMENT STUDIES ..................................................................................... 97 6.3.1 Summary of IV rabbit treatment studies ................................................................... 97 6.3.2 AR021 ........................................................................................................................ 98 6.3.3 AR033 ...................................................................................................................... 105 6.3.4 NIAID1030 .............................................................................................................. 114 2 Reference ID: 3859664 6.3.5 NIAID1045 .............................................................................................................. 120 6.4 MONKEY POST-EXPOSURE PROPHYLAXIS STUDIES ........................................................ 127 6.4.1 Summary of monkey post-exposure prophylaxis studies ......................................... 127 6.4.2 AP107 ...................................................................................................................... 127 6.4.3 AP301 ...................................................................................................................... 132 6.4.4 AP307 ...................................................................................................................... 139 6.5 RABBIT POST-EXPOSURE PROPHYLAXIS STUDIES .......................................................... 147 6.5.1 Summary of rabbit post-exposure prophylaxis studies ........................................... 147 6.5.2 AR004 ...................................................................................................................... 147 6.5.2 AR007 ...................................................................................................................... 152 6.5.4 AR012 ...................................................................................................................... 156 6.5.5 AR034 – Phase I ...................................................................................................... 161 6.5.6 AR035 ...................................................................................................................... 172 6.5.7 AR037 ...................................................................................................................... 178 6.5.8 AR0315 .................................................................................................................... 185 6.6 MONKEY PRE-EXPOSURE PROPHYLAXIS STUDY ............................................................ 191 6.6.1 Summary of monkey pre-exposure prophylaxis study ............................................. 191 6.6.2 AP305 ...................................................................................................................... 191 6.7 RABBIT PRE-EXPOSURE PROPHYLAXIS STUDIES ............................................................ 198 6.7.1 Summary of rabbit pre-exposure prophylaxis studies ............................................ 198 6.7.2 AR001 ...................................................................................................................... 198 6.7.3 AR003 ...................................................................................................................... 203 6.8 RE-CHALLENGE STUDY (AR034 PHASE II) ..................................................................... 208 6.9 SUMMARY OF ALL REVIEWED MONOTHERAPY STUDIES .................................................. 209 3 Reference ID: 3859664 LIST OF TABLES Table 1: List of all treatment studies included in analysis ............................................................ 15 Table 2: Survival proportions in monotherapy treatment studies in cynomolgus monkeys (mITT population) .................................................................................................................................... 17 Table 3: Survival proportions in monotherapy treatment studies in cynomolgus monkeys (bacteremic population) ................................................................................................................ 19 Table 4. Pearson correlation coefficients between challenge dose, log10 bacteremia,