RKER-065 enhanced muscle and bone in a progressive murine model of Duchenne muscular dystrophy


Pre-Clinical Research

Poster Number: S44


Remya Nathan, Keros Therapeutics, Morgan Cahill, Keros Therapeutics

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.