Schmitt, Esther K; Ndayisaba, Gilles; Yeka, Adoke; Asante, Kwaku Poku; Grobusch, Martin P; Karita, Etienne; Mugerwa, Henry; Asiimwe, Stephen; Oduro, Abraham; Fofana, Bakary; +10 more... Doumbia, Seydou; Su, Guoqin; Csermak Renner, Katalin; Venishetty, Vinay Kumar; Sayyed, Sarfaraz; Straimer, Judith; Demin, Ivan; Barsainya, Sarita; Boulton, Caroline; Gandhi, Preetam; (2021) Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria. Clinical Infectious Diseases, 74 (10). pp. 1831-1839. ISSN 1058-4838 DOI: https://doi.org/10.1093/cid/ciab716
Permanent Identifier
Use this Digital Object Identifier when citing or linking to this resource.
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).
Item Type | Article |
---|---|
Faculty and Department | Faculty of Infectious and Tropical Diseases > Dept of Disease Control |
PubMed ID | 34410358 |
Elements ID | 175780 |
Download
Filename: Schmitt_et al_2021_Efficacy _of_Cipargamin_(KAE609)_in_a_Randomized_Phase_II_Dose.pdf
Licence: Creative Commons: Attribution 4.0
Download