Ozanimod Preserves Multiple Sclerosis Cognition in New 3-Year Analysis

A newly presented ad hoc analysis of the phase 3b ENLIGHTEN study (NCT04140305) showed that cognitive performance remained largely preserved over a 3-year period in adults with relapsing multiple sclerosis (RMS) treated with ozanimod (Zeposia; BMS). Presented at the 2026 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 27-29, Charlotte, North Carolina, investigators also observed a trend indicating that participants with greater whole brain volume had lower odds of cognitive impairment across multiple time points.¹

The analysis included 171 participants with available Symbol Digit Modalities Test (SDMT) data at baseline and at least 1 postbaseline assessment. Among the cohort, 78.9% were women, 86.0% were White, and 70.2% were treatment-naive at study entry. At 1 year, unimpaired cognitive performance was reported in 85.1% of participants (143 of 168; 95% CI, 78.8-90.1). This rate remained consistent over time, with 88.4% of participants maintaining unimpaired cognitive performance at 2 years (129 of 146; 95% CI, 82.0-93.1) and 85.4% at 3 years (70 of 82; 95% CI, 75.8-92.2).

ENLIGHTEN, a phase 3b, multicenter, open-label study, evaluated ozanimod at doses of 0.92 mg over 3 years in adults with RMS. The trial assessed cognitive performance using the SDMT as the primary end point, and secondary end points included changes in whole brain volume and regional brain volumes measured by MRI. Participants underwent SDMT testing and MRI assessments at baseline and annually throughout the study period.

Presented by lead author John DeLuca, PhD, senior vice president for Research and Training at Kessler Foundation, the current analysis examined the proportion of participants with unimpaired cognitive performance, defined as an SDMT score greater than 44, at baseline and annual follow-up visits through a June 20, 2025, data cutoff. The analysis also explored associations between cognitive performance and brain volume over time by comparing the percentages and odds of unimpaired cognition across whole brain volume.

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At baseline, the cohort’s mean age was 39.8 (SD, 10.7) years, mean time since symptom onset was 4.2 (SD, 5.7) years, and mean time since diagnosis was 1.1 (SD, 1.3) years. Participants experienced a mean of 0.8 (SD, 0.8) relapses in the year prior to enrollment, and mean whole brain volume measured 1506.0 (SD, 132.9) cm³. The median Expanded Disability Status Scale score was 2.0, with a range of 0 to 4.0. At baseline, the mean SDMT score was 53.4 (SD, 11.7) points. Overall, 138 of 171 participants (80.7%; 95% CI, 74.0-86.3) met criteria for unimpaired cognitive performance.

At baseline, unimpaired cognitive performance was reported in 42 of 51 participants (82.4%) in the high-whole brain volume tertile compared with 40 of 52 participants (76.9%) in the low-whole brain volume tertile (OR, 1.4; 95% CI, 0.5-4.2; P = .6259). At 1 year, authors noted that rates of unimpaired cognitive performance were 88.0% (44 of 50 participants) in the high-whole brain volume tertile and 76.0% (38 of 50 participants) in the low-whole brain volume tertile (OR, 2.3; 95% CI, 0.7-8.2; P = .1923).

By 2 years, results showed that unimpaired cognitive performance was observed in 37 of 39 participants (94.9%) in the high-whole brain volume group compared with 32 of 40 participants (80.0%) in the low-whole brain volume group (OR, 4.6; 95% CI, 0.8-47.0; P = .0872). At 3 years, unimpaired cognitive performance was reported in 13 of 15 participants (86.7%) in the high-whole brain volume tertile and 9 of 15 participants (60.0%) in the low-whole brain volume tertile (OR, 4.3; 95% CI, 0.6-50.9; P = .2148).

Overall, investigators noted that these findings suggest that early identification of patients in the lowest whole brain volume tertile could help inform clinical counseling among adults with RMS. Furthermore, the results of the study suggested that reduced brain atrophy associated with earlier ozanimod initiation could potentially contribute to preservation of cognitive performance.

Ozanimod, a sphingosine 1-phosphate receptor modulator, was first approved by the FDA for relapsing MS in 2020.² In a prior analysis of ENLIGHTEN, results revealed that greater change in glial fibrillary acidic protein (GFAP) over 1 year correlated with increased gadolinium-enhancing lesion volume and reduced left ventricular volume (LVV).³ The analysis featured 162 patients with GFAP and MRI data from the study, 68% of whom were treatment naïve. After 1 year of open-label treatment with 0.92 mg of ozanimod, the mean GFAP concentration was reduced from 115.0 pg/mL (SD, 81.1) at baseline (n = 175) to 103.2 pg/mL (SD, 77.1; n = 174).

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REFERENCES
1. DeLuca J, Bergsland N, Dwyer M, et al. Relationship Between Cognitive Function and Brain Volume Outcomes in People With Relapsing Multiple Sclerosis in the Phase 3b ENLIGHTEN Study: 3-Year Results. Presented at: 2026 CMSC Annual Meeting; May 27-29; Charlotte, North Carolina. Abstract DMT30.
2. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s ZEPOSIA® (ozanimod), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis. News release. Briston Myers Squibb. March 26, 2020. Accessed May 26, 2026. https://news.bms.com/news/corporate-financial/2020/US-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-ZEPOSIA-ozanimod-a-New-Oral-Treatment-for-Relapsing-Forms-of-Multiple-Sclerosis/default.aspx
3. Morrow S, Shapiro L, Bal AB, Riolo J, Harris S. P028. Relationship Between Glial Fibrillary Acidic Protein and Radiologic Outcomes in Patients with Early Relapsing Multiple Sclerosis: Year 1 Interim Analysis of the ENLIGHTEN Trial of Ozanimod. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. Abstract P028.