M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18–55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with (). Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50–1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1–7 h after dosing, and a long half-life was observed (146–193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35–55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg). The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis. Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.

中文翻译：

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新型疟原虫真核翻译延伸因子 2 抑制剂 M5717 的安全性、药代动力学和抗疟活性：首次人体、随机、安慰剂对照、双盲、单次剂量递增研究和志愿者感染研究


M5717 是第一个作为抗疟药进入临床开发阶段的疟原虫翻译延伸因子 2 抑制剂。我们的目的是表征 M5717 在健康志愿者中的安全性、药代动力学和抗疟活性。这项首次人体研究是在澳大利亚昆士兰州布里斯班进行的一项由两部分组成的单中心临床试验。第一部分是一项双盲、随机、安慰剂对照、单剂量递增研究，参与者被纳入九个剂量组之一（50、100、200、400、600、1000、1250、1800 或 2100 mg）并随机分配 (3:1) 至 M5717 或安慰剂。每个剂量组均采用前哨给药策略，其中两名参与者（一名分配至 M5717，一名分配至安慰剂）最初被随机分配并给药。随机化时间表由独立、非盲态的统计学家以电子方式生成。第二部分是一项开放标签、非随机志愿者感染研究，使用诱导血期疟疾模型，其中参与者被纳入三个剂量组。年龄在 18-55 岁、无生育潜力的健康男性和女性有资格被纳入；志愿者感染研究中的个体被要求未患过疟疾。通过不良事件的频率和严重程度评估安全性和耐受性（单次剂量递增研究的主要结果和志愿者感染研究的次要结果）。还对 M5717 的药代动力学特征进行了表征（志愿者感染研究的主要结果和单次剂量递增研究的次要结果）。 通过寄生虫减少率和相应的寄生虫清除半衰期评估寄生虫清除动力学（志愿者感染研究的主要结果）；确定第 28 天之前的复发发生率（志愿者感染研究的次要结果）。测试了复发寄生虫的基因突变（探索性结果）。试验已注册为（）。 2017 年 8 月 28 日至 2019 年 6 月 14 日期间，对 221 名受试者进行了资格评估，其中 66 名男性参加了单次剂量递增研究（50-1800 mg 队列每组 8 名，将 3 种 M5717 随机分配到一种安慰剂，并且2100 mg 队列中的 2 名患者，将一种 M5717 随机分配到一种安慰剂）和 22 名男性参加了志愿者感染研究（150 mg 队列中 6 名，400 mg 和 800 mg 队列中各 8 名）。无严重不良事件；所有与 M5717 相关的不良事件的严重程度均为轻度或中度且短暂，在剂量高于 1250 mg 时观察到发生频率增加。在单次剂量递增研究中，安慰剂组 17 名受试者中有 3 名发生了与治疗相关的不良事件； 50 mg、100 mg 或 200 mg 组中没有个体； 400 mg、1000 mg 和 1250 mg 组各 6 名个体之一； 600 mg 组中六人中的两人；以及 1800 毫克和 2100 毫克组的所有个体。在志愿者感染研究中，150 mg 或 800 mg 组的参与者没有发生与 M5717 相关的不良事件，而 400 mg 组的 8 名参与者中有一名发生了 M5717 相关的不良事件。 在 1800 mg 或 2100 mg 组中观察到短暂的口腔感觉减退（三名受试者）和视力模糊（四名受试者），构成未知风险；因此，在 2100 mg 队列中的两名哨兵个体给药后，进一步给药暂停。最大血药浓度出现在给药后 1-7 小时，并且观察到较长的半衰期（剂量≥200 mg 时为 146-193 小时）。所有参与者均出现寄生虫清除，并且是双相的，其特征是初始缓慢清除持续 35-55 小时（半衰期 231·1 小时 [95% CI 40·9 未达到]，150 mg，60·4 小时 [38· 6 至 138·6] 400 mg，24·7 小时 [20·4 至 31·3] 800 mg），然后快速清除（半衰期 3·5 小时 [3·1 至 4·0] 150 mg 为 3·9 小时 [3·3 至 4·8]，400 mg 为 3·9 小时 [3·3 至 4·8]，800 mg 为 5·5 小时 [4·8 至 6·4]。服用 150 mg 的 6 名个体中有 3 名（50%）出现复发，服用 400 mg 的 8 名个体中有 2 名（25%）出现复发。在四例寄生虫复发病例中检测到与耐药性相关的基因突变（其中两名个体服用 150 毫克，两名个体服用 400 毫克）。 M5717 的安全性、药代动力学和抗疟活性支持其作为单剂量抗疟联合疗法或疟疾预防的组成部分的开发。 Wellcome Trust 和德国达姆施塔特 Merck KGaA 的医疗保健业务。