POS0341 DECONVOLUTION OF TRANSCRIPTOMICS CHANGES IN DEUCRAVACITINIB-TREATED SUBJECTS REVEALS NOVEL MECHANISTIC EFFECTS OF TYK2 INHIBITION IN LUPUS

• Published in: Annals of the rheumatic diseases Vol. 83; no. Suppl 1; pp. 266 - 267
• Main Authors: Vital, E. M., Arriens, C., Kahlenberg, J. M., Crow, M. K., Saxena, A., Wu, C., Hu, Y., Hobar, C., Coles, A., Catlett, I. M.
• Format: Journal Article
• Language: English
• Published: Kidlington BMJ Publishing Group Ltd and European League Against Rheumatism 01.06.2024; Elsevier Limited
• Subjects: Allosteric properties; Autoantibodies; c-Met protein; Clinical Trial; Clinical trials; Dendritic cells; Gene expression; Gene set enrichment analysis; Genetics; Immunoregulation; Kinases; Lupus; Lymphocytes B; Lymphocytes T; Macrophages; Memory cells; Molecular modelling; Outcome measures; Patients; Pharmacodynamics; Placebos; Plasma cells; Psoriasis; Randomized controlled trial; Ribonucleic acid; RNA; Scientific Abstracts; Systemic lupus erythematosus; Transcriptomes; Transcriptomics; Tyk2 protein
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2024-eular.1880

Background:Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with moderate to severe plaque psoriasis. Deucravacitinib inhibits TYK2-mediated signaling of certain cytokines, such as type I interferons (IFNs), involved in systemic lupus erythematosus (SLE). Patients with SLE have common molecular manifestations, including elevated IFN and B-cell activity, elevated autoantibody levels, and reduced complement levels. In the 48-week, double-blind, phase 2 PAISLEY trial (NCT03252587) in patients with active SLE, deucravacitinib 3 mg twice daily (BID) met its primary endpoint of SLE Responder Index-4 (SRI[4]) response rate at week 32 and all secondary endpoints at week 48. A deeper understanding of cellular and molecular mechanisms is important in the development of optimized therapies for patients with SLE.Objectives:To perform a gene set enrichment and cellular deconvolution analysis on RNA-sequencing data from the PAISLEY trial to identify additional mechanistic insights into the effect of deucravacitinib in SLE.Methods:RNA-sequencing was performed on samples collected from patients with active SLE who were randomized 1:1:1:1 in PAISLEY to placebo (n=90) or deucravacitinib 3 mg BID (n=91), or 6 mg BID (n=93), or 12 mg QD (once daily) (n=89). Samples were analyzed up to the primary endpoint at 32 weeks. Pharmacodynamic and differential gene expression analysis was conducted using linear mixed-effects models for Differential Expression for Repeated Measures (DREAM) in R. Single-sample gene set enrichment analysis (ssGSEA) was performed using public predefined gene modules from MSigDB Hallmark and BloodGen3. xCell was used to digitally portray the blood cellular heterogeneity landscape.Results:Compared to placebo, pharmacodynamic analysis of whole transcriptome profiles identified 73, 122, and 392 genes modulated by deucravacitinib 3 mg BID, 6 mg BID, and 12 mg QD groups, respectively, at week 32 (adjusted p < 0.05). Many IFN-regulated genes were normalized by deucravacitinib treatment. ssGSEA and cellular deconvolution further identified SLE-relevant gene sets modulated by deucravacitinib (Figure 1). Gene sets representing naive and memory B lymphocytes were marginally increased, consistent with the increase in circulating lymphocytes. In contrast, plasma cell modules were reduced (Figure 2A). Regulatory T cell gene sets were increased in SLE compared with healthy controls, and further increased with deucravacitinib treatment (Figure 2B); in contrast, Th1 gene expression was marginally decreased. Gene expression associated with several myeloid cell types was reduced by deucravacitinib, including macrophage and activated dendritic cell (DC) (Figure 2C and D) signatures; complement gene signatures were also decreased. In contrast, conventional DC and immature DC signatures increased.Conclusion:RNA sequencing whole blood transcriptome profiling revealed expected, as well as novel, gene expression changes in deucravacitinib-treated subjects. As expected, deucravacitinib normalized expressions of IFN-regulated genes and reduced plasma cell gene signatures. Surprisingly, deconvolution revealed normalization of dendritic cell populations and increased regulatory T cell gene signature. These findings are consistent with the robust efficacy observed.Figure 1.Changes in gene sets identified by xCell deconvolutionFigure 2.Transcript scores according to predicted cell composition via ssGSEA or xCell for (A) plasma cells; (B) regulatory T cells; (C) activated dendritic cells; (D) macrophages across the timepoints of the studyREFERENCES:NIL.Acknowledgements:We would like to thank the patients and their families who made this study possible, as well as the clinical teams who participated. This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Angela R. Eder, PhD, of Nucleus Global, and funded by Bristol Myers Squibb.Disclosure of Interests:Edward M. Vital AstraZeneca, Bristol Myers Squibb, UCB, Roche, Novartis, Lilly, AbbVie, Otsuka, Aurinia, Pfizer, AstraZeneca, Sandoz, Cristina Arriens AstraZeneca and Aurinia, AstraZeneca and Bristol Myers Squibb; Advisory or review panel: AstraZeneca, Aurinia, Bristol Myers Squibb, GSK, and Kezar, J Michelle Kahlenberg AstraZeneca, Eli Lilly, GSK, Bristol Myers Squibb, Avion Pharmaceuticals, Provention Bio, Aurinia Pharmaceuticals, Ventus Therapeutics, Exo Therapeutics, DangerBio, and Boehringer Ingelheim, Q32 Bio, Celgene/Bristol Myers Squibb, Ventus Therapeutics, Rome Therapeutics, and Janssen, Mary K. Crow AMPEL BioSolutions, AstraZeneca, Bristol Myers Squibb, GSK, and Lilly, Gilead Sciences, Amit Saxena AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, GSK, and Kezar Life Sciences, Chun Wu Bristol Myers Squibb, Bristol Myers Squibb, Yanhua Hu Bristol Myers Squibb, Bristol Myers Squibb, Coburn Hobar Bristol Myers Squibb, Bristol Myers Squibb, Adrian Coles Bristol Myers Squibb, Bristol Myers Squibb, Ian M. Catlett Bristol Myers Squibb, Bristol Myers Squibb.