Pharmacodynamic analysis of TYK2 inhibition by deucravacitinib: results from the phase 2 PAISLEY SLE trial in patients with active systemic lupus erythematosus.

OBJECTIVES: The objective of this paper is to evaluate pharmacodynamic changes in immune-related pathways and serological biomarkers mediated by tyrosine kinase 2 (TYK2) inhibition in patients with systemic lupus erythematosus (SLE) treated with deucravacitinib, an oral, selective TYK2 inhibitor, in the phase 2 PAISLEY SLE trial. METHODS: Whole-blood transcripts, serum proteins, blood cell subsets, and antibody profiles were analysed via chemical ligation-dependent probe amplification assays, immunoassays, and clinical laboratory assays in 363 patients with SLE from the PAISLEY SLE trial and up to 60 commercially sourced healthy volunteer samples matched demographically to patients. Chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes in whole-blood samples collected in 4 independent studies. All analyses were descriptive. RESULTS: At screening, 42 genes and 75 proteins were differentially expressed in patients with SLE vs healthy volunteers. Deucravacitinib treatment resulted in rapid and sustained reductions in interferon (IFN) levels and expression of IFN-responsive genes, IFN-inducible proteins, B-cell pathway markers, and serological biomarkers and increases in complement 3 and 4 expression with similar kinetics vs placebo. Deucravacitinib treatment reduced an IFN signature score in IFN-high and IFN-low subgroups and anti-double-stranded DNA antibody titres in the IFN-high subgroup. CONCLUSIONS: Deucravacitinib demonstrated suppression of IFN and B-cell pathway biomarkers in patients with SLE, supporting its continued evaluation in ongoing phase 3 trials (Program for Evaluation of TYK2 [POETYK] SLE-1 [NCT05617677] and POETYK SLE-2 [NCT05620407]).