{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:13:06Z","timestamp":1790197986324,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The NLRP3 inflammasome is a central mediator of innate immunity and a key driver of inflammatory and neurodegenerative diseases. VENT\u201002 is orally bioavailable, central nervous system\u2010penetrant, selective small\u2010molecule inhibitor of NLRP3. This first\u2010in\u2010human, randomized, double\u2010blind, placebo\u2010controlled study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of VENT\u201002 freebase in healthy volunteers. The study consisted of single and multiple ascending dose phases, a food\u2010effect cohort, and a cerebrospinal fluid sampling cohort. VENT\u201002 was safe and well tolerated at single doses up to 1600\u2009mg and at multiple doses up to 200\u2009mg twice daily (b.i.d.), with only mild treatment\u2010related adverse events at these dose levels. At 400\u2009mg b.i.d., moderate treatment\u2010emergent adverse events occurred in 5 of 12 participants (41.7%). VENT\u201002 was rapidly absorbed in plasma, with a median\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    of 1.5\u20132.0\u2009h in fasted state and had a terminal half\u2010life of 10\u201314\u2009h at doses up to 500\u2009mg. Exposure was dose\u2010proportional up to 500\u2009mg, and a high\u2010fat, high\u2010calorie meal did not affect exposure significantly. VENT\u201002 demonstrated central nervous system penetration, with a cerebrospinal fluid\u2010to\u2010plasma unbound concentration ratio of 0.43. VENT\u201002 dose\u2010dependently inhibited release of IL\u20101\u03b2 and IL\u201018 ex\u00a0vivo in whole blood, with complete inhibition throughout the dosing interval at \u2265\u2009200\u2009mg b.i.d. VENT\u201002 also dose\u2010dependently attenuated IL\u20106 levels in plasma. In conclusion, 1 week of VENT\u201002 b.i.d. dosing was found to be safe and tolerable at doses achieving complete systemic NLPR3\u2010inhibition. These findings support further clinical development of VENT\u201002 in inflammatory and neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1111\/cts.70578","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:50:12Z","timestamp":1777607412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["First\u2010In\u2010Human Safety, Pharmacokinetics, and Pharmacodynamics of VENT\u201002 Freebase, a CNS\u2010Penetrant NLRP3 Inhibitor"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2663-3773","authenticated-orcid":false,"given":"Lisanne C. 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