Relapse-Associated Worsening and Progression-Independent Relapse Activity in Ozanimod-Treated Participants With Relapsing Multiple Sclerosis From the Radiance and Daybreak Trials

BACKGROUND: Ozanimod treatment was associated with significantly fewer relapses than interferon beta-1a (IFN) in phase 3 relapsing multiple sclerosis (RMS) trials and provided sustained control of disability progression for up to 5 years in an open-label study. OBJECTIVES: To determine the incidence and predictors of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in participants in the RADIANCE and DAYBREAK trials. METHODS: Participants in phase 3 RADIANCE (NCT02047734) were randomly assigned oral ozanimod 0.46 mg/day or 0.92 mg/day or intramuscular IFN 30 μg/week for 24 months, and completers were eligible to enroll in an ozanimod 0.92-mg open-label extension trial (DAYBREAK [phase 3; NCT02576717]; data cutoff: February 1, 2022). In participants continuously treated with ozanimod 0.92 mg or those who initially received IFN, we assessed 6-month confirmed disability progression (CDP; ≥ 1-point increase in Expanded Disability Status Scale [EDSS] score from baseline, confirmed after 6 months), and participants were considered to have RAW if CDP onset occurred ≤ 90 days of a relapse or PIRA if CDP onset occurred without relapse or > 90 days after a relapse. For relapse with incomplete recovery, baseline EDSS was reset > 90 days after relapse onset to identify the next PIRA event. Kaplan-Meier analysis and univariable Cox proportional hazards regression assessed incidence over time and predictors, respectively. P values were determined via Wald χ2 test. RESULTS: A total of 363 participants who received continuous ozanimod 0.92 mg and 346 who switched from IFN were included. In up to 8 years of follow-up, 75.9% of participants were free of 6-month CDP. Among participants with CDP, 44.3% and 54.5% of those treated with continuous ozanimod had RAW or PIRA, respectively; 8% had both. Of the participants who switched from IFN to ozanimod, 57.8% and 43.4% had RAW or PIRA, respectively; 4.8% had both. RAW was observed in 10.7% of participants treated with continuous ozanimod and 13.9% of those who switched from IFN to ozanimod; PIRA was observed in 13.2% of participants treated with continuous ozanimod and 10.4% of those who switched from IFN to ozanimod. In both treatment groups, predictors of RAW with nominal P < .05 included RADIANCE baseline EDSS score (positive association) and whole brain, cortical gray matter, and thalamic volumes (negative associations); these variables were not predictors of PIRA. CONCLUSIONS: In ozanimod-treated participants with RMS, RAW and PIRA contributed similarly to disability progression over 8 years. Higher baseline EDSS scores and lower baseline whole brain, cortical gray matter, and thalamic volumes were predictive of RAW. FUNDING: Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.