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LSO-077 Identification of an interferon 5-gene signature score as a pharmacodynamic and potential predictive biomarker for deucravacitinib treatment in a phase 2 trial in patients with systemic lupus erythematosus
  1. Chun Wu1,
  2. Yanhua Hu1,
  3. Mary K Crow2,
  4. Amit Saxena3,
  5. Christina Arriens4,5,
  6. Coburn Hobar6,
  7. Adrian Coles7 and
  8. Ian M Catlett8
  1. 1Informatics and Predictive Sciences, Bristol Myers Squibb, USA
  2. 2Rheumatology, Hospital for Special Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, USA
  3. 3Medicine, Division of Rheumatology, NYU Grossman School of Medicine, USA
  4. 4Arthritis and Clinical Immunology, Rheumatology, Oklahoma Medical Research Foundation, USA
  5. 5Medicine, University of Oklahoma Health Sciences Center, USA
  6. 6Clinical Development, Bristol Myers Squibb, USA
  7. 7Global Biometrics and Data Sciences, Bristol Myers Squibb, USA
  8. 8Translational Medicine, Bristol Myers Squibb, USA


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.

Abstract LSO-77 Figure 1

IFN 5-gene signature score with k-means clustering-derived cutpoint in the PAISLEY trial

Abstract LSO-77 Table 1

Clinical response at week 32


  1. Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39.

  2. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51.

  3. Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print).

  • Deucravacitinib
  • systemic lupus erythematosus
  • interferon-regulated genes

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