A Randomized Trial Evaluating the Prophylactic Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation

Abstract

Background: DSM265 is a selective inhibitor of Plasmodium dihydroorotate dehydrogenase that fully protected against controlled human malarial infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites when administered 1 day before challenge and provided partial protection when administered 7 days before challenge.

Methods: A double-blinded, randomized, placebo-controlled trial was performed to assess safety, tolerability, pharmacokinetics, and efficacy of 1 oral dose of 400 mg of DSM265 before CHMI. Three cohorts were studied, with DSM265 administered 3 or 7 days before direct venous inoculation of sporozoites or 7 days before 5 bites from infected mosquitoes.

Results: DSM265-related adverse events consisted of mild-to-moderate headache and gastrointestinal symptoms. DSM265 concentrations were consistent with pharmacokinetic models (mean area under the curve extrapolated to infinity, 1707 µg*h/mL). Placebo-treated participants became positive by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and were treated 7-10 days after CHMI. Among DSM265-treated subjects, 2 of 6 in each cohort were sterilely protected. DSM265-treated recipients had longer times to development of parasitemia than placebo-treated participants (P < .004).

Conclusions: This was the first CHMI study of a novel antimalarial compound to compare direct venous inoculation of sporozoites and mosquito bites. Times to qRT-PCR positivity and treatment were comparable for both routes. DSM265 given 3 or 7 days before CHMI was safe and well tolerated but sterilely protected only one third of participants.

Keywords: CHMI; DSM265; Plasmodium; RT-PCR; preerythrocytic; prophylaxis.

Figure 1.

DSM265 study design and main interventions. Time line of each of the 3 cohorts in days. Day of sporozoite administration is indicated as day 0. DSM265 or placebo was administered 3 or 7 days before controlled human malarial infection (CHMI), as shown. Pipette symbols indicate days (or hours, on dosing days) with quantitative reverse transcription–polymerase chain reaction (qRT-PCR) testing for parasite 18S ribosomal RNA, and blood drops indicate days with pharmacokinetic testing. Telephone follow-up was conducted 3 and 6 months after CHMI (not depicted). DVI, direct venous inoculation; PK, pharmacokinetic.

Figure 2.

Study population allocation.

Figure 3.

Primary efficacy assessment of time to ≥250 parasites/mL. Kaplan-Meier estimates of the cumulative proportion of participants who were parasitemic, as determined by quantitative reverse transcription–polymerase chain reaction, with an estimated ≥250 parasites/mL. A, Combined results for all 3 cohorts among placebo-recipient controls (solid black line) and DSM265 recipients (red dashed line). B, Results for cohort 1 (C1) only, with controlled human malarial infection (CHMI) induced by direct venous inoculation (DVI) 3 days after dosing, among placebo-recipient controls (solid black line) and DSM265 recipients (red dashed line). C, Results for cohort 2a (C2a; CHMI induced by DVI) and cohort 2b (C2b; CHMI induced by mosquito bite) among placebo-recipient controls (cohort 2a [C2a], solid black line; cohort 2b [C2b], solid red line) and DSM265 recipients (C2a, dashed black line; C2b, dashed red line). D, Results for C1 (black lines) as compared to C2a and C2b (C2ab; red lines). Log-rank tests were used to compare time to ≥250 parasites/mL between treatment groups and cohorts.

Figure 4.

Pharmacokinetic assessment of DSM265 plasma concentrations. Individual subject plasma concentrations of DSM265 (A) or metabolite DSM450 (B). Solid lines indicate participants who were not protected and were eventually treated with atovaquone-proguanil, whereas dashed lines indicate sterilely protected participants.

Figure 5.

Parasite densities measured by quantitative reverse transcription–polymerase chain reaction for participants in each of 3 cohorts. The bracket in cohort 1 indicates 1 participant with evident gametocytemia after treatment as described in the text. ND, not detected.