Background/Purpose: Deucravacitinib is a novel, oral, allosteric agent that selectively inhibits intracellular signaling by binding to the tyrosine kinase 2 (TYK2) pseudokinase domain rather than to the conserved active site in the kinase domain. The high functional selectivity for TYK2 versus other signaling tyrosine kinases has been confirmed in cell- and whole blood–based assays.¹ Kinase selectivity should provide a differentiated risk/benefit profile due to potent TYK2 inhibition and minimal activity against other kinases. In a 1-year, double-blind, Phase 2 trial (NCT03881059), deucravacitinib was efficacious and well tolerated versus placebo in patients with active PsA.² The objective of this analysis was to understand the selectivity profile of deucravacitinib for TYK2 versus Janus kinase (JAK) 1/2/3, compared with the approved JAK inhibitors tofacitinib (Tofa), upadacitinib (Upa), and baricitinib (Bari), at clinically relevant doses and plasma concentrations.

Methods: In vitro whole-blood assays were established to measure the activity of common intracellular pairings of signaling tyrosine kinases (JAK1/3, JAK2/2, and TYK2/JAK2). Deucravacitinib, Tofa, Upa, and Bari concentrations providing half-maximal inhibition (IC₅₀) of relevant signaling readouts were determined. Whole-blood IC₅₀ values were plotted against known pharmacokinetic profiles of these agents at doses evaluated in Phase 3 trials, including approved doses. Time durations when concentrations were greater than IC₅₀ and projected average daily inhibition were evaluated.

Results: At clinically relevant doses and exposures, deucravacitinib steady-state plasma concentrations were higher than the TYK2 whole-blood IC₅₀ for a considerable part (9–18 hours) of the day. The maximal plasma concentration (C_max) of deucravacitinib was 8- to 17-fold lower than the JAK1/3 whole-blood IC₅₀ and >48- to >102-fold lower than the JAK2/2 whole-blood IC₅₀, indicating lack of meaningful inhibition of JAK1/2/3 by deucravacitinib at clinically relevant doses. Average daily inhibition of TYK2 by deucravacitinib ranged from 50% to 69%. Tofa, Upa, and Bari exhibited varying degrees of daily average inhibition at steady-state against JAK1/3 (70%–94%) and JAK2/2 (23%–67%). Projected C_max values of Tofa, Upa, and Bari were 17- to 33-fold lower than TYK2 IC₅₀, indicating minimal or no meaningful inhibition of TYK2.

Conclusion: Deucravacitinib has high functional selectivity for TYK2 at clinically relevant doses and plasma concentrations. In contrast, Tofa, Upa, and Bari inhibit JAK1/2/3 to varying degrees but do not inhibit TYK2 at clinically relevant concentrations. These results indicate that deucravacitinib is a distinct class of signaling kinase inhibitor compared with JAK1/2/3 inhibitors. Studies in multiple immune-mediated inflammatory diseases including plaque psoriasis, psoriatic arthritis, lupus, and inflammatory bowel disease will further assess the safety and efficacy of deucravacitinib.

References:
1. Burke JR et al. Sci Transl Med. 2019;11:1-16.
2. Mease PJ et al. Presented at the 2020 ACR Convergence, American College of Rheumatology; Nov 5-9, 2020.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibition-of-tyrosine-kinase-2-with-deucravacitinib-compared-with-janus-kinase-1-2-3-inhibitors/