Loftus, Edward V.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P 1 and S1P 5 , demonstrated superior efficacy and safety vs placebo for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in a phase 3 study (True North). In this post-hoc analysis, we evaluated the impact of prior biologic exposure on response to ozanimod. METHODS: True North consisted of two cohorts. In cohort 1, patients with UC received double-blind treatment with once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo. In cohort 2, patients received open-label once daily ozanimod 0.92 mg. Ozanimod responders after a 10-week induction were re-randomized to double-blind maintenance with ozanimod 0.92 mg or placebo through week 52. Outcomes based on prior biologic exposure (biologic-naïve, 1 biologic, and 2+ biologics) and prior biologic type (anti-tumor necrosis factor [TNF] agents, vedolizumab, or both) were analyzed for clinical remission, clinical response, endoscopic improvement, and mucosal healing. Patients exposed to only a JAK inhibitor were excluded from the analysis. RESULTS: A total of 992 patients (n = 213 placebo and n = 426 ozanimod in cohort 1, n = 353 ozanimod in cohort 2) were included in the analysis for induction; 616 were biologic-naïve, 162 had exposure to 1 biologic, and 214 were exposed to 2 or more biologics. At baseline, biologic-exposed patients had more prior corticosteroid use, longer disease duration, and more extensive disease than biologic-naïve patients. During induction, greater therapeutic effects of ozanimod were generally seen in biologic-naïve vs biologic-exposed patients, and ozanimod-treated patients had greater responses on nearly all reported endpoints at week 10 (cohort 1). Clinical remission was achieved in 23% vs 6.6% of patients on ozanimod vs placebo who were biologic naïve, 17.2% vs 8.3% on 1 prior biologic, and 3.7% vs 2.5% on 2 or more biologics. Clinical response was reached in 53% vs 28% of patients on ozanimod vs placebo who were biologic naïve, 50% vs 33% on 1 biologic, and 27% vs 15% on 2 or more biologics. During maintenance, ozanimod-treated patients had greater responses on all endpoints versus placebo, with similar proportions of patients achieving clinical response to ozanimod regardless of prior biologic exposure (61% for biologic naïve, 60% for 1 biologic, and 55% for 2 or more biologics). At week 52, the proportion of patients on ozanimod with clinical remission was similar in the 1-biologic and 2+-biologic exposure groups (28% and 26%, respectively), and proportions of patients on ozanimod with endoscopic improvement and mucosal healing were similar for the 1-biologic and biologic-naïve groups (47% and 50%, 30%, and 33%, respectively). Among patients with inadequate response to prior anti-TNF agents, vedolizumab, or both at baseline, treatment effects favored ozanimod vs placebo on these endpoints in all three groups during both induction and maintenance. CONCLUSION: Ozanimod improved clinical, endoscopic, and histologic outcomes in both biologic-exposed and -naïve patients. Patients with prior biologic use may require additional time to respond to treatment. Outcomes were improved with ozanimod regardless of prior use of anti-TNF agents and vedolizumab.