# ACE-031 (ActRIIB-Fc)

> ACE-031 (ramatercept) is a dimeric fusion protein that links a fragment of human activin receptor type IIB to the Fc region of human IgG1. It acts as a soluble decoy that binds myostatin and related muscle-limiting signals. In a phase 1 trial in healthy postmenopausal women it increased lean mass, but it is not approved and is prohibited by WADA.

Canonical: https://peptideproperties.com/compounds/ace-031/

## Identity

- **Class:** Growth Factors, IGF & Myostatin Pathway
- **Also known as:** Ramatercept, ActRIIB-IgG1

## Key facts

- Generic name: ramatercept; development code ACE-031
- Class: soluble activin receptor type IIB (ActRIIB) Fc-fusion ligand trap
- Structure: dimer of ActRIIB fragment linked to human IgG1 Fc
- Phase 1 mean half-life: 10 to 15 days
- Not approved as a medicine; no PubChem record
- Prohibited under section S4.3 of the WADA 2024 Prohibited List

## What Is ACE-031?

ACE-031, also known by the generic name ramatercept, is a dimeric fusion protein that joins a fragment of human activin receptor type IIB (ActRIIB, gene ACVR2B) to the Fc portion of human immunoglobulin G1 (IgG1). It has not been approved as a medicine and is prohibited in sport by the World Anti-Doping Agency (WADA).[1]ACE-031 works as a soluble decoy receptor. Instead of blocking the receptor on muscle cells, it circulates and binds myostatin and other negative regulators of muscle mass, so fewer of those signals reach muscle tissue.[2]The only human study of ACE-031 among the cited papers is a phase 1 single ascending-dose trial in healthy postmenopausal women, which reported increases in lean mass and thigh muscle volume.[2] A larger body of animal research uses soluble ActRIIB-Fc proteins of the same design to probe muscle growth, cachexia, metabolism and fertility.[3][4]

## Chemical Structure and Molecular Identity

ACE-031 is a recombinant Fc-fusion protein, so it has no PubChem compound record, and no formula, molecular weight or CAS number is listed here. Each molecule is a dimer: two chains, each pairing the ligand-binding portion of human ActRIIB with a human IgG1 Fc segment.[1]The Fc portion is the constant region of an antibody. In ACE-031 it holds the two receptor fragments together as a dimer and, in the phase 1 trial, the molecule showed a mean half-life of 10 to 15 days.[2]PropertyDetailGeneric nameRamaterceptDevelopment codeACE-031Molecule typeDimeric Fc-fusion protein (ActRIIB fragment + human IgG1 Fc)Target ligands describedMyostatin and other negative regulators of muscle massMean half-life (phase 1)10 to 15 daysPubChem recordNoneFc-fusion design also gives analysts a test for authenticity. In a 2025 anti-doping study, the protease IdeS, which cleaves IgG Fc regions, could not cleave black-market ACE-031 products, confirming that they contained no Fc-fusion protein.[1]

## Research History and Development

ACE-031 grew out of research showing that soluble ActRIIB-Fc "traps" could block myostatin pathway signaling and enlarge muscle in mice. In normal or cachectic mice, ActRIIB-Fc led to muscle hypertrophy or prevented muscle loss.[3]Human testing reached a published phase 1 stage. In a double-blind, placebo-controlled trial, 48 healthy postmenopausal women were randomized 3:1 to ACE-031 (one of several dose levels, given once) or placebo. The study assessed safety, pharmacokinetics and pharmacodynamics.[2]Related ligand traps later reached the market for other indications. A 2026 review reported clinical approval of luspatercept, described there as an ActRIIB-Fc ligand trap for anemia, and sotatercept, an ActRIIA-Fc trap for pulmonary arterial hypertension. The review noted that neither agent consistently increased skeletal muscle mass in clinical trials.[5]Newer designs try to narrow the ligand profile. Researchers built ActRIIB:ALK4-Fc, a heterodimer that pairs the extracellular domains of ActRIIB and its natural type I partner ALK4, to sequester muscle-inhibiting ligands while sparing BMP9, a ligand that homodimeric ActRIIB-Fc also binds.[6]

