Improved GFAP Levels With Ozanimod Linked to Slower Relapsing MS Progression

Sarah A. Morrow, MD, FRCPC, FAAN

An interim analysis of the phase 3 ENLIGHTEN trial (NCT04140305), a study of ozanimod (Zeposia; BMS) in adults with early relapsing multiple sclerosis (MS), 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). All told, the study data highlighted the relationship between astrocyte damage and imaging parameters, and the beneficial impact that ozanimod has on both measures.

Led by Sarah A. Morrow, MD, FRCPC, FAAN, director of the London Multiple Sclerosis Clinic at the University of Western Ontario, 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, an FDA-approved medication, 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).

Presented at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida, baseline GFAP level (n = 162) was found to be significantly positively correlated with baseline T1 lesion count (P = .030), T1 hypointense lesion volume (P = .34), T2 lesion count (P = .22), T2 hyperintense lesion volume (P = .32), and LVV (P = .032). On the flip, significant negative correlations were observed with cortical grey matter volume (CGMV; P = –0.19) and thalamic volume (P = –0.32).

Coming into the study, the mean age was 39.7 years (SD, 10.3), mean years since MS onset was 4.0 (SD, 5.6), and mean number of relapses in the prior 12 months was 0.75 (SD, 0.74). Among 143–148 patients with available data, baseline GFAP demonstrated similar correlations with outcomes at 1 year: T1 lesion count (P = 0.28), T1 lesion volume (P = 0.32), T2 lesion count (P = 0.20), T2 lesion volume (P = 0.31), LVV (P = 0.33), CGMV (P = -0.17), and total brain volume (TV; P = -0.35). Additionally, baseline GFAP showed a negative correlation with whole brain volume at 1 year (P = -0.17). Changes in GFAP over 1 year correlated positively with changes in gadolinium-enhancing lesion volume (P = 0.18; n = 146) and negatively with LVV (P = -0.19; n = 142).

READ MORE: 3-Year Findings Highlight Potential Therapeutic Benefits of GA Depot in Progressive MS

Ozanimod, a sphingosine 1-phosphate receptor (S1P) modulator, was first approved by the FDA for relapsing MS in 2020, followed by an expanded approval to treat ulcerative colitis in 2021. By modulating S1P1 receptors, ozanimod prevents lymphocytes from exiting lymph nodes and entering the bloodstream. Taken as a once-daily oral capsule, its receptor selectivity reduces the risk of adverse events compared with earlier S1P modulators like fingolimod.

ENLIGHTEN, an open-label study, was originally intended to describe changes in cognitive processing speed, measured by the Symbol Digits Modalities Test (SDMT), in patients with relapsing MS on ozanimod over a 3-year period. An additional interim analysis presented at ACTRIMS Forum 2025 comprised 177 patients, with mean baseline SDMT scores of 53.2, California Verbal Learning Test Second Edition (CVLT-II) baseline scores of 53.6, and Brief Visuospatial Memory Test-Revised (BVMT-R) scores of 24.7 at baseline.²

Over one year, patients showed a mean percentage improvement of 9.6% in SDMT scores, 6.2% in CVLT-II scores, and 3.7% in BVMT-R scores. Nearly half of the patients (48.1%, or 81 out of 168) experienced clinically meaningful improvement in SDMT scores. The average changes from baseline to year 1 were 3.4 points for SDMT, 2.7 points for CVLT-II, and a negligible -0.0 points for BVMT-R, indicating varied cognitive test performance improvements.

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REFERENCES
1. 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.
2. DeLuca J, Gudesblatt M, Zivadinov R, et al. P323. Changes in Cognitive Functioning in Ozanimod-Treated Patients with Early Relapsing Multiple Sclerosis: Year 1 Interim Analysis of the ENLIGHTEN Study. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT P323.