Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria

Abstract

Background: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. 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 Plasmodium 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 polymerase chain reaction (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 >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.

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

Clinical trials registration: ClinicalTrials.gov (NCT03334747).

Keywords: KAE609; cipargamin; efficacy; falciparum malaria; sub-Saharan Africa.

Figure 1.

Study design. Abbreviations: QD, daily; SD, single dose.

Figure 2.

Mean parasite count over time (at scheduled visits only) by treatment group.

Figure 3.

Individual patient parasite counts over time by treatment group; 1 point per patient per visit.

Figure 4.

PCR-corrected ACPR by treatment group. Abbreviations: ACPR, adequate clinical and parasitological response; CI, confidence interval; PCR, polymerase chain reaction; QD, daily.

Figure 5.

Exposure–response scatterplot for PRR24 and AUC0-24h for cipargamin-treated patients. Black symbols represent data with parasitemia counts at 24 hours above the limit of detection; gray symbols represent data with parasitemia counts at 24 hours below the limit of detection; black solid line: local regression line; gray-shaded area: confidence interval around the local regression line. Abbreviations: AUC0-24h, area under the concentration-time curve from zero to 24 hours; LOD, limit of detection; PRR24, parasite reduction ratio at 24 hours.