Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study.
Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study.
复制标题
DOI：
10.1016/s1473-3099(21)00252-8
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Bagchus WM
中科院分区：
文献类型：
--
作者：
McCarthy JS;Yalkinoglu Ö;Odedra A;Webster R;Oeuvray C;Tappert A;Bezuidenhout D;Giddins MJ;Dhingra SK;Fidock DA;Marquart L;Webb L;Yin X;Khandelwal A;Bagchus WM
M5717是第一个达到临床开发的疟原虫翻译延伸因子2抑制剂。我们的目的是在健康志愿者中验证M5717的安全性、药代动力学和抗疟活性。这项首次人体研究是一项在澳大利亚昆士兰州布里斯班进行的两部分、单中心临床试验。第一部分是一项双盲、随机、安慰剂对照、单次剂量递增研究，受试者入组9个剂量队列（50、100、200、400、600、1000、1250、1800或2100 mg）之一，并随机分配（3：1）至M5717或安慰剂组。每个剂量队列采用哨兵给药策略，其中2例受试者（1例分配至M5717组，1例分配至安慰剂组）最初接受随机化和给药。随机化时间表由独立的非盲统计学家以电子方式生成。第二部分是一项开放标签、非随机的志愿者感染研究，使用恶性疟原虫诱导的血液期疟疾模型，参与者被纳入三个剂量队列。年龄在18 - 55岁之间的无生育能力的健康男性和女性有资格入选;志愿者感染研究中的个体要求为疟疾初治者。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局和志愿者感染研究的次要结局）。还描述了M5717的药代动力学特征（志愿者感染研究的主要结局和单次剂量递增研究的次要结局）。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局）;确定直至第28天的复发率（志愿者感染研究的次要结局）。检测复发性寄生虫的基因突变（探索性结局）。该试验在www.example.com（NCT 03261401）上注册。在2017年8月28日至2019年6月14日期间，对221名受试者进行了合格性评估，其中66名男性入组了单次剂量递增研究（50 - 1800 mg队列每个队列8例，将3例M5717随机分配至1例安慰剂组，2100 mg队列2例，随机分配一个M5717组和一个安慰剂组），22名男性参加志愿者感染研究（150 mg组6名，400 mg和800 mg组各8名）。无严重不良事件;所有M5717相关不良事件的严重程度均为轻度或中度，且为一过性，在剂量高于1250 mg时观察到频率增加。在单次剂量递增研究中，安慰剂组17名受试者中有3名发生了治疗相关不良事件; 50 mg、100 mg或200 mg组中无一例发生; 400 mg、1000 mg和1250 mg组各6名受试者中有1名发生了治疗相关不良事件; 600 mg组6名受试者中有2名发生了治疗相关不良事件;以及1800 mg和2100 mg组的所有个体。在志愿者感染研究中，150 mg或800 mg组无受试者发生M5717相关不良事件，400 mg组8例受试者中有1例发生M5717相关不良事件。在1800 mg或2100 mg组中观察到一过性口腔感觉减退（3例受试者）和视力模糊（4例受试者），构成未知风险;因此，在2100 mg队列中的2例哨兵个体给药后暂停进一步给药。给药后1 - 7 h出现最大血药浓度，观察到半衰期较长（≥ 200 mg剂量下为146 - 193 h）。寄生虫清除发生在所有参与者和双相，其特点是最初的缓慢清除持续35 - 55小时（150 mg的半衰期为231·1 h [95% CI 40·9至未达到]，400 mg为60·4 h [38·6至138·6]，800 mg为24·7 h [20·4至31·3]），随后快速清除（150 mg的半衰期为3.5 h [3.1至4.0]，400 mg为3.9 h [3.3至4.8]，800 mg为5.5 h [4.8至6.4]）。150 mg剂量组6例患者中有3例（50%）复发，400 mg剂量组8例患者中有2例（25%）复发。在4例寄生虫复发病例中检测到与耐药性相关的基因突变（2例患者接受150 mg剂量，2例患者接受400 mg剂量）。M5717的安全性、药代动力学和抗疟活性支持其开发为单剂量抗疟联合治疗或疟疾预防的组成部分。Wellcome Trust和Merck KGaA（达姆施塔特，德国）的医疗保健业务。
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 Plasmodium falciparum 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 ClinicalTrials.gov (NCT03261401). 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.