Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study

Abstract

Background: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity.

Methods: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2).

Findings: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (C_max) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (t_max) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log₁₀ parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001).

Interpretation: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment.

Funding: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

Figure 1

Trial profile In part 1, single ascending doses of DSM265 (25–1200 mg) were tested in eight cohorts in fasted conditions. Participants in the 250 mg cohort were to return at least 21 days after the first DSM265 dose to receive DSM265 in fed conditions. The 400 mg dose cohort was repeated (400 mg-rep) due to a biopharmaceutical issue in the preparation of the study medication. Part 2 (induced blood-stage malaria) started after documentation of safety and pharmacokinetics data of the 150 mg dose in part 1.

Figure 2

DSM265 plasma concentration versus time profiles under fasted conditions Geometric mean plasma concentrations of participants in different dose cohorts following administration of single doses of DSM265. Time 0 h corresponds to time of drug administration. For the 400 mg cohort, only data for the repeated cohort are represented. For all cohorts, n=6, except for the 250 mg dose cohort (n=8) and the 400 mg dose cohort (n=5). Error bars represent SDs.

Figure 3

Parasite clearance profiles Participants were inoculated on day 0 and treated either with DSM265 (150 mg, red lines) or mefloquine (10 mg/kg, blue lines) on day 8 (vertical dashed line). Thin lines show individual curves and thick lines represent the mean.