Background

Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533.

Methods

A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia). Part 1 was a double-blind, randomised, placebo-controlled, sequential ascending dose study and part 2 was an open-label, randomised, two-period crossover, pilot food effect study. A phase 1b, open-label, volunteer infection study (VIS) was conducted at Nucleus Network (Herston, QLD, Australia). Eligible participants were adults aged 18–55 years, with a bodyweight of at least 50 kg and BMI of 18–32 kg/m² and participants in the VIS were malaria-naive. In part 1 of the FIH study, six cohorts of up to eight participants were randomly assigned (3:1) to a single oral MMV533 dose (5, 10, 20, 50, 100, and 160 mg) or placebo using an automated system, with study staff and participants masked to treatment allocation, and follow-up until day 28. In part 2, MMV533 30 mg was administered open-label to one cohort of nine participants assigned by simple randomisation (1:1) to the fasted–fed (n=4) or fed–fasted (n=5) groups. After a 21-day washout period, fed and fasted groups crossed over with follow-up until day 42. In the VIS, seven participants were assigned using simple randomisation (1:1:1) to three dosing groups of 20 mg (n=3), 35 mg (n=2), or 100 mg (n=2) after parasitaemia was detected, with follow-up until day 28. The primary outcomes were treatment emergent adverse events and relationship to MMV533 for the FIH study assessed in the safety population, and in the VIS primary outcomes were parasite reduction ratio over 48 h (log₁₀PRR₄₈), parasite clearance half-life (PCT_1/2), and lag phase assessed in the pharmacodynamic population. MMV533 pharmacokinetics was a secondary outcome for both studies, evaluated in the pharmacokinetic population. The studies are registered with ClinicalTrials.gov, NCT04323306 and NCT05205941 (completed).

Findings

The FIH study was conducted between July 31, 2020, and Sept 27, 2022, and the VIS between March 31 and Aug 9, 2022. 335 adults were assessed for eligibility, 71 enrolled, and 69 randomly assigned (53 in part 1 and nine in part 2 of the FIH study, and seven in the VIS). 32 (45%) of 71 participants were female and 39 (55%) were male. In part 1, 24 (63%) of 38 participants had an adverse event after MMV533 administration with no apparent relationship to dose versus six (50%) of 12 after placebo. Treatment-related adverse events were reported for four (11%) participants receiving MMV533 and one (8%) receiving placebo, with no relationship to dose. In part 2, adverse events were reported for three (38%) of eight participants when fasted and four (44%) of nine when fed, with no apparent influence of food. Time to maximum plasma concentration was 4·0–6·0 h, and apparent half-life was 103·8–127·2 h. After a high-fat meal, the geometric mean ratio (fed:fasted) of MMV533 AUC_0-last was 112·0 (90% CI 89·6–140·0). In the VIS for MMV533 100 mg, log₁₀PRR₄₈ was 2·27 (1·99–2·56), PCT_1/2 was 6·36 h (5·64–7·28), and lag phase was 2 h.

Interpretation

An acceptable safety and tolerability profile, confirmed parasiticidal activity, and a long half-life support progression of MMV533 into clinical trials in patients with malaria as a component of new antimalarial combination therapies.

Funding

MMV Medicines for Malaria Venture and Bill & Melinda Gates Foundation.

中文翻译：

---

MMV533 的安全性、耐受性、药代动力学和抗疟活性：一项 1a 期首次人体、随机、递增剂量和食物效应研究，以及一项 1b 期恶性疟原虫志愿者感染研究

 背景

需要新型抗疟药来解决对青蒿素和伴侣药物的新耐药性。我们进行了两项试验，以评估候选药物 MMV533 的安全性、耐受性、药代动力学和对血液期恶性疟原虫的活性。

 方法

在 Nucleus Network（澳大利亚维多利亚州墨尔本）进行了 1a 期首次人体 （FIH） 试验。第 1 部分是一项双盲、随机、安慰剂对照、序贯递增剂量研究，第 2 部分是一项开放标签、随机、两期交叉、试点食物效应研究。在 Nucleus Network（澳大利亚昆士兰州赫斯顿）进行了一项 1b 期、开放标签、志愿者感染研究 （VIS）。符合条件的参与者是 18-55 岁的成年人，体重至少 50 公斤，BMI 为 18-32 kg/m 2，VIS 的参与者未患疟疾。在 FIH 研究的第 1 部分中，使用自动化系统将 6 个队列（最多 8 名参与者）随机分配 （3：1） 至高接受单次口服 MMV533 剂量（5、10、20、50、100 和 160 毫克）或安慰剂，研究人员和参与者对治疗分配不知情，并随访至第 28 天。在第 2 部分中，MMV533 30 mg 以开放标签方式给药给一组 9 名参与者，这些参与者通过简单随机化 （1：1） 分配到禁食 （n=4） 或进食禁食 （n=5） 组。在 21 天的清除期后，进食和禁食组交叉随访至第 42 天。在 VIS 中，在检测到寄生虫血症后，使用简单随机 （1：1：1） 将 7 名参与者分配到 20 mg （n=3）、35 mg （n=2） 或 100 mg （n=2） 的三个给药组，并随访至第 28 天。在安全人群中评估的 FIH 研究的主要结局是治疗中出现的不良事件和与 MMV533 的关系，在 VIS 中，主要结局是 48 小时内寄生虫减少比 （log₁₀PRR₄₈）、寄生虫清除半衰期 （PCT_1/2） 和滞后期在药效学人群中评估。 MMV533 药代动力学是两项研究的次要结局，在药代动力学人群中进行评估。这些研究在 ClinicalTrials.gov、NCT04323306 和 NCT05205941（已完成）注册。

 发现

FIH 研究于 2020 年 7 月 31 日至 2022 年 9 月 27 日进行，VIS 于 2022 年 3 月 31 日至 8 月 9 日进行。335 名成年人接受了资格评估，71 名入组，69 名随机分配（FIH 研究的第 1 部分 53 名，第 2 部分 9 名，VIS 中的 7 名）。71 名参与者中有 32 名 （45%） 是女性，39 名 （55%） 是男性。在第 1 部分中，38 名参与者中有 24 名 （63%） 在服用 MMV533 后发生不良事件，与剂量没有明显关系，而安慰剂后 12 名参与者中有 6 名 （50%）发生不良事件。4 名 （11%） 接受 MMV533 的参与者和 1 名 （8%） 接受安慰剂的参与者报告了与治疗相关的不良事件，与剂量无关。在第 2 部分中，8 名参与者中有 3 名 （38%） 在禁食时报告了不良事件，9 名参与者中有 4 名 （44%） 在进食时报告了不良事件，没有食物的明显影响。达到最大血浆浓度的时间为 4·0–6·0 小时，表观半衰期为 103·8–127·2 小时。高脂肪餐后，MMV533 AUC_0-last 的几何平均比值 （fed：fasted） 为 112·0 （90% CI 89·6–140·0）。在 MMV533 100 mg 的 VIS 中，对数₁₀PRR₄₈ 为 2·27 （1·99–2·56），PCT_1/2 为 6·36 小时 （5·64–7·28），滞后期为 2 小时。

 解释

可接受的安全性和耐受性概况、经证实的杀寄生虫活性以及 MMV533 作为新的抗疟联合疗法的组成部分进入疟疾患者的临床试验的长半衰期支持进展。

 资金

MMV Medicines for Malaria Venture和Bill & Melinda Gates Foundation。