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P218 is a highly selective dihydrofolate reductase inhibitor with potent in vitro activity against pyrimethamine-resistant  Plasmodium falciparum . This single-center, randomized, double-blind, placebo-controlled phase Ib study evaluated P218 safety, pharmacokinetics, and chemoprotective efficacy in a  P. falciparum  sporozoite ( Pf SPZ) volunteer infection study (VIS). Consecutive dose safety and tolerability were evaluated (cohort 1), with participants receiving two oral doses of P218 1,000 mg 48 hours apart ( n  = 6), or placebo ( n  = 2). P218 chemoprotective efficacy was assessed (cohorts 2 and 3) with direct venous inoculation of 3,200 aseptic, cryopreserved  Pf SPZ (NF54 strain) followed 2 hours later with two P218 doses of 1,000 mg (cohort 2,  n  = 9) or 100 mg (cohort 3,  n  = 9) administered 48 hours apart, or placebo ( n  = 6). Parasitemia was assessed from day 7 using quantitative PCR targeting the  var  gene acidic terminal sequence (varATS qPCR). By day 28, all participants in cohort 2 (P218 1,000 mg) and 8/9 in cohort 3 (P218 100 mg) were sterilely protected post- Pf SPZ VIS, confirming P218  P. falciparum  chemoprotective activity. With placebo, all six participants became parasitemic (geometric mean time to positive parasitemia 10.6 days [90% CI: 9.9–11.4]). P218 pharmacokinetics were similar in participants with or without induced infection. Adverse events of any cause occurred in 45.8% (11/24) of participants who received P218 and 50.0% (4/8) following placebo; all were mild/moderate in severity, transient, and self-limiting. There were no clinically relevant changes in laboratory parameters, vital signs, or electrocardiograms. P218 displayed excellent chemoprotective efficacy against  P. falciparum  with favorable safety and tolerability.

Chemoprotective Antimalarial Activity of P218 against Plasmodium falciparum: A Randomized, Placebo-Controlled Volunteer Infection Study