First‐in‐human study of deucravacitinib: A selective, potent, allostericsmall‐molecule inhibitor of tyrosine kinase 2
Autor: | Ian M. Catlett, Urvi Aras, Lars Hansen, Yali Liu, Di Bei, Ihab G. Girgis, Bindu Murthy |
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Rok vydání: | 2022 |
Předmět: | |
Zdroj: | Clinical and Translational Science. 16:151-164 |
ISSN: | 1752-8062 1752-8054 |
DOI: | 10.1111/cts.13435 |
Popis: | This randomized, double-blind, single- and multiple-ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small-molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half-life of 8-15 h, and 1.4-1.9-fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)-12/IL-18-induced interferon (IFN)γ production ex vivo in a dose- and concentration-dependent manner. Following in vivo challenge with IFNα-2a, deucravacitinib demonstrated dose-dependent inhibition of lymphocyte count decreases and expression of 53 IFN-regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first-in-human study, deucravacitinib inhibited IL-12/IL-23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune-mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus. |
Databáze: | OpenAIRE |
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