DOP113 Residual TYK2 signalling is associated with non-response to vedolizumab and systemic TNF inhibitors among patients with ulcerative colitis: post hoc analyses of mucosal transcriptome data
Authors: Paraskevopoulou M , Tang J , Saha B , Sugiura A , Arunachalam V , Farahmand S , Hou R , Arevalo J , Agboton C , Panchal P , Singh N , Petrakis I , Desch N , Schreiber S 
Published: January 2025

Abstract

Background
Understanding the cellular and molecular mechanisms underlying response to treatment in patients with inflammatory bowel disease (IBD) is crucial to guide the development of new drugs. We have used transcriptomic approaches to assess biomarkers of response to treatment among patients with active ulcerative colitis (UC) receiving the integrin inhibitor vedolizumab (VDZ) or systemic tumor necrosis factor (TNF) inhibitor therapy.

Methods
In VARSITY, 769 patients with moderately to severely active ulcerative colitis were randomized to receive VDZ (n = 383) or adalimumab (ADA; n = 386) for 52 weeks; superiority was demonstrated for VDZ relative to ADA for the primary endpoint of clinical remission at Week 52 (31.3% vs 22.5%; p = 0.006).1 An unbiased cell and gene/pathway module analysis was conducted using pre-treatment (baseline), Week 14, and Week 52 intestinal biopsy samples from responders and non-responders to treatment, with response defined according to the primary endpoint. Longitudinal analysis was conducted focusing on tyrosine kinase 2 (TYK2)-dependent signalling pathways, including type I interferon (IFN) and interleukin (IL)-23. In addition, cell–cell signalling network analysis was conducted using single-cell RNA-seq data from patients with UC.2

Results
Using single-cell transcriptomic data to assess downstream targets of ligand molecules,2 distinct but overlapping signalling networks were observed for α4β7 integrin, IL-23 and TNF. Cell and gene/pathway module analysis of transcriptomic data from VARSITY identified biomarkers at baseline, Week 14, and Week 52 associated with non-response to VDZ at Week 52, including CD4+, CD8+, B-cell and fibroblast cell subsets, and elevated transcription of gene modules associated with JAK/STAT and IFN signalling. Similar regulation differences were seen for response to ADA at Weeks 14 and 52, but, contrary to VDZ, no predictors of ADA response were identified at baseline. Targeted longitudinal analysis demonstrated enrichment of IL-23 and type I IFN pathways among VDZ and ADA non-responders throughout the study, and incomplete resolution of IL-23 and Type I IFN pathway modulation among treatment responders.

Conclusion
Elevations in gene modules associated with TYK2-dependent signalling were identified as biomarkers of non-response to both VDZ and ADA, suggestive of mechanistic complementarity between α4β7 integrin, TNF and TYK2 inhibition. These results have been further validated in additional transcriptomic studies of VDZ and infliximab.3,4. Findings support further investigation of the role of TYK2 inhibitors in IBD, irrespective of prior response to VDZ or ADA.

References
1.Sands BE, Peyrin-Biroulet L, Loftus EV, Jr., et al. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med. Sep 26 2019;381(13):1215-1226. doi:10.1056/NEJMoa1905725
2.Smillie CS, Biton M, Ordovas-Montanes J, et al. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell. Jul 25 2019;178(3):714-730 e22. doi:10.1016/j.cell.2019.06.029
3.Arijs I, De Hertogh G, Lemaire K, et al. Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. PLoS One. Nov 24 2009;4(11):e7984. doi:10.1371/journal.pone.0007984
4.Arijs I, De Hertogh G, Lemmens B, et al. Effect of vedolizumab (anti-alpha4beta7-integrin) therapy on histological healing and mucosal gene expression in patients with UC. Gut. Jan 2018;67(1):43-52. doi:10.1136/gutjnl-2016-312293