First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2
Abstract 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 (...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13435 |
| _version_ | 1828063179774623744 |
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| author | Ian M. Catlett Urvi Aras Lars Hansen Yali Liu Di Bei Ihab G. Girgis Bindu Murthy |
| author_facet | Ian M. Catlett Urvi Aras Lars Hansen Yali Liu Di Bei Ihab G. Girgis Bindu Murthy |
| author_sort | Ian M. Catlett |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-10T22:39:07Z |
| format | Article |
| id | doaj.art-160d05762f494727925f54c50e945cba |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-10T22:39:07Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-160d05762f494727925f54c50e945cba2023-01-16T08:07:54ZengWileyClinical and Translational Science1752-80541752-80622023-01-0116115116410.1111/cts.13435First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2Ian M. Catlett0Urvi Aras1Lars Hansen2Yali Liu3Di Bei4Ihab G. Girgis5Bindu Murthy6Bristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USAAbstract 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.https://doi.org/10.1111/cts.13435 |
| spellingShingle | Ian M. Catlett Urvi Aras Lars Hansen Yali Liu Di Bei Ihab G. Girgis Bindu Murthy First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 Clinical and Translational Science |
| title | First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 |
| title_full | First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 |
| title_fullStr | First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 |
| title_full_unstemmed | First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 |
| title_short | First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2 |
| title_sort | first in human study of deucravacitinib a selective potent allosteric small molecule inhibitor of tyrosine kinase 2 |
| url | https://doi.org/10.1111/cts.13435 |
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