Background: 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.
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 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.
Results: 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).
Conclusions: Therapeutic dosing of GS-6034 dose dependently slowed disease progression and demonstrated efficacy in all measures of disease activity.