## Mechanisms Studied in Research

ActRIIB-Fc proteins act as ligand traps: they bind TGF-beta family ligands that would otherwise signal through activin type II receptors. These receptors are shared by activins, GDF11 and myostatin and drive Smad2/3 signaling involved in muscle regulation, blood cell production and vascular balance.[5]The ligand range is broad. In one study, ActRIIB:Fc, used as a decoy that binds and sequesters activin, lowered follicle-stimulating hormone (FSH) in mice.[7] Surface plasmon resonance work showed that homodimeric ActRIIB-Fc also trapped the vascular regulator bone morphogenetic protein 9 (BMP9), whereas an engineered ActRIIB:ALK4-Fc heterodimer did not.[6]Receptor biology adds a further layer. Antibody studies found that myostatin and activins bind both ActRIIA and ActRIIB, and that blocking only one receptor gave partial signaling blockade and small muscle gains, while blocking both gave the maximal response.[3]Muscle metabolism is also affected. In mice, four months of ActRIIB-Fc treatment downregulated porin, an ADP/ATP shuttle, reduced oxidative phosphorylation, reduced capillary density, and altered regulators such as Pparβ, Pgc1α and Pdk4.[4] In a lung cancer cachexia model, researchers identified activin A, another ActRIIB ligand, as a likely driver of wasting and used ActRIIB-Fc as the decoy to counter it.[8]

## Key Findings From Published Studies

Human evidence for ACE-031 is limited to one phase 1 study; most other findings come from mice and monkeys treated with ActRIIB-Fc proteins.
### Human study
In healthy postmenopausal women, single-dose ACE-031 was generally well tolerated, with injection-site erythema among the adverse events. Exposure rose linearly across dose levels. In the highest-dose group, mean total body lean mass rose 3.3% by DXA and thigh muscle volume rose 5.1% by MRI at day 29. Serum biomarkers suggested effects on bone and fat metabolism.[2]
### Animal studies

- In mouse models of Duchenne muscular dystrophy, amyotrophic lateral sclerosis and disuse atrophy, the related heterodimer ActRIIB:ALK4-Fc increased muscle mass and function.[6]
- In mdx mice, a model of Duchenne muscular dystrophy, prolonged ActRIIB-Fc treatment caused extreme muscle fatigability, raised serum lactate and produced a severe metabolic myopathy.[4]
- In a mouse lung cancer cachexia model, ActRIIB-Fc combined with the ghrelin receptor agonist anamorelin increased lean mass, restored activity and improved survival; anamorelin alone did not. The benefit was limited to female mice and depended on ovarian function.[8]
- In 14 juvenile male rhesus macaques infected with simian immunodeficiency virus, ActRIIB.Fc produced greater gains in lean mass and body weight than placebo, without changing CD4 counts or viral copy numbers. Treated animals also had greater upper arm circumference and higher muscle myostatin expression.[9]
- In midlife female SAMP8 mice, ActRIIB:Fc lowered FSH, prevented egg chromosome and spindle misalignments and increased litter sizes.[7]
### Analysis of black-market products
Of 14 black-market products sold as ACE-031, 12 contained an ActRIIB-reactive protein, but mass spectrometry showed it was full-length human ActRIIB rather than ACE-031, mixed with many other proteins. A detection method developed for luspatercept also detected these products in serum.[1]Because black-market ACE-031 proved to be a different protein, identity confirmation by mass spectrometry and Fc-fusion testing on a certificate of analysis is essential.

