3-Year ENLIGHTEN Analysis Links Lower Neurofilament Light Chain Levels to Improved Cognition in Early MS: John DeLuca, PhD

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"We know that persons with MS who have cognitive problems early in the disease are the ones who are going to show dramatic progression—not just on cognition, but on brain parameters and everyday life."

The ENLIGHTEN study (NCT04140305) was a multicenter, longitudinal, open-label, single-arm phase 3b/4 trial designed to evaluate the effects of ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) on cognitive processing speed in adults with early relapsing multiple sclerosis (RMS).¹ The study enrolled approximately 250 patients aged 18 to 65 years who had been diagnosed with RMS within the previous 5 years, had an Expanded Disability Status Scale (EDSS) score of 3.5 or less, and had received no more than 1 prior disease-modifying therapy.

In the study, participants received ozanimod for 3 years, with the primary endpoint assessing clinically meaningful improvement in cognitive processing speed as measured by the Symbol Digit Modalities Test (SDMT), defined as a ≥4-point or ≥10% increase from baseline.¹

Secondary and exploratory outcomes included changes in brain volume and MRI disease activity, patient-reported outcomes, disability measures, and biomarkers such as neurofilament light chain (NfL), as well as their associations with cognitive performance, including processing speed, verbal memory, and visual memory.² Assessments were conducted longitudinally to better characterize the relationship between treatment, neuroaxonal injury, brain structure, and cognitive outcomes in early MS.³

Findings from a 3-year analysis of the ENLIGHTEN study were presented at the 2026 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 27-29 in Charlotte, North Carolina. The presentation highlighted new data on the relationship between biomarkers of neuroaxonal injury and cognitive outcomes in patients with early RMS treated with ozanimod. To provide additional perspective on the findings and their potential clinical implications, NeurologyLive® spoke with John DeLuca, PhD, senior vice president for research at the Kessler Foundation, during the meeting.

In the interview, DeLuca, who is also a professor in physical medicine and rehabilitation at Rutgers New Jersey Medical School, discussed emerging evidence linking reductions in NfL levels with improvements in cognitive outcomes among patients with MS. The conversation highlighted associations between declining NfL levels and gains in cognitive processing speed, verbal memory, and visual memory over a 3-year period. DeLuca emphasized the clinical importance of identifying cognitive dysfunction early in the disease course, noting that patients with early cognitive deficits are often at greater risk for long-term progression and disability.

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REFERENCES
1. Riolo JV, Yang L, Rano T, et al. Effect of the S1P1/5 receptor modulator ozanimod on cognitive processing speed in subjects with relapsing multiple sclerosis: design of the ENLIGHTEN study. Int J MS Care. 2020;22(Suppl 2):29.
2. Morrow SA, Shapiro LP, Basu Bal A, et al. Characterization of neurological biomarkers in patients with early relapsing multiple sclerosis and comparison to healthy controls: year 1 interim analysis of the ENLIGHTEN study of ozanimod. Neurology. 2025;104(7 Suppl 1):2218.
3. Morrow SA, Shapiro LP, Basu Bal A, et al. Relationship between plasma neurofilament light chain, cognition, and brain volume in the ENLIGHTEN trial of ozanimod. Presented at: Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting; 2025. Int J MS Care. 2025;27(Suppl 1).