PAISLEY phase II post hoc analysis: Gene modulation with deucravacitinib in SLE

Results from a post hoc analysis of the phase II PAISLEY trial (NCT03252587), evaluating whole-blood transcriptome profiling in patients with systemic lupus erythematosus (SLE) treated with deucravacitinib, were recently published in the Annals of the Rheumatic Diseases by Vital et al. The aim of the study was to examine immunopathogenic mechanisms and pathways associated with tyrosine kinase 2 (TYK2) and to further characterize the mechanism of action of deucravacitinib in SLE.  

Key data: RNA sequencing (RNA-seq) was performed on samples from 363 patients with SLE and 56 healthy volunteers from baseline to Week 32. At baseline, 527 differentially expressed genes (DEGs) were identified in patients with SLE vs healthy volunteers (adjusted p < 0.05). Within 2–3 days, 56, 36, and 13 SLE-related genes were significantly modulated towards normal in the 3 mg twice daily (BID), 6 mg BID, and 12 mg once daily (QD) groups, respectively. By Week 32, deucravacitinib significantly modulated the expression of 461, 833, and 2,529 genes in the 3 mg BID, 6 mg BID, and 12 mg QD groups, respectively. Regulatory T-cell (Treg) signatures were enriched in a dose-dependent manner with deucravacitinib vs placebo, while plasma cell signature enrichment was reduced. 

Key learning: Whole-blood RNA-seq profiling demonstrated that deucravacitinib modulated multiple SLE-relevant pathways, including plasma cell reduction and Treg enrichment, providing novel mechanistic insights into TYK2 inhibition and supporting continued evaluation in the phase III POETYK SLE-1 and POETYK SLE-2 trials.