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ACE-031 is a novel, muscle-building agent that is being developed for the treatment of patients with neuromuscular diseases 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 completely human, 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.

Treatment with 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.

Non-Clinical Results – 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 Results – Recently, Acceleron completed a clinical study of ACE-031 in healthy volunteers. These subjects received a single dose of ACE-031 across a range of dose levels. At higher doses, the effects of ACE-031 on skeletal muscle were encouraging. After a single dose of ACE-031, subjects developed roughly 1 kilogram (over 2 pounds) of muscle at 2 weeks. Moreover, ACE-031 was well-tolerated at all dose levels, with only mild or transient side effects observed.

Effects of Single-Dose Treatment of ACE-031 on Lean Mass (Human)

Acceleron is developing ACE-031 for the treatment of patients with neuromuscular diseases, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), with the goal of improving strength and preserving physical function. By affecting the muscle directly, ACE-031 may one day offer hope to patients suffering from these debilitating diseases. 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.

Regulation of myostatin activity and muscle growth, Lee SJ et. al., PNAS, 98:9306-9311, 2001.