Pharmacodynamic analysis of the PAISLEY SLE trial of deucravacitinib in patients with SLE

Results from a pharmacodynamic analysis of the randomized, double-blind, placebo-controlled phase II PAISLEY SLE trial (NCT03252587), evaluating deucravacitinib in patients with active systemic lupus erythematosus (SLE), were published in Annals of the Rheumatic Diseases by Kahlenberg et al. Patients were randomized to receive deucravacitinib 3 mg twice daily (BID; n = 91), 6 mg BID (n = 93), 12 mg once daily (QD; n = 89), or placebo (n = 90). The aim of this analysis was to assess the effects of deucravacitinib on markers of tyrosine kinase 2 (TYK2)-mediated immune pathways and serological biomarkers.

Key data: At screening, 28 genes and 75 proteins were differentially expressed in patients with SLE vs healthy volunteers, with >1.5-fold change (adjusted p < 0.05). Deucravacitinib rapidly reduced IFN-α and IFN-λ protein levels by Week 2 (IFN-α: 12 mg QD, p < 0.05; IFN-λ: p < 0.001 across doses), with reductions sustained through Week 48 (IFN-α: p < 0.05–0.001 across doses; IFN-λ: p < 0.001 across doses). Deucravacitinib also reduced B-cell pathway markers including BAFF and CD338, anti-double-stranded DNA (dsDNA) antibody titers, and key chemokines and cytokines implicated in the pathophysiology of SLE, including CCL19, CXCL10, MCP-1, MCP-2, IL-18, and IL-2RA, while increasing complement 3 (C3) and C4 vs placebo. An IFN 5-gene signature (MX1, HERC5, IFIT1, RSAD2, and EIF2AK2) was identified and validated, classifying 78% of patients as IFN-high and 22% as IFN-low; deucravacitinib reduced IFN signature score in both groups.

Key learning: Deucravacitinib demonstrated broad suppression of IFN and B-cell pathway biomarkers in patients with SLE, supporting its potential to address diverse SLE phenotypes. Further evaluation is ongoing in the phase III POETYK SLE-1 (NCT05617677) and -2 (NCT05620407) trials.