Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial
Abstract
Background: Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis.
The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis. Methods: SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries.
We enrolled participants aged 18-55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0.0-5.0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1.0 mg or 0.5 mg or weekly intramuscular interferon beta-1a 30 μg.
Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population.
Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014-002320-27.
Findings: Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1.0 mg (n=447), ozanimod 0.5 mg (n=451), or interferon beta-1a (n=448). 91 (6.8%) participants discontinued the study drug (29 in the ozanimod 1.0 mg group; 26 in the ozanimod 0.5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0.35 (0.28-0.44) for interferon beta-1a, 0.18 (95% CI 0.14-0.24) for ozanimod 1.0 mg (rate ratio [RR] of 0.52 [0.41-0.66] vs interferon beta-1a; p<0.0001), and 0.24 (0.19-0.31) for ozanimod 0.5 mg (RR 0.69 [0.55-0.86] vs interferon beta-1a; p=0.0013).
Few ozanimod-treated participants discontinued treatment because of adverse events (13 [2.9%] who received ozanimod 1.0 mg; seven [1.5%] who received ozanimod 0.5 mg; and 16 [3.6%] who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported.
The incidence of serious adverse events was low and similar across treatment groups (13 [2.9%] participants who received ozanimod 1.0 mg; 16 [3.5%] who received ozanimod 0.5 mg; and 11 [2.5%] who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.
Interpretation: In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.