Effect of novel antimalarial ZY-19489 on Plasmodium falciparum viability in a volunteer infection study

Bridget E Barber and colleagues1Barber BE Fernandez M Patel HB et al.Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.Lancet Infect Dis. 2022; 22: 879-890Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar published a first-in-human study of the antimalarial activity of ZY-19489, a novel triaminopyrimidine, in healthy volunteers. In this study, rapid initial parasite clearance, with a half-life of approximately 7 h, occurred in all 15 participants after administration of a single dose of either 200 mg, 300 mg, or 900 mg, with the rate of initial clearance being dose-independent. This observation suggests that the maximal killing rate might saturate at doses as low as 200 mg. However, we have previously shown that parasite clearance, as measured by quantitative PCR (qPCR), might not fully capture the parasite killing activity of antimalarial drugs.2Rebelo M Pawliw R Gower J et al.Parasite viability as a superior measure of antimalarial drug activity in humans.J Infect Dis. 2021; 223: 2154-2163Crossref PubMed Scopus (5) Google Scholar Previously, we developed a method to assess parasite viability after in-vivo exposure to an antimalarial drug,2Rebelo M Pawliw R Gower J et al.Parasite viability as a superior measure of antimalarial drug activity in humans.J Infect Dis. 2021; 223: 2154-2163Crossref PubMed Scopus (5) Google Scholar which was used to compare total circulating parasite number (traditionally measured by microscopy or PCR) with viable parasite number (measured by an ex-vivo viability assay) in another volunteer infection study.3Watts RE Odedra A Marquart L et al.Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: a randomised volunteer infection study.PLoS Med. 2020; 17e1003203 Crossref PubMed Google Scholar Our analysis revealed that parasites are rendered non-viable by artesunate more rapidly than previously thought,2Rebelo M Pawliw R Gower J et al.Parasite viability as a superior measure of antimalarial drug activity in humans.J Infect Dis. 2021; 223: 2154-2163Crossref PubMed Scopus (5) Google Scholar suggesting that measuring circulating parasite number and its decline after drug administration (referred to as parasite clearance) alone might not accurately assess in-vivo drug activity.4Hastings IM Kay K Hodel EM How robust are malaria parasite clearance rates as indicators of drug effectiveness and resistance?.Antimicrob Agents Chemother. 2015; 59: 6428-6436Crossref PubMed Scopus (50) Google Scholar, 5Khoury DS Zaloumis SG Grigg MJ Haque A Davenport MP Malaria parasite clearance: what are we really measuring?.Trends Parasitol. 2020; 36: 413-426Summary Full Text Full Text PDF PubMed Scopus (8) Google Scholar In a similar exploratory analysis of the ZY-19489 study by Barber and colleagues,1Barber BE Fernandez M Patel HB et al.Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.Lancet Infect Dis. 2022; 22: 879-890Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar we investigated parasite viability using samples from nine participants given a single dose of either 200 mg (n=2), 300 mg (n=5), or 900 mg (n=2) of oral ZY-19489 (appendix). The mean half-lives of viable parasites were 3·7 h (95% CI 2·8–4·5) for 200 mg and 2·3 h (1·7–3·0) for 300 mg (appendix). Parasite viability half-life was too rapid to be accurately assessed in both participants dosed with 900 mg, but the half-life was observed to be less than 0·7 h (appendix). These half-lives are substantially shorter than the traditional parasite clearance half-lives measured by qPCR. Moreover, by contrast to the absence of an exposure effect on traditional parasite clearance half-life (r=0·15; p=0·71; Spearman's test), we observed a strong correlation (albeit of marginal significance) between the rate of decline of parasite viability and peak in-vivo drug concentration (r=–0·75; p=0·066) in participants dosed with 200 mg or 300 mg (appendix). Participants who were given 900 mg had viable parasite concentrations less than the level of detection and were thus excluded from this analysis (appendix). In conclusion, measuring parasite viability rather than parasite clearance, we observed shorter half-lives and an exposure effect with the novel ZY-19489 antimalarial drug. These findings highlight the value of measuring parasite viability in early stage drug trials; the clinical implications should be investigated in field clinical trials. KK is employed by Cadila Healthcare. JJM is employed by the Medicines for Malaria Venture. All other authors declare no competing interests. GR and JG contributed equally. Cadila Healthcare and the Medicines for Malaria Venture funded the main clinical trial of ZY-19489, from which these exploratory data were obtained. The Medicines for Malaria Venture is supported by a grant from the Bill & Melinda Gates Foundation (grant number INV-007155). DSK and MR contributed equally to this Correspondence and share last authorship. Download .pdf (.36 MB) Help with pdf files Supplementary appendix Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection studyThe safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. Full-Text PDF