The early preclinical and clinical development of cipargamin (KAE609), a novel antimalarial compound

Background: Cipargamin (KAE609) is a novel spiroindolone class drug for the treatment of malaria, currently undergoing phase 2 clinical development. This review provides an overview and interpretation of the pre-clinical and clinical data of this possible next-generation antimalarial drug published to date.

Methods: We systematically searched the literature for studies on the preclinical and clinical development of cipargamin. PubMed and Google Scholar databases were searched using the terms ‘cipargamin’, ‘KAE609ʹ or ‘NITD609’ in the English language; one additional article was identified during revision. Nineteen of these in total 43 papers identified reported original studies; 13 of those articles were on pre-clinical studies and 6 reported clinical trials.

Results: A total of 20 studies addressing its preclinical and clinical development have been published on this compound at the time of writing. Cipargamin acts on the PfATP4, which is a P-type Na + ATPase disrupting the Na + homeostasis in the parasite. Cipargamin is a very fast-acting antimalarial, it is active against all intraerythrocytic stages of the malaria parasite and exerts gametocytocidal activity, with transmission-blocking potential. It is currently undergoing phase 2 clinical trial to assess safety and efficacy, with a special focus on hepatic safety.

Conclusion: In the search for novel antimalarial drugs, cipargamin exhibits promising properties, exerting activity against multiple intra-erythrocytic stages of plasmodia, including gametocytes. It exhibits a favourable pharmacokinetic profile, possibly allowing for single-dose treatment with a suitable combination partner. According to the clinical results of the first studies in Asian malaria patients, a possible safety concern is hepatotoxicity.