BACKGROUND: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. METHODS: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). FINDINGS: . INTERPRETATION: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. FUNDING: Cadila Healthcare and Medicines for Malaria Venture.
| Authors | Barber, Bridget E; Fernandez, Melissa; Patel, Hardik Babubhai; Barcelo, Catalina; Woolley, Stephen D; Patel, Harilal; Llewellyn, Stacey; Abd-Rahman, Azrin N; Sharma, Sunil; Jain, Mukul; Ghoghari, Ashok; Di Resta, Ilaria; Fuchs, Aline; Deni, Ioanna; Yeo, Tomas; Mok, Sachel; Fidock, David A; Chalon, Stephan; Möhrle, Jörg J; Parmar, Deven; McCarthy, James S; Kansagra, Kevinkumar |
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| Journal | The Lancet. Infectious diseases |
| Pages | 879-890 |
| Volume | 22 |
| Date | 1/01/2022 |
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| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/S1473-3099(21)00679-4 |