P418 Filgotinib decreases molecular markers of JAK1 signal transduction in Crohn’s disease: concordance with endoscopy and histopathology

• Published in: Journal of Crohn's and colitis 2020-01, Vol.14 (Supplement_1), p.S381-S381
• Main Authors: Reinisch, W, Brodbeck, J, Galien, R, Grant, E, Hébuterne, X, Kłopocka, M, Petryka, R, Roblin, X, Serone, A, Tasset, C, Yoon, O K, Zaboli, S, Vermeire, S
• Format: Article
• Language: English
• ISSN: 1873-9946; 1876-4479
• DOI: 10.1093/ecco-jcc/jjz203.547

Abstract Background Filgotinib (FIL) is a JAK1 inhibitor under phase 3 clinical evaluation for treatment of IBD. We conducted a post hoc analysis in a subset of patients with moderately to severely active CD from FITZROY (NCT02048618) to assess the effect of FIL (200 mg QD) on molecular markers of JAK1-related signalling (STAT1 and STAT3 phosphorylation) within epithelium (Ep) and non-Ep regions of intestinal mucosa and explore their correlation to histologic and endoscopic indices. Methods Biopsies were collected at baseline (BL) and week 10 (W10) from the most affected area of each predefined bowel segment (ileum, ascending, transverse, descending colon, and rectum). Within-subject matched biopsies for all segments from FIL (n = 42) and placebo (PBO; n = 18) treated patients were scored for histologic (GHAS) and endoscopic (SES-CD) disease activity totalling to 300 segments. Using specific antibodies and IHC, %pSTAT1 and %pSTAT3 positive nuclei within Ep and non-Ep regions of each biopsy were quantified using machine learning (Visiopharm v.2019.06). Basal pSTAT levels assessed from 182 nondiseased (SES-CD = 0 and GHAS = 0) segments were used to determine a threshold for categorising segments as either low or high molecular disease activity (MDA). Agreement between endoscopy or histology and MDA was evaluated by κ and % agreement by segment and all segments combined. Results Median basal pSTAT1 was similar between colonic Ep and non-Ep regions (1%–2%), but higher in ileal Ep (5%). Median basal pSTAT3 was higher in non-Ep (3%–5%) vs. Ep (1%–2%) regions across all segments. At BL, MDA was elevated in segments with ulceration (~10%, pSTAT1 and pSTAT3). In segments with GHAS activity subscore ≥2 at BL, both Ep MDA (10%–30%) and non-Ep MDA were elevated (25%–35%) and correlated to histologic activity. In segments with low BL MDA, significantly fewer segments with FIL showed MDA worsening at W10 compared with PBO (both pSTAT1 and pSTAT3). In segments with high BL MDA, FIL treatment improved significantly more segments than PBO; this was evident for pSTAT3 only (table). Concordance between MDA and endoscopy was mostly fair to moderate (κ 0.3–0.5), whereas MDA and histology showed moderate to good concordance (κ 0.4–0.8). Table. Effect of FIL on Ep and non-Ep regions within segments pSTAT BL MDA W10 change Ep Non-Ep FIL PBO P FIL PBO P pSTAT1 Low Worsen −0.168 −0.348