ACE-031 is a novel, muscle-building agent that is being developed for the treatment of patients with Duchenne Muscular Dystrophy with the goal of improving strength and preserving physical function.

What is ACE-031?

ACE-031 is an investigational protein therapeutic that builds muscle and increases strength by inhibiting molecules that bind to and signal through a cell surface receptor called Activin Receptor Type IIB (ActRIIB). ACE-031 is a recombinant fusion protein that is produced by joining a portion of the human ActRIIB receptor to a portion of a human antibody. This creates a freely circulating, decoy version of ActRIIB which removes proteins, such as GDF-8 (myostatin) and other related molecules that limit the growth and strength of muscle.

The Role of ActRIIB Signaling and Muscle Growth

Muscle growth is regulated by proteins in the TGF-β protein superfamily that serve as “on” or “off” switches for muscle production. Several molecules including GDF-8 interact with the ActRIIB receptor and send an “off” signal to stop muscle production. In the absence of these “off” switch molecules that signal through the ActRIIB receptor, muscle mass increases dramatically.

Decreased ActRIIB Signaling Results in Muscle Growth

In nature, this effect has been observed in numerous species, particularly in animals that have been bred for increased musculature and strength. For example, Belgian Blue cattle lack the gene for GDF-8, which is one of several molecules that activate the ActRIIB receptor. A deficiency of this protein results in cattle with tremendously developed musculature and strength. Similar effects have been observed in other species, including rodents, dogs and even humans.

ACE-031 Builds Skeletal Muscle

Treatment with ACE-031 promotes muscle growth by inhibiting ActRIIB signaling. ACE-031 binds to proteins that signal through the ActRIIB receptor to limit muscle growth. When ACE-031 binds to these proteins, it prevents them from interacting with the ActRIIB receptor, thus allowing muscle to grow. Moreover, because ACE-031 prevents GDF-8 and other proteins that regulate muscle mass from signaling through the ActRIIB receptor, its effects on lean muscle exceed those of inhibitors of GDF-8 (myostatin) alone.

When animals are treated with ACE-031, they experience growth in lean muscle and are considerably stronger than their untreated counterparts. This has been shown in several species, and in both healthy animals and in animals with diseases associated with muscle weakness and wasting.

Clinical Development Status

Acceleron has completed a single dose study (A031-01) of ACE-031 in healthy volunteers. For a description of the study design, click here.

A second study in healthy volunteers (A031-02), evaluating multiple doses of ACE-031, has been completed. For more information on the study design, click here.

A Phase 2 study in patients with Duchenne Muscular Dystrophy (A031-03) was initiated in Canada. The main purpose of this study is to determine if ACE-031 is safe and well-tolerated in children with DMD. Another purpose of this study is to obtain preliminary information regarding the effects of ACE-031 on muscle size, strength, and function in patients with DMD. For more information on this study, click here. An extension study (A031-06) was also initiated in Canada for boys who participated in the A031-03 study. For more information on this study, click here.

During the course of clinical trials in healthy adults and in DMD boys, some participants experienced minor nosebleeds, gum bleeding, and/or small dilated blood vessels within the skin. These events all resolved fully upon discontinuation of treatment. By themselves, the minor bleeding events and dilated blood vessels were not considered to be a serious safety concern for study subjects. However, based on review of these safety data with the FDA and Health Canada, Acceleron has terminated the A031-03 DMD study and has suspended enrollment and dosing in the follow-on extension study. Pending further analysis of safety data and discussion with health authorities, a new ACE-031 trial for DMD will be planned.

References

A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs, Mosher DS et al. PLoS Genet 3(5): e79, 2007.

Regulation of muscle growth by multiple ligands signaling through activin type II receptors, Lee SJ et. al., PNAS 102:18117-18122, 2005.

Inhibition of myostatin in adult mice increases skeletal muscle mass and strength, Whittemore LA et al., Biochem Biophys Res Commun. 2003 Jan 24;300(4):965-71.