{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:36:53Z","timestamp":1791549413037,"version":"4.3.4"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["207813\/Z\/17\/Z"],"award-info":[{"award-number":["207813\/Z\/17\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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)\u2013corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All single or multiple cipargamin doses \u226550 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 &amp;gt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of &amp;gt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trials Registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov (NCT03334747).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciab716","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T16:33:34Z","timestamp":1629218014000},"page":"1831-1839","source":"Crossref","is-referenced-by-count":92,"title":["Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated\n                    <i>Plasmodium falciparum<\/i>\n                    Malaria"],"prefix":"10.1093","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-9887","authenticated-orcid":false,"given":"Esther K","family":"Schmitt","sequence":"first","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Ndayisaba","sequence":"additional","affiliation":[{"name":"Rinda Ubuzima , Kigali , Rwanda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adoke","family":"Yeka","sequence":"additional","affiliation":[{"name":"Infectious Diseases Research Collaboration , Busia , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwaku Poku","family":"Asante","sequence":"additional","affiliation":[{"name":"Kintampo Health Research Centre , Kintampo North Municipality , Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P","family":"Grobusch","sequence":"additional","affiliation":[{"name":"Centre de Recherches M\u00e9dicales en Lambar\u00e9n\u00e9 , Lambar\u00e9n\u00e9 , Gabon"},{"name":"Amsterdam University Medical Centers , Amsterdam , The Netherlands"},{"name":"University of T\u00fcbingen , T\u00fcbingen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Karita","sequence":"additional","affiliation":[{"name":"Center for Family Health Research , Kigali , Rwanda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Mugerwa","sequence":"additional","affiliation":[{"name":"Joint Clinical Research Centre , Kampala , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Asiimwe","sequence":"additional","affiliation":[{"name":"Kabwohe Clinical Research Center and Mbarara University of Science and Technology , Mbarara , Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Oduro","sequence":"additional","affiliation":[{"name":"Navrongo Health Research Centre , Navrongo , Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakary","family":"Fofana","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center , Sotuba , Mali"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seydou","family":"Doumbia","sequence":"additional","affiliation":[{"name":"University Clinical Research Center , Bamako , Mali"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqin","family":"Su","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover , New Jersey , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Csermak Renner","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay Kumar","family":"Venishetty","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research , Hyderabad , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarfaraz","family":"Sayyed","sequence":"additional","affiliation":[{"name":"Novartis Healthcare Pvt Ltd , Hyderabad , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Straimer","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research , Emeryville, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Demin","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarita","family":"Barsainya","sequence":"additional","affiliation":[{"name":"Novartis Healthcare Pvt Ltd , Hyderabad , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Boulton","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preetam","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"2022053122495254000_CIT0001","doi-asserted-by":"crossref","first-page":"101765","DOI":"10.1016\/j.tmaid.2020.101765","article-title":"The early preclinical and clinical development of cipargamin (KAE609), a novel antimalarial compound","volume":"36","author":"Bouwman","year":"2020","journal-title":"Travel Med Infect Dis"},{"key":"2022053122495254000_CIT0002","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa1315860","article-title":"Spiroindolone KAE609 for falciparum and vivax malaria","volume":"371","author":"White","year":"2014","journal-title":"N Engl J Med"},{"key":"2022053122495254000_CIT0003","author":"US Food and Drug Administration."