Tests show the myostatin inhibitor ACE031 can safely increase muscle size, a finding that could benefit many forms of neuromuscular disease
ACE031, a laboratory-modified protein developed by Acceleron Pharma of Cambridge, Mass., has shown promise as a therapy to increase muscle mass, based on results of a trial in healthy volunteers. The company will now test it in Duchenne muscular dystrophy (DMD).
Kenneth Attie, vice president for medical research at Acceleron, and colleagues, presented the findings April 14, 2010, at the annual meeting of the American Academy of Neurology (AAN), held in Toronto.
The investigational protein ACE031 is designed to build muscle and increase strength by preventing the interaction of naturally occurring muscle-inhibiting proteins, such as myostatin, with their docking sites (receptors) on muscle fibers.
Myostatin and other muscle-growth limiters normally dock on these muscle-fiber receptors and send signals through them.
ACE031 lures myostatin away from its natural receptor and renders it powerless to limit the growth of muscles.
About the new findings
The investigators measured safety, tolerability, lean muscle mass, muscle volume and markers of bone and fat metabolism in 48 healthy, postmenopausal women who received a single subcutaneous injection of ACE031 or a placebo.
ACE031 was given at six different dosage levels. In each dosage group, six women received the drug and two others received a placebo injection.
In general, the drug was safe and well tolerated. There were no drug-related serious adverse events, and no one produced antibodies to ACE031 (which would have indicated rejection of the laboratory-engineered protein by the immune system).
The long half-life of ACE031 in the body may permit dosing of only one or two injections per month, the researchers said.
In the group that received 1 milligram per kilogram of body weight of ACE031, there was an average increase of 3.5 percent in thigh-muscle volume. In the group that received 3 milligrams per kilogram of body weight of ACE031, there was an increase of thigh-muscle volume of up to 5.1 percent.
There were increases in calf-muscle volume, but they were not as great, the investigators reported.
They also noted increases in biological markers of bone formation and decreases in biological markers of bone destruction in the ACE031-treated women compared to the placebo groups.
The investigators are now beginning a study of ACE031 in DMD. For details, see Study of ACE-031 in Subjects With Duchenne Muscular Dystrophy.
Meaning for people with neuromuscular diseases
The drug has the potential to help patients with a variety of neuromuscular diseases, because almost all these disorders involve loss of muscle mass and strength.
Inhibitors of myostatin have received much attention from the neuromuscular disease research community, ever since it was found several years ago that people and animals with a genetic deficiency of myostatin appear to have large muscles and good strength without apparent ill effects.
A few years ago, an experimental drug called MYO029, an antibody that blocks myostatin, was developed and tested by Wyeth Pharmaceuticals (now part of Pfizer). In 2008, the company announced the drug was safe and well tolerated but that it did not improve muscle strength or function and did not increase muscle growth in trial participants.
ACE031 is a different type of molecule from MYO029 and may prove more effective. Acceleron describes ACE031 as an ActRIIB signaling inhibitor, a molecule that blocks myostatin and related proteins from singaling through the ActRIIB receptor. (For details, see Frequently Asked Questions on Acceleron's site.)
If tests in DMD are promising, it's possible ACE031 could be developed for treatment for this and other neuromuscular diseases.