Abstract TMP110: Elezanumab Decreases Neuronal Damage And Improves Functional Recovery In A Rabbit Model Of Permanent Middle Cerebral Artery Occlusion

Abstract

Introduction: Current acute interventions for ischemic stroke aim to restore perfusion of affected tissue. There is an unmet need for therapies that protect neurons from ischemic damage and/or enhance natural repair processes to restore function. In humans, the neuronal growth and survival inhibitor RGMa (repulsive guidance molecule A) is upregulated following ischemic stroke. Elezanumab is a novel, humanized monoclonal antibody targeting RGMa. Preclinical evidence in traumatic and ischemic models of CNS damage suggest a protective and regenerative mechanisms for elezanumab following CNS damage. Methods: 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 IgG control was administered 6 hours post occlusion or 24 hours post occlusion (10 mg/kg). Animals were dosed weekly through 28 days. Functional ability was assessed using the Neuromotor Score, a composite of sensorimotor performance tasks. Ex vivo MRI, histology, and fluid biomarker analyses were performed. Results: MCAO consistently reduced cerebral blood flow by ~60% and resulted in neuromotor dysfunction. All doses of elezanumab demonstrated statistically significantly improved neuromotor function and recovery rate versus controls when dosed 6 hours post occlusion. The 10 mg/kg group dosed 24 hours post occlusion did not show a statistically significant functional improvement versus controls. Infarct volumes, plasma neurofilament light chain levels, and histological evidence of microglial proliferation were all significantly reduced with elezanumab treatment versus controls, including in the delayed elezanumab treatment group. Conclusions: Elezanumab treatment was associated with improved functional recovery and reduced markers of neuronal damage. Collectively, these data support a neuroprotective role for elezanumab in this translational model of acute ischemic stroke. Elezanumab is now being tested in a Phase 2a clinical trial for acute ischemic stroke.