Tafenoquine for Prevention of Malaria July 26, 2018 60 Degrees Pharmaceuticals, LLC Antimicrobial Drugs Advisory Committee Meeting 1 Overview Geoffrey Dow, PhD Chief Scientific Officer & CEO 60 Degrees Pharmaceuticals, LLC 2 Global Burden of Malaria P. falciparum 216,000,000 cases annually P. vivax 8,550,000 cases annually Tatem (2017). Malaria Impact and Burden WHO (2017). World Malaria Report 3 Current Approaches to Malaria Elimination Fall Short Number of cases 2010 2011 2012 2013 2014 2015 2016 Lower 95% Cl 218,000,000 207,000,000 199,000,000 191,000,000 191,000,000 192,000,000 196,000,000 Estimated total 237,000,000 225,000,000 217,000,000 210,000,000 210,000,000 211,000,000 216,000,000 Upper 95% Cl 278,000,000 267,000,000 262,000,000 256,000,000 256,000,000 257,000,000 263,000,000 New Therapeutics With Different Labeling Required? . Multiple dosing . Longer duration of dosing . Asymptomatic & non-immune subjects WHO (2017). World Malaria Report 4 US Malaria Burden 1973-2013 Cullen KA, Mace KE, Arguin PM. Malaria Surveillance — United States, 2013. MMWR Surveill Summ 2016;65(No. SS-2)(No. SS-2):1–22. DOI: http://dx.doi.org/10.15585/mmwr.ss6502a1 96% of malaria cases due to failure to comply with malaria chemoprophylaxis 5 This just isn’t good enough! Severe malaria is entirely preventable 6 Vision: Malaria Prevention with ARAKODA 0 0 malaria cases pediatric deaths amongst deployed from falciparum malaria U.S. service members 0 malaria cases in U.S. 0 outbreaks in returning travelers elimination regions 7 ARAKODA – Target Label Claims Description & Target Label Claims Attribute Description API Name ● Tafenoquine succinate Presentation ● 100 mg tablets Indication ● Prevention of malaria in adults for up to six months dosing Dosing ● Loading dose: 200 mg once per day for 3 days within one week of travel ● During travel: 200 mg once per week ● Following travel: 200 mg once within 1 week of return from travel Efficacy ● During travel: Protective efficacy (95% CI) = 100% (93-100%) ● Post exposure: Protective efficacy equivalent to primaquine (30 mg x 14 days) Common AEs ● GI distress, back pain, certain infections Contraindications ● Severe G6PD deficiency ● Pregnancy - G6PD status of fetus cannot be determined “All parasites, everywhere, with a safe, simple dosing regimen” 8 ARAKODA Compared to Standard of Care Kills all Pf Single Dose Global # Tabs for 1 Neurologic G6PD Test Drug Dosing and Pv Post- use MO trip* Liability Required stages Exposure Daily No Yes No 72 No No Weekly No No No 25 Yes No Daily No Yes No 51 No No ARAKODA Weekly Yes Yes Yes 16 No Yes * Includes loading or pre-travel doses, post-travel doses, and 14 days of post-exposure primaquine (the latter only for Malarone®, Doxycycline, and Lariam®) 9 Malaria Lifecycle 10 Malaria Lifecycle & Mode of Action of ARAKODA ARAKODA is active against all the mammalian stages of malaria • Exact mechanism of action is not known 11 Tolerability of Primaquine for Malaria Prophylaxis 6 MO Baird (1992) 12 MO Fryauff (1995) • Primaquine and placebo equally well tolerated following daily administration up to 12MO 12 Adverse Event Labeling for Primaquine Prophylaxis Adverse drug reactions. Most common mild/moderate adverse drug reactions (ADRs): abdominal pain, nausea, vomiting. Severe hemolysis in persons with G6PD deficiency. Met- hemoglobinemia occurs, but is not reported to be clinically significant at dosages used for prophylaxis. In studies, 0-2% of persons have reported a severe reaction and 0-2% have discontinued prophylaxis because of ADRs. No specific warnings for neuropsychiatric events Hill (2006) 13 ARAKODA is an Improved Primaquine Analog F3C O CH3 5 4 5 4 O 6 3 O 6 3 2 2 8 N 8 N OMe HN HN NH2 NH2 PRIMAQUINE ARAKODA ● Half-Life: 6h ● Half-Life: 14 days ● Kills hepatic stages ● Kills hepatic stages ● Weak activity against blood stages ● Kills blood stages in vivo ● No evidence of neurologic liability ● No evidence of neurologic from clinical literature liability from Sponsor database 14 Primaquine and Mefloquine Act Differently Defining Structural Feature Activation in vivo ACTIVE OXIDATIVE SPECIES DIRECT ACTION PRIMAQUINE MEFLOQUINE (8-AMINOQUINOLINE) (4-QUINOLINE METHANOL) ● Kills parasites following activation ● Direct antiparasitic effect ● Kills hepatic stages ● No effect on hepatic stages ● Weak activity against blood stages ● Potent blood schizonticide ● No evidence of neurologic liability ● Increases frequency of neuropsychiatric from clinical literature events relative to standard of care 15 Important Clinical Studies of ARAKODA Study 030 043 045 033 057 60PH02 60PH04 Year(s) Conducted 2000 1997 1998 1999-2000 2003-2006 2017 Ongoing Study Design* PC, MQ MQ PC, MQ MQ PC PC PC Efficacy & Parameters Assessed Safety & Efficacy Safety & Efficacy