Long-Term Cardiac Safety of Ozanimod in Phase 3 Clinical Program of Ulcerative Colitis and Relapsing Multiple Sclerosis

Introduction Sphingosine-1-phosphate receptor modulators may be associated with bradycardia and atrioventricular conduction delays. In a previous analysis, first-dose ozanimod had minimal effects on cardiac function.

Objectives This analysis evaluated long-term cardiac safety following continuous ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) in the phase 3 ulcerative colitis (UC) True North (TN) trial and multiple sclerosis (MS) 12-mo SUNBEAM and 24-mo RADIANCE trials.

Methods In TN, patients (pts) received double-blind ozanimod or placebo (Cohort 1) or open-label ozanimod (Cohort 2) in the induction period; pts with clinical response to ozanimod at 10 wks were rerandomised to double-blind ozanimod or placebo maintenance treatment. ECGs were monitored at screening, Day 1, Wk-10, and Wk-52; heart rate (HR) was monitored at every visit. In the MS trials, ECGs were monitored at screening, baseline, Day 15, and end of treatment (EOT); HR was monitored similarly at the beginning, then every 3 mo until EOT. Cardiac-related treatment-emergent AEs (TEAEs) were reported.

Results In TN, continuous ozanimod was not associated with clinically significant changes in HR or ECG. The incidence of cardiac-related TEAEs with ozanimod during induction was low (1.4% in Cohort 1 and 2.2% in Cohort 2); in Cohort 1 and Cohort 2, respectively, bradycardia (0.5% and 0.8%), palpitations (0.5% and 0.3%), and tachycardia (0.5% and 0.3%) were the most common cardiac-related TEAEs associated with ozanimod. In maintenance, cardiac-related TEAEs were reported in 1.3% of pts on continuous ozanimod. Cardiac-related serious AEs (SAEs) were uncommon (angina pectoris, coronary artery stenosis, pericarditis in 1 patient each). In the pooled MSstudies, no clinically significant HR or ECG changes were associated with chronic treatment up to Mo 24. The incidence of cardiac-related TEAEs was low with ozanimod (3.4%). Two patients experienced cardiac-related SAEs resulting in hospitalization with ozanimod (asymptomatic sinus bradycardia and symptomatic supraventricular tachycardia). Discontinuations due to cardiac-related TEAEs with ozanimod were low in TN (1 angina pectoris case and 2 bradycardia cases during induction in Cohort 2) and the MS trials (1 supraventricular tachycardia case in SUNBEAM).

Conclusion Ozanimod had a manageable long-term cardiac safety profile with a low incidence of bradycardia and few serious long-term cardiac safety findings in the phase 3 UC and MS trials.

Publikationsverlauf

Artikel online veröffentlicht:
19. August 2022