{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:03:04Z","timestamp":1792000984724,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T00:00:00Z","timestamp":1699920000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007013","name":"F. Hoffmann-La Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The NLRP3 inflammasome drives release of pro\u2010inflammatory cytokines including interleukin (IL)\u20101\u03b2 and IL\u201018 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo\u2010controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL\u20101\u03b2 inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Selnoflast was well\u2010tolerated. Plasma concentrations increased rapidly after oral administration, reaching T\n                      <jats:sub>max<\/jats:sub>\n                      1\u00a0h post\u2010dose. Mean plasma concentrations stayed above the IL\u20101\u03b2 IC\n                      <jats:sub>90<\/jats:sub>\n                      level throughout the dosing interval (mean C\n                      <jats:sub>trough<\/jats:sub>\n                      on Day 1 and Day 5: 2.55\u00a0\u03bcg\/mL and 2.66\u00a0\u03bcg\/mL, respectively). At steady state, post\u2010dose selnoflast concentrations in sigmoid colon (5\u201020\u00a0\u03bcg\/g) were above the IC\n                      <jats:sub>90<\/jats:sub>\n                      . Production of IL\u20101\u03b2 was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL\u201018 levels. There were no meaningful differences in the expression of an IL\u20101\u2010related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Selnoflast was safe and well\u2010tolerated. Selnoflast 450\u00a0mg QD achieved plasma and tissue exposure predicted to maintain IL\u20101\u03b2 IC\n                      <jats:sub>90<\/jats:sub>\n                      over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL\u20101\u03b2 in tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ISRCTN16847938<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.1471","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T06:24:53Z","timestamp":1699943093000},"source":"Crossref","is-referenced-by-count":68,"title":["A randomized, double\u2010blind phase 1b study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of the NLRP3 inhibitor selnoflast in patients with moderate to severe active ulcerative colitis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4506-7264","authenticated-orcid":false,"given":"Barbara","family":"Klughammer","sequence":"first","affiliation":[{"name":"F. 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