Objective: To assess safety, pharmacokinetics (PK), pharmacodynamics and biomarkers of muscle damage in healthy adults and adults with Becker muscular dystrophy (BMD).
Background: Fast (Type II) muscle fibers are affected early and disproportionately in BMD and DMD. EDG-5506 targets fast skeletal myosin, without effects on slow, cardiac, or smooth muscle myosin. In animal models of DMD, EDG-5506 decreased muscle damage biomarkers and fibrosis, while increasing muscle strength and habitual activity.
Design: Ascending EDG-5506 doses (5-40 mg daily) were administered orally for 14 days in healthy adults, with assessments of safety, plasma and muscle PK. Pharmacodynamics was measured by involuntary fast twitch of the quadriceps induced by non-invasive magnetic stimulation. Additionally, seven ambulatory adults with BMD were enrolled to assess safety, PK and effects of EDG-5506 or placebo on dystrophic muscle after 14 days.
Results: 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 demonstrating positive effects in animal models of DMD. In healthy adults and in BMD, muscle concentrations were substantially greater than plasma, consistent with high affinity of EDG-5506 for fast fiber myosin. Involuntary quadriceps twitch indicated dose-dependent increases in receptor occupancy in healthy adults, without change in voluntary muscle strength in either group. In BMD, EDG-5506 was well-tolerated and reduced multiple muscle damage biomarkers (>66%, p<0.001) with reversion of plasma proteome signature of BMD toward normal.
Conclusions: EDG-5506 demonstrated favorable safety and PK profiles at dose levels that demonstrated pharmacodynamic responses in healthy adults, and showed robust reductions in muscle damage biomarkers in adults with BMD. By targeting fast fiber myosin to protect dystrophic muscle, EDG-5506 has potential to be a novel disease-modifying approach in BMD and DMD regardless of mutation type, and Phase 2 studies are planned.