Kuemmerle Andrea, Singh Nand, Gossen Denis, Janin Annick, Sharma Raman, Cahn Anthony, Gibson Rachel A, Menakuru Somasekhara R, Lambourne Erin, Dove Tom, Gamo Francisco-Javier, Sanz Laura, Bestgen Benoit, Chalon Stephan
MMV Medicines for Malaria Venture, Geneva, Switzerland.
Quotient Sciences, Nottingham, UK.
Br J Clin Pharmacol. 2025 Jun;91(6):1821-1833. doi: 10.1111/bcp.70000.
To evaluate the safety, tolerability and pharmacokinetics in healthy participants of orally administered MMV367 (GSK3772701), a novel antimalarial interfering with Plasmodium falciparum acyl coenzyme A synthetase 10/11 function.
This first-in-human study enrolled 47 healthy male and female participants. Part 1 was a randomised, double-blind, placebo-controlled study in which four sequential fasted cohorts received MMV367 single ascending doses (100, 300, 750 and 1500 mg) or placebo (six active, two placebo per cohort). Part 2 was a randomised, open-label crossover (fed-fasted) pilot food-effect study of MMV367 440 mg (n = 8). In Part 3 MMV367 400 mg was administered once daily for 3 days in a single cohort (six active, two placebo).
Treatment-emergent adverse events (TEAEs) occurred in 36.8% (14/38) of participants receiving MMV367 vs 44.4% (4/9) with placebo. There were two MMV367-related TEAEs, and no serious or severe TEAEs or clinically relevant changes in electrocardiograms, vital signs or laboratory tests. In Part 1 (fasted), maximum plasma concentrations occurred between 2.0 and 5.0 h post dose, with a geometric mean half-life of 16.5-18.4 h. Approximate dose proportionality was demonstrated across the dose range (100-1500 mg). In Part 2, MMV367 relative bioavailability (fed vs fasted) was 161.4% (90% confidence interval 148.3, 175.6) for maximum observed concentration (C), 130.4% (122.2, 139.1) for the area under the curve (AUC) until the last measurable concentration and 132.9% (124.1, 142.3) for AUC extrapolated to infinity. In Part 3, geometric mean day 1:3 exposure ratios (geometric co-efficient of variability) were 1.9 (4.9%) for C and 2.1 (7.7%) for the AUC for the defined interval between doses after once-daily dosing for 3 days.
MMV367 demonstrated acceptable safety, tolerability and pharmacokinetic profiles supporting further development as an antimalarial drug.
评估口服新型抗疟药MMV367（GSK3772701）在健康受试者中的安全性、耐受性和药代动力学，该药物可干扰恶性疟原虫酰基辅酶A合成酶10/11的功能。
这项首次人体研究招募了47名健康男性和女性受试者。第1部分是一项随机、双盲、安慰剂对照研究，四个连续的空腹队列接受MMV367单次递增剂量（100、300、750和1500毫克）或安慰剂（每个队列6名活性受试者、2名安慰剂受试者）。第2部分是一项MMV367 440毫克的随机、开放标签交叉（进食-空腹）食物效应预试验（n = 8）。在第3部分中，一个队列（6名活性受试者、2名安慰剂受试者）每天服用一次MMV367 400毫克，持续3天。
接受MMV367的受试者中36.8%（14/38）出现治疗中出现的不良事件（TEAE），接受安慰剂的受试者中这一比例为44.4%（4/9）。有两例与MMV367相关的TEAE，没有严重或重度TEAE，心电图、生命体征或实验室检查也没有临床相关变化。在第1部分（空腹）中，最大血浆浓度出现在给药后2.0至5.0小时之间，几何平均半衰期为16.5 - 18.4小时。在整个剂量范围（100 - 1500毫克）内显示出近似的剂量比例关系。在第2部分中，MMV367的相对生物利用度（进食与空腹），最大观察浓度（C）为161.4%（90%置信区间148.3, 175.6），至最后可测量浓度的曲线下面积（AUC）为130.4%（122.2, 139.1），外推至无穷大的AUC为132.9%（124.1, 142.3）。在第3部分中，连续3天每日给药后，定义剂量间隔内的几何平均第1天:第3天暴露比（变异系数几何均值），C为1.9（4.9%），AUC为2.1（7.7%）。
MMV367表现出可接受的安全性、耐受性和药代动力学特征，支持其作为抗疟药物进一步开发。
