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FDA ADVISORY COMMITTEE BRIEFING DOCUMENT Tecovirimat for the Treatment of Smallpox Disease Antimicrobial Division Advisory Commi

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FDA ADVISORY COMMITTEE BRIEFING DOCUMENT Tecovirimat for the Treatment of Smallpox Disease Antimicrobial Division Advisory Commi Tecovirimat Briefing Document SIGA Technologies, Inc. Antimicrobial Drugs Advisory Committee Meeting FDA ADVISORY COMMITTEE BRIEFING DOCUMENT Tecovirimat for the Treatment of Smallpox Disease Antimicrobial Division Advisory Committee Meeting May 1, 2018 FINAL ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Page 1 of 83 Tecovirimat Briefing Document SIGA Technologies, Inc. Antimicrobial Drugs Advisory Committee Meeting TABLE OF CONTENTS Page TABLE OF CONTENTS ............................................................................................................. 2 LIST OF TABLES ........................................................................................................................ 5 LIST OF FIGURES ...................................................................................................................... 6 LIST OF ABBREVIATIONS ...................................................................................................... 8 1. EXECUTIVE SUMMARY ................................................................................................... 10 1.1 Introduction ....................................................................................................................... 10 1.2 Background and Unmet Medical Need ............................................................................. 11 1.3 Nonclinical Development Program ................................................................................... 12 1.3.1 In Vitro and In Vivo Pharmacology ....................................................................... 12 1.4 Clinical Pharmacokinetics and Pharmacology .................................................................. 24 1.4.1 Pharmacokinetics .................................................................................................. 24 1.5 Clinical Safety ................................................................................................................... 25 1.5.1 Pivotal Safety Study SIGA-246-008 ..................................................................... 25 1.5.2 Other Safety Findings ........................................................................................... 26 1.5.3 Human Dose Justification Based on Animal Efficacy, Exposure-Response Relationship and Safety Data ................................................................................ 26 1.6 Benefit/Risk Summary ...................................................................................................... 27 2. BACKGROUND/OVERVIEW ............................................................................................ 29 2.1 Overview of Orthopoxvirus Infections ............................................................................. 29 2.1.1 Orthopoxvirus Biology ......................................................................................... 29 2.1.2 Variola Infection and Smallpox Disease in Humans ............................................ 29 2.1.3 Medical Countermeasures Against Smallpox Disease .......................................... 31 3. PRODUCT BACKGROUND ............................................................................................... 32 3.1 Product Description ........................................................................................................... 32 3.2 Mechanism of Action ........................................................................................................ 32 3.3 Proposed Indication and Dosing ....................................................................................... 32 3.4 Regulatory History ............................................................................................................ 33 4. NONCLINICAL SAFETY .................................................................................................... 35 4.1 Summary of Nonclinical Study Results ............................................................................ 35 4.2 Safety Pharmacology ........................................................................................................ 35 Page 2 of 83 Tecovirimat Briefing Document SIGA Technologies, Inc. Antimicrobial Drugs Advisory Committee Meeting 4.3 Nonclinical Pharmacokinetics ........................................................................................... 35 4.4 Toxicology ........................................................................................................................ 36 4.4.1 Single and Repeat Dose Studies ............................................................................ 36 4.4.2 Genotoxicity .......................................................................................................... 37 4.4.3 Reproductive and Developmental Toxicity .......................................................... 37 4.4.4 Other Toxicity Studies .......................................................................................... 38 4.4.5 Summary of Observed Toxicities in Nonclinical Studies ..................................... 38 5. VIROLOGY ........................................................................................................................... 39 5.1 Antiviral Potency, Selectivity, and Spectrum of Antiviral Activity ................................. 39 5.2 Effect of Tecovirimat on the Formation of Enveloped Virus and Dissemination in Cell Culture ............................................................................................................................... 40 5.3 Summary ........................................................................................................................... 42 6. BIOPHARMACEUTICS AND CLINICAL (Human) PHARMACOKINETICS ........... 43 6.1 Pharmacokinetics/Pharmacodynamics .............................................................................. 43 6.1.1 Absorption and Exposure ...................................................................................... 43 6.1.2 Distribution and Protein Binding .......................................................................... 43 6.1.3 Metabolism ............................................................................................................ 43 6.1.4 Elimination ............................................................................................................ 43 6.1.5 Excretion ............................................................................................................... 43 6.1.6 Dose Proportionality ............................................................................................. 44 6.1.7 Accumulation and Time-dependency ................................................................... 44 6.1.8 Food Effect ............................................................................................................ 44 6.1.9 Special Populations ............................................................................................... 44 6.1.10 Drug-Drug Interaction ........................................................................................... 45 6.1.11 Pharmacodynamic Studies: Thorough QTc .......................................................... 45 7. EFFICACY ............................................................................................................................. 46 7.1 Summary of Efficacy Results in Nonhuman Primates ...................................................... 46 7.1.1 NHP Model Development ..................................................................................... 46 7.1.2 Study Design Elements Common to All NHP Studies ......................................... 48 7.1.3 Pivotal NHP Studies .............................................................................................. 49 7.2 Summary of Efficacy Results in Rabbits .......................................................................... 59 7.2.1 Rabbit Model Development .................................................................................. 59 Page 3 of 83 Tecovirimat Briefing Document SIGA Technologies, Inc. Antimicrobial Drugs Advisory Committee Meeting 7.2.2 Study Design Elements Common to All Rabbit Studies ....................................... 60 7.2.3 Pivotal Rabbit Studies ........................................................................................... 61 7.2.4 Overall Summary of NHP and Rabbit Efficacy .................................................... 65 8. CLINICAL OVERVIEW ...................................................................................................... 68 8.1 Summary of Safety Results ............................................................................................... 68 8.2 Overall Safety Population ................................................................................................. 68 8.3 Demographics and Duration of Study Drug Administration ............................................ 68 8.4 Treatment-Emergent Adverse Events (TEAEs) ................................................................ 69 8.5 Deaths ................................................................................................................................ 70 8.6 Serious TEAEs .................................................................................................................. 70 8.7 Discontinuation of Dosing Due to TEAEs ........................................................................ 70 8.8 Events of Interest .............................................................................................................
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