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Single-Dose Tafenoquine 300 Mg for Radical Cure of Plasmodium Vivax Malaria

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Single-Dose Tafenoquine 300 Mg for Radical Cure of Plasmodium Vivax Malaria CO-1 Single-Dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria July 12, 2018 GlaxoSmithKline Antimicrobial Drugs Advisory Committee Meeting CO-2 Introduction Jörg-Peter Kleim Medicine Development Leader, Tafenoquine GlaxoSmithKline CO-3 Plasmodium vivax Malaria: Global Health Problem Global effort to eradicate malaria around world GSK and Medicines for Malaria Venture (MMV) developed Tafenoquine (TQ) as part of Global Health program Needed for orphan indication in US Tafenoquine would also assist global malaria eradication efforts . Aligns with US initiatives and global treatment efforts CO-4 Tafenoquine 300 mg Single-dose tafenoquine (TQ) 300 mg in combination with standard chloroquine (CQ) . Efficacious treatment for relapse prevention of P. vivax malaria . Similar safety profile to currently-approved primaquine (PQ) + CQ . High treatment compliance First new treatment for prevention of relapse in > 60 years CO-5 Tafenoquine Inactivates Dormant Liver Stage Molecular mechanism of action of tafenoquine is unknown P. vivax can hide in patient’s liver for weeks or months Dormant liver stage causes malaria relapses, without need for another infected mosquito bite Primaquine only current medicine to inactivate dormant liver stage and prevent relapse . 14-day treatment and compliance can be difficult Tafenoquine offers novel, single-dose treatment for relapse prevention CO-6 Tafenoquine: 8-Aminoquinoline Analogue of Primaquine Primaquine Tafenoquine Half-life: 6 hours Half-life: 15 days CO-7 Tafenoquine Regulatory History Originally discovered by Walter Reed Army Institute of Research 13 studies support radical cure indication . 3 randomized, double-blind studies conducted outside US . Pivotal study: Study 582 Part 2 . Supportive studies: Study 582 Part 1 and Study 564 20 additional studies analyzed for safety Orphan Drug status (Jan 2013) Breakthrough Therapy designation (Dec 2013) CO-8 Proposed Indication and Dosing Indicated for radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older Recommended dosing and administration . Single 300 mg dose co-administered with chloroquine CO-9 Clinical Overview Single-dose TQ 300 mg with standard doses of CQ . 70% reduction in risk of recurrence of P. vivax malaria at 6 months compared with chloroquine alone (p < 0.001) Consistent efficacy across supportive studies Acceptable safety profile and similar to 14-day PQ regimen Primary risk: hemolysis in patients with G6PD deficiency . Appropriately managed with labeling and G6PD testing . No cases of clinical hemolysis in studies No increased risk of clinically relevant hemoglobin decline, ophthalmic, CNS, hepatic, or QT prolongation events CO-10 Agenda J. Kevin Baird, PhD Unmet Need Eijkman Oxford Clinical Research Unit University of Oxford Study Design and Justin A. Green, MD, PhD Efficacy Results GlaxoSmithKline Safety Results Alison Webster, MD GlaxoSmithKline Clinical Perspective Ric Price, MD Menzies School of Health Research CO-11 Additional Responders University of Rochester Departments of Neurology and Gretchen Birbeck, MD, MPH Medical Center Public Health Christian Baumann, PhD GSK