ACE-031 Research

Human development of ACE-031 ended in 2011. A randomized Phase 2 trial in ambulatory boys with Duchenne muscular dystrophy was stopped after its second dosing regimen, for safety ^[1]. The sponsor-filed registry record for that trial, NCT01099761, gives the reason as "Based on preliminary safety data." An open-label extension, NCT01239758, was terminated on the same grounds. No sponsor has taken the compound into humans since. This article sets out what the published record shows, what it does not show, and who produced it.

What ACE-031 is, and why its identity sits in a protein registry

ACE-031, also called ramatercept, is not a peptide. It is a recombinant fusion protein combining the extracellular ligand-binding region of human activin receptor type IIB with the Fc region of human IgG1. The FDA substance registry records it as a glycosylated protein of two identical 343-residue subunits, with sixteen disulfide links. It works as a circulating decoy, capturing ligands that would otherwise signal through that receptor, including myostatin, activin A, activin B and GDF-11.

Because it is a protein rather than a small molecule, PubChem holds no compound record for ACE-031. PubChem compound searches under that name, under ramatercept, and under the CAS number carried on legacy substance registry entries all return nothing. That CAS number does resolve to substance registry entries. Its identity is recorded in a protein substance registry instead of a chemical compound database. The FDA protein substance registry holds a molecular formula and the full subunit sequence for ramatercept, and both describe a two-subunit glycoprotein rather than a small molecule. Because it is not a peptide, a peptide purity percentage on a vendor listing does not describe it.

The Duchenne trial and why it was halted

The trial was randomized, double-blind and placebo-controlled ^[1]. Twenty-four boys were dosed, nine in each of two active groups and six on placebo. A planned third group was never dosed. Campbell and colleagues report that the study "was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias" ^[1].

The same human paper also states that ACE-031 "was not associated with serious or severe adverse events" ^[1]. Both statements are true at once. The registry record posted zero serious adverse events in every arm. The events that ended the trial were graded non-serious, and they ended it anyway.

The posted adverse event table for NCT01099761 shows the signal concentrated in the more intensively exposed group. Nosebleeds occurred in 1 of 9 boys in the lower-exposure group, 5 of 9 in the higher-exposure group, and 0 of 6 on placebo. Telangiectasias, which are small dilated vessels in the skin, occurred in 0 of 9, 5 of 9 and 0 of 6. The registry's own primary endpoint, subjects with drug-related adverse reactions, was 1 of 9, 6 of 9 and 0 of 6.

Acceleron Pharma and Shire were the two companies developing the compound. They stated publicly in April 2011 that participants had minor nosebleeds, gum bleeding, or small dilated blood vessels within the skin. They also stated that these events resolved fully on stopping treatment. Gum bleeding appears nowhere in the posted adverse event table for this trial. That April 2011 wording survives as quotation in later reporting, because the sponsor's original release is no longer retrievable.

What ACE-031 research shows about muscle mass and strength

In that human trial, percent change in total lean body mass by DXA was 3.6% and 4.1% in the two active groups, against 2.6% on placebo. Standard errors were 1.3, 1.5 and 1.8, so the arms overlap heavily. Neither the registry record nor the trial paper reports that lean mass difference as statistically significant ^[1]. Muscle strength by hand-held myometry was flat and indistinguishable from placebo in all four muscle groups measured. Knee extension declined in all three groups.

The six-minute walk result is quoted often, and it rests on small subgroups. The paper reports "a trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant)" ^[1]. The registry data show the apparent separation is carried by the older stratum, where the placebo group fell 47.6 meters. Stratum sizes are not reported, and the whole trial had six placebo subjects.

The only human study of ACE-031 whose own report describes statistically significant increases was a single-dose Phase 1 trial in 48 healthy postmenopausal women ^[2]. At day 29, that single dose had raised total body lean mass by 3.3% on DXA and thigh muscle volume by 5.1% on MRI in the highest-exposure women, both at P = 0.03 ^[2]. That study measured no strength or function endpoint. No human study of ACE-031 has demonstrated a strength or functional benefit.

One academic review reads the Duchenne data differently. Rybalka and colleagues describe ACE-031 and three other myostatin-pathway drugs as producing mild but statistically significant increases in muscle or lean mass on imaging in human Duchenne patients ^[5]. That conflicts with the trial's own registry record and with its published paper, neither of which reports the lean mass difference as statistically significant ^[1]. The registry record and the trial paper report this trial directly, while the review summarizes a whole class of drugs.

The proposed mechanism for the vascular events

The leading explanation is that a homodimeric ActRIIB-Fc trap captures more than its intended targets. Kumar and colleagues write that such a construct increases skeletal muscle mass by sequestering the SMAD2/3-pathway ligands activin A, activin B, GDF8 and GDF11 ^[4]. The same sentence adds that it "is also thought to cause undesirable vascular effects by sequestering the SMAD1/5/8-pathway ligand BMP9" ^[4]. BMP9 signals through ALK1 and endoglin to maintain endothelial quiescence. Loss of function in those same genes causes hereditary hemorrhagic telangiectasia, whose cardinal features are nosebleeds and mucocutaneous telangiectasia.

This account is a hypothesis. No human mechanistic study has confirmed BMP9 sequestration in people who received ACE-031. The Kumar paper is an in vitro protein engineering study ^[4]. Its conflict of interest statement records that all authors are or have been employees of Acceleron Pharma, and that all own or have owned stock in it ^[4]. The explanation for why this molecule affected blood vessels is therefore the patent holder's own.

Preclinical promise, and a class that failed in humans

Rodent work supported the clinical program. Soluble activin type IIB receptor administration promoted skeletal muscle growth independent of fiber type in mice ^[6]. Targeting the same receptor improved muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy ^[7][8]. Those animal results predicted neither the human efficacy shortfall nor the vascular findings.

Other drugs aimed at the same pathway failed separately in humans. A Phase 2 trial of domagrozumab in 120 boys with Duchenne muscular dystrophy missed its primary endpoint ^[10]. The difference from placebo on the four-stair climb was 0.27 seconds, 95% CI -7.4 to 7.9, p = 0.94, with no significant between-group differences in any secondary clinical endpoint ^[10]. Taldefgrobep alfa produced robust dose-dependent suppression of free myostatin in humans, yet its Phase 2/3 trial did not meet its pre-specified futility threshold, and the program was terminated in 2019 ^[11]. An academic review of the class reports mild gains in muscle mass in human trials, and no matching improvement in strength ^[5].

What products sold as ACE-031 actually contain

An accredited anti-doping laboratory analyzed 14 black-market products sold as ACE-031 ^[3]. Only 12 contained any ACVR2B-immunoreactive protein at all. Mass spectrometry and immunoblotting showed that those 12 contained full-length human activin receptor IIB rather than ACE-031 ^[3]. IdeS protease could not cleave them, which confirmed the absence of an Fc fusion. Those same 12 products contained many other proteins besides the main compound ^[3].

Eleven of the twelve carried His-tags, which are purification tags added during recombinant production ^[3]. The genuine molecule is a glycosylated protein made in mammalian cells, and those eleven came from a bacterial expression system instead. Of the remaining two products, one contained black-market follistatin 344, and one contained no protein at all, with the growth hormone secretagogue ipamorelin identified instead ^[3]. None of the 14 was ACE-031. The investigators declined to give the black-market products to humans, stating that doing so was not ethically justifiable, and they used rats instead ^[3]. That analysis was funded by the World Anti-Doping Agency and a German federal ministry, and its authors declare no conflicts of interest ^[3]. The paper also records that ACE-031 is prohibited at all times under the 2024 WADA list ^[3]. The WADA listing sits in the hormone and metabolic modulators section, and it applies in competition and out of competition. That prohibition reaches anyone who competes in a tested sport.

Regulatory status

ACE-031 is not approved by any regulator, anywhere, for any indication. The FDA's own drug label and approved-drug databases hold no record for ramatercept. No marketing application was ever filed, so nothing was withdrawn from any market and nothing was refused. Development was discontinued by Acceleron Pharma, the sponsor. Acceleron and Shire ended their collaboration on 2 May 2013 and confirmed that the ACE-031 program would not be restarted. The two companies stated that additional animal and laboratory toxicology work showed the findings do not support further development. Those 2013 sponsor statements also survive as quotation in later reporting rather than as retrievable documents.

Two kinds of record are commonly mistaken for approvals. Acceleron announced in August 2010 that the FDA had granted orphan drug designation and Fast Track designation for Duchenne muscular dystrophy. Both designations trace to that announcement, and neither has been verified against the FDA's primary designation database. Either way, that was seven months before the trials were halted, and a designation is a development incentive rather than an approval. Separately, the FDA substance registry entry for ramatercept carries a status field reading "approved", which refers to validation of that record and not to any drug approval.

Two related molecules from the same original company are approved, and their approvals say nothing about ACE-031. Sotatercept is an activin receptor type IIA trap approved for pulmonary arterial hypertension in adults. Luspatercept is a modified ActRIIB-Fc trap approved for anemia in beta thalassemia and in certain myelodysplastic syndromes. Both differ from ACE-031 in receptor or modification, in indication and in safety record.

Who produced the evidence

Every human study of ACE-031 was sponsored, run and co-authored by Acceleron Pharma, which held the patent and was later acquired by Merck. The Phase 1 paper lists its first author at Acceleron's Department of Medical Research ^[2]. PubMed carries no affiliation for its other nine authors, though several appear with Acceleron affiliations elsewhere. The Duchenne trial paper has an academic first author and Canadian and US clinical sites, and four of its ten authors carry Acceleron affiliations ^[1].

The Duchenne trial paper's abstract closes by calling myostatin inhibition a promising therapeutic approach for Duchenne muscular dystrophy ^[1]. That verdict sits inside the paper reporting the terminated trial. The foundational rodent pharmacology is likewise sponsor work ^[6].

