P012 Ozanimod Reduced Fecal Calprotectin Levels in Patients with Ulcerative Colitis in the Phase 3 True North Study

BACKGROUND: Ozanimod is an orally-administered sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P1 and S1P5 receptor subtypes. Ozanimod demonstrated efficacy and safety for up to 52 weeks of treatment in patients with moderately-to-severely active ulcerative colitis (UC) in the double-blind, randomized, phase 3 True North study. Fecal calprotectin (FCP), which occurs as a consequence of neutrophils in the gastrointestinal tissue from an inflammatory process, is strongly correlated with endoscopic activity in UC. The aim of this analysis was to assess the change in FCP in a prespecified biomarker analysis of patients in the True North study. METHODS: True North was a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of oral ozanimod HCl 1 mg/day (equivalent to ozanimod 0.92 mg) vs placebo once daily over a 10-week induction period and a 42-week maintenance period in patients with moderately-to-severely active UC. In the induction period, patients in Cohort 1 were randomized to receive double-blind ozanimod or placebo and patients in Cohort 2 received open label ozanimod. Patients in either cohort who responded to ozanimod at week 10 were re-randomized to receive double-blind ozanimod or placebo for the maintenance period up to week 52. FCP was assessed at baseline, week 10, and week 52. The proportion of patients with FCP response stratified by baseline FCP was evaluated at weeks 10 and 52. RESULTS: At baseline, mean FCP levels were 2509 µg/g in patients randomized to ozanimod (n = 422) and 3440 µg/g in those randomized to placebo (n = 214) in Cohort 1. A total of 451 patients who responded to ozanimod in the induction period (Cohort 1 and Cohort 2) were re-randomized in the maintenance period and had FCP data; 226 continued to receive ozanimod (mean baseline FCP, 2284 µg/g) and 225 received placebo (mean baseline FCP, 2987 µg/g). FCP levels were significantly improved with ozanimod vs placebo in both induction and maintenance periods. Mean (SD) change in FCP with ozanimod vs placebo was -470.2 (6887.9) µg/g vs 21.1 (7919.1) µg/g at week 10 (P = 0.002) and -1575.1 (4427.9) µg/g vs -463.3 (7370.6) µg/g at week 52 (P = 0.019). Of patients with elevated FCP at baseline using cutoffs of >50 and >150 µg/g, significantly more patients had reduced FCP levels below those respective cutoffs at week 10 with ozanimod vs placebo: 21% vs 6% and 33% vs 9.5% for baseline FCP >50 and >150 µg/g, respectively (P < 0.001, both). At week 52, patients with elevated FCP at baseline who remained on ozanimod were significantly more likely to have FCP levels below these cutoffs vs those clinical responders re-randomized to placebo, 46% vs 24% and 57% vs 38% for baseline FCP >50 and >150 respectively (P < 0.01, both). CONCLUSION: In patients with moderately-to-severely active UC, ozanimod led to significant reductions in FCP during induction and maintenance therapy, with a greater proportion of patients achieving FCP response with ozanimod vs placebo across multiple baseline FCP cutoffs. These results are consistent with the inhibition of inflammation in the gut by ozanimod in patients with moderate-to-severe UC.

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