• Nicholas J White, Tran T Duong, Chirapong Uthaisin, François Nosten, Aung P Phyo, Borimas Hanboonkunupakarn, Sasithon Pukrittayakamee, Podjanee Jittamala, Kittiphum Chuthasmit, Ming S Cheung, Yiyan Feng, Ruobing Li, Baldur Magnusson, Marc Sultan, Daniela Wieser, Xiaolei Xun, Rong Zhao, Thierry T Diagana, Peter Pertel, and F Joel Leong.
• From the Mahidol-Oxford Tropical Medicine Research Unit (MORU) (N.J.W.) and the Department of Clinical Tropical Medicine (B.H., S.P., P.J.), Faculty of Tropical Medicine, Mahidol University, Bangkok, Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot (F.N., A.P.P.), Phusing Hospital, 83/1 Tambon Huay Tikchu, Phusing District, Srisaket (K.C.), and Mae Ramat District Hospital, Mae Ramat District, Tak (C.U.) - all in Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom (N.J.W., F.N.); National Institute for Malariology, Parasitology and Entomology, Tu Liem District, Hanoi (D.T.T.); Novartis Institutes for BioMedical Research (M.S.C., M.S., D.W.) and Novartis Pharma (B.M.) - both in Basel, Switzerland; Novartis Institutes for BioMedical Research (Y.F., R.Z.) and Novartis Pharma (China) (X.X.), Shanghai, and Novartis Institutes for BioMedical Research, Beijing (R.L.) - all in China; Novartis Institute for Tropical Diseases, Singapore (T.T.D., F.J.L.); and Novartis Institutes for BioMedical Research, Cambridge, MA (P.P.).
• N. Engl. J. Med. 2016 Sep 22; 375 (12): 115211601152-60.

BackgroundKAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites.MethodsWe conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg).ResultsMedian parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts.ConclusionsKAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01753323 .).

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