ActRIIB-Fc fusion (~77.5 kDa) Phase 2 Halted
ACE-031
A recombinant ActRIIB-Fc fusion protein that traps myostatin and related TGF-β ligands; Phase II DMD trial halted in 2011 due to vascular adverse events driven by off-target BMP9/10 sequestration.
In Plain English:
ACE-031 is a large fusion protein — not a short peptide — made by attaching the binding domain of the activin type IIB receptor (ActRIIB) to a human antibody backbone (IgG1 Fc). It works like a sponge: floating in the bloodstream and catching myostatin, the molecule your body uses to cap muscle growth. In clinical trials on boys with Duchenne muscular dystrophy, it produced encouraging lean-mass increases and slowed decline on the 6-minute walk test. The trials were stopped in 2011 when participants developed nosebleeds and small dilated blood vessels (telangiectasia), later traced to ACE-031 also catching BMP-9 and BMP-10 — proteins that maintain vessel wall integrity. Development was formally abandoned in 2013. Black-market vials are sold as research chemicals, but gel-electrophoresis analysis (Reichel et al., 2025) has confirmed adulteration and mislabelling in this market. WADA prohibits it in all competition, in and out of season.
Research Maturity
Phase 2 Halted (47 PubMed papers on ACE-031 / ActRIIB-Fc; 2 human RCTs (Phase 1 + halted Phase 2)+ Studies)
Focus
Body Composition
Muscle Wasting Disorders
Origin
Recombinant fusion protein produced in CHO (Chinese hamster ovary) cells. Comprises the extracellular domain of human activin receptor type IIB (ActRIIB / ACVR2B) fused via a linker to the Fc region (hinge-CH2-CH3) of human IgG1. Developed by Acceleron Pharma (programme licensed to Shire); INN: Ramatercept. CAS 1621169-52-5. PubChem CID 118732224.
Mechanism
ACE-031 acts as a soluble decoy receptor, sequestering myostatin (GDF-8) and related TGF-β superfamily ligands — including GDF-11, activin A, activin B, BMP-9, and BMP-10 — before they can bind cell-surface ActRIIA/ActRIIB receptors on skeletal muscle. Blockade prevents SMAD2/3 phosphorylation and downstream transcription of atrogenes (MuRF1, MAFbx), de-repressing protein synthesis and satellite-cell proliferation. The broad ligand-capture profile is also the source of its key adverse effect: BMP-9 (GDF-2) and BMP-10 signal through the ALK1 receptor on endothelial cells to maintain vascular homeostasis; their sequestration destabilises vessel walls, producing telangiectasia and epistaxis.
Outcome
Phase 1 (healthy postmenopausal women, single-dose, n=48, PMID 23169607): 3.3% lean-mass gain and 5.1% increase in thigh-muscle volume at 3 mg/kg; half-life 10–15 days; well-tolerated at lower doses. Phase 2 (DMD boys, multi-dose, NCT01099761, PMID 27462804): trend toward maintained 6-minute walk test distance vs. placebo decline; increased lean body mass and bone mineral density; trial terminated after second dosing cohort due to epistaxis and telangiectasias. Non-human primate study (marmoset, 2025 bioRxiv preprint, PMID 41256654): significant increases in body weight, lean mass, and EDL isometric twitch force vs. controls.
