Session Type: Poster Session B
Session Time: 8:30AM-10:30AM
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 (Cmax) 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 Cmax 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.
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.
To cite this abstract in AMA style:Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, Patel A, Shen J, Girgis I, Banerjee S, Throup J. Selective Inhibition of Tyrosine Kinase 2 with Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/selective-inhibition-of-tyrosine-kinase-2-with-deucravacitinib-compared-with-janus-kinase-1-2-3-inhibitors/. Accessed September 26, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibition-of-tyrosine-kinase-2-with-deucravacitinib-compared-with-janus-kinase-1-2-3-inhibitors/