Pharmacodynamic Response to Deucravacitinib, an Oral, Selective, Allosteric TYK2 Inhibitor, in a Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled Psoriasis Trial

Abstract

Background: Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23-driven T-helper (Th)17 pathways play a key role in chronic inflammation in psoriasis. In a phase 2 trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 and type-I interferon pathway expression in the skin of patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement of psoriatic lesions.

Objectives: The aim of this study was to identify biomarkers of psoriatic disease in serum from patients enrolled in the phase 2 trial and to assess the effects of deucravacitinib on those biomarkers.

Methods: Serum biomarkers from Olink proteomics and other quantitative assays were evaluated for a pharmacodynamic response to deucravacitinib treatment and correlation with psoriasis disease activity measures.

Results: Serum biomarkers associated with the IL-23/Th17 pathway [IL-17A, IL-17C, IL-19, IL-20, beta-defensin, and peptidase inhibitor 3 (PI3)] were upregulated in patients with psoriasis versus healthy controls. Deucravacitinib treatment reduced IL-17A (adjusted mean change from baseline at Day 85; 12 mg once daily versus placebo; -0.240 versus -0.067), IL-17C (-14.850 versus -1.664), IL-19 (-96.445 versus -8.119), IL-20 (-0.265 versus -0.064), beta-defensin (-65,025.443 versus -7553.961), and PI3 (-14.005 versus -1.360) expression. Reductions in serum biomarker expression occurred in a dose- and time-dependent manner, with significant reductions from baseline seen with deucravacitinib doses ≥ 3 mg twice daily (P ≤ 0.05). Biomarker expression correlated with disease activity measures such as Psoriasis Area and Severity Index (PASI) at baseline. Biomarker expression also correlated with PASI scores at Week 12.

Conclusion: IL-23/Th17 pathway expression in the serum of patients with psoriasis is an indicator of disease activity and response to deucravacitinib treatment.

Trial registration number: NCT02931838.

Keywords: Cytokine; Deucravacitinib; Pharmacodynamics; Psoriasis; Tyrosine kinase 2.

Fig. 1

Proteins differentially expressed at baseline in serum from patients with psoriasis compared with healthy controls. Serum biomarker expression at baseline was compared in patients with psoriasis and in healthy controls using Olink proteomics technology. The Olink proteomics analysis evaluated 276 serum biomarkers in three cardiovascular disease and inflammation panels (Olink Cardiovascular II, Olink Cardiovascular III, and Olink Inflammation). a Cardiovascular II: there were five upregulated proteins [(log₂FC > 0): GH, CCL17, IL-6, FABP2, KIM1; none were significant] and 87 down-regulated proteins [(log₂FC < 0); 71 were significant (adjusted P < 0.05)] in patients with psoriasis compared with healthy controls. b Cardiovascular III: there were six up-regulated proteins (Ep-CAM, IGFBP-1, LDL receptor, PI3, SCGB3A2, SELE; PI3 was significant) and 86 down-regulated proteins (77 were significant). c Inflammation: there were 11 upregulated proteins (IL-17A, IL-17C, CASP-8, CCL20, IL-1α, MCP-3, IL-20, IL-24, CCL19, CXCL9, and CDCP1; five were significant) and 81 down-regulated proteins (60 were significant). Upregulated proteins are shown in red and down-regulated proteins are shown in blue. AMPs antimicrobial peptides, CCL chemokine ligand, IFN interferon, IL interleukin, JAK Janus kinase, mDC myeloid dendritic cell, pDC plasmacytoid dendritic cell, PI3 peptidase inhibitor 3, PMNs polymorphonuclear leukocytes, PsO patients with psoriasis, Th T helper, TNF tumor necrosis factor

Fig. 2

Serum biomarker expression at baseline in patients with psoriasis and in healthy controls and in patients with psoriasis receiving deucravacitinib treatment over 12 weeks. a IL-17A and IL-17C. b IL-19 and IL-20. c beta-defensin and PI3. *P < 0.05 versus Day 1. ^†P < 0.05 versus placebo; ^‡P < 0.01 versus Day 1; ^§P < 0.01 versus placebo; ^#P < 0.001 versus Day 1; ^¶P < 0.001 versus placebo; obtained from mixed-effects model. BID twice daily, DEUC deucravacitinib, IL interleukin, LOD limit of detection, NPX normalized protein expression, PI3 peptidase inhibitor 3, PsO patients with psoriasis, QC quality control, QD every day, QOD every other day, SE standard error

Fig. 3

IL-17A expression at baseline in patients with psoriasis and in healthy controls and in patients with psoriasis receiving deucravacitinib treatment over 12 weeks. a IL-17A. b Correlation of IL-17A between Simoa and Olink. ^*P < 0.05 versus Day 1; ^†P < 0.05 versus placebo; ^‡P < 0.01 versus Day 1; ^§P < 0.01 versus placebo; ^#P < 0.001 versus Day 1; ^¶P < 0.001 versus placebo; obtained from mixed-effects model. BID twice daily, IL interleukin, LOD limit of detection, NPX normalized protein expression, QD every day, QOD every other day, Simoa single molecule array

Fig. 4

Correlation between serum biomarker expression and PASI and BSA involvement at baseline and during treatment. a IL-17A. b IL-19. c Beta-defensin. d PI3. BSA body surface area, IL interleukin, PASI Psoriasis Area and Severity Index, PI3 peptidase inhibitor 3

Fig. 5

Correlation between serum biomarker expression and PASI at Week 12. a IL-17A. b IL-19. c beta-defensin. d PI3. Dashed line indicates the upper limit of the 95% confidence interval for healthy controls: IL-19, 16.05; BD2, 2799.83; PI3, 6.22. BID twice daily, IL interleukin, NPX normalized protein expression, PASI Psoriasis Area and Severity Index, PASI 25/50/75/90/100  ≥ 25/50/75/90/100% reduction from baseline in PASI, PI3 peptidase inhibitor 3, QD every day, QOD every other day