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

Author:

Schmitt Esther K1ORCID,Ndayisaba Gilles2,Yeka Adoke3,Asante Kwaku Poku4,Grobusch Martin P567,Karita Etienne8,Mugerwa Henry9,Asiimwe Stephen10,Oduro Abraham11,Fofana Bakary12,Doumbia Seydou13,Su Guoqin14,Csermak Renner Katalin1,Venishetty Vinay Kumar15,Sayyed Sarfaraz16,Straimer Judith17,Demin Ivan1,Barsainya Sarita16,Boulton Caroline1,Gandhi Preetam1

Affiliation:

1. Novartis Pharma AG, Basel, Switzerland

2. Rinda Ubuzima, Kigali, Rwanda

3. Infectious Diseases Research Collaboration, Busia, Uganda

4. Kintampo Health Research Centre, Kintampo North Municipality, Ghana

5. Centre de Recherches Médicales en Lambaréné, Lambaréné, Gabon

6. Amsterdam University Medical Centers, Amsterdam, The Netherlands

7. University of Tübingen, Tübingen, Germany

8. Center for Family Health Research, Kigali, Rwanda

9. Joint Clinical Research Centre, Kampala, Uganda

10. Kabwohe Clinical Research Center and Mbarara University of Science and Technology, Mbarara, Uganda

11. Navrongo Health Research Centre, Navrongo, Ghana

12. Malaria Research and Training Center, Sotuba, Mali

13. University Clinical Research Center, Bamako, Mali

14. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

15. Novartis Institutes for BioMedical Research, Hyderabad, India

16. Novartis Healthcare Pvt Ltd, Hyderabad, India

17. Novartis Institutes for BioMedical Research, Emeryville, California, USA

Abstract

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).

Funder

Wellcome Trust

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

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