ACE-031 (ACVR2B)

ACE-031 description

Engineered decoy receptor ACE-031 is synthetic version of transmembrane protein receptor ACVR2B (activin receptor type IIB). ACE-031 is strong myostatin inhibitor: It binds with high affinity to myostatin (GDF-8), thus preventing myostatin from binding and activating its natural ACVR2B receptor and suppressing of muscle growth (preventing myostatin from delivering the muscle growth-limiting signal). In this way, ACE-031 significantly helps in the development and maintenance of muscles. Due to this property and ability, ACE-031 can help in patients with a symptom of neuromuscular diseases (muscle weakness and worsening).

Myostatin (GDF-8)

Myostatin (GDF-8) is a myokine, released by myocytes, it is a member of the TGF beta protein family. Myostatin (GDF-8) acts on muscle cells’ autocrine function to inhibit muscle cell growth and differentiation. In humans it is encoded by the MSTN gene, and the MSTN gene is located on the long (q) arm of chromosome 2 at position 32.2. Human Myostatin with total molecular weight is 25.0 kDa consists of 2 identical subunits, each consisting of 109 amino acid residues.

ACE-031 history

ACE-031 being developed by Acceleron Pharma for the treatment of Duchenne Muscular Dystrophy (DMD). They started Phase I clinical trials on ACE-031 in Canada in September 2008, with 48 patients involved. This study was concluded in July 2009. Then, in year 2010 ACE-031 received orphan designation from the US Food and Drug Administration (FDA) for treating DMD disease. Phase II clinical trials was started in April 2010, with 24 patients involved. At the end however, the clinical development of ACE-031 was suddenly ended in February 2011 and did not continue.

Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy is a fatal genetic disorder that is characterised by a gradual weakening of muscle strength and functions, due to genetic mutations. This leads to worsening of skeletal muscles and results in non-functional scar and fatty tissue. Duchenne muscular dystrophy patients experience a relentless decline in muscular strength, which spoils their ability to breathe, walk and live independently. This obscure disease affects boys and occurs in 1 out of every 3,500 male births, is estimated that there are more than 100 000 patients in the USA only.

Performed clinical trials and ACE-031 results

In ACE-031 phase I clinical trials started in September 2008, 48 Duchenne muscular dystrophy patients were involved. In the primary outcome measure the safety and tolerability of the ACE-031 were estimated. After administering once for 29 days by subcutaneous injection with doses of 0.02 to 3 mg/kg to boys with DMD, the muscle volume has increased by 3.5% when compared to 0.2% in placebo patients.

In the secondary outcome measure, pharmacokinetic (PK) and pharmacodynamic (PD) effects of the ACE-031 were evaluated. In phase II clinical trials started in April 2010, a total of 24 subjects treated for a period of 12 weeks were enrolled into the study; 18 received ACE-031 and 6 placebo. 

The pharmacodynamic effects of ACE-031 treatment were assessed by a battery of motor function test that included the 6-Minute Walk Test, the 10-Minute Walk/Run Test, the 4-Stair Climb Test and the Gower Maneuver (GW). Muscle strength was assessed by hand-held myometry and fixed system testing. Body composition (i.e., spine BMD, lean mass, and fat mass) was assessed by whole body and lumbar spine DXA scans. Pulmonary function was assessed by forced vital capacity (FVC), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP).

ACE-031 safety was evaluated through observation of the incidence and severity of adverse events. ACE-031 was generally well-tolerated, not associated with serious or severe adverse events. But the study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias.

Scientifically investigated possible benefits of ACE-031

• • Can help in patients with a symptom of neuromuscular diseases, promising Duchenne muscular dystrophy treatment 
  • Significantly helps in the development and maintenance of muscles
  • Strong anabolic & anti-catabolic effects, preventing muscle loss
  • Reduction of excess body fat

ACE-031 possible side-effects

In clinical trials were observed during treatment with ACE-031 by some participants these side effects:

• • Pain or irritation at the injection site
  • Nasal bleeding
  • Gum bleeding
  • Widespread blood vessels
  • Increased body temperature

However, most of these side effects have completely disappeared after discontinuation of treatment and ACE-031 use. Between words: It turns out that muscles are not only undergoing rapid growth but also blood vessels.

ACE-031 FAQ

Are Myostatin inhibitors in sport illegal?

YES: In 2008, the World Anti-Doping Agency banned substances that inhibit myostatin. However, if myostatin drugs do reach the medical market, they could help tens of thousands of patients with genetic diseases like muscular dystrophy.

What is ACE-031?

ACE-031 is scientifically engineered synthetic version of transmembrane protein receptor ACVR2B (activin receptor type IIB)

What is DMD?

DMD – Duchenne muscular dystrophy is a fatal genetic disorder with a gradual weakening of muscle strength and functions, due to genetic mutations.

What is ACE-031 used for?

ACE-031 being developed by Acceleron Pharma for the treatment of Duchenne Muscular Dystrophy (DMD).

Is Myostatin a hormone?

YES: Myostatin is an autocrine and paracrine hormone produced by muscle cells that inhibits muscle differentiation and growth.

What is the result of low levels of Myostatin?

The lack of myostatin promotes growth of skeletal muscle, and blockade of its activity has been proposed as a treatment for various muscle-wasting disorders.

Can you inhibit Myostatin?

YES: ACE-031 is strong and potent inhibitor of Myostatin GDF-8.

What is a Myostatin deficiency?

Myostatin-related muscle hypertrophy is a rare genetic condition characterized by reduced body fat and increased skeletal muscle size.

Why is Myostatin important?

Myostatin is a negative regulator of myoblast proliferation and differentiation.

Which genes are involved in muscle growth?

IGF-1 controls muscle growth with help from the myostatin (MSTN) gene (GDF-8), which produces the myostatin protein.

ACE-031 dosage

Despite the fact that in the scientific studies and clinical trials performed, are mentioned also higher doses of ACE-031, rather (in accordance with our opinion) a safer dose should be considered not more than 100-200 mcg of ACE-031 in single injection.

Overview

ACE-031 is scientifically engineered synthetic version of transmembrane protein receptor ACVR2B (activin receptor type IIB), that binds with high affinity to myostatin (GDF-8). It was developed by Acceleron Pharma for the treatment of Duchenne Muscular Dystrophy (DMD).  ACE-031 significantly helps in the development and maintenance of muscles. Clinical trial and scientific studies with ACE-031 demonstrated that the drug directly enhances muscle mass and strength in preclinical models of neuromuscular diseases. ACE-031 haves strong ability to prevent muscle loss or restore lost muscle resulting from a disease or its treatment. ACE-031 was generally well-tolerated, not associated with serious or severe adverse events, but Acceleron Pharma studies was stopped in February 2011 and did not continue.