Sr. Director, Global Regulatory Affairs Navin Goyal, PhD GSK Director, Clinical Pharmacology Medical Director, Global Clinical Safety Liz Hardaker, MD GSK and Pharmacovigilance Jim Harvey, PhD GSK Director, Non-clinical Toxicology Katie Rolfe GSK Director, Statistics and Programming Investigator, Drug Metabolism and Maxine Taylor GSK Pharmacokinetics CO-12 Unmet Need J. Kevin Baird, PhD Professor of Malariology Eijkman Oxford Clinical Research Unit (Jakarta, Indonesia) University of Oxford CO-13 P. vivax is Most Widespread Human Malaria ~200 cases imported to US by travelers in 20153 64% of malaria cases in 2.5 billion living at Americas due risk of infection1 to P. vivax2 1. Price, 2007; Hwang, 2014; 2. World Health Organization, 2017; 3. Center for Disease Control, 2018; 4. Howes, 2016 CO-14 While Rare, Small Local Outbreaks Reported in US Caused by local transmission by American anopheles mosquitoes 63 outbreaks of malaria in US from 1957–20061 . Annual range 1–32 subjects Outbreak reported in Houston in 2017 Frequently raise concerns and require public health resources 1. Filler, CDC, 2006. [includes all malarias] CO-15 P. vivax Malaria: Parasitic Disease That Can Relapse from Liver Stage Skin Dormant Infected Gametocytes hypnozoite hepatocyte LIVER Symptoms of acute STAGE malaria attack BLOOD STAGE Develops without symptoms Infected red blood cells Image adapted from Lima, 2016 CO-16 Symptoms Include Fever, Chills, Vomiting, Malaise, Headache, and Myalgia Increasing evidence that burden, economic impact and severity of disease from P. vivax have been underestimated1 Even with access to antimalarials, severe and fatal infections occur1 . Splenic rupture, severe anemia, respiratory distress, and possibly coma Review of > 12,000 P. vivax cases in travelers returning to US2 . 0.1% resulted in death . 1.3% severe cases: acute respiratory distress syndrome, cerebral malaria, renal or hepatic dysfunction, severe anemia or thrombocytopenia and shock 1. Price, 2007; 2. Hwang, 2014 CO-17 Risk of Relapse is a Serious Clinical Threat Without Treatment of Liver Stage 2,495 US soldiers repatriated from Asia Pacific 1943-1945 1000 Episodes Incidence 1 to 3 9% 4 to 6 13% 800 7 to 9 20% 10 to 14 35% 15 to 19 14% 600 20 to 24 6% Number of 25 to 34 3% Patients ≥ 35 1% 400 200 0 1 to 3 4 to 6 7 to 9 10 to 14 15 to 19 20 to 24 25 to 34 35+ Kitchen, in Boyd M, 1949. Number of Relapses CO-18 Serious Public Health Threat: > 80% of Clinical Attacks Caused by Relapse Clinical attacks of P. vivax derived from hypnozoites 1 . 98% near Thai-Myanmar PQ 0.75 border1 . 0.5 82% in Papua New Placebo (PL) Guinea2 0.25 Proportion uninfected by PCR 0 1. Adekunle, 2015; 2. Robinson, 2015 CO-19 Goal of P. vivax Malaria Treatment is Radical Cure P. vivax can be refractory to current elimination efforts . Persistence of mosquito vectors . Relapse from dormant liver stage . Can lead to outbreaks where malaria previously eliminated Suppressive chemoprophylaxis (prevention) widely available in US Treatment required to prevent local transmission and relapse CO-20 Selection of Current US CDC Treatment Options Option Blood Stage Treatment Liver Stage Treatment 1st Chloroquine (x 3 days) Atovaquone-proguanil or 2nd artemether-lumefantrine Primaquine phosphate (x 14 days) Quinine sulfate combinations 3rd (+ doxycycline, tetracycline, or clindamycin) 4th Mefloquine Center for