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Randomized Controlled Trial
. 2023 Jan;16(1):151-164.
doi: 10.1111/cts.13435. Epub 2022 Nov 22.

First-in-human study of deucravacitinib: A selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2

Ian M Catlett  1 , Urvi Aras  1 , Lars Hansen  1 , Yali Liu  1 , Di Bei  1 , Ihab G Girgis  1 , Bindu Murthy  1
Affiliations
Randomized Controlled Trial

First-in-human study of deucravacitinib: A selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2

Ian M Catlett et al. Clin Transl Sci. 2023 Jan.

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.

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Conflict of interest statement

I.M.C., U.A., I.G.G., and B.M. are employees of Bristol Myers Squibb and receive salaries and stock commensurate with employment. L.H., Y.L., and D.B. were employees of Bristol Myers Squibb at the time this research was conducted.

Figures

FIGURE 1
FIGURE 1
Pharmacokinetics of deucravacitinib in healthy subjects (a) over 24 h following administration of a single‐dose and (b) over one dosing interval at steady‐state on day 12 following multiple‐doses. Lower limit of quantitation = 0.200 ng/ml. Error bars represent SD. BD, twice daily; QD, once daily; SD, standard deviation. Panel (b) was previously presented at EULAR 2017 (poster SAT0226); copyright the authors.
FIGURE 2
FIGURE 2
(a) Mean IFNγ production over time following stimulation with IL‐12 (plus IL‐18 adjuvant; single‐ascending dose cohort). (b) Relationship between target engagement, measured as inhibition of IL‐12/IL‐18–mediated IFNγ production, and steady‐state plasma concentration of deucravacitinib (multiple‐ascending dose cohort). Adjusted concentration is shown as a three‐fold dilution of the blood sample was performed prior to ex vivo stimulation. IFN, interferon; IL, interleukin. Panel b has been adapted from a figure that was previously presented at EULAR 2017 (poster SAT0226); copyright the authors.
FIGURE 3
FIGURE 3
Deucravacitinib inhibition of IFN‐regulated gene expression after IFNα‐2a challenge, based on an aggregated panel of 52 selected genes. (a) Mean percentage of inhibition, (b) Median percentage of inhibition. Error bars represent standard error of the mean. BID, twice daily; IFN, interferon; QD, once daily. Previously presented at EULAR 2017 (poster SAT0226); copyright the authors.
FIGURE 4
FIGURE 4
Changes in lymphocyte count upon in vivo IFNα‐2a challenge. Error bars represent standard error of the mean. BID, twice daily; IFN, interferon; QD, once daily. Previously presented at EULAR 2017 (poster SAT0226); copyright the authors.
See this image and copyright information in PMC

References

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