Rebound Effect Not Observed With Multiple Sclerosis Therapy Ozanimod

Ralf Gold, MD

An analysis of DAYBREAK, a phase 3, single-arm, open-label extension study (NCT02576717), revealed that treatment with ozanimod (Zeposia; BMS) did not result in higher-than-expected disease activity indicative of a rebound effect in either women or men with relapsing multiple sclerosis (MS). While relapse rates were slightly higher among women, these findings were consistent with previously reported rates.

Rebound effect, referring to clinical and/or radiological worsening of disease activity, is a well-documented concern with certain disease-modifying therapies for MS, particularly when they are discontinued or switched. Typically occurring within weeks to a few months after discontinuation, rebound effect may manifest as new or worsening relapses, increased gadolinium-enhancing lesions on MRI, and sometimes severe disability progression.

Presented at the 2025 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 28-31, in Phoenix, Arizona, the analysis comprised 2494 DAYBREAK participants, with more women (n = 1120) than men (n = 559) included. After discontinuing ozanimod, a sphingosine 1-phosphate receptor (S1P) modulator, 42 women (3.8%) and 13 (2.3%) men had an MS relapse during follow-up. Overall, relapses occurred a median of 69 days (range, 3-141 days) after ozanimod discontinuation in women vs 43 days (range, 16-90) in men.

Led by Ralf Gold, MD, chair of the department of neurology at the University of Bochum, women experienced a median increase of 1.0 (range, 0-3.0) in Expanded Disability Status Scale (EDSS) score at relapse whereas men experienced increases of 0.5 (range, 0-2.0). Notably, 6 of 42 women (14.3%) and 1 of 13 men (7.7%) showed EDSS increases of greater than or equal to 2.0. Furthermore, while there was a small proportion of patients who initiated another disease-modifying therapy during the follow-up period (4.6% of women; 4.6% of men), only 1 female participant relapsed while using another medication. This patient was concurrently using fingolimod, another approved therapy.

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One woman participant, whose relapse caused an EDSS score to increase by 0.5 points, had the only relapse that was considered severe by study investigators. The women eventually partially recovered within 36 days. Additional data revealed that while there were a higher proportion of women whose relapse led to hospitalization (28.6% vs 15.4%), more women completely recovered from relapse than men (81.0% vs 61.5%). Notably, an additional 16.7% of women and 30.8% of men had a partial recovery; 1 woman (2.4%) and 1 man (7.7%) did not recover.

Ozanimod was first approved by the FDA in 2020 as a treatment for relapsing MS and later had its indication expanded to include ulcerative colitis in 2021. Since its approval, there have been several analyses stemming from DAYBREAK, as well as several other phase 3 studies, demonstrating ozanimod’s impact on measures of disease activity and progression.

One such analysis, presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, showed that after 72 months, the adjusted annualized relapse rate was 0.098 (95% CI, 0.082-0.117) among ozanimod-treated patients. In addition, 67% of patients at the time were relapse-free. At 60 months, 17.2% and 15.2% of patients had 3- and 6-month confirmed disability progression, with stable MRI lesion activity across T2 and gadolinium-enhancing measures.²

Another long-term analysis of DAYBREAK showed that ozanimod had a significant and sustained effects on brain volume loss (BVL) among patients with relapsing MS. Overall, patients who received continuous ozanimod 0.92 mg demonstrated stable and low rates of whole brain volume (WBV) through month 60 of the open-label extension (OLE; annualized least square mean [LSM] percent change from parent baseline: RADIANCE, –0.27; SUNBEAM: –0.35). Compared with those who switched from interferon-beta-1a, patients who received continuous ozanimod had statistically significantly (nominal P <.05) lower LSM percent reductions in WBV through OLE month 48 in RADIANCE and OLE month 60 in SUNBEAM.³

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REFERENCES
1. Gold R, Selmaj KW, Berkovich R, et al. (PLA-A1) No Rebound Observed Following Ozanimod Discontinuation in Female and Male Participants in the DAYBREAK Open-Label Extension Study. Presented at: 2025 CMSC Annual Meeting; May 28-31. Abstract PLA-A1.
2. Selmaj KW, Steinman L, Comi G, et al. Long-term Safety and Efficacy of Ozanimod in Relapsing Multiple Sclerosis: Final Analysis of the DAYBREAK Open-label Extension Study. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. P090.
3. Cohen J, Arnold D, DeLuca J, et al. Whole Brain, Cortical Grey Matter, and Thalamic Volume Changes During 5–7 Years of Ozanimod in Relapsing MS: Final Results From the DAYBREAK Open-Label Extension Study. Presented at ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. ABSTRACT 1623/141