{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:13:10Z","timestamp":1793283190901,"version":"4.5.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:p>\n                    For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)\u201017A may represent a convenient alternative to IL\u201017A\u2010targeting monoclonal antibodies. This first\u2010in\u2010human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL\u201017A target engagement profile of single or multiple oral doses of the small molecule IL\u201017A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10\u20132,000\u2009mg) or multiple ascending dose (MAD; dose range 100\u20131,000\u2009mg daily for 14\u2009days) cohorts. The study enrolled 91 participants (SAD,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200951 and MAD,\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200940) aged 21\u201365\u2009years (71% men). LY3509754 had a time to maximum concentration (\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) of 1.5\u20133.5\u2009hours, terminal half\u2010life of 11.4\u201319.1\u2009hours, and exhibited dose\u2010dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL\u201017A levels within 12\u2009hours of dosing. Four participants from the 400\u2010mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091) and 1,000\u2010mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset \u2265\u200912\u2009days post\u2010last LY3509754 dose), consistent with drug\u2010induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte\u2010rich, moderate\u2010to\u2010severe lobular inflammation. We theorize that the DILI relates to an off\u2010target effect rather than IL\u201017A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once\u2010daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3185","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T06:50:30Z","timestamp":1706683830000},"page":"1152-1161","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of\n                    <scp>IL\u201017A<\/scp>\n                    (\n                    <scp>LY3509754<\/scp>\n                    ): A Phase I Randomized Placebo\u2010Controlled Study"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2365-5360","authenticated-orcid":false,"given":"Amita","family":"Datta\u2010Mannan","sequence":"first","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Regev","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-5623","authenticated-orcid":false,"given":"David E.","family":"Coutant","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Dropsey","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Foster","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Bracknell Berkshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9967-3868","authenticated-orcid":false,"given":"Spencer","family":"Jones","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Poorbaugh","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan","family":"Wang","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Woodman","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.021"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00746-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00184-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-018-8702-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2147\/ITT.S240891"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01682"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.36849\/JDD.2020.4645"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314258"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60125-8"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2019.1554053"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2147\/PPA.S242336"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.16746"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3003"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e8346"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-017-0709-1"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40257-022-00720-0"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2021.128229"},{"key":"e_1_2_9_18_1","unstructured":"U.S. Food and Drug Administration.Bioanalytical Method Validation: Guidance for Industry. <https:\/\/www.fda.gov\/media\/70858\/download> (2018). 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