BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. METHODS: For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. RESULTS: Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. CONCLUSION: In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

BACKGROUND: True North is a phase 3, randomized, double-blind, placebo-controlled trial conducted at 285 sites in 30 countries (NCT02435992). Treatment with once-daily ozanimod (an oral sphingosine 1-phosphate [S1P] receptor modulator selectively targeting S1P1 and S1P5) in patients with moderately-to-severely active ulcerative colitis (UC) showed significant improvements in primary and all key secondary endpoints. Here we report findings on the consistency of clinical and endoscopic endpoints in the global and North American population. METHODS: In True North, patients received either double-blind treatment with ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or matching placebo, or open-label ozanimod 0.92 mg over a 10-week induction period. Patients with clinical response to ozanimod at Week 10 were re-randomized 1:1 to receive double-blind maintenance treatment with ozanimod 0.92 mg or placebo through Week 52. The primary endpoint was proportion of patients in clinical remission at Weeks 10 and 52; key secondary endpoints included clinical response and endoscopic improvement. The global population included 1012 patients who received at least 1 dose of study medication during induction, and 457 who received at least 1 dose of study medication during maintenance. Here, we examine the results from the patients in the North American sites. RESULTS: A total of 247 patients were enrolled in North America, of which 167 received double-blind ozanimod (n=107) or placebo (n=60) during induction. At baseline, 41.1% and 48.3% of patients in the ozanimod and placebo groups, respectively, had previously received a biologic treatment for UC. At Week 10, 15.9% and 3.3% of patients in the ozanimod and placebo groups, respectively, achieved clinical remission. In addition, 46.7% and 15.0% achieved clinical response and 26.2% and 10.0% achieved endoscopic improvement in the ozanimod and placebo groups, respectively. In patients with prior exposure to tumor necrosis factor inhibitor (TNFi), the proportion with clinical response favored ozanimod (35.7%) vs placebo (11.5%), while the proportion with clinical remission and endoscopic improvement did not favor ozanimod. In patients with no prior TNFi exposure, greater responses were seen with ozanimod vs placebo for all 3 endpoints. During maintenance, 105 patients from North America were re-randomized to treatment with ozanimod (n=56) or placebo (n=49). At Week 52, 39.3% and 12.2% of patients in the ozanimod and placebo groups, respectively, achieved clinical remission. In addition, 58.9% and 26.5% achieved clinical response and 50.0% and 16.3% achieved endoscopic improvement in the ozanimod and placebo groups, respectively. The proportion of patients with clinical remission, clinical response, and endoscopic improvement favored ozanimod vs placebo regardless of prior TNFi use. These outcomes from the North American population are generally consistent with those previously reported from the global population. CONCLUSION: In this post-hoc analysis, consistent with the global population, ozanimod treatment for up to 52 weeks in North American patients with moderately-to-severely active UC showed benefits on clinical and endoscopic endpoints.