Background/Purpose: Deucravacitinib is a novel, oral, selective tyrosine kinase 2 (TYK2) inhibitor with a unique mechanism of action that has demonstrated efficacy in patients (pts) with psoriasis and PsA. TYK2 selectively mediates cytokine signaling restricted to specific inflammatory pathways (eg, IL-23, IL-12, and Type I interferons), whereas Janus kinase (JAK) 1/2/3 signaling is involved in broader immune responses, as well as in hematopoietic pathways and in lipid metabolism. Use of JAK1/2/3 inhibitors is associated with signature changes in laboratory variables in the blood. The current study assessed the effects of deucravacitinib on biomarkers of TYK2- vs JAK1/2/3–mediated pathways, as well as of joint disease, in patients with PsA.

Methods: A double-blind Phase 2 trial (NCT03881059) enrolled 203 pts with PsA randomized 1:1:1 to deucravacitinib 6 mg once daily (QD), 12 mg QD, or placebo (PBO).¹ Levels of biomarkers of interest and lymphocyte subsets in the blood were measured by immunoassays, flow cytometry, and standard methods from baseline (BL) through Week 16.

Results: BL serum concentrations of IL-23‒driven IL-17A and IL-17‒induced β-defensin 2 and IL-19 were elevated and significantly correlated with severity of skin involvement by Psoriasis Area and Severity Index scores (ρ≥0.4; P< 0.0001). Both deucravacitinib doses, but not PBO, reduced IL-17A, β-defensin 2 (Figure 1), and IL-19 over time. Serum levels of IFN-I‒driven chemokine ligand 9 (CXCL9) and CXCL10, and Type I/II IFN-inducible proteins, either remained stable or decreased after deucravacitinib treatment vs PBO. TNF-α levels remained stable in deucravacitinib-treated pts but increased in the PBO group. At BL, the neoepitope marker of Type IV collagen degradation mediated by MMPs (C4M) was positively associated with Psoriatic Arthritis Disease Activity Score (PASDAS; ρ=0.29; P< 0.0001). BL MMP3 concentrations showed modest and positive correlations with swollen joint count (ρ=0.24; P< 0.001), PASDAS (ρ=0.21; P< 0.01), and Disease Activity Index in Psoriatic Arthritis (ρ=0.19; P< 0.01). MMP3 (Figure 1) and C4M were suppressed in deucravacitinib- but not PBO-treated pts. NK cell counts remained stable and small increases in hemoglobin were observed after treatment with deucravacitinib (Figure 2). There were no clinically meaningful changes in mean levels of serum cholesterol, creatinine, neutrophils, and platelets over time with deucravacitinib treatment.

Conclusion: Deucravacitinib suppressed biomarkers of IL-23/IL-17 and IFN-I pathways concomitant with clinical symptom improvements in deucravacitinib-treated PsA pts. Joint damage is associated with an increase in MMP3, and suppression of C4M and MMP3 by deucravacitinib suggested an improvement in extracellular matrix turnover upon TYK2 pathway inhibition. Differentiation of deucravacitinib from JAK1/2/3 inhibitors was evidenced by the lack of adverse effects of deucravacitinib on hematologic and serum chemistry variables that are known to change with JAK1/2/3 inhibitors.

Reference: 1. Mease PJ et al. Presented at the 2020 ACR Convergence, American College of Rheumatology; Nov 5-9, 2020.