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ARAKODA™ (TAFENOQUINE SUCCINATE) TABLETS for the PREVENTION of MALARIA in ADULTS NDA 210607 Briefing Document for the Antimicr

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ARAKODA™ (TAFENOQUINE SUCCINATE) TABLETS for the PREVENTION of MALARIA in ADULTS NDA 210607 Briefing Document for the Antimicr 60 Degrees Pharmaceuticals LLC ARAKODA for Malaria Prophylaxis Antimicrobial Drugs Advisory Committee Meeting ARAKODA™ (TAFENOQUINE SUCCINATE) TABLETS FOR THE PREVENTION OF MALARIA IN ADULTS NDA 210607 Briefing Document for the Antimicrobial Drugs Advisory Committee Meeting Date: July 26, 2018 Sponsor: 60 Degrees Pharmaceuticals, LLC 1025 Connecticut Ave. NW, Suite 1000 Washington DC, 20036 ADVISORY COMMITTEE BRIEFING MATERIALS AVAILABLE FOR PUBLIC RELEASE 1 60 Degrees Pharmaceuticals LLC ARAKODA for Malaria Prophylaxis Antimicrobial Drugs Advisory Committee Meeting Table of Contents 1. Executive Summary ............................................................................................................... 8 1.1. Proposed Indication .................................................................................................. 8 1.2. Dosage Form, Route of Administration, and Dosing Regimen ................................ 8 1.3. Introduction .............................................................................................................. 8 1.4. Unmet Need .............................................................................................................. 9 1.4.1. Military Perspective .................................................................................... 9 1.5. Tafenoquine Product History ................................................................................... 9 1.6. Chemical Structure ................................................................................................. 10 1.6.1. Tafenoquine Mechanism of Action and Overview of Anti-Malarial Activity ...................................................................................................... 10 1.7. Nonclinical Toxicology .......................................................................................... 11 1.7.1. Nonclinical Assessment of Neurotoxicity ................................................. 11 1.8. Overview of Tafenoquine Clinical Development Program .................................... 11 1.9. Clinical Pharmacology ........................................................................................... 12 1.9.1. Pharmacokinetics ....................................................................................... 12 1.9.2. Minimum Plasma Trough Levels needed for Efficacy .............................. 12 1.10. Summary of Clinical Data ...................................................................................... 12 1.10.1. Efficacy ..................................................................................................... 12 1.10.1.1. Results of Key/Pivotal Efficacy Trials .................................. 13 1.10.1.2. Efficacy: Prophylaxis while in the Endemic Region and Post- Exposure ................................................................................ 15 1.10.2. Safety ......................................................................................................... 16 1.10.2.1. Gastrointestinal Effects .......................................................... 17 1.10.2.2. Hematological Effects ............................................................ 17 1.10.2.3. Cardiac Effects ....................................................................... 17 1.10.2.4. Eye Disorders ......................................................................... 17 1.10.2.5. Nervous System Disorders ..................................................... 18 1.10.2.6. Psychiatric Disorders ............................................................. 18 1.11. Conclusion .............................................................................................................. 19 2. Introduction ......................................................................................................................... 20 2.1. Malaria Parasite Life Cycle .................................................................................... 20 2.2. Malaria: The Clinical Picture ................................................................................. 21 2.3. Malaria Epidemiology ............................................................................................ 22 2.4. Unmet Medical Need for Malaria Prophylaxis in the Endemic Region ................. 22 2.4.1. Current CDC-Recommended Drugs for Malaria Chemoprophylaxis (in- County Use) ............................................................................................... 22 2.4.1.1. Atovaquone/Proguanil (Malarone) ........................................ 23 2.4.1.2. Doxycycline ........................................................................... 23 2.4.1.3. Mefloquine ............................................................................. 23 2.4.1.4. Primaquine ............................................................................. 24 2.4.2. Existing Therapies and the Risk of Poor Compliance ............................... 25 2.4.3. Summary of Deficiencies in Current CDC-Recommended Drugs for Malaria Prophylaxis .................................................................................. 25 2.5. Unmet Medical Need for Post Exposure Prophylaxis ............................................ 27 2.6. Unmet Need: The Military Perspective .................................................................. 27 3. Tafenoquine Product Information ....................................................................................... 29 2 60 Degrees Pharmaceuticals LLC ARAKODA for Malaria Prophylaxis Antimicrobial Drugs Advisory Committee Meeting 4. Tafenoquine Clinical Development and Regulatory History .............................................. 30 4.1. Tafenoquine Clinical Development ........................................................................ 30 4.2. Overview of Tafenoquine Clinical Development Program .................................... 30 4.3. Tafenoquine Regulatory History ............................................................................ 37 5. Clinical Pharmacology ........................................................................................................ 38 5.1. Minimum Trough Plasma Tafenoquine Concentrations Needed for Efficacy ....... 38 5.2. Biopharmaceutics Studies Summary ...................................................................... 38 6. Microbiology ....................................................................................................................... 40 6.1. Postulated Mechanism of Action of Tafenoquine .................................................. 40 6.2. Antimalarial Activities of Tafenoquine .................................................................. 40 6.2.1. In vitro Pharmacology ............................................................................... 40 6.2.2. In vivo Studies in Animal Models ............................................................. 41 7. Nonclinical Toxicology ....................................................................................................... 42 7.1. Assessment of Neurobehavioral Toxicity in Rats and Monkeys ............................ 42 7.2. Assessment of Neurotoxicity in Rhesus Monkeys ................................................. 43 7.3. Nonclinical Assessment of Cardiotoxicity ............................................................. 47 8. Evaluation of Efficacy ......................................................................................................... 48 8.1. Definition of Endpoints .......................................................................................... 48 8.2. Derivation of the Recommended Prophylaxis Regimen ........................................ 48 8.3. Pivotal/Key Prophylaxis Trials: Controlled Clinical Studies Pertinent to the Clinical Indication .................................................................................................. 49 8.4. Demographics and Baseline Characteristics .......................................................... 51 8.5. Efficacy in Key Studies Supporting the Intended Use of the Product for Prophylaxis of Malaria in the Endemic Region ...................................................... 52 8.5.1. Phase 3 Prophylaxis Study (Study 033) .................................................... 52 8.5.1.1. Study 033: Tafenoquine Noninferiority vs. Mefloquine ........ 53 8.5.2. Study 043 ................................................................................................... 55 8.5.3. Study 045 ................................................................................................... 55 8.5.4. Study 044 ................................................................................................... 58 8.5.5. Pf Treatment Study in the Human Challenge Model Study TQ-2016-02 . 59 8.5.6. Plasmodium vivax Treatment Study in the Field: Study 058 .................... 60 9. Comparison and Analysis Across Studies ........................................................................... 64 9.1. Study Populations ................................................................................................... 64 9.2. Comparison of Efficacy Results of Prophylaxis Studies in the Endemic Region .. 66 9.3. Comparison of Results of Subpopulations Relevant to Prophylaxis Studies in the Endemic Region ..................................................................................................... 67 10. Analysis of Clinical Information Relevant to Dosing Recommendations ........................... 70 11. Persistence
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