DOP046Molecular and cellular signatures accompanying early disease clearance in Ulcerative Colitis patients treated with vedolizumab in the VERDICT trial

Abstract Background Combined clinical, endoscopic, and histologic remission (also known as disease clearance) may be associated with improved outcomes and disease modification.1 The ongoing VERDICT trial (NCT04259138) aims to prospectively compare treatment targeting corticosteroid-free (CSF) symptomatic+endoscopic+histologic remission to CSF symptomatic remission featuring algorithms based upon early introduction of vedolizumab (VDZ). Treatment target groups include CSF symptomatic remission (Mayo rectal bleeding subscore=0) (Group 1), CSF symptomatic+endoscopic remission (Mayo endoscopic subscore≤1) (Group 2), and CSF symptomatic+endoscopic+histologic remission (Geboes score2B.0) (Group 3). We characterised gene expression signatures in bionaïve Group 3 patients according to target achieved by week 16 (W16) and mapped them to colonic cell subsets. Methods Patients with baseline and W16 colonic biopsies were included in analyses. Differential gene expression (DGE) analysis utilised DESeq2. Pathway analysis utilised clusterProfiler and gene set variation analysis. Gene co-expression network (GCN) modules were identified and annotated using Molecular Signature Database Hallmark and Reactome pathways. Cell-type enrichment analysis utilised a human UC single-cell atlas.2 Results As of 29 Feb 2024, baseline and W16 biopsy samples were available from 122 patients who achieved symptomatic remission (n = 20), symptomatic+endoscopic remission (n = 6), disease clearance (n = 66), and those who did not achieve any remission outcome (non-remitters NR; n = 30) by W16. Baseline characteristics of the patients were similar (Table 1). Minimal impact on DGE from baseline to W16 was observed in NR (36 genes) whereas shifts in the abundance of 10,000 differentially expressed genes were observed with disease clearance, including downregulation of core inflammatory genes and upregulation of immunometabolic genes (Fig 1A). The magnitude of difference in DGE was generally reduced when compared with patients with other remission outcomes. Patients with disease clearance were distinguished from all other patients at W16 by a set of 120 GCN transcriptional modules. In patients achieving disease clearance, there was enrichment of gene modules leading to restoration of the epithelial barrier and metabolism, and downregulation of fibro-inflammation (Fig 1B). These modules were linked to pathways involving phosphorylation and kinase signalling, apical junctions, and fatty acid and xenobiotic metabolism. Conclusion Distinct transcriptomic signatures were observed in bionaïve patients with UC achieving CSF disease clearance in response to VDZ by W16 that may represent predictive biomarkers for early UC disease clearance and/or next-generation therapeutic targets. References: 1.D’Amico F, Magro F, Siegmund B, et al. Disease clearance as a new outcome in ulcerative colitis: a systematic review and expert consensus. Inflamm Bowel Dis. 2024;30(6):1009-1017. doi:10.1093/ibd/izad159 2.Smillie CS, Biton M, Ordovas-Montanes J, et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell. 2019;178(3):714-730.e22. doi:10.1016/j.cell.2019.06.029 Conflict of interest: Powell, Nick: Grant: Takeda, BMS, Pfizer, Astra-Zeneca Personal Fees: Abbvie, Abivax, Allergan, Astra-Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma UK Ltd, Ferring, Galapagos, GSK, Janssen, MSD, Roche, Pfizer, Sobi, Takeda, Tillotts Mehandru, Saurabh: Grant: Genentech, Brystol Myers Squib (BMS) Personal Fees: AbbVie, Adacyte, Alimentiv, Atticus, Brystol Myers Squib (BMS), Cabaletta, Georgia Immune, Merck, Novartis Silverberg, Mark: Speaker for Abbvie, Janssen, Takeda, Pfizer, Ferring, Novartis, and Lilly. Advisor for Abbvie, Janssen, Takeda, Pfizer, Ferring, Gilead, Amgen, Merck, and Lilly. Research for Abbvie, Janssen, Takeda, Pfizer, and Gilead. Consults for Abbvie, Janssen, Takeda, Pfizer, and Lilly. Peyrin-Biroulet, Laurent: Grant: Takeda, Fresenius Kabi, Celltrion, Medac, MSD Personal Fees: Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par’ Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia. Other: SUPPORT TRAVEL : Abbvie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots. Hernandez-Rocha, Cristian: I have received travel support from Johnson & Johnson (ECC0 conference 2024). I have received grant support from the Chilean National Research and Development Agency (ANID). Grant: FONDECYT regular #1230757 FONIS SA24I0002 Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Alimentiv BV, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Agomab, Alimentiv, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Glaxo Smith Kline, Pfizer, Immunic, Johnson and Johnson, Merck, Polpharma, Procise Diagnostics, Prometheus Biosciences, Takeda, Ventyx Moran, Gordon: Gordon Moran has received research grants from Astra Zeneca, Bristol Myers Squibb, Jansen and Pfizer. He has received consulting fee from Alimentiv, Satisfai Health, Takeda, Abbvie, Jansen, Motilent, and Pfizer. He has received speaker honoraria from Abbvie, Jansen and Bristol Myers Squibb. He has received financial support for attending international meetings from Jansen and Abbvie. Sebastian, Shaji: Grant: Takeda, Tillots pharma, Biogen, Pfizer, Abbvie, Johnson & Johnson, Olympus -Odin Vision Personal Fees: Tillots, Johnson & Johnson, Olympus Odin Vision, AbbVie, Takeda, Merck, Pharmacosmos, Amgen, Eli Lilly, BMS, Odin Vision Non-financial Support: Tillots, Takeda, AbbVie, Celltrion, Johnson & Johnson, Eli Lilly, Alphasigma, Ferring Pharma Travis, Simon: Research Support: AbbVie, Celgene, Celsius, ECCO, Galapagos, GSK, Helmsley Trust, IOIBD, Janssen, Lilly, Pfizer, Takeda, UKIERI, 35Bio, Vifor, and Norman Collisson Foundation Consulting Fees: Alimentiv Apexian Apollo Arcturis AstraZeneca BMS Clario Cosmo Dova Health Endpoint Health EQrX Equillium Ferring Galapagos Genentech/Roche Gilead GSK Janssen Iterative Health Lilly Mestag Microbiotica ONO Pfizer Phesi Protagonist Sanofi Satisfai Sensyne Health Spyre Takeda Teva Theravance Tr1X Bio Speaker fees: BMS, Ferring, GSK, Janssen, Lilly, Pfizer, Sun Pharma, Takeda. Share options: Dova Health Inc Filice, Melissa: Employee of Alimentiv Inc. Massimino, Luca: Employee of Alimentiv Inc. Picard, Jeremy: Employee of Alimentiv Inc. Sangiorgi, Bruno: Employee of Alimentiv Inc. Shackelton, Lisa: Consulting fees from Alimentiv, Inc. Smith, Michelle: Employee of Alimentiv Inc. Teft, Wendy: Employee of Alimentiv Inc. Arunachalam, Vinayagam: Employee of Takeda Pharmaceuticals. Agboton, Christian: Employee of Takeda Pharmaceuticals. Farahmand, Saman: Employee of Takeda Pharmaceuticals. Freire, Marcelo: I am an employee with Takeda and hold shares of the company. Paraskevopoulou, Maria: Other: Maria Paraskevopoulou is employee and shareholder of Takeda