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

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.