A single dose combination study with the experimental antimalarials artefenomel and DSM265 to determine safety and antimalarial activity against blood-stage Plasmodium falciparum in healthy volunteers.

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum induced blood stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on Day 0 and received a single oral dose of artefenomel and DSM265 on Day 7. Cohort 1 (n=8) received 200 mg artefenomel/100 mg DSM265 and Cohort 2 (n=5) received 200 mg artefenomel/50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel/DSM265 plasma concentrations. There were no treatment related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to that of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 PRR48 2.80 for Cohort 1 and 2.71 for Cohort 2; parasite clearance half-life 5.17 hours for Cohort 1 and 5.33 hours for Cohort 2). Recrudescence occurred in 5/8 subjects in Cohort 1 between Day 19-28 and in 5/5 subjects in Cohort 2 between Day 15-22. Low level gametocytemia (1-330 female gametocytes/mL) was detected in all subjects from Day 14. The results of this single dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria.