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ACE-031

Also known as ramatercept, ActRIIB-Fc, ACVR2B-Fc, soluble activin receptor type IIB fusion protein

A myostatin-trapping receptor fusion protein whose clinical development was stopped for vascular bleeding events.

early-clinical Recovery & tissue research chemical

At a glance

Category
Recovery & tissue
Status
research chemical
Made from
recombinant A recombinant dimeric fusion protein (activin receptor type IIB extracellular domain linked to human IgG1 Fc) produced in cell culture; a glycosylated protein of this size cannot be made by chemical peptide synthesis.
Route
subcutaneous
Half-life
Long, on the order of 10-15 days, as expected for an Fc fusion protein recycled through the neonatal Fc receptor. This mean half-life was measured in the phase 1 single-ascending-dose study 2, and the 2-4 week dosing intervals used in the DMD trial reflect it 1.
Onset
Measurable increases in lean mass were detectable within 4 weeks of a single dose - total lean mass was up 3.3% by DXA at day 29 in the 3 mg/kg cohort 2
Molecular weight
approximately 78-80 kDa for the glycosylated dimer
Sequence
Not a peptide. A recombinant dimeric fusion protein: the extracellular domain of human activin receptor type IIB linked to the Fc portion of human IgG1.

Development discontinued. Acceleron Pharma and Shire halted the Duchenne muscular dystrophy trials in 2011 on safety grounds - the programme had been on clinical hold since February 2011 - and announced on 2 May 2013 that they had concluded the collaboration and would not restart development 5. The extension study record on ClinicalTrials.gov is marked terminated "based on preliminary safety data" 6. ACE-031 is not approved anywhere and is not in development. It is nonetheless sold as a research chemical.

Doping status: Prohibited. Decoy activin receptors are named explicitly, with ACE-031 given as the example, under WADA S4.3.

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Myostatin and related TGF-beta superfamily ligands restrain skeletal muscle growth by signalling through activin receptor type IIB. ACE-031 is the extracellular ligand-binding domain of that receptor, fused to an antibody Fc region to make it a stable, long-circulating dimer. It works as a decoy: it binds circulating ligands before they can reach the receptor on muscle. The Fc fusion is what gives it a two-week half-life and allows monthly dosing.

It worked. In healthy postmenopausal women, a single subcutaneous dose produced statistically significant increases in total lean body mass and thigh muscle volume within a month 2 - an unusually clean pharmacodynamic result for a first-in-human study. Effects on bone turnover markers and fat mass were also seen.

The failure was one of selectivity, and it is the central fact about this compound. Activin receptor IIB does not bind only myostatin. It also binds activin A and B, GDF-11, and - critically - BMP9 and BMP10. BMP9 and BMP10 signalling through ALK1 and endoglin on endothelial cells is essential for vascular quiescence and integrity; the same pathway is disrupted in hereditary haemorrhagic telangiectasia, a genetic disease whose cardinal features are recurrent nosebleeds and cutaneous telangiectasias. ACE-031 mopped up BMP9 and BMP10 along with myostatin, and produced a phenocopy of that disease.

This is why the programme was stopped and why the whole class moved on. Later agents in this space were deliberately made more selective: bimagrumab targets the receptor with an antibody, and apitegromab, domagrozumab and landogrozumab neutralise myostatin or its precursor directly rather than blocking the receptor. The lesson - that broad ligand trapping at ActRIIB carries vascular risk - is the compound's main scientific legacy.

What the research shows

ACE-031 has genuine controlled human data, which is unusual among compounds in this category, and that data is what condemns it. A phase 1 single-ascending-dose study in 48 healthy postmenopausal women showed real increases in muscle mass. The subsequent phase 2 in boys with Duchenne muscular dystrophy was stopped early after the second dosing regimen because of epistaxis and telangiectasias, and the drug was permanently discontinued in 2013. It did not fail for lack of effect; it failed on safety.

Research in humans

Two published trials. Attie and colleagues (Muscle & Nerve, 2013) randomised 48 healthy postmenopausal women 3:1 to a single subcutaneous dose of ACE-031 (0.02-3 mg/kg) or placebo, and reported a 3.3% increase in total lean mass by DXA (p = 0.03) and a 5.1% increase in thigh muscle volume by MRI (p = 0.03) at day 29 in the 3 mg/kg group 2. Campbell and colleagues (Muscle & Nerve, 2017) reported the randomised, double-blind, placebo-controlled ascending-dose trial in ambulatory boys with Duchenne muscular dystrophy, dosed subcutaneously every 2-4 weeks. The study was stopped after the second dosing regimen because of epistaxis and telangiectasias 1. Efficacy signals were trends only and not statistically significant: a trend toward preservation of six-minute walk distance against decline on placebo, and trends toward increased lean mass and bone mineral density with reduced fat mass 1.

Animal and lab research

ActRIIB-Fc constructs produce large, reproducible increases in muscle mass across species, including in dystrophic mouse models, and also increase bone mass. The vascular liability was not anticipated from those models, which is itself instructive about the limits of preclinical safety screening for this target.

Caveats. The DMD trial was terminated before its planned dose escalation completed, so the efficacy question was never answered - the trends reported are hypothesis-generating at best, from an incomplete study in a small paediatric population. The phase 1 study was single-dose only, so it says nothing about what repeated administration does, which is precisely where the harm emerged. There is no long-term human safety data because the programme was stopped. Anyone using this compound today is using a drug that a sponsor withdrew from development after observing bleeding events in children.

What it is used for

  • Duchenne muscular dystrophy - the discontinued clinical indication, tested in ambulatory boys before the trial was stopped 1
  • Investigated for muscle wasting, sarcopenia and cancer cachexia before discontinuation
  • Sold and used in bodybuilding for muscle hypertrophy, notwithstanding the reason it was withdrawn

Dosing

Dose
Trial doses: 0.02-3 mg/kg subcutaneously in the phase 1 single-dose study; the DMD phase 2 used repeated subcutaneous dosing and was stopped during escalation.
Frequency
every 2-4 weeks in the DMD trial, reflecting the two-week half-life
Route
subcutaneous
Duration
Not established. The repeat-dose study was terminated on safety grounds.
  • There is no safe established dosing regimen for this compound. The regimen that was being tested is the one that was stopped, after the second dosing regimen, for epistaxis and telangiectasias 1.
  • The vascular adverse events emerged with repeated dosing 1; the single-dose phase 1 study reported ACE-031 as generally well tolerated, with injection site erythema as the notable adverse event 2. A tolerated first dose provides no reassurance about the second and third.
  • Because of the long half-life of 10-15 days 2, if adverse effects appear there is no rapid way to withdraw the drug. Exposure persists for weeks after the last injection. This is a materially different risk profile from a short-acting peptide.
  • A small bodybuilding self-dosing scene does exist and is captured in the section below. It is thin compared with the peptide compounds in this category, because ACE-031 is an 80 kDa Fc-fusion protein that is expensive and hard to source rather than a simple synthetic peptide, and the doses that circulate bear no rational relationship to the trial doses.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Phase 1 single ascending dose in healthy volunteers

published trial

Source: Muscle & Nerve, 2013

Single dose0.02-3 mg/kg subcutaneously, one administration per participant, escalated between cohorts

One dose, in healthy adults. It says nothing about repeated administration, which is where the vascular adverse events in the trial below appeared.

Phase 2 trial in Duchenne muscular dystrophy (terminated)

published trial

Source: Muscle & Nerve, 2017

Repeat dosingsubcutaneous injection every 2-4 weeks, with escalation between cohorts
Terminationthe study was stopped during escalation after epistaxis and telangiectasias appeared

This is reproduced because it is the regimen that was stopped, not one that was completed — there is no schedule for this compound that anyone finished. With a half-life of around two weeks, exposure persists for weeks after the last injection, so there is no quick way to withdraw the drug once such effects appear.

Bodybuilding self-dosing pattern (user-reported)

user protocol — not validated

Source: Bodybuilding forums; a small and largely dormant scene

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

Reported doseroughly 1 mg every one to two weeks, or about 0.5 mg once weekly, subcutaneously
Reported rationale for the low doseusers note the trial-level dose of around 20 mg per week is prohibitively expensive, so they inject far less
Reported stackingsometimes combined with follistatin or other purported myostatin inhibitors, compounding blockade of the same pathway

This is a genuine but marginal practice, and the doses are not derived from anything: the trials used weight-based dosing in the 0.02-3 mg/kg range 2, while the flat 0.5-1 mg amounts users inject are chosen mainly by what they can afford, not by any pharmacological reasoning. The single most important fact is what they are injecting: a biologic whose development was permanently halted because it caused nosebleeds and telangiectasias in the children it was trialled in 15. Its two-week half-life means that if those vascular effects appear there is no way to withdraw it quickly. Combining it with follistatin stacks blockade of the same pathway and should be expected to stack the risk. Sourcing is a further problem in itself, since an 80 kDa glycosylated Fc-fusion protein cannot be verified for identity, correct folding or aggregation by the buyer, and aggregated material is markedly more immunogenic.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
1 mg
Solvent
bacteriostatic water (0.9% benzyl alcohol)
Storage
Reconstituted at 2-8 °C, never frozen. Lyophilised powder at 2-8 °C or frozen, protected from light. No stability data exist for grey-market material.

Worked example

1 mg vial + 1 ml bacteriostatic water = 1 mg/ml. Note that trial dosing was weight-based in mg/kg, so a 1 mg vial is a small fraction of a studied dose for an adult.

Do not shake. An 80 kDa glycosylated Fc fusion protein aggregates readily on agitation, and aggregated Fc fusions are considerably more immunogenic than monomeric protein. Let the diluent run down the vial wall. Discard if cloudy or if particulates are visible.

Work it out for ACE-031

Safety

Side effects

  • Epistaxis (nosebleeds) - a trial-stopping adverse event 1, attributed to off-target inhibition of BMP9 and BMP10
  • Telangiectasias - dilated small vessels visible on the skin, the second trial-stopping finding 1
  • Gingival bleeding - the sponsors described participants experiencing minor nosebleeds, gum bleeding and small dilated blood vessels in the skin, which resolved after treatment stopped 5
  • Injection site reactions - injection site erythema was reported in the phase 1 single-dose study 2
  • Anti-drug antibody formation, a general risk with Fc fusion proteins that is amplified by aggregated material
  • Theoretical effects on erythropoiesis and reproductive endocrinology from activin blockade
  • Rapid muscle hypertrophy without corresponding tendon adaptation, a recognised concern across myostatin-pathway agents

Do not use if

  • Any bleeding disorder, anticoagulant or antiplatelet therapy, or personal or family history of hereditary haemorrhagic telangiectasia - the drug produces a pharmacological phenocopy of that disease
  • Active or previous malignancy - activin A is growth-inhibitory in several epithelial tissues and blocking it is not obviously safe in that setting
  • Pregnancy and breastfeeding: no data; the pathway is central to developmental biology
  • Children and adolescents - ambulatory boys with Duchenne muscular dystrophy were the population in which the trial-stopping events were observed 1
  • Competitive athletes under the WADA code: prohibited at all times under S4.3, "Agents preventing activin receptor IIB activation", where ACE-031 is named as the example of a decoy activin receptor and which is a non-Specified substance class 4

Interactions

Not systematically studied. Combination with anticoagulants or antiplatelet agents is mechanistically ill-advised given the bleeding signal. Combining ACE-031 with follistatin, bimagrumab or myostatin antibodies compounds blockade of the same pathway and should be expected to compound its risks. No formal interaction studies were completed before the programme was discontinued.

Sources