Increased Levels of Neurofilament Light and GFAP Confirmed During Acute Stroke

Author(s):

Elezanumab's biomarker analysis in stroke patients underscores its potential as a neuroprotective therapy for acute ischemic stroke management.

Matthew Szapacs

In a longitudinal biomarker analysis of a phase 2a trial (NCT04309474) assessing elezanumab, an agent specific to repulsive guidance molecule A (RGMa), findings showed increased levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) during acute stroke, which diminished over time with different temporal patterns.¹

Presented at the 2024 International Stroke Conference (ISC) held February 7-9, in Phoenix, Arizona, the preliminary analysis included 34 patients, aged 30-90 years old, with acute ischemic stroke, and 31 healthy adults. Participants were randomly assigned 1:1 to elezanumab or placebo by intravenous (IV) infusion within 24 hours of “last known normal” and every 4 weeks thereafter for 48 weeks for a total of 13 doses. Coming into the study, patients had a National Institute of Health Stroke Scale (NIHSS) total score of 7 to 21.

Presented by Matthew Szapacs, scientific director of Precision Medicine – Neuroscience at AbbVie, baseline NIHSS total score for the cohort was 10.9 (SD, 4.3), with elevated NfL and GFAP concentrations observed on day 1 in patients with stroke vs healthy adults. Specifically, investigators observed mean NfL concentrations of 48.7 pg/mL in patients with stroke vs 13.9 pg/mL for healthy adults. Mean concentrations of GFAP were 746.0 pg/mL vs 137.2 pg/mL, respectively.

As noted, the levels of these neuroaxonal biomarkers diminished over time, with peak NfL and GFAP elevations occurring at day 28 and days 2-4 days, respectively. The study, which was double-blinded in nature, also showed that NfL and GFAP concentrations were lower at week 52 than day 1. Protein, mRNA, and miRNA, assessed with omics approaches, will be included in forthcoming analyses, the study authors noted.

"Final unblinded results will provide a robust natural time course of specific biomarkers of neurodegeneration including GAP43," Szapacs et al wrote.¹ "Identifying relevant post stroke biomarkers with directed and exploratory omics may allow development of validated assays to assess efficacy and support decision making in clinical trials."

Also known as ABT-555, elezanumab is a fully human monoclonal antibody directed against RGMa. RGMa is a potent modulator of axonal growth, myelination, and downstream immunoregulatory molecules that are key factors for inhibiting neuronal and oligodendroglial regeneration and functional recovery after central nervous system (CNS) trauma or inflammation. Previous research has shown that RGMa neutralization can be a novel approach that may provide neurorestoration/regeneration and functional recovery in a variety of degenerative CNS diseases.²

At last year’s ISC meeting, elezanumab was evaluated in a rabbit permanent middle cerebral artery occlusion (MCAO) model of acute ischemic stroke by injection of an autologous blood clot. In replicate experiments, elezanumab (1, 10, and 40 mg/kg) or immunoglobulin control was administered 6 hours post occlusion or 24 hours post occlusion (10 mg/kg). Results showed that all doses of elezanumab demonstrated statistically significantly improved neuromotor function and recovery rate versus controls when dosed 6 hours post occlusion.³

The animal model also revealed that elezanumab-treated patients had significant reductions in infarct volumes, plasma NfL levels, and histological evidence of microglial proliferation. Investigators concluded that collectively, these data support a neuroprotective for the agent in a translational model of acute ischemic stroke.

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REFERENCES
1. Szapacs M, Mollon J, Challagundla M, et al. Longitudinal biomarker analysis in patients with ischemic stroke: exploratory targeted an omics assessment from a phase 2a clinical trial. Presented at: ISC 2024; February 7-9; Phoenix, Arizona. POSTER WP275
2. Kalluri HV, Rosebraugh MR, Misko TP, Ziemann A, Liu W, Cree BA. Phase 1 evaluation of elezanumab in healthy and multiple sclerosis participants. Ann Neurol. 2023;93(2):285-296. doi:10.1002/ana.26503
3. Smith E, Dreher I, Droescher M, et al. Elezanumab decreases neuronal damage and improves functional recovery in a rabbit model of permanent middle cerebral artery occlusion. STROKE. 2023;54:ATMP110. doi:10.1161/str.54.suppl_1