P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis

Abstract

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.

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs

“…In addition, no cases of second‐ or third‐degree AV block were observed 113 . In phase 2 and phase 3 RCTs of ozanimod in UC, following the first dose, the mean decrease in heart rate was marginal (0.7 beats per minute from baseline) within the first 5 h, and returned to baseline after 6 h 114 …”

“…In addition, no cases of second-or third-degree AV block were observed. 113 In phase 2 and phase 3 RCTs of ozanimod in UC, following the first dose, the mean decrease in heart rate was marginal (0.7 beats per minute from baseline) within the first 5 h, and returned to baseline after 6 h. 114 Pooled data across phase 3 RCTs in patients with UC and multiple sclerosis indicate that the risk of bradycardia with ozanimod was low and primarily occurs in the induction period. Additionally, the use of ozanimod for longer periods was not associated with an increased risk of MACE.…”

Clinician’s Guide to Using Ozanimod for the Treatment of Ulcerative Colitis

“…Post hoc analyses of phases 2 and 3 clinical trial data confirmed that the ozanimod dose titration schema mitigates first-dose cardiac effects in patients with UC and MS; transient and minimal reductions in heart rate occurred with the first dose of ozanimod, and there were few [<1%] first-dose, cardiac AEs with ozanimod in patients with or without a history of cardiac disorders. 46 Additional post hoc analyses of phase 3 clinical trial data demonstrated a low incidence of cardiac AEs [≤2.2%] and no increased risk of thromboembolic events or major adverse cardiac events [eg, cardiovascular death, myocardial infarction, stroke] with up to 1 year of ozanimod treatment in patients with UC; discontinuations due to cardiac AEs were low [<1%] and there were no cardiovascular-related deaths. 47 , 48 A similar incidence of cardiac AEs [2.8%] was reported in patients with MS with up to 5 years of ozanimod treatment in an OLE that enrolled patients from phase 1–3 trials.…”