ACE-031 (Neuromuscular Disease treatment)
(Activin Type 2B)
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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.
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.
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.
Single Ascending Dose Phase 1 Study - Acceleron completed a clinical study of ACE-031 (A031-01) in 48 healthy postmenopausal women. These subjects received a single dose of ACE-031 across a range of dose levels. For a description of the study design, click here. For the poster presentation of the study results click here and click here for the accompanying press release.
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 altered biomarkers of fat metabolism (increased adiponectin and decreased leptin) and bone formation and resorption (increased BSAP and decreased CTX) at single doses of 1 and 3 mg/kg.
ACE-031 was generally well-tolerated at all dose levels. No serious adverse events were observed. The majority of adverse events were mild and transient.
Multiple Ascending Dose Phase 1 Study - A study in healthy postmenopausal women (A031-02), evaluating multiple doses of ACE-031, is currently ongoing. For more information on the study design, click here. Acceleron has presented preliminary results from this study. Click here for the poster presentation of these results and click here for the accompanying press release. As this study is not complete, final results are not yet available.
A031-02 randomized 60 subjects in 6 cohorts of 10 subjects each to receive ACE-031 or placebo (8:2) at dose levels ranging from 0.1 to 3 mg/kg given by SC injection every two or four weeks for a total of three or two doses, respectively, over a four week period. Subjects were followed for 12 weeks after their last dose. Although this safety study was not powered to assess statistically significant changes in endpoints, multiple exploratory statistical analyses were performed on the data.
Consistent with the findings of the single dose study (A031-01), multiple doses of ACE-031 given to healthy postmenopausal women were generally well tolerated and resulted in rapid and sustained effects on muscle, bone and fat. The most common adverse events were injection site reactions, headache and nosebleeds. The majority of adverse events were mild and transient. ACE-031 had a half-life of approximately 12 days, supportive of dosing every 2-4 weeks.
Mean total body lean mass measured by DXA at day 36 increased by 5.2% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks. This was statistically significant compared to the 0.4% increase in the placebo group (p=0.008) and was sustained through day 57. Significant increases were also seen at doses of 2 and 3 mg/kg every 4 weeks.
Mean thigh muscle volume measured by MRI at day 36 increased by 4.1% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks compared to 1.1% in the placebo group (p=0.012). Significant increases were also seen at 2 mg/kg given every 4 weeks. No statistically significant changes were observed in grip strength or functional tests in this healthy volunteer safety study.
Total Whole Body Lean Body Mass (DXA)
% Change (Mean +/- SE)
Thigh Muscle Volume (MRI)
% Change (Mean +/- SE)
ACE-031 treatment led to a rapid and significant increase in a biomarker of bone formation (BSAP) and decrease in a biomarker of bone resorption (CTX) versus placebo. Consistent with these effects, lumbar spine bone mineral density by DXA increased up to 3.4% in the 2 mg/kg every 4 week group from baseline to day 113, compared with a decrease of 1.5% in the placebo group (p=0.001).
ACE-031 treatment also led to significantly altered biomarkers of fat metabolism (increased adiponectin and decreased leptin) by day 8. Total body fat mass measured by DXA decreased up to 8.2% from baseline at day 113 in the 3 mg/kg every 4 week group compared with an increase of 0.5% in the placebo group (p=0.024).
Acceleron is developing ACE-031 for the treatment of patients with neuromuscular diseases, such as Duchenne Muscular Dystrophy (DMD), 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.
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.
Our Recommended Dosage
Inject 1ml bacteriostatic water into vial
Draw out 1iu per day and inject bilaterally at growth site
Draw out 5iu on day 1 and inject bilaterally at growth site
Then another 5iu on day 5 and inject bilaterally at growth site
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