Association between endo-histological outcomes and colonic mucosal transcriptomic profiles in patients with ulcerative colitis receiving filgotinib

Fernando Magro; Gerhard Rogler; Brian G Feagan; Laurent Peyrin-Biroulet; Alessandra Oortwijn; Laure Cougnaud; Margaux Faes; Yasmina Bauer; Matthew Randall; Christine Rudolph; Walter Reinisch

doi:10.1093/ecco-jcc/jjaf228

Association between endo-histological outcomes and colonic mucosal transcriptomic profiles in patients with ulcerative colitis receiving filgotinib

J Crohns Colitis. 2026 Jan 22:jjaf228. doi: 10.1093/ecco-jcc/jjaf228. Online ahead of print.

Authors

Fernando Magro¹, Gerhard Rogler², Brian G Feagan^{3

4}, Laurent Peyrin-Biroulet^{5

6}, Alessandra Oortwijn⁷, Laure Cougnaud⁸, Margaux Faes⁹, Yasmina Bauer¹⁰, Matthew Randall¹¹, Christine Rudolph¹², Walter Reinisch¹³

Affiliations

¹ CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal.
² Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
³ Alimentiv Inc, London, ON, Canada.
⁴ Western University, London, ON, Canada.
⁵ Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, Vandœuvre-lès-Nancy, F-54500, France.
⁶ Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.
⁷ Alfasigma BV, Utrecht, Netherlands.
⁸ Open Analytics NV, Antwerp, Belgium.
⁹ Galapagos NV, Mechelen, Belgium.
¹⁰ Department of Biomedicine and Clinics of Respiratory Medicine, University Hospital Basel, University of Basel, Switzerland.
¹¹ Alfasigma Schweiz AG, Zofingen, Switzerland.
¹² Alfasigma GmBH, Munich, Germany.
¹³ Department of Internal Medicine III, Division Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria.

PMID: 41569324
DOI: 10.1093/ecco-jcc/jjaf228

Abstract

Background: Filgotinib, a Janus kinase 1-preferential inhibitor, is approved for the treatment of moderately to severely active ulcerative colitis (UC).

Aim: To assess the effects of filgotinib on endo-histological outcomes and tissue RNA sequencing data from the SELECTION trial (NCT02914522).

Methods: This analysis assessed single and composite endo-histological improvement and remission endpoints at week (W) 10 and W58 in patients with moderately to severely active UC receiving once-daily filgotinib 200 mg (FIL200) or 100 mg, or placebo. Post hoc RNA sequencing analysis was performed on colonic mucosal biopsies from baseline and W10. Comparisons were made between patients who did and did not achieve endo-histological outcomes at W10 and treatment arms.

Results: Greater proportions of patients achieved single and composite endo-histological improvement and remission endpoints with FIL200 than placebo at W10 and W58 (endo-histological remission, W10: 6.7% vs 1.8%; P = 0.0021; W58: 12.1% vs 5.1%; P = 0.0485). Differentially expressed genes between baseline and W10 that were associated with histologic remission at W10 had upregulated and downregulated expression opposite to that of an active UC signature. Patients treated with FIL200, achieving endoscopic improvements or histological remission, exhibited reduced neutrophil-related gene expression (eg, neutrophil migration, P <0.0001) and enriched gene expression for mitochondrial activity and epithelial repair compared with those without (eg, PADI2, log2(fold change) = 2, P <0.0001).

Conclusions: Filgotinib improved endo-histological outcomes in patients with UC, with a dose-dependent effect on transcription. Gene expression changes and enriched pathways suggest that achieving endoscopic and histological endpoints in patients receiving FIL was associated with the restoration of mucosal homeostasis.

Keywords: gene expression; mucosal repair; ulcerative colitis.

Associated data

ClinicalTrials.gov/NCT02914522