ACE-031
for Duchenne Muscular Dystrophy
ACE-031 is an investigational protein therapeutic that increases skeletal muscle by preventing growth inhibitors in the TGF-β superfamily from interacting with receptors on muscle cells called activin type IIB receptors (ActRIIB). Acceleron is developing ACE-031 in collaboration with Shire for treatment of Duchenne muscular dystrophy (DMD).
Mechanism of Action
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 myostatin (GDF8), interact with the ActRIIB receptor and send an “off” signal to stop muscle growth. When these “off” switch molecules are absent or blocked, muscle mass increases dramatically. There is substantial evidence of the role of GDF8 and related molecules in muscle growth. Cattle, rodents, dogs, and even humans with naturally occurring mutations in GDF8 have markedly increased musculature and strength.
ACE-031 is a recombinant fusion protein consisting of the extracellular portion of the human ActRIIB receptor linked to a portion of a human antibody. This creates a freely circulating, decoy version of ActRIIB which interferes with myostatin and other related members of the TGF-β superfamily that normally limit the growth and regeneration of muscle.
In animal models of muscle disease, including a model of DMD, the mdx mouse, treatment with ACE-031 or a rodent version of the molecule increased skeletal muscle mass and strength. In Phase 1 studies in healthy postmenopausal women, treatment with ACE-031 resulted in dose-dependent increases in lean mass. These results suggest that ACE-031 may have potential to increase muscle mass and improve strength and function in human muscle diseases such as DMD.
Disease Overview
DMD is a debilitating and fatal genetic disorder characterized by the progressive loss of muscle strength and function. It primarily affects boys and occurs in approximately 1 in every 3,500 male births. DMD is caused by genetic mutations that result in the absence of dystrophin, a protein necessary to maintain the structural integrity of muscle fibers.
This condition leads to damage and deterioration of skeletal muscles, which eventually become infiltrated by non-functional scar and fatty tissue. As a result, boys with DMD experience a relentless decline in muscle strength that impairs their ability to walk, breathe and live independently. Many spend the majority of their lives using wheelchairs and eventually lose their upper body function as well. Few survive beyond their late-20s when their heart and respiratory muscles weaken and eventually fail.
Clinical Need
No therapies are currently approved for the treatment of DMD. Although corticosteroids have been shown to improve walking capacity and preserve respiratory function, their benefits are temporary and are often accompanied by undesirable side effects including weight gain and progressive bone loss.
There is a tremendous unmet need for therapies that preserve or improve muscle quality, strength and function for boys with DMD. In a mouse model of DMD, treatment with a mouse form of ACE-031 increased muscle mass and strength, reduced intramuscular fat and fibrosis, increased expression of utrophin (a structurally and functionally related protein to dystrophin) and reduced release of creatine kinase (a marker of muscle injury).
Whereas there are various types of mutations in the dystrophin gene that cause DMD, there is a need for therapies that could be broadly applicable for patients. Unlike experimental therapies that target specific dystrophin genetic mutations, ACE-031 targets proteins that regulate muscle growth and thus may be applicable to DMD patients regardless of their dystrophin genotype.
We are designing clinical trials to evaluate the potential for ACE-031 to provide disease-modifying effects on muscle quality that translate into durable benefits on strength and function for boys with DMD. Acceleron is partnering with research and clinical institutions worldwide and has built strong collaborations with the following organizations to advance the development of ACE-031 in DMD:
Parent Project Muscular Dystrophy
Muscular Dystrophy Association
Clinical Trials
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 repeated doses of ACE-031, has also been completed. For more information on the study design, click here.
A Phase 2 study in patients with Duchenne muscular dystrophy (A031-03) has been conducted in Canada. The main purpose of the study was to determine if ACE-031 is safe and well-tolerated in children with DMD. Another purpose of the study was 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.
In all of the clinical trials conducted to date, increases in muscle mass were observed with ACE-031 treatment. 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. The majority of these events 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 preliminary safety data with the FDA and Health Canada, Acceleron ended the A031-03 DMD study and the follow-on extension study, A031-06.
Acceleron remains committed to the development of ACE-031. We intend to resume studies of ACE 031 in DMD as soon as possible pending further analysis of safety data and following discussions with regulatory agencies.