P-274 Therapeutic Dosing of Filgotinib (GS-6034) Is Efficacious in the Mouse DSS Model of Colitis

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Background:Janus kinase (JAK) family proteins, JAK1, JAK2, JAK3, and TYK2, are key non-receptor tyrosine kinases, activated by gc chain cytokines, interferons, and other growth factors. Genetic dysregulation of JAK family members results in defects in immune and inflammatory responses and systems. Tofacitinib, the first approved JAK inhibitor in an inflammatory disease indication, that is rheumatoid arthritis (RA), validated the key pathologic roles of JAK pathway in humans. Recently observed clinical benefits of Tofacitinib and other JAK inhibitors in inflammatory disorders including inflammatory bowel disease reassured the distorted JAK pathways in a broad range of inflammatory/immune diseases. However, the adverse events, measured in these clinical trials such as enhanced rate of infection, anemia, neutropenia, and hyperlipidemia urged to develop a more specific JAK inhibitor, which maintains benefits and limits adverse events. Filgotinib (GS-6034) is a selective JAK1 inhibitor. Recently completed clinical phase 2 in RA and Crohn's disease demonstrated benefits in patients. Previously, preclinical benefits of GS-6034 were demonstrated in a preventive mode in a murine model of dextran sulfate sodium (DSS)-induced colitis. Here, we evaluated preclinical benefits of therapeutic dosing of GS-6034 in the DSS-induced colitis model.Methods:Colitis was induced in female C57BL/6 mice (n = 15/group) by 4% DSS in drinking water for 7 days. GS-6034 (30, 10, and 3 mg/kg) was orally administered once daily beginning on Day 5, once disease had been established, until Day 14 at study completion. Efficacy was assessed via metrics of colitis including disease activity index (DAI: stool consistency, hemoccults, and body weight change) and histopathological measures (inflammation, gland loss, erosion, and hyperplasia).Results:All animals were included in the evaluation. Thirty milligram per kilogram of GS-6034 demonstrated efficacy in all measures including body weight change, stool consistency, hemoccults, colon length and weight, and histopathological assessment. Ten milligram per kilogram of GS-6034 demonstrated efficacy in some measures including body weight change and colon length and weight. Disease-induced body weight loss was improved in 30 and 10 mg/kg of GS-6034 groups (37% and 28%, respectively; vehicle as 0%; sham as 100%; P < 0.05 to vehicle). DAI score was lower in 30 mg/kg of GS-6034 group (67% to vehicle as 100%, P < 0.05 to vehicle) and showed a trend of reduction in 10 mg/kg of GS-6034 group. Normal stool consistency was well maintained in 30 mg/kg GS-6034 group throughout the study period (185% to vehicle as 100%, P < 0.05 to vehicle). None of animals in 30 mg/kg GS-6034 group showed diarrhea throughout the study period. The median ratio of colon weight/length (mg/cm) was 34 in 30 and 10 mg/kg of GS-6034 groups versus 45 in vehicle group (P < 0.05 to vehicle; 22 in sham group). The sum of histopathology measures was 3.9 in 30 mg/kg of GS-6034 group versus 6.8 in vehicle group (P < 0.05 to vehicle).Conclusions:Therapeutic dosing of GS-6034 slowed disease progression and demonstrated efficacy in all measures of disease activity.

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