Fast Skeletal Myosin Modulator EDG-5506 Confers Additional Protection to mdx Mice Receiving Glucocorticoid Treatment


Pre-Clinical Research

Poster Number: 72


Angela Peter, PhD, Edgewise Therapeutics, Ying Qian, MS, Edgewise Therapeutics, Breanne Stamper, PhD, Edgewise Therapeutics, Dennis Claflin, PhD, University of Michigan, Susan Brooks, PhD, University of Michigan, Stephen Schlachter, BS, Edgewise Therapeutics, Marc Evanchik, Edgewise Therapeutics, Alan Russell, PhD, Edgewise Therapeutics

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness due to repeated cycles of injury, incomplete regeneration and fibrosis. Glucocorticoids (GC), such as deflazacort and prednisone, slow disease progression in DMD and considered standard of care. Preclinical data in mdx mice suggest that glucocorticoids improve membrane repair and muscle regeneration via upregulation of annexin repair proteins (1). The fast skeletal muscle myosin modulator, EDG-5506, protects skeletal muscle in models of muscular dystrophy by reducing contraction stress to prevent
degeneration. We sought to understand whether the previously reported protective effects of EDG-5506 would be retained in the background of glucocorticoid administration. Mdx mice (8 weeks old) received daily treatment with deflazacort (1.2 mg/kg) and/or EDG-5506 (3 mg/kg) for 9 weeks. At the end of the study, forelimb grip strength (FGS), in situ force and membrane stability, as determined by lower-body Evan’s Blue Dye (EBD) uptake and plasma creatine kinase (CK) were assessed. Significant improvements in mean and max FGS were noted in mice treated with a combination of EDG-5506 and GC. In situ force measurements showed mice treated with both GC and EDG-5506 or EDG-5506 alone had stronger baseline force than the vehicle group or the GC only group. After lengthening injury, force drop was improved with the combination treatment. In addition, combination treatment animals also showed reduced EBD uptake and reduced plasma CK when compared to animals receiving deflazacort alone. In summary, sarcomere stabilization via EDG-5506 provided muscle protection in mdx mice when administered with or without GC treatment. In addition, combination treatment showed additional improvements in FGS and cross-sectional force development. These data in the mdx model support myosin modulation with EDG-5506 has positive effects both with and without GC background therapy. This finding has potential relevance to its use in DMD, and a clinical trial is ongoing.

1.Quattrocelli M, Barefield DY, Warner JL, Vo AH, Hadhazy M, Earley JU, et al. Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy. J Clin Invest. 2017;127(6):2418-32.