Whole blood transcriptome profiling in patients treated with deucravacitinib and novel mechanistic insights into TYK2 inhibition in lupus: results from a post hoc analysis of the PAISLEY SLE phase 2 trial.

Abstract

To further understand the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY SLE trial. RNA sequencing (RNA-seq) was performed on samples collected from baseline to week 32 in 363 patients and 56 healthy volunteers. Pharmacodynamics of differentially expressed genes (DEGs) were analysed with linear mixed-effects models using the statistical software package DREAM (differential expression for repeated measures). Single-sample gene set enrichment analysis (ssGSEA) was performed using MSigDB Hallmark and BloodGen3 gene modules. The xCell R package was used to digitally portray the blood cellular heterogeneity landscape. At baseline, 527 DEGs were identified in patients with SLE vs healthy volunteers (log₂ fold change >1; adjusted P < .05). Deucravacitinib modulated up to 2529 genes and SLE-relevant gene sets, including interferon-regulated genes. ssGSEA showed that plasma cell gene sets decreased and myeloid cell gene sets reverted towards normal levels with deucravacitinib; xCell deconvolution revealed significant enrichment of dendritic cell populations with deucravacitinib vs placebo. At baseline, regulatory T-cell gene sets were increased in patients with SLE vs healthy volunteers and further increased with deucravacitinib. There were some variable, dose-dependent increases in naïve and memory B lymphocytes. Whole blood transcriptome profiling via RNA-seq revealed both expected and novel gene expression changes with deucravacitinib across multiple pathogenic pathways. These data demonstrate successful targeting of pathophysiologic immune mechanisms that should be validated in future studies and support continued evaluation of deucravacitinib in the phase 3 POETYK SLE trials.