Mediators of Filgotinib Treatment Effects in Ulcerative Colitis: Exploring Circulating Biomarkers in the Phase 2b/3 SELECTION Study.

BACKGROUND

We utilized patient samples from the large, phase 2b/3 SELECTION trial to identify circulating biomarkers of ulcerative colitis (UC) and potential early mediators of filgotinib treatment effects.

METHODS

Samples were collected at baseline and during the induction phase of the SELECTION trial. Evaluated biomarkers comprised serum and stool proteins (measured by enzyme-linked immunosorbent assay), whole-blood cell counts, and whole-blood RNA-seq-derived gene-expression factors identified via exploratory factor analysis. Biomarker levels were assessed by baseline disease severity (endoscopy/bleeding/stool and Mayo Clinic Score) and biologic status (naive vs experienced). Effects of filgotinib on biomarker levels, including week 4 biomarker changes that may mediate week 10 clinical improvements, were assessed.

RESULTS

The biomarker analysis set included 598 biologic-naive patients and 592 biologic-experienced patients. Systemic inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], serum amyloid A [SAA], and platelet cell counts) had the strongest positive correlations with baseline UC disease severity. CRP, IL-6, SAA, and neutrophil activation biomarkers (including neutrophil gelatinase-associated lipocalin [NGAL], tumor necrosis factor ɑ, and oncostatin M [OSM]), as well as platelet, neutrophil, and monocyte cell counts were increased in biologic-experienced versus biologic-naive patients. Gene-expression-derived plasmablast and cell proliferation factors were positively correlated with disease severity; B cell, T-cell activation, and plasmacytoid dendritic cell factors were negatively correlated. Filgotinib reduced nearly all proinflammatory biomarkers correlated with baseline UC disease activity; reduced SAA, CRP, IL-6, NGAL, and OSM at week 4 were identified as mediators of improved week 10 clinical scores.

CONCLUSIONS

Filgotinib significantly impacted circulating biomarkers related to UC pathology. Several proinflammatory and neutrophil activation biomarkers may be early mediators of filgotinib treatment effects.

CLINICALTRIALS.GOV IDENTIFIER: NCT02914522.