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Poster presentations: Clinical: Therapy and Observation 2020

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

W. Reinisch1, J. Brodbeck2, R. Galien3, E. Grant2, X. Hébuterne4, M. Kłopocka5, R. Petryka6, X. Roblin7, A. Serone2, C. Tasset8, O.K. Yoon2, S. Zaboli2, S. Vermeire9

1Division Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria, 2Gilead Sciences, Inc., Foster City, USA, 3Galapagos SASU, Parc Biocitech, Romainville, France, 4Department of Gastroenterology and Nutrition and Archet 2 Hospital, Centre Hospitalier Universitaire de Nice and University Côte d’Azur Nice, France, 5NC Department of Gastroenterology and Nutrition, University in Toruñ and Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland, 6NZOZ ViVamed, Zamiejska 17 03-580, Warsaw, Poland, 7Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France, 8Galapagos NV, Generaal De Wittelaan L11A3, Mechelen, Belgium, 9Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium

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

pSTATBL MDAW10 changeEpNon-Ep
FILPBOPFILPBOP
pSTAT1LowWorsen−0.168−0.348<0.05−0.173−0.394<0.05
HighImprove0.4360.286NS0.3900.327NS
pSTAT3LowWorsen−0.115−0.375<0.005−0.109−0.382<0.005
HighImprove0.4490.241<0.050.4420.232<0.05

Data are proportions of segments; bold indicates a significant difference between FIL v PBO

Conclusion

Filgotinib treatment improved JAK1-related MDA within the mucosa of CD patients. Concordance between MDA and clinical indices was highest with histology.