Patients with Duchenne muscular dystrophy (DMD) have reduced muscle mass and function. They also exhibit low bone strength, leading to higher risk of fractures. Long-term corticosteroid use, the current standard of care, can further reduce muscle and bone mass.
The TGF-β superfamily of ligands, including myostatin and activins, signal through activin type II receptors (ActRII) and negatively regulate muscle and bone mass and function. KER-065 is an investigational, modified ActRII-Fc ligand trap designed to target these ligands to promote muscle and bone growth and function.
RKER-065, a research form of KER-065, was evaluated for effects on muscle and bone in the phenotypically progressive D2.mdx mouse model. Control DBA2/J received vehicle (WT-veh) while D2.mdx mice were administered vehicle (D2.mdx-veh) or RKER-065 (10 mg/kg, QW; D2.mdx-tx).
At day 42, D2.mdx-veh mice had significantly (p=0.02) reduced lean mass gain from baseline compared to WT-veh. D2.mdx-tx mice had significantly increased lean mass compared to WT-veh and D2.mdx-veh (p<0.0001 for both). Baseline grip strength for D2.mdx cohorts was significantly (p<0.0001) reduced compared to WT-veh. At end of treatment, D2.mdx-tx mice exhibited significantly increased grip strength compared to D2.mdx-veh (p=0.02). Histological analysis showed increased expression of sarcolemma utrophin in D2.mdx-tx compared to D2.mdx-veh, potentially contributing to improved muscle strength observed with RKER-065 treatment. Additionally, D2.mdx-veh trended towards reduced bone volume fraction (BV/TV) and trabecular number (Tb.N) with a significant decrease in trabecular thickness (Tb.Th) (p=0.002) compared to WT-veh in the distal femur. In contrast, D2.mdx-tx mice had significantly increased BV/TV, Tb.Th and Tb.N (p=0.0012, p=0.0004, p=0.0001; respectively) when compared to D2.mdx-veh and improvements compared to WT-veh.
These data demonstrated RKER-065 reversed muscle atrophy, improved muscle function and ameliorated bone loss in a DMD model. This further supports clinical development of KER-065 as a potential treatment for dystrophic patients and supports that targeting this pathway warrants investigation.