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THE FIRST JAK1-SELECTIVE INHIBITOR, FILGOTINIB, DISPLAYS SIMILAR MOLECULAR ACTIVITY IN THE GUT OF MICE WITH DSS-INDUCED COLITIS AND IN CULTURES OF COLON BIOPSIES FROM INFLAMMATORY BOWEL DISEASE PATIENTS P1586 Carole Delachaume1, Veerle De Vriendt2, Debby Laukens3, Béatrice Vayssière1, Didier Merciris1,Steve De Vos2, Marie-Christine Ceccotti1, Christelle David1, Laetitia Perret1, Martine De Vos3, Reginald Brys2 and René Galien1 SASU, Romainville, France; 2Galapagos NV, Mechelen, Belgium; 3Ghent University Hospital, Ghent, Belgium Filgotinib prevents mouse colitis Introduction control DSS/30 mg/kg filgotinib 5 4 3 2 1 Control control 27 DSS/vehicle 23 DSS/filgotinib DSS/vehicle 19 vehicle ** 0 1 2 3 4 5 6 7 8 15 9 10 11 12 13 14 15 16 time (days) Fig. 1. Efficacy of filgotinib on disease activity index and colon stretching DSS/filgotinib Chronic mouse colitis model control DSS/vehicle DSS/filgotinib 0.1mm 0.1mm 0.015 0.010 0.005 Fig. 6. Efficacy of 5µM filgotinib on STAT3 phosphorylation Fig. 4. Efficacy of filgotinib on STAT3 phosphorylation 4 JAK1-dependent Mx1 SOCS3 2 inflammation TNFa IL6 JAK1-dependent inflammation MX1 IL6 ** 0 0.1mm filgotinib 0.000 6 colon lesion score Chronic colitis induction in Balb/c mice: 4% dextran sodium sulphate (DSS) in drinking water for 5/7 days in 3 successive periods. Treatments: 30 mg/kg Filgotinib QD orally for 16 days Disease Activity Index score (DAI): composite score based on daily assessment of weight loss, rectal bleeding and stool consistency. Histology: scoring of severity and extent of inflammation and epithelial damage, cell infiltration by immunohistochemistry (IHC) JAK/STAT target engagement in colon tissue was evaluated by measuring STAT3 phosphorylation using IHC and gene expression by qPCR Filgotinib blocks JAK/STAT signaling in IBD patient colon biopsies 0.020 0 Methods DSS/vehicle colon/intestine length (%) disease activity index Filgotinib (known as GLPG0634) is a JAK inhibitor selective for JAK1 over the 3 other family members (JAK2, JAK3 and TYK2) in biochemical and human whole blood assays. It is efficacious in arthritis and colitis mouse models. Filgotinib is currently being assessed as a treatment for Crohn’s disease (CD) in a Phase 2 study. The objective of this study was to compare signalling mechanisms, in particular JAK1 inhibition-related effects, regulated by filgotinib in mouse IBD model and in ex vivo human colon biopsies. Filgotinib blocks JAK/STAT signaling in mouse colitis pSTAT3 staining index 1Galapagos ** *** *** *** ** ** SOCS3 ** * TNFa * *** Fig. 2. Efficacy of filgotinib on colon lesion histological score 15 10 ** 0 T cell 8 20 5 Macrophage *** 6 *** 4 2 0 Fig. 5. Efficacy of filgotinib on JAK1-dependent and inflammation genes 4 *** T cell surface (%) 25 Neutrophil cell surface (%) Inflamed biopsies fromresults 8 IBDafter patients were(left) treated withoral filgotinib 5µM Figurecolon 1. Pharmacokinetic s.c. dosing and after dosing (right) and JAK/STAT target engagement was evaluated by measuring STAT3 phosphorylation after 24h using immunoassay and gene expression after 18h by qPCR cell density (cells/mm2) IBD patient colon biopsy culture Fig. 7. Efficacy of filgotinib 5µM on JAK1-dependent and inflammation genes 3 *** 2 *** 1 0 Fig. 3. Efficacy of filgotinib on inflammation-driven immune cell infiltration Disclosures: AbbVie has provided funding to Galapagos for the development of GLPG0634 C. Delachaume, V. De Vriendt, B. Vayssière, D. Merciris, S. De Vos, M.C. Ceccotti, C. David, L. Perret, R. Brys and R. Galien are employees of Galapagos This work was supported by a grant from IWT, N°120550 Conclusions These data highlight the importance of JAK1/STAT3 pathway observed in both pre-clinical mouse colitis model & human colon biopsy culture, further pointing out the role of JAK1 in the etiology of IBD. These data suggest that filgotinib, a JAK1-selective inhibitor, may be beneficial in treating CD patients and support its evaluation in a clinical study. Poster available online at: www.glpg.com © Copyright 2015 Galapagos NV