The newest and most favorable result on ACE-031 is sponsor-linked too. A 2026 animal study in common marmosets reports greater muscle mass and increased ex vivo force production ^[9]. Its competing interests statement records that co-authors were former employees of the company holding the patent ^[9]. It is a non-human primate study published fifteen years after the human program was halted, and it reports nothing about human safety.

The unflattering findings come from both sides. The registry record and the trial paper that carry the negative results are themselves sponsor-filed and sponsor co-authored ^[1]. Two independent contributions stand out: the black-market analysis, funded by an anti-doping body ^[3], and an academic review of why the class failed ^[5]. The academic review's own conflict of interest statement declares that its first author is a consultant to a pharmaceutical company ^[5].

Conclusion

The human evidence base for ACE-031 is two published trials covering 72 dosed subjects, one of them terminated for safety. At least two of the four registered trials never posted results. The 70-subject multiple-dose Phase 1 study that completed in 2011 has neither posted results nor a located publication. Its repeat-exposure safety data in healthy volunteers never reached the public record. The terminated open-label extension posted no results either. What remains is a small, sponsor-generated body of work showing lean mass changes without strength changes, alongside a vascular signal in children that ended the program.

Frequently Asked Questions

Is ACE-031 approved anywhere? No. It is not approved by any regulator, anywhere, for any indication, and no marketing application was ever filed. Acceleron Pharma, the sponsor, announced orphan and Fast Track designations in August 2010, and a designation is a development incentive rather than an approval. The FDA substance registry status field reading "approved" refers to validation of that record, not to drug approval.

Does ACE-031 have a CAS number or a molecular formula? It is a protein rather than a small molecule, and PubChem holds no compound record for ACE-031 or for ramatercept. A CAS number does appear on legacy substance registry entries, and a PubChem compound search for that number returns nothing either. The FDA protein substance registry does hold a molecular formula and the full subunit sequence for ramatercept. Both describe a two-subunit glycoprotein rather than a small molecule.

Were the adverse events that stopped the Duchenne trial serious? The published paper states that ACE-031 was not associated with serious or severe adverse events ^[1], and the registry record posted zero serious adverse events in every arm. The trial was stopped after its second dosing regimen anyway, for nosebleeds and telangiectasias ^[1]. Both statements are true at once, and the non-serious grading did not prevent the program from ending.

Has black-market material sold as ACE-031 been tested? Yes. An accredited anti-doping laboratory tested 14 products and found that none of them was ACE-031 ^[3]. Twelve contained full-length activin receptor IIB with no Fc fusion, alongside many other proteins. One contained follistatin 344, and one contained no protein at all, with ipamorelin identified instead ^[3].

References

1. 1

   Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: results of a randomized, placebo-controlled clinical trial. Muscle Nerve. 2017;55(4):458-464. PMID 27462804.
2. 2

   Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013;47(3):416-423. PMID 23169607.
3. 3

   Reichel C, Filip T, Gmeiner G, Thevis M. Gel electrophoretic detection of black market ACE-031. Drug Test Anal. 2025;17(10):1934-1946. PMID 40312924.
4. 4

   Kumar R, Grinberg AV, Li H, et al. Functionally diverse heteromeric traps for ligands of the transforming growth factor-beta superfamily. Sci Rep. 2021;11(1):18341. PMID 34526551.
5. 5

   Rybalka E, Timpani CA, Debruin DA, et al. The failed clinical story of myostatin inhibitors against Duchenne muscular dystrophy: exploring the biology behind the battle. Cells. 2020;9(12):2657. PMID 33322031.
6. 6

   Cadena SM, Tomkinson KN, Monnell TE, et al. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. J Appl Physiol (1985). 2010;109(3):635-642. PMID 20466801.
7. 7

   Pistilli EE, Bogdanovich S, Goncalves MD, et al. Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. Am J Pathol. 2011;178(3):1287-1297. PMID 21356379.
8. 8

   Carlson CG, Bruemmer K, Sesti J, et al. Soluble activin receptor type IIB increases forward pulling tension in the mdx mouse. Muscle Nerve. 2011;43(5):694-699. PMID 21462203.
9. 9

   Cadena SM, Bogdanovich S, Khurana TS, et al. ACE-031, a soluble activin type IIB receptor, increases muscle mass and strength in the common marmoset (Callithrix jacchus). PLoS One. 2026;21(2):e0342666. PMID 41686840.
10. 10

    Wagner KR, Abdel-Hamid HZ, Mah JK, et al. Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy. Neuromuscul Disord. 2020;30(6):492-502. PMID 32522498.
11. 11

    Muntoni F, Byrne BJ, McMillan HJ, et al. The clinical development of taldefgrobep alfa: an anti-myostatin adnectin for the treatment of Duchenne muscular dystrophy. Neurol Ther. 2024;13(1):183-219. PMID 38190001.