RKER-065, a novel ActRII ligand trap, counteracted the deleterious musculoskeletal effects of chronic glucocorticoid treatment in young mice


Pre-Clinical Research

Poster Number: S38


Michael Linzey, PhD, Keros Therapeutics, Gehua Zhen, MD, Keros Therapeutics, Remya Nathan, Keros Therapeutics, Morgan Cahill, Keros Therapeutics, Mark St. Pierre, Keros Therapeutics, Ffolliott Fisher, PhD, Keros Therapeutics, Lorena Lerner, Keros Therapeutics, Jenn Lachey, PhD, Keros Therapeutics, Jasbir Seehra, PhD, Keros Therapeutics

Glucocorticoids are the standard of care for boys with Duchenne muscular dystrophy (DMD), with treatment starting shortly after diagnosis (generally at 4-5 years old), resulting in better long-term outcomes. However, chronic glucocorticoid use has a catabolic effect on muscle and bone, highlighted by muscle loss and an increased risk of lumbar fractures. TGF-β family members, including activin A, activin B and myostatin, are potent negative regulators of musculoskeletal growth. RKER-065 is the research form of KER-065, an investigational, modified type II activin receptor ligand trap that inhibits these ligands. This study aims to determine if RKER-065 prevents the negative musculoskeletal effects of glucocorticoids in young mice.

Two-week-old male C57BL/6 mice received vehicle (Veh, PBS, i.p., QD) or prednisolone (Pred; 4mg/m2, i.p., QD), and either tris-buffered saline (TBS, i.p., BW) or RKER-065 (10mg/kg, i.p, BW), for 8 weeks. All animals were assessed for body weight, lean mass, grip strength, lumbar spine bone mineral density (BMD), and bone micro-architecture.

Chronic treatment with prednisolone (Pred-TBS) resulted in 61% less lean mass than vehicle-treated (Veh-TBS) mice. Co-treatment with RKER-065 and prednisolone increased lean mass to levels similar to Veh-TBS mice, suggesting protection against prednisolone-induced muscle atrophy. There were also corresponding changes observed in muscle function. The grip strength of the Pred-TBS group was lower than Veh-TBS (p=0.069), while the Pred-RKER-065 group’s grip strength was increased (p=0.0003) compared to Pred-TBS treatment. Prednisolone treatment was associated with decreased lumbar spine BMD. Compared to Pred-TBS treatment, co-treatment with RKER-065 was associated with improved BMD and a significant increase in the trabecular bone volume fraction.

Our data demonstrate that RKER-065 can attenuate the negative musculoskeletal effects of chronic glucocorticoid use in young mice. Therefore, KER-065 has the potential to improve muscle mass, muscle function, and bone health in DMD patients receiving chronic glucocorticoid treatment.