P1586 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 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 1Galapagos SASU, Romainville, France; 2Galapagos NV, Mechelen, Belgium; 3Ghent University Hospital, Ghent, Belgium Filgotinib prevents mouse colitis Filgotinib blocks JAK/STAT signaling in mouse colitis Filgotinib blocks JAK/STAT signaling in IBD patient colon biopsies Introduction 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. control DSS/vehicle DSS/30 mg/kg filgotinib Control DSS/vehicle DSS/filgotinib control ** vehicle filgotinib DSS/vehicle Methods Chronic mouse colitis model 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 IBD patient colon biopsy culture Inflamed colon biopsies from 8 IBD patients were treated with filgotinib 5µM and JAK/STAT target engagement was evaluated by measuring STAT3 phosphorylation after 24h using immunoassay and gene expression after 18h by qPCR DSS/filgotinib Fig. 1. Efficacy of filgotinib on disease activity index and colon stretching Fig. 6. Efficacy of 5µM filgotinib on STAT3 phosphorylation control DSS/vehicle DSS/filgotinib Fig. 4. Efficacy of filgotinib on STAT3 phosphorylation IL6 MX1 SOCS3 TNFa JAK1-dependent inflammation ** * IL6 Mx1 SOCS3 TNFa ** *** JAK1-dependent inflammation 0.1mm 0.1mm 0.1mm Fig. 2. Efficacy of filgotinib on colon lesion histological score Figure 1. Pharmacokinetic results after s.c. dosing (left) and after oral dosing (right) *** ** Neutrophil Macrophage T cell Fig. 7. Efficacy of filgotinib 5µM on JAK1-dependent and inflammation genes Fig. 5. Efficacy of filgotinib on JAK1-dependent and inflammation genes 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. 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 Poster available online at: www.glpg.com