Suzan Am Bouwman1, Rella Zoleko-Manego2, Katalin Csermak Renner3, Esther K Schmitt3, Ghyslain Mombo-Ngoma2, Martin P Grobusch4. 1. Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam Infection & Immunity, Amsterdam Public Health, University of Amsterdam, Meibergdreef 9, 1100 DD, Amsterdam, the Netherlands; Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon. 2. Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Department of Medicine University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Novartis Pharma AG, Global Health Development Unit, Basel, Switzerland. 4. Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam Infection & Immunity, Amsterdam Public Health, University of Amsterdam, Meibergdreef 9, 1100 DD, Amsterdam, the Netherlands; Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon; Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany. Electronic address: m.p.grobusch@amc.uva.nl.
Abstract
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', 'KAE609' 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 intra-erythrocytic 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.
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', 'KAE609' 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 intra-erythrocytic 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 malariapatients, a possible safety concern is hepatotoxicity.
Authors: Gilles Ndayisaba; Adoke Yeka; Kwaku Poku Asante; Martin P Grobusch; Etienne Karita; Henry Mugerwa; Stephen Asiimwe; Abraham Oduro; Bakary Fofana; Seydou Doumbia; Jay Prakash Jain; Sarita Barsainya; Gerd A Kullak-Ublick; Guoqin Su; Esther K Schmitt; Katalin Csermak; Preetam Gandhi; David Hughes Journal: Malar J Date: 2021-12-20 Impact factor: 2.979
Authors: Deyun Qiu; Jinxin V Pei; James E O Rosling; Vandana Thathy; Dongdi Li; Yi Xue; John D Tanner; Jocelyn Sietsma Penington; Yi Tong Vincent Aw; Jessica Yi Han Aw; Guoyue Xu; Abhai K Tripathi; Nina F Gnadig; Tomas Yeo; Kate J Fairhurst; Barbara H Stokes; James M Murithi; Krittikorn Kümpornsin; Heath Hasemer; Adelaide S M Dennis; Melanie C Ridgway; Esther K Schmitt; Judith Straimer; Anthony T Papenfuss; Marcus C S Lee; Ben Corry; Photini Sinnis; David A Fidock; Giel G van Dooren; Kiaran Kirk; Adele M Lehane Journal: Nat Commun Date: 2022-09-30 Impact factor: 17.694
Authors: Oriana Kreutzfeld; Stephanie A Rasmussen; Aarti A Ramanathan; Patrick K Tumwebaze; Oswald Byaruhanga; Thomas Katairo; Victor Asua; Martin Okitwi; Stephen Orena; Jennifer Legac; Melissa D Conrad; Samuel L Nsobya; Ozkan Aydemir; Jeffrey Bailey; Maelle Duffey; Brett R Bayles; Akhil B Vaidya; Roland A Cooper; Philip J Rosenthal Journal: Antimicrob Agents Chemother Date: 2021-08-02 Impact factor: 5.938