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).

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

“…There was no obvious relationship between LFT abnormalities and cipargamin dose or exposure. Exposure to cipargamin in this trial was higher or comparable to previous trials [ 1 ], with no evidence of an increase in hepatic events. In addition, patients receiving both cipargamin and artemether–lumefantrine during the study did not show an increased rate of LFT abnormalities.…”

“…This study paves the way for the further development of this novel anti-malarial. In addition to the good tolerability of cipargamin, this study has confirmed its potency and rapid onset of parasiticidal activity with parasite clearance times of around 8 h for doses of 50 mg or higher [ 1 ]. Furthermore, cipargamin is potent against artemisinin-resistant parasites including the R561H mutant, which is spreading in Rwanda [ 2 ].…”

“…Furthermore, cipargamin is potent against artemisinin-resistant parasites including the R561H mutant, which is spreading in Rwanda [ 2 ]. However, when used as monotherapy, treatment-emerging mutations were detected in patients experiencing recrudescences [ 1 ]. Cipargamin will be developed in fixed-dose combination with a partner drug and liver safety aspects remain to be considered for selection of partner compounds and monitored in future clinical trials.…”

“…Secondary objectives included overall safety and tolerability, pharmacokinetic parameters and efficacy. Here, hepatic and general safety assessments are described, while efficacy and pharmacokinetics are reported elsewhere [ 1 ].…”

“…There is a need to develop new anti-malarials as emerging resistance to artemisinin derivatives threatens to undermine progress in malaria control. Cipargamin (KAE609/NITD609) is a novel anti-malarial spiroindolone analogue compound with promising and potent activity in clinical studies [ 1 – 3 ]. Spiroindolones disrupt sodium and osmotic homeostasis in Plasmodium species by inhibiting PfATP4, a plasma membrane Na+-ATPase [ 4 ].…”