POS0005 BASELINE BIOMARKERS PREDICT BETTER RESPONSES TO DEUCRAVACITINIB, AN ORAL, SELECTIVE TYROSINE KINASE 2 (TYK2) INHIBITOR, IN A PHASE 2 TRIAL IN PSORIATIC ARTHRITIS

Abstract

BackgroundDeucravacitinib (DEUC) is a novel, oral, selective TYK2 inhibitor with a unique allosteric mechanism of action that has demonstrated efficacy in patients with psoriasis (PsO)1 and psoriatic arthritis (PsA).2 TYK2 mediates signalling of select immune cytokines, eg, interleukin (IL) 23, IL-12, and Type I interferons, whereas the related Janus kinases (JAK) 1/2/3 mediate signalling of a wider array of cytokines and mediators involved in inflammatory, developmental, metabolic, and hematopoietic pathways. DEUC reduced inflammatory markers associated with skin and joint manifestations but did not result in laboratory abnormalities associated with inhibition of JAK1/2/3 in a PsA trial.3ObjectivesTo identify baseline biomarkers that predict response to DEUC in patients with PsA.MethodsThe double-blind Phase 2 trial (NCT03881059) enrolled 203 patients with PsA randomised 1:1:1 to placebo (PBO), DEUC 6 mg once daily (QD), or 12 mg QD.2 Molecular profiling of baseline serum samples was performed by immunoassays. Clinical response at Week 16 was measured by ≥20% improvement from baseline in American College of Rheumatology Improvement Criteria (ACR 20) and ≥75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) scores.ResultsBiomarkers of the IL-23/T helper cell type 17 pathway, including IL-17A, IL-17‒induced β-defensin 2 (BD2), and IL-19, were associated with higher PASI but not Psoriatic Arthritis Disease Activity Scores overall at baseline. PASI 75 responders in DEUC-treated groups had higher baseline levels of IL-17A compared with nonresponders. In contrast, PASI 75 responders in PBO-treated patients had lower baseline expression of IL-17A, BD2, and IL-19 compared with nonresponders. In patients treated with DEUC 12 mg QD, greater reductions in BD2 were observed in the PASI 75 responder group compared with nonresponder group. When patients were dichotomised by median baseline biomarker level, higher clinical responses in both PASI 75 and ACR 20 were achieved in those with higher baseline overall biomarker levels in the DEUC-treated groups compared with the PBO group. Higher baseline expression of IL-23 biomarkers IL-17A, IL-19, and BD2 enriched ACR 20 response in patients treated with DEUC compared with PBO (OR=5.64, 6.68, and 4.99, respectively). While greater benefit was observed in high-biomarker groups, the low-biomarker populations still manifested clinical responses although not significant (Figure 1).ConclusionPatients who had higher expression of IL-23 pathway biomarkers were more likely to benefit from DEUC compared with placebo in skin and joint manifestations of PsA. These results reinforce the value of TYK2 inhibition in patients with IL-23‒mediated diseases. The potential value of IL-23-pathway markers in predicting higher responses to DEUC should be further explored in larger trials.