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. FUNDING: Celgene International II.

Center for Neuroinflammation and Experimental Therapeutics and Multiple Sclerosis Division Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Center for Neurology Lodz Poland; Collegium Medicum Department of Neurology University of Warmia and Mazury Olsztyn Poland

Department of Biostatistics Celgene Corporation Summit NJ USA

Department of Clinical Development Celgene Corporation Summit NJ USA

Department of Neurology and Center for Clinical Neuroscience 1st Medical Faculty Charles University Prague Czech Republic

Department of Neurology and Neurological Sciences Beckman Center for Molecular Medicine Stanford University Medical Center Stanford CA USA

Department of Neurology Medical Faculty Heinrich Heine University Dusseldorf Germany

Department of Neurology San Raffaele Scientific Institute Vita Salute San Raffaele University Milan Italy

Division of Neurology St Michael's Hospital University of Toronto Toronto ON Canada; Department of Neurology Neuroimmunology Centre d'Esclerosi Múltiple de Catalunya Hospital Universitario Vall d'Hebron Barcelona Spain

Drug Safety Celgene Corporation Summit NJ USA

Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Cleveland OH USA

Neurologic Clinic and Policlinic University Hospital and University of Basel Basel Switzerland

NeuroRx Research and Montreal Neurological Institute McGill University Montreal QC Canada

Weill Institute for Neurosciences Department of Neurology University of California San Francisco San Francisco CA USA

Comment In

Lancet Neurol. 2019 Nov;18(11):983-985. doi: 10.1016/S1474-4422(19)30333-3. PubMed

References provided by Crossref.org

Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review

Concurrent administration of serotonergic antidepressants and ozanimod in participants with relapsing multiple sclerosis from the open-label extension DAYBREAK trial

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis

SARS-CoV-2 vaccination and infection in ozanimod-treated participants with relapsing multiple sclerosis

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial

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ClinicalTrials.gov
NCT02294058