Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis.

Abstract

BACKGROUND:

Psoriasis, a chronic inflammatory disease dependent on the IL-23/TH17 pathway, is initiated through plasmacytoid dendritic cell activation and type I IFN induction in the skin. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, blocks IL-23, IL-12, and type I IFN signaling in cellular assays.

OBJECTIVE:

We investigated changes in IL-23/TH17 and type I IFN pathway biomarkers and gene responses as well as measures of selectivity for TYK2 over Janus kinases (JAKs) 1-3 in patients with moderate to severe psoriasis receiving deucravacitinib.

METHODS:

Deucravacitinib was evaluated in a randomized, placebo-controlled, dose-ranging trial. Biopsy samples from nonlesional (day 1) and lesional skin (days 1, 15, and 85) were assessed for changes in IL-23/IL-12 and type I IFN pathway biomarkers by quantitative reverse-transcription polymerase chain reaction, RNA sequencing, and immunohistochemistry. Laboratory markers were measured in blood. Percentage change from baseline in Psoriasis Area and Severity Index (PASI) score was assessed.

RESULTS:

IL-23 pathway biomarkers in lesional skin returned toward nonlesional levels dose-dependently with deucravacitinib. IFN and IL-12 pathway genes were normalized. Markers of keratinocyte dysregulation, keratin-16, and β-defensin genes approached nonlesional levels with effective doses. Select laboratory parameters affected by JAK1-3 inhibition were not affected by deucravacitinib. Greater improvements in PASI scores, correlated with biomarker changes, were seen with the highest doses of deucravacitinib versus lower doses or placebo.

CONCLUSION:

Robust clinical efficacy with deucravacitinib treatment was associated with decreases in IL-23/TH17 and IFN pathway biomarkers. The lack of effect seen on biomarkers specific to JAK1-3 inhibition supports selectivity of deucravacitinib for TYK2; larger confirmatory studies are needed.

• Authors: Ian M Catlett, Yanhua Hu, Lu Gao, Subhashis Banerjee, Kenneth Gordon, James G Krueger
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 149 Issue 6 Pg. 2010-2020.e8 (06 2022) ISSN: 1097-6825 [Electronic] United States
• PMID: 34767869 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Heterocyclic Compounds
• Interferon Type I
• Interleukin-23
• Interleukin-12
• TYK2 Kinase
• deucravacitinib

Topics

• Biomarkers (metabolism)
• Heterocyclic Compounds (therapeutic use)
• Humans
• Interferon Type I
• Interleukin-12
• Interleukin-23
• Psoriasis (metabolism)
• TYK2 Kinase (antagonists & inhibitors)