Efficacy of cipargamin (KAE609) in a randomized, Phase II dose-escalation study in adults in sub-Saharan Africa with uncomplicated Plasmodium falciparum malaria

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in Phase II. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere).

METHODS: This Phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa, in adults with uncomplicated P. falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and PCR-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed.

RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was over 75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional.

CONCLUSION: Cipargamin, at single doses of 50 mg to 150 mg was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of over 65% in adults with uncomplicated P. falciparum malaria and recrudescent parasites frequently harboured a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner.

CLINICAL TRIALS REGISTRATION: NCT03334747.