Elezanumab for the treatment of spinal cord injury: assessing the clinical development journey to date

INTRODUCTION: Traumatic spinal cord injury (SCI) is a debilitating condition with serious neurological and quality of life impact. Despite advances in surgical, medical and rehabilitation care, there are no approved therapies that promote neural repair and regeneration in the injured spinal cord. Repulsive Guidance Molecule a (RGMa) is a potent neurite growth inhibitor that also regulates neuronal survival and differentiation, playing a critical role during neural development. In the adult central nervous system (CNS), RGMa is expressed at low basal levels and rapidly upregulated in multiple cell types following SCI. RGMa-neogenin signaling induces growth cone collapse and axonal inhibition, while also contributing to neuronal cell death and neuroinflammatory responses, thereby limiting recovery. Human monoclonal antibodies targeting RGMa, including elezanumab, have shown neuroprotective and neuroregenerative effects in rodent and non-human primate models, supporting further clinical investigation. AREAS COVERED: This review summarizes the pathophysiology of traumatic SCI and the upregulation of RGMa in the injured spinal cord. In particular, the authors highlight RGMa signaling mechanisms in the CNS and discuss the early development of human anti-RGMa monoclonal antibodies. EXPERT OPINION: Two concurrent, independent clinical trials of anti-RGMa antibodies offer a unique opportunity for cross-validation and to compare treatment responses across patient populations. However, these trials have only recently been completed, and results are not yet reported. However, these trials have only recently been completed, and results are not yet reported. The translation of SCI therapeutics to clinical practice is historically challenging and the controlled conditions of preclinical studies may not fully reflect human SCI or patient variability.