},{"key":"2022053122495254000_CIT0004","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1126\/science.1260867","article-title":"Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates","volume":"347","author":"Straimer","year":"2015","journal-title":"Science"},{"key":"2022053122495254000_CIT0005","doi-asserted-by":"crossref","first-page":"e01940","DOI":"10.1128\/AAC.01940-16","article-title":"Estimation of the in vivo MIC of cipargamin in uncomplicated Plasmodium falciparum malaria","volume":"61","author":"Hien","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0006","doi-asserted-by":"crossref","first-page":"6209","DOI":"10.1128\/AAC.03393-14","article-title":"A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers","volume":"58","author":"Leong","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0007","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1126\/science.1193225","article-title":"Spiroindolones, a potent compound class for the treatment of malaria","volume":"329","author":"Rottmann","year":"2010","journal-title":"Science"},{"key":"2022053122495254000_CIT0008","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1128\/AAC.06377-11","article-title":"The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector","volume":"56","author":"van Pelt-Koops","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0009","doi-asserted-by":"crossref","first-page":"e00087","DOI":"10.1128\/AAC.00087-18","article-title":"Cell swelling induced by the antimalarial KAE609 (cipargamin) and other PfATP4-associated antimalarials","volume":"62","author":"Dennis","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0010","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1021\/cb500616x","article-title":"Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials","volume":"10","author":"Flannery","year":"2015","journal-title":"ACS Chem Biol"},{"key":"2022053122495254000_CIT0011","first-page":"e0154166.11","article-title":"Evidence of a mild mutator phenotype in Cambodian Plasmodium falciparum malaria parasites","volume":"11","author":"Lee","year":"2016","journal-title":"PLoS One"},{"key":"2022053122495254000_CIT0012","doi-asserted-by":"crossref","first-page":"e01423","DOI":"10.1128\/AAC.01423-20","article-title":"Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood stage Plasmodium falciparum","volume":"65","author":"McCarthy","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0013","doi-asserted-by":"crossref","first-page":"378","DOI":"10.4269\/ajtmh.19-0846","article-title":"Liver enzyme elevations in plasmodium falciparum volunteer infection studies: findings and recommendations","volume":"103","author":"Chughlay","year":"2020","journal-title":"Am J Trop Med Hyg"},{"key":"2022053122495254000_CIT0014","author":"World Health Organization."},{"key":"2022053122495254000_CIT0015","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature12876","article-title":"A molecular marker of artemisinin-resistant Plasmodium falciparum malaria","volume":"505","author":"Ariey","year":"2014","journal-title":"Nature"},{"key":"2022053122495254000_CIT0016","first-page":"e01500","article-title":"Critical evaluation of molecular monitoring in malaria drug efficacy trials and pitfalls of length-polymorphic markers","volume":"61","author":"Messerli","year":"2016","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122495254000_CIT0017","volume-title":"Guideline for the treatment of malaria","author":"World Health Organization.","year":"2015","edition":"3"},{"key":"2022053122495254000_CIT0018","article-title":"High prevalence of P. falciparum K13 mutations in Rwanda is associated with slow parasite clearance after treatment with artemether-lumefantrine","author":"Straimer","journal-title":"J Infect Dis"},{"key":"2022053122495254000_CIT0019","volume-title":"Report on antimalarial drug efficacy, resistance and response: 10 years of surveillance (2010\u20132019)","author":"World Health Organization.","year":"2020"},{"key":"2022053122495254000_CIT0020","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N Engl J Med"},{"key":"2022053122495254000_CIT0021","author":"World Health Organization."},{"key":"2022053122495254000_CIT0022","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/S1473-3099(21)00142-0","article-title":"Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study","volume":"21","author":"Uwimana","year":"2021","journal-title":"Lancet Infect Dis"},{"key":"2022053122495254000_CIT0023","first-page":"CD000256","article-title":"Artemisinin derivatives for treating uncomplicated malaria","volume":"2","author":"McIntosh","year":"2000","journal-title":"Cochrane Database Syst Rev"},{"key":"2022053122495254000_CIT0024","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1056\/NEJMoa1602250","article-title":"Antimalarial activity of KAF156 in falciparum and vivax malaria","volume":"375","author":"White","year":"2016","journal-title":"N Engl J Med"},{"key":"2022053122495254000_CIT0025","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.pt.2021.04.006","article-title":"Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials","volume":"37","author":"Duffey","year":"2021","journal-title":"Trends Parasitol"},{"key":"2022053122495254000_CIT0026","doi-asserted-by":"crossref","first-page":"E5455","DOI":"10.1073\/pnas.1414221111","article-title":"(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium","volume":"111","author":"Jim\u00e9nez-D\u00edaz","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022053122495254000_CIT0027","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/S1473-3099(19)30611-5","article-title":"Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a\/b trial","volume":"20","author":"Gaur","year":"2020","journal-title":"Lancet Infect Dis"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciab716\/40833831\/ciab716.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/74\/10\/1831\/43893666\/ciab716.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/74\/10\/1831\/43893666\/ciab716.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T18:53:27Z","timestamp":1654023207000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/74\/10\/1831\/6354946"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,8,19]]},"published-print":{"date-parts":[[2022,5,30]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciab716","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5,15]]},"published":{"date-parts":[[2021,8,19]]}}}