ACE-031 (ACVR2B-Fc)

Overview

ACE-031 is a soluble form of the activin type IIB receptor (ActRIIB) fused to an IgG1 Fc domain. It functions as a decoy receptor, binding and neutralizing myostatin and other TGF-beta superfamily members that normally limit muscle growth. Originally developed by Acceleron Pharma for Duchenne muscular dystrophy (DMD), ACE-031 reached Phase 2 clinical trials before development was halted due to vascular side effects including nosebleeds and telangiectasia. In healthy volunteers, a single dose produced significant increases in lean mass and reductions in fat mass within 29 days.

ACE-031 acts as a ligand trap for members of the TGF-beta superfamily. By mimicking the extracellular domain of the ActRIIB receptor, it intercepts myostatin (GDF-8), activin A, activin B, and GDF-11 before they can bind cell-surface receptors and activate Smad2/3 signaling. Blocking this pathway removes the natural brake on muscle protein synthesis and satellite cell proliferation, resulting in rapid skeletal muscle hypertrophy. The Fc fusion domain extends circulating half-life through FcRn-mediated recycling and provides bivalent ligand binding.

Phase 1 data showed statistically significant lean mass increases (average +1.7%) after a single IV dose in healthy postmenopausal women.

Phase 2 trial in DMD patients showed improvements in lean body mass and bone mineral density, but trial was halted due to vascular adverse events.

Preclinical models demonstrate robust prevention of muscle loss in disease states through myostatin pathway inhibition.

Phase 1 trial subjects showed concurrent fat mass reductions alongside lean mass gains, suggesting favorable nutrient partitioning.

Mechanism

No. ACE-031 is a soluble activin receptor that acts as a ligand trap, while follistatin directly binds myostatin. Both ultimately inhibit myostatin signaling, but through different mechanisms. Theoretically combined use might be synergistic, but clinical data on combinations doesn't exist.

Research areas

• ACE-031 is a soluble form of the activin type IIB receptor (ActRIIB) fused to an IgG1 Fc domain. It functions as a decoy receptor, binding and neutralizing myostatin and other TGF-beta superfamily members that normally limit muscle growth. Originally developed by Acceleron Pharma for Duchenne muscular dystrophy (DMD), ACE-031 reached Phase 2 clinical trials before development was halted due to vascular side effects including nosebleeds and telangiectasia. In healthy volunteers, a single dose produced significant increases in lean mass and reductions in fat mass within 29 days.
• ACE-031 acts as a ligand trap for members of the TGF-beta superfamily. By mimicking the extracellular domain of the ActRIIB receptor, it intercepts myostatin (GDF-8), activin A, activin B, and GDF-11 before they can bind cell-surface receptors and activate Smad2/3 signaling. Blocking this pathway removes the natural brake on muscle protein synthesis and satellite cell proliferation, resulting in rapid skeletal muscle hypertrophy. The Fc fusion domain extends circulating half-life through FcRn-mediated recycling and provides bivalent ligand binding.
• Phase 1 data showed statistically significant lean mass increases (average +1.7%) after a single IV dose in healthy postmenopausal women.
• Phase 2 trial in DMD patients showed improvements in lean body mass and bone mineral density, but trial was halted due to vascular adverse events.
• Preclinical models demonstrate robust prevention of muscle loss in disease states through myostatin pathway inhibition.
• Phase 1 trial subjects showed concurrent fat mass reductions alongside lean mass gains, suggesting favorable nutrient partitioning.
• DMD trial data showed increases in bone mineral density, consistent with known effects of ActRIIB pathway modulation on bone metabolism.
• ACE-031 has never been approved for human use and clinical development was discontinued. Any product sold as ACE-031 is of unknown origin and quality. The compound is a complex fusion protein sensitive to degradation, making DIY sourcing extremely risky with high contamination likelihood.

Research notes

• Nosebleeds (epistaxis) - most frequently reported adverse event
• Gum bleeding
• Telangiectasia (dilated small blood vessels visible on skin)
• Skin erythema (redness)
• Minor injection site reactions
• Recurrent or severe nosebleeds
• Development of new or worsening telangiectasia
• Unexplained bleeding from any site
• Signs of hereditary hemorrhagic telangiectasia-like syndrome
• Severe skin reactions or widespread erythema
• NEVER approved for human use - clinical development discontinued
• History of bleeding disorders or vascular malformations
• Concurrent anticoagulant or antiplatelet therapy
• Known hypersensitivity to Fc fusion proteins
• Pregnancy or breastfeeding

Pharmacokinetics

• ACE-031 acts as a ligand trap for members of the TGF-beta superfamily. By mimicking the extracellular domain of the ActRIIB receptor, it intercepts myostatin (GDF-8), activin A, activin B, and GDF-11 before they can bind cell-surface receptors and activate Smad2/3 signaling. Blocking this pathway removes the natural brake on muscle protein synthesis and satellite cell proliferation, resulting in rapid skeletal muscle hypertrophy. The Fc fusion domain extends circulating half-life through FcRn-mediated recycling and provides bivalent ligand binding.

References

• pubmed.ncbi.nlm.nih.gov/28131562/
• pubmed.ncbi.nlm.nih.gov/15473835/
• pubmed.ncbi.nlm.nih.gov/23539721/
• pubmed.ncbi.nlm.nih.gov/24691811/

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