P.124 EDG-5506 targets fast skeletal myosin and reduces muscle damage biomarkers in a phase 1 trial in Becker muscular dystrophy (BMD)

Abstract

To assess safety, pharmacokinetics (PK), pharmacodynamics and biomarkers of muscle damage in healthy adults and adults with BMD. Fast (Type II) muscle fibers are affected early and disproportionately in dystrophinopathies. EDG-5506 targets fast skeletal muscle myosin, and in animal models of Duchenne muscular dystrophy (DMD), decreased muscle damage biomarkers and fibrosis, while increasing muscle strength and habitual activity. Ascending EDG-5506 doses (5-40 mg daily) were administered orally for 14 days in healthy adults who underwent assessments of safety, plasma and muscle PK, and biomarkers. Seven ambulatory adults with BMD were enrolled to assess safety, PK and effects of EDG-5506 or placebo in the setting of dystrophic muscle after 14 days. EDG-5506 was well-tolerated at all doses in healthy adults. Most common adverse events were somnolence and dizziness, which were mild and transient. Plasma and muscle exposures exceeded exposures that had demonstrated positive effects in animal models of DMD. In healthy adults and in participants with BMD, muscle concentrations substantially exceeded those in plasma, consistent with high affinity of EDG-5506 for fast fiber myosin. Muscle strength was maintained in all cohorts. In BMD participants, EDG-5506 was well-tolerated and significantly reduced creatine kinase, myoglobin, and fast skeletal muscle troponin I (TNNI2). In a plasma proteomic panel (SOMAscan), proteins associated with muscle damage and muscle metabolism were elevated in participants with BMD when compared to healthy controls. This panel of proteins decreased significantly with EDG-5506, particularly for those proteins that become elevated in response to exercise. EDG-5506 demonstrated favorable safety and PK profiles at dose levels that resulted in robust reductions in muscle damage biomarkers in adults with BMD. By targeting fast skeletal muscle myosin to protect dystrophic muscle, EDG-5506 has potential to be a novel disease-modifying approach in DMD and BMD regardless of mutation type. Phase 2 studies in BMD and DMD are planned.