Molecular and clinical effects of selective TYK2 inhibition with deucravacitinib in psoriasis.

ABSTRACT Background Psoriasis, a chronic inflammatory disease dependent on the interleukin (IL)-23/T helper cell 17 (Th17) pathway, is initiated through plasmacytoid dendritic cell activation and type I interferon induction in the skin. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, blocks IL-23, IL-12, and type I interferon signaling in cellular assays. Objective Investigate changes in IL-23/Th17- and type I interferon-pathway biomarkers and gene responses, and 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. Biopsies from non-lesional (Day 1) and lesional skin (Days 1, 15, and 85) were assessed for changes in IL-23/IL-12 and type I interferon pathway biomarkers by quantitative reverse-transcription polymerase chain reaction, RNA sequencing, and immunohistochemistry. Laboratory markers were measured in blood. Percent change from baseline in Psoriasis Area and Severity Index (PASI) score was assessed. Results IL-23 pathway biomarkers in lesional skin returned toward non-lesional levels dose-dependently with deucravacitinib. Interferon and IL-12 pathway genes were normalized. Markers of keratinocyte dysregulation, keratin-16, and β-defensin genes approached non-lesional levels with effective dosages. Select laboratory parameters impacted by JAK1–3 inhibition were unaffected by deucravacitinib. Greater improvements in PASI scores, correlated with biomarker changes, were seen with the highest dosages of deucravacitinib versus lower dosages or placebo. Conclusion Robust clinical efficacy with deucravacitinib treatment was associated with decreases in IL-23/Th17 and interferon pathway biomarkers. The lack of effect seen on biomarkers specific to JAK1–3 inhibition support selectivity of deucravacitinib for TYK2; larger studies are needed to further confirm.