Disease Control, 2018 CO-21 Primaquine Effectiveness Dependent on Treatment Adherence 0.15 Self-administered therapy 0.10 Log rank test p = 0.021 Nelson-Alden Cumulative Hazard 0.05 Directly-observed therapy 0.00 0 20 40 60 80 100 Time (days) Primaquine treatment compliance as low as 30%1,4 Primaquine efficacy reduced 3- to 4-fold when ≥ 3 of 14 doses missed1,2,3,4 1. Abreha, 2017; 2. Takeuchi, 2010; 3. Douglas, 2017; 4. Khantikul, 2009 CO-22 G6PD Testing Can Protect Patients from 8-Aminoquinoline-Induced Hemolysis 8-aminoquinolines cause hemolysis in G6PD deficiency Identified risk can be mitigated with G6PD testing G6PD deficiency high in many malaria endemic areas . Co-incidence with malaria common Sex-linked condition . Exclude patients from treatment Diagnostic tests for G6PD deficiency readily available in US CO-23 Summary Untreated liver stage of P. vivax infection causes malaria relapse P. vivax is widespread globally . Cases reported in both endemic areas and countries that have previously eliminated malaria Primaquine is only treatment option to prevent relapse . Poor adherence limits effectiveness Need for simple, single-dose regimen for radical cure of P. vivax malaria Successful attack on hypnozoite reservoir of P. vivax likely to result in collapse of transmission cycle CO-24 Efficacy Justin A. Green, MD, PhD Project Physician, Tafenoquine Clinical Development GlaxoSmithKline CO-25 Key Tafenoquine Efficacy Studies Study Phase Treatment Groups N Role CQ 54 TQ 50 mg + CQ 55 TQ 100 mg + CQ 57 Study 582 Part 1 Phase 2b Dose finding TQ 300 mg + CQ 57 TQ 600 mg + CQ 56 PQ 15 mg + CQ 50 CQ 133 Study 582 Part 2 Phase 3 TQ 300 mg + CQ 260 Pivotal PQ 15 mg + CQ 129 TQ 300 mg + CQ 166 Study 564 Phase 3 Supportive PQ 15 mg + CQ 85 . CQ = chloroquine x 3 days . TQ = tafenoquine single dose . PQ = primaquine x 14 days CO-26 Clinical Pharmacology of Tafenoquine 300 mg 300 Administer with food . Increased absorption . 100 Improved GI tolerability Linear PK up to 1200 mg TQ 50 Conc. t1/2 ~15 days (ng/mL) 20 No impact of age, race, weight, gender, or G6PD deficiency on PK 5 Slow metabolism . No major circulating 0 1 2 3 4 5 6 7 8 9 10 metabolites Time (weeks) CO-27 Study 582 (Part 1): Rationale for 300 mg Single Dose TQ Treatment 100% TQ 600 mg + CQ TQ 300 mg + CQ 80% PQ + CQ Recurrence- 60% TQ 50 mg + CQ free TQ 100 mg + CQ (%) 40% CQ 20% 0% 0 30 60 90 120 150 180 210 Time (days) N at risk PQ + CQ 50 49 44 37 37 37 11 0 CQ 54 52 39 31 26 24 11 0 TQ 50 mg + CQ 55 54 46 43 34 32 8 0 TQ 100 mg + CQ 57 55 46 38 33 30 7 0 TQ 300 mg + CQ 57 56 56 53 50 50 18 0 TQ 600 mg + CQ 56 55 53 50 49 46 11 0 CO-28 Study 582 (Part 2): Statistical Analysis Plan 90% recurrence-free efficacy in TQ arm with 30% treatment difference to CQ Study overpowered for efficacy comparisons . Original sample size: N=600 Slow recruitment and global shortage of study chloroquine . Smaller sample size negotiated . Still powered for significance CO-29 Study 582 (Part 2) Design: Multi-Center, Double- Blind, Placebo-Controlled Study Placebo CQ N=133 CQ: Days 1 to 3 Followed for 6 months TQ: Day 1 or 2 Randomized TQ 300 mg + CQ N=522 N=260 CQ: Days 1 to 3 Followed for 6 months PQ: Days 1–14 PQ + CQ N=129 CQ: Days 1 to 3 Followed for 6 months CO-30 Study 582 (Part 2): Key Inclusion / Exclusion Criteria Microscopically diagnosed P.
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