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

Abstract

Introduction: Traumatic spinal cord injury (SCI) is a debilitating condition with serious neurological and quality of life impact. Despite advances in surgical, medical and rehabilitative care, no approved therapies currently promote neural repair or regeneration. Repulsive Guidance Molecule a (RGMa) is a potent inhibitor of neurite growth that also regulates neuronal survival and differentiation during development. In the adult central nervous system (CNS), RGMa is expressed at low levels and rapidly upregulated in multiple cell types following SCI. RGMa-neogenin signaling induces growth cone collapse, inhibits axonal regeneration, and contributes to neuronal death and neuroinflammation, limiting recovery. Human monoclonal antibodies targeting RGMa, including elezanumab, have shown neuroprotective and neuroregenerative effects in preclinical models, supporting clinical investigation.

Areas covered: This review outlines SCI pathophysiology, RGMa upregulation after injury, key CNS signaling mechanisms, and the early development of anti-RGMa monoclonal antibodies.

Expert opinion: Two concurrent, independent clinical trials of anti-RGMa antibodies offer a unique opportunity for cross-validation and comparison across patient populations. However, these trials were recently 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 capture the complexity and variability of human SCI.