{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:26:25Z","timestamp":1788459985791,"version":"build-2803163510"},"reference-count":32,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"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":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>ESK\u2010001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune\u2010mediated diseases. In 2 phase I studies, a first\u2010in\u2010human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple\u2010dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK\u2010001 in healthy participants using a randomized, double\u2010blind, placebo\u2010controlled study design. ESK\u2010001 was rapidly absorbed with systemic exposures generally increasing dose\u2010proportionally across all cohorts. The mean terminal half\u2010life ranged from 8 to 13\u2009h with no to minimal accumulation of ESK\u2010001 following q.d. doses and ~2\u2010fold accumulation following Q12 doses. Less than 1% of unchanged ESK\u2010001 was eliminated in urine. ESK\u2010001 inhibited the downstream TYK2 pathway as shown by inhibition of pSTAT1 expression. Transcriptomic analysis of unstimulated whole blood samples confirmed dose\u2010dependent inhibition of Type I IFN\u2010induced genes and <jats:italic>SIGLEC1<\/jats:italic>, a novel TYK2\u2010responsive biomarker. By correlating PK exposure data with PD readouts, a strong PK\/PD relationship was demonstrated. There were no deaths, serious treatment\u2010emergent adverse events (TEAEs), nor severe TEAEs, and most TEAEs were mild in severity. In conclusion, ESK\u2010001 was generally safe and well\u2010tolerated in healthy participants, showed linear dose\u2010dependent PK characteristics, and maximally inhibited TYK2\u2010dependent pathways with a predictable concentration\u2010dependent PK\/PD relationship. These findings were used to select the dose range of ESK\u2010001 for the STRIDE phase II trial in plaque psoriasis and to support further clinical development of ESK\u2010001 in other TYK2\u2010mediated diseases.<\/jats:p>","DOI":"10.1111\/cts.70094","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T06:40:52Z","timestamp":1732776052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitor\u00a0ESK\u2010001 using a randomized, double\u2010blind, placebo\u2010controlled study design"],"prefix":"10.1111","volume":"17","author":[{"given":"Sibel","family":"Ucpinar","sequence":"first","affiliation":[{"name":"Alumis Inc  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce 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