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