White Nicholas J, Duong Tran T, Uthaisin Chirapong, Nosten François, Phyo Aung P, Hanboonkunupakarn Borimas, Pukrittayakamee Sasithon, Jittamala Podjanee, Chuthasmit Kittiphum, Cheung Ming S, Feng Yiyan, Li Ruobing, Magnusson Baldur, Sultan Marc, Wieser Daniela, Xun Xiaolei, Zhao Rong, Diagana Thierry T, Pertel Peter, Leong F Joel
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):1152-60. doi: 10.1056/NEJMoa1602250.
KAF156 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.
We 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).
Median 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.
KAF156 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 .).
KAF156属于一类新型抗疟药（咪唑并哌嗪），对疟原虫的无性和有性血液阶段以及红细胞前期肝脏阶段均有活性。
我们在泰国和越南的五个中心开展了一项2期开放标签的两部分研究，以评估KAF156在成人急性间日疟或恶性疟患者中的抗疟疗效、安全性和药代动力学特征。在接受多剂量治疗（400mg，每日一次，共3天）的间日疟或恶性疟患者队列中评估寄生虫清除率，随后在接受单剂量（800mg）的另一组恶性疟患者中评估28天的治愈率。
在接受多剂量方案治疗后，10例恶性疟患者的寄生虫清除时间中位数为45小时（四分位间距，42至48小时），10例间日疟患者为24小时（四分位间距，20至30小时）；在接受单剂量治疗后，21例恶性疟患者的寄生虫清除时间中位数为49小时（四分位间距，42至54小时）。在接受单剂量治疗并随访28天的21例患者中，1例再次感染，7例复发感染（治愈率67%；95%可信区间，46%至84%）。KAF156的平均（±标准差）终末消除半衰期为44.1±8.9小时。在这项小型研究中未出现严重不良事件。最常见的不良事件包括窦性心动过缓、血小板减少、低钾血症、贫血和高胆红素血症。2例患者出现2级或更高等级的呕吐，其中1例在接受800mg单剂量后因反复呕吐而停药。与多剂量队列相比，随访时间更长的单剂量队列报告的不良事件更多。
在少数非复杂性间日疟或恶性疟成人患者中，KAF156显示出抗疟活性，且无明显安全问题。（由诺华公司等资助；ClinicalTrials.gov编号，NCT01753323。）