Safety & Efficacy Safety & Efficacy Safety Safety Safety Non-immune military Population Residents of Residents of Residents of population (deployed Residents of Residents of Residents of Characteristics malaria- malaria-endemic malaria- to malaria-endemic US and UK Australia Australia endemic area area endemic area (all Healthy Adults) area) Bobonaro District and Kassena Maryland, USA Nyanza Nyanza Province, capitol (Dili) of East Brisbane, Multiple sites in Study Location Nankana and Berkshire, Province, Kenya Kenya Timor (now Timor Queensland Australia and US District, Ghana UK Leste) Number of Subjects 300 104 ARAKODA 55 ARAKODA 93 ARAKODA 492 ARAKODA 81 ARAKODA 12 ARAKODA (ARAKODA; ARAKODA** 101 MQ 0 MQ 46 MQ 162 MQ 0 MQ 0 MQ Mefloquine (M); 0 MQ 101 PC 61 PC 94 PC 0 PC 39 PC 4 PC Placebo (P)) 300 PC Duration of Study 24 weeks 10-15 weeks 13 weeks 26±4 weeks 24 weeks 10 days 52 weeks Drug Dosing Safety Follow-up after 4 weeks 4 weeks 4 weeks 24 weeks 24 weeks 21 days 12 weeks Study Drug Dosing *All studies were randomized and double blinded, comparators were PC = placebo or MQ = mefloquine **Size of Safety Database at filing: 825; Size of Safety Database at 60PH04 Completion: 1125 16 Deployment is a Risk Factor for Neuropsychiatric Events Psychologically-attributed war-related illnesses have included (Hyams (1996), Jones (2002)): . “nostalgia” (US Civil War); . shell shock or trench neurosis (World War I); . battle fatigue, combat exhaustion, or operational fatigue (World War II and the Korean Conflict); . post-traumatic stress disorder (PTSD) (Vietnam War and Persian Gulf War) Diagnoses of mental illnesses, especially PTSD and depression, increased substantially among returned US military personnel who had been deployed to Iraq or Afghanistan (Seal (2009), Plumb (2014), McGlinchey (2017), Nissen (2017), Primack (2017), Qi (2016)). In almost all studies of war-related illnesses, a suitable control population is unavailable, and the single unifying theme is that a unique (military) population is intensely scrutinized after experiencing an exceptional, life- threatening set of exposures (Hyams (1996)). In the rare studies that do report on comparisons deployed and non-deployed personnel, or comparisons between pre- and post-deployment mental health status, these studies support a negative effect of deployment on mental health (Hermes (2014), Hom (2017), Jaksic (2017)). 17 Timor Deployment Considered “Warlike” by Australian Government - Waller (2012) . Psychologically-attributed Study 033 – ADF deployed to East Timor (2000-2001), a “warlike” military operation. Australian government: “Warlike operations” = military activities where force is authorized and casualties are expected . Specific traumatic exposures reported by ADF deployed to East Timor: . danger of being injured or killed (71% of ADF reported this); . witness to human degradation and misery on a large scale (58%); . saw dead bodies (49%) or handled dead bodies (28%); . feared you had been exposed to a toxic agent, contagious disease, or injury (31%); . heard of a close friend or co-worker injured or killed (30%); . present when a close friend or co-worker was injured or killed (13%). Other stressors: threat of danger (67%) and health concerns (52%). Among all ADF personnel deployed to East Timor: 7.2% developed PTSD and 6.9% had a long-term high level of psychological stress at 7-9 years after deployment 18 Burden of Diagnosed Neuropsychiatric Illness Following Mefloquine and Malarone Administration in US Military Personnel Antimalarial Mefloquine Malarone Deployment Status Not Deployed Deployed Not Deployed Deployed Total Incidence of Neuropsychiatric 58.59/ 98.27/ 57.92/ 98.46/ Adverse Reactions per 1000 Person 10,847 25,691 10,261 2,620 Years/Number of Personnel* Increase Associated With Deployment (%) 68% 70% Individual Neuropsychiatric Endpoints: . No statistical difference amongst deployed individuals . Incidence of PTSD higher amongst non-deployed individuals administered mefloquine relative to Malarone *Excluding tinnitus Eick-Cost (2017) 19 Important Nonclinical Studies of ARAKODA Key Findings: . Comprehensive nonclinical safety package. All available information submitted to FDA and TGA for review. In the 35 in vivo acute and chronic dose toxicology studies (with mice – 2 years; rats – 2 years; dogs – 1 year) as well as 15 pharmacology studies (mice, rats, dogs, and monkeys), no neurotoxicity observed . Major organ risk is lung (phospholipodosis, dog only), liver (centrilobular inflammation, apoptosis and fatty change, increased plasma transaminases) and kidney (tubular nephrosis, necrosis, and dilation [rat only, 13 wks]) . ARAKODA: . has no safety pharmacology risk for lung and brain. No clinical risk to the heart from QT prolongation.