{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:02:08Z","timestamp":1790654528215,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0014181","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000}}],"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GSK","award":["NCT04504435"],"award-info":[{"award-number":["NCT04504435"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"\n Background<\/jats:title>\n \n Visceral leishmaniasis (VL) is a neglected tropical disease caused by kinetoplastid parasites. If left untreated, VL has a case fatality >90%, making treatment essential for patient survival. Existing therapies have several limitations that impact treatment outcomes, including toxicity, requirement for parenteral administration, long treatment duration, and development of parasite resistance, driving the need for newer therapies. This Phase 1 first-time-in-human study evaluated the tolerability, safety, and pharmacokinetics (PK) of GSK3494245, a novel highly selective\n Leishmania<\/jats:italic>\n kinetoplastid proteasome inhibitor.\n <\/jats:p>\n <\/jats:sec>\n \n Methodology<\/jats:title>\n This was a randomized, double-blind, placebo-controlled, single ascending dose study evaluating the oral administration of GSK3494245 in healthy participants aged 18 to \u226455 years (NCT04504435). The study was conducted at a single center in the United Kingdom between October 2020 and January 2024.<\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n GSK3494245 had an acceptable safety profile following administration of single doses of up to 240\u2009mg in healthy male participants. All adverse events (AEs) were considered resolved or recovered, with most AEs being of mild or moderate severity. One serious AE of mild tachycardia was reported. The increase in exposure was slightly more than dose-proportional and approximately proportional under fasted and fed conditions, respectively. The median time to reach the maximum plasma concentration (C\n max<\/jats:sub>\n ) ranged from 0.50 to 1.79 hours, and the geometric mean of the elimination half-life ranged from 1.04 to 2.27 hours. Two participants met the C\n max<\/jats:sub>\n stopping criterion.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n GSK3494245 showed an acceptable safety profile over the dose range studied. However, based on its observed PK profile, GSK3494245 is unlikely to achieve the effective dose while ensuring safe exposure within the once- or twice-daily monotherapy target product profile recommended by the Drugs for Neglected Diseases initiative.<\/jats:p>\n <\/jats:sec>\n \n Clinical Trial Registration<\/jats:title>\n \n NCT Number (\n www.clinicaltrials.gov<\/jats:ext-link>\n ): NCT04504435\n <\/jats:p>\n \n EudraCT, CTIS<\/jats:bold>\n : 2019-004492-39\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pntd.0014181","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:46:57Z","timestamp":1778694417000},"page":"e0014181","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety and pharmacokinetics of GSK3494245, a highly selective Leishmaniasis kinetoplastid proteasome inhibitor for the treatment of visceral leishmaniasis: A Phase 1, randomized, single ascending dose escalation study in healthy participants"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9494-5720","authenticated-orcid":true,"given":"Mischka","family":"Moodley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michalis","family":"Kostapanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Iavarone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marguerite","family":"Bracher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia M.","family":"Lavezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Davy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya","family":"Bhat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hema","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel K.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Miles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"pntd.0014181.ref001","doi-asserted-by":"crossref","first-page":"102999","DOI":"10.1016\/j.parint.2024.102999","article-title":"Epidemiology of Leishmaniasis: Risk factors for its pathology and infection","volume":"105","author":"H Kato","year":"2025","journal-title":"Parasitol Int"},{"key":"pntd.0014181.ref002","unstructured":"WHO. 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