P072. GLPG0634, the first selective JAK1 inhibitor, shows strong activity in the mouse DSS-colitis model
D. Merciris1, C. Delachaume2, V. De Vriendt3, A.-L. Boutet4, L. Perret1, M.-C. Ceccotti2, S. De Vos3, A. Monjardet4, R. Brys5, R. Galien6, 1Galapagos SASU, Histology, Romainville, France, 2Galapagos SASU, in vivo pharmacology, Romainville, France, 3Galapagos NV, Cell-based assays, Mechelen, Belgium, 4Galapagos SASU, DMPK, Romainville, France, 5Galapagos NV, Inflammation therapeutic area, Mechelen, Belgium, 6Galapagos SASU, Inflammation therapeutic area, Romainville, France
GLPG0634 is a JAK inhibitor that has been shown to be selective for JAK1 over JAK2 in human whole blood and over JAK3 and TYK2 in biochemical assays. GLPG0634 showed a favorable safety and efficacy profile in two 4-week Phase 2A studies in rheumatoid arthritis (RA) patients and is being assessed as a treatment for Crohn's disease (CD) in a Phase 2 study. Here, we report the strong efficacy of GLPG0634 in the mouse DSS-induced colitis model.
Chronic colitis was induced by adding 4% dextran sodium sulfate (DSS) to drinking water of Balb/c mice that were administered 10 and 30 mg/kg GLPG0634 QD during the 17 days of the study. Disease score was evaluated daily by measuring weight loss, rectal bleeding, and stool consistency. Colon length was quantified at the end of the study. Histological scoring of disease was based on an evaluation of severity and extent of inflammation and epithelial damage. Target engagement in the colon was evaluated by measuring STAT phosphorylation, using immunohistochemistry and the 5-Plex STAT kit on Luminex for confirmation. Serum proteins were quantified by Luminex multi-analyte technology. GLPG0634 concentrations in plasma were measured by LC-MS/MS.
Macroscopic disease scoring indicated strong and moderate protection against experimental colitis by GLPG0634 30 mg/kg and 10 mg/kg, respectively, which was subsequently confirmed in the colon length readout. Histological scoring revealed 43% and 19% lower disease severity for mice treated with GLPG0634 at 30 and 10 mg/kg, respectively, compared to controls. Colons from DSS-treated mice displayed higher STAT3 phosphorylation levels, which were prevented by co-treatment with 30 mg/kg GLPG0634, while no effect of disease or treatment with GLPG0634 was observed on pSTAT1 and pSTAT5. Colitis-induced blood markers of inflammation (CRP, CCL4, CXCL1, CXCL2) and neutrophil activation (MPO) could be prevented by treatment with GLPG0634. Finally, pharmacokinetic analysis showed that maximum GLPG0634 plasma concentration (Cmax) was 10-fold lower than JAK2 IC50, which excluded any contribution from JAK2 inhibition.
These data demonstrate for the first time that JAK1 inhibition is sufficient for achieving strong efficacy in the pre-clinical mouse DSS-induced colitis model. This protection was observed at both the macroscopic and histologic level and correlated with the inhibition of STAT3 phosphorylation in the colon and lower inflammation markers in the serum. These data suggest that GLPG0634 may be beneficial at treating CD patients and support its testing in a clinical study.