P047 Therapeutic dosing of filgotinib (GS-6034, GLPG0634) is efficacious in the mouse DSS model of colitis
Kim S., Zheng J., Lu B., Alonzo D., Kanwar B., Smith V.
Gilead Sciences, Inc, Foster City, United States
Janus kinase (JAK) family proteins, JAK1, JAK2, JAK3, and TYK2, are key non-receptor tyrosine kinases, activated by common gamma chain cytokines, interferons, and other growth factors. Filgotinib (GS-6034) is a selective JAK1 inhibitor. Recently completed clinical phase 2 trials in RA and Crohn's disease demonstrated clinical benefits in patients with an acceptable safety profile relative to pan-JAK inhibitors. 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.
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 disease activity index (DAI: stool consistency, hemoccults, and body weight change) and histopathological measures (inflammation, gland loss, erosion, and hyperplasia), both accepted metrics of colitis.
All animals were included in the evaluation. 30 mg/kg of GS-6034 demonstrated efficacy in all measures including body weight change, stool consistency, hemoccults, colon length and weight, and histopathological assessment. 10 mg/kg 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 vs. 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 vs. 6.8 in vehicle group (p<0.05 to vehicle).
Therapeutic dosing of GS-6034 dose dependently slowed disease progression and demonstrated efficacy in all measures of disease activity.