ACE-031
ACVR2B-Fc / ActRIIB-Fc
ACE-031 is a soluble form of the activin receptor type IIB (ActRIIB) fused to an IgG1 Fc domain, developed by Acceleron Pharma as a decoy receptor to trap myostatin and related TGF-beta ligands before they can signal through their natural receptors. By sequestering myostatin, activin A, and GDF-11, it was designed to promote muscle growth and inhibit muscle wasting. Clinical development was discontinued due to safety concerns including epistaxis and telangiectasias observed in Duchenne muscular dystrophy trials.
Mechanism of Action
Soluble activin receptor type IIB fusion protein that acts as a decoy receptor, binding and neutralizing myostatin, activin, GDF-11, and other TGF-beta superfamily ligands. Removes multiple negative regulators of muscle growth simultaneously.
Research Protocols
For research purposes only. Not medical advice.
Clinical trial protocols used 0.3-3mg/kg intravenously every 2 weeks. Research was halted after Phase 2 due to epistaxis and telangiectasia in Duchenne muscular dystrophy patients.
Research Notes
Clinical Research Status
ACE-031 completed a Phase 2 trial in boys with Duchenne muscular dystrophy (DMD) but was discontinued in 2011 after safety signals including nosebleeds, gum bleeding, and skin telangiectasias (dilated blood vessels) emerged. A Phase 1 trial in healthy postmenopausal women demonstrated dose-dependent increases in lean body mass and thigh muscle volume. Acceleron subsequently developed ACE-083 (a locally-acting version) and ACE-2494 with modified selectivity, though neither has achieved approval for muscle indications.
Key Published Findings
The Phase 1 trial showed a single dose of ACE-031 increased lean body mass by up to 1.0 kg and decreased fat mass, with sustained effects over 4 weeks post-dose. The DMD Phase 2 trial was halted after dose-limiting vascular effects (epistaxis, telangiectasia) were observed at higher doses. Research determined that the broad ligand-trapping profile, particularly inhibition of BMP-9 and BMP-10 (which regulate vascular homeostasis), caused the vascular adverse effects rather than myostatin inhibition itself.
Safety Profile
The primary safety concern was vascular effects attributed to BMP-9/10 inhibition: epistaxis (nosebleeds), telangiectasias, and gum bleeding, which are manifestations of disrupted vascular integrity similar to hereditary hemorrhagic telangiectasia. These vascular effects were dose-dependent and reversible upon discontinuation. The lesson from ACE-031's failure is that broadly targeting the ActRIIB ligand family produces unacceptable off-target vascular effects, necessitating more selective approaches to myostatin inhibition.
Comparison to Related Compounds
ACE-031's broad ligand trap approach contrasts with more selective myostatin-specific antibodies (stamulumab, domagrozumab) that avoid BMP-9/10 inhibition. Follistatin similarly neutralizes multiple TGF-beta family members but through a different mechanism and has not shown the same vascular toxicity pattern. Acceleron's subsequent ACE-083, a locally-injected compound, attempted to avoid systemic vascular effects but was also discontinued in FSHD trials due to insufficient efficacy.
Community Observations
ACE-031's clinical failure is frequently cited as a cautionary example of how broad-spectrum target approaches in the myostatin pathway carry unpredictable risks from inhibiting related ligands. The compound demonstrated that pure myostatin inhibition alone may not be sufficient for clinically meaningful muscle gains, while non-selective approaches produce unacceptable side effects. Researchers have largely moved toward more targeted approaches (anti-myostatin antibodies, bimagrumab targeting ActRII directly) informed by ACE-031's failure mode.
Half Life
~10-15 days
Reconstitution
Sterile saline for IV infusion
Storage
Lyophilized
Store at -20C. Protect from light.
Reconstituted
Prepare fresh for each administration.
US Legal Status
Also Known As
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