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Abstract
Background Tyrosine kinase 2 (TYK2) mediates cytokine pathways (eg, Type I IFN) linked with SLE pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved for the treatment of adults with plaque psoriasis.1 2 Deucravacitinib was efficacious in a phase 2 SLE trial.3 We developed a customized IFN 5-gene signature score, assessed the pharmacodynamic effects of deucravacitinib on the IFN score, and evaluated the score’s association with SLE disease activity and clinical response in the phase 2 trial.
Methods Patients were randomized equally to placebo or deucravacitinib (3 mg BID, 6 mg BID, or 12 mg QD). DxTerity chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes from whole blood. IFN genes were selected based on distribution, correlations, hierarchical clustering, and consistency of k-means clusters. Serum proteins, blood cell subsets, and antibodies were measured by immunoassays and flow cytometry. SRI(4) and BICLA were measured at weeks 32 and 48.
Results An IFN 5-gene (MX1, HERC5, IFIT1, RSAD2, and EIF2AK2) signature score was identified and used to classify patients into IFN-high or IFN-low subgroups (figure 1). Higher baseline score was associated with higher baseline SLEDAI and CLASI scores, higher IFN activity biomarker (eg, IFNα, IFNλ, BAFF, CXCL10) and anti-dsDNA levels, and lower complement and lymphocyte counts. Baseline score was not predictive of SRI(4) response. A higher baseline score was associated with a significantly higher probability of BICLA response with deucravacitinib 3 mg BID relative to placebo (P=0.014). Deucravacitinib reduced the score from weeks 4 through 44 by >50%.
Conclusions These data support the IFN 5-gene signature score as a biomarker to classify patients with SLE into IFN-high or IFN-low subgroups; however, clinical response by IFN score was inconsistently improved (table 1). IFN-regulated gene expression performs well as a pharmacodynamic biomarker to confirm deucravacitinib mechanism of action and to aid in phase 3 dose selection.
IFN 5-gene signature score with k-means clustering-derived cutpoint in the PAISLEY trial
Clinical response at week 32
References
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Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51.
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