## Regulatory and Research Status

ACE-031 is not an approved drug. It remains an investigational molecule and is banned in sport under section S4.3 of the WADA 2024 Prohibited List because of its potential performance-enhancing properties.[1]Despite the lack of approval, ACE-031 is sold as a research chemical on the black market, and testing found that products labeled ACE-031 contained a different protein entirely.[1] In rats, the black-market material remained detectable in serum for up to 48 hours, although the authors cautioned that the detection window in humans may differ.[1] Anti-doping laboratories can screen for products sold as ACE-031 with a gel electrophoresis and Western blot protocol originally developed to detect luspatercept, another ActRIIB-Fc fusion protein, in human serum.[1]Within the wider class, luspatercept and sotatercept have received approval for blood and vascular disorders rather than muscle wasting.[5] Researchers studying ActRIIB blockade for neuromuscular disease have also cautioned that its metabolic side effects argue against using it in isolation.[4]

## FAQ

**What is ACE-031?**
ACE-031, generic name ramatercept, is a dimeric fusion protein made of a human activin receptor type IIB fragment joined to the Fc portion of human IgG1. It circulates as a decoy receptor that binds myostatin and other negative regulators of muscle mass. It has been tested in a phase 1 trial but is not approved as a medicine.

**Is ACE-031 FDA approved?**
No. A 2025 anti-doping study states that ACE-031 has not been pharmaceutically approved. The related ligand traps luspatercept and sotatercept have been approved, but for anemia and pulmonary arterial hypertension, and a 2026 review noted that neither consistently increased skeletal muscle mass in clinical trials. ACE-031 is also prohibited under the WADA Prohibited List.

**Is ACE-031 the same as ramatercept?**
Yes. Ramatercept is the generic name for ACE-031, the development code used in the published phase 1 trial. Both names refer to the dimeric fusion protein that combines a human activin receptor type IIB fragment with the Fc part of human IgG1. It is also referred to as ActRIIB-Fc or ActRIIB-IgG1.

**What does the research on ACE-031 show?**
In a phase 1 trial in 48 healthy postmenopausal women, single-dose ACE-031 was generally well tolerated, and the highest-dose group showed a 3.3% rise in lean mass and a 5.1% rise in thigh muscle volume at day 29. Animal studies with ActRIIB-Fc proteins show muscle gains, but also fatigability and metabolic myopathy in dystrophic mice.

**How is ACE-031 different from bimagrumab?**
ACE-031 is a soluble receptor fusion protein that traps ligands such as myostatin before they reach muscle. Bimagrumab is an antibody that binds the activin type II receptors themselves, both ActRIIA and ActRIIB, at the ligand binding site. Research on bimagrumab found that blocking both receptors gave the maximal muscle response in mice.

**Do black-market ACE-031 products contain ACE-031?**
In one 2025 study, they did not. Of 14 products tested, 12 contained an ActRIIB-reactive protein, but mass spectrometry identified it as full-length human ActRIIB rather than the Fc-fusion protein ACE-031. The IdeS protease, which cleaves Fc regions, could not cleave the products, and many other proteins were also present.

## References

1. Reichel C, Filip T, Gmeiner G, et al. Gel Electrophoretic Detection of Black Market ACE-031. Drug testing and analysis 2025. PMID: 40312924
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. PMID: 23169607
3. Morvan F, Rondeau JM, Zou C, et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proceedings of the National Academy of Sciences of the United States of America 2017. PMID: 29109273
4. Relizani K, Mouisel E, Giannesini B, et al. Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy. Molecular therapy : the journal of the American Society of Gene Therapy 2014. PMID: 24861054
5. Tsuchida K. Clinical Applications of Ligand Traps Targeting Activin Type II Receptors. Anti-inflammatory & anti-allergy agents in medicinal chemistry 2026. PMID: 41487000
6. Li J, Fredericks M, Cannell M, et al. ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders. The Journal of clinical investigation 2021. PMID: 33586684
7. Bernstein LR, Mackenzie AC, Lee SJ, et al. Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice. Endocrinology 2016. PMID: 26713784
8. Queiroz AL, Dantas E, Ramsamooj S, et al. Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer. Nature communications 2022. PMID: 35941104
9. O'Connell KE, Guo W, Serra C, et al. The effects of an ActRIIb receptor Fc fusion protein ligand trap in juvenile simian immunodeficiency virus-infected rhesus macaques. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2015. PMID: 25466897