{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:21:58Z","timestamp":1791912118624,"version":"4.3.4"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Receptor\u2010interacting serine\/threonine kinase 1 (RIPK1) regulates inflammatory signaling and induces apoptosis and necroptosis. Pharmacological inhibition of RIPK1 kinase activity has demonstrated efficacy in animal models of neurodegenerative, autoimmune and inflammatory diseases. SIR9900 is a potent and selective novel small molecule RIPK1 inhibitor. This first\u2010in\u2010human, phase I, randomized, double\u2010blind, placebo\u2010controlled study evaluated the safety, pharmacokinetics, and pharmacodynamics of single (3\u2013200\u2009mg) and multiple (3\u201360\u2009mg daily for 10\u2009days) ascending oral doses of SIR9900 in healthy adult (18\u201364\u2009years,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200980) and elderly participants (\u2265\u200965\u2009years, multiple doses 30\u2009mg,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098). The study included a food effect component. Overall, SIR9900 was safe and well tolerated with no concerning dose\u2010dependent trends in safety observed. SIR9900 was rapidly absorbed with a plasma maximum concentration time (\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) of 3.0\u20134.0\u2009h and plasma half\u2010life (\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2<\/jats:sub>\n                    ) of 31.92\u201337.75\u2009h following single doses. Similar\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    and\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2<\/jats:sub>\n                    results were observed following multiple doses. Systemic exposure to SIR9900 increased in a dose\u2010proportional manner and was similar between adult and elderly participants. No appreciable food effect was observed. The cerebrospinal fluid to unbound plasma ratio was 1.15. A robust pharmacodynamic effect was demonstrated with approximately 90% peripheral target engagement at 3\u2009h post\u2010dose, and sustained RIPK1 inhibition over the 10\u2010day treatment period. The promising safety, pharmacokinetic, and pharmacodynamic profile of SIR9900 with central nervous system penetrating potential in healthy adult and elderly participants supports its further clinical development in patients with inflammatory and degenerative diseases, particularly in the central nervous system.\n                  <\/jats:p>","DOI":"10.1111\/cts.70151","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T12:39:06Z","timestamp":1739795946000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Safety, Pharmacokinetics and Target Engagement of a Novel Brain Penetrant\n                    <scp>RIPK1<\/scp>\n                    Inhibitor (\n                    <scp>SIR9900<\/scp>\n                    ) in Healthy Adults and Elderly Participants"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-9128","authenticated-orcid":false,"given":"Ofer Michael","family":"Gonen","sequence":"first","affiliation":[{"name":"Nucleus Network Pty Ltd  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2491-4348","authenticated-orcid":false,"given":"Tim","family":"Porter","sequence":"additional","affiliation":[{"name":"Avance Clinical Pty Ltd  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2929-8791","authenticated-orcid":false,"given":"Buwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Sironax Aus Pty Ltd (a Subsidiary of Sironax Ltd)  Sydney New South Wales 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