| Autor: |
Chughlay MF; 1Medicines for Malaria Venture, Geneva, Switzerland., El Gaaloul M; 1Medicines for Malaria Venture, Geneva, Switzerland., Donini C; 1Medicines for Malaria Venture, Geneva, Switzerland., Campo B; 1Medicines for Malaria Venture, Geneva, Switzerland., Berghmans PJ; 2SGS Life Sciences, Antwerp, Belgium., Lucardie A; 2SGS Life Sciences, Antwerp, Belgium., Marx MW; 3ICON Clinical Research GmbH, Langen, Germany., Cherkaoui-Rbati MH; 1Medicines for Malaria Venture, Geneva, Switzerland., Langdon G; 4PTx Solutions, London, United Kingdom., Angulo-Barturen I; 5GlaxoSmithKline, Tres Cantos, Madrid, Spain., Viera S; 5GlaxoSmithKline, Tres Cantos, Madrid, Spain., Rosanas-Urgell A; 6Institute of Tropical Medicine, Antwerp, Belgium., Van Geertruyden JP; 7University of Antwerp, Antwerp, Belgium., Chalon S; 1Medicines for Malaria Venture, Geneva, Switzerland. |
| Abstrakt: |
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 (PfSPZ) 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 PfSPZ (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-PfSPZ 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. |
