ACE-031 (Ramatercept)

What it is

ACE-031 is not a peptide from the chemistry lab but a biotechnologically produced protein: a dimeric fusion protein made of a fragment of the human activin receptor type IIB and the Fc portion of human IgG1, which keeps it in the blood for a long time. It was developed by Acceleron Pharma, for a time together with Shire, under the nonproprietary name ramatercept.

Three approaches target the same signaling pathway, and they should be kept apart. Follistatin is an endogenous protein that binds myostatin; bimagrumab is an antibody that attaches to the receptor; ACE-031 is a soluble replica of the receptor that traps the messengers before they arrive at the muscle cell. The World Anti-Doping Agency lists all three separately.

How it is supposed to work

Myostatin, technically GDF-8, is the body’s own brake on muscle growth: it binds to the activin receptor type IIB and limits muscle building via this signal. Animals without functioning myostatin are strikingly muscular — the starting point of the entire drug class.

ACE-031 does not act on the cell’s receptor but in front of it. As a soluble replica, it binds myostatin and other ligands of the same family, including activin A, and keeps them away from the actual receptor. The advantage of this breadth: it works more strongly than blocking myostatin alone. The disadvantage is the same sentence read backwards — the decoy also traps what it is not supposed to trap.

This is exactly where the program failed. The vascular side effects are attributed to the concomitant blockade of BMP9 and BMP10, two factors that are important for the stability of small blood vessels and the function of the inner lining of the vessels.

What was measured in humans

Phase 1 was conducted in 48 healthy postmenopausal women, double-blind and placebo-controlled, with a single dose between 0.02 and 3 mg/kg under the skin. The half-life was 10 to 15 days. In the highest dose group, total lean mass increased by 3.3 percent on day 29 (DXA) and thigh muscle volume by 5.1 percent (MRI), both statistically significant.

Phase 2 was conducted in ambulatory boys with Duchenne muscular dystrophy: 24 participants, 18 on ACE-031 under the skin every two to four weeks, 6 on placebo, 12 weeks of treatment, primary endpoint safety. Here too lean mass increased, by 3.6 and 4.1 percent versus 2.6 percent under placebo, and bone density of the lumbar spine increased by 4.4 percent in the higher regimen.

What did not increase was strength. Hand-held myometry remained practically unchanged in all groups; for knee extension, the figures were minus 3.6 and minus 3.3 percent versus minus 3.7 percent under placebo. In the 6-minute walk test, things looked better for the treated boys aged 10 and over — plus 4.5 and minus 3.2 meters versus minus 47.6 meters under placebo — but the scatter was large and the difference not significant.

The termination

The study was ended after the second dosing regimen. In the higher regimen, 5 of 9 boys had nosebleeds and 5 of 9 telangiectasias, that is, small dilated blood vessels in the skin; in the lower regimen, nosebleeds occurred in 1 of 9, and under placebo neither occurred in 6 participants. There were no serious events. The extension study with 11 participants was stopped for the same reason.

Clinical development was suspended in February 2011. On May 2, 2013, Acceleron and Shire ended their collaboration on ACE-031, stating that they would not resume development of this program. No new human data have appeared since.

What happened in animals

Eight-week-old mice weighed on average 16 percent more than control animals after 28 days of ACE-031; muscle wet weights increased by 33 percent in the soleus, 44 percent in the plantaris and 46 percent in the gastrocnemius, and fiber cross-sectional area in the plantaris by 57 percent — in both fiber types, unlike with pure myostatin inhibition. In 2026 a study in marmosets followed: 14 weeks of ACE-031, afterwards more lean mass than at the start and more strength in the isolated muscle.

What is sold on the gray market

A finding of its own, and a clear one. 14 black-market products on sale were examined in the laboratory. Only 12 contained a protein that responded to the activin receptor at all — and these 12 contained not ACE-031 but the complete human activin receptor IIB without the Fc portion, confirmed with a protease that cleaves Fc fusion proteins and found nothing to cleave here.

According to this analysis, what is sold as ACE-031 is a different molecule. The study figures on this page do not apply to it.

What the studies show

Attie et al., Muscle Nerve 2013 — phase 1 in 48 women

Double-blind, placebo-controlled single-dose escalation, 48 healthy postmenopausal women, randomized 3:1 to ACE-031 (0.02 to 3 mg/kg subcutaneously) or placebo. Half-life 10 to 15 days. In the 3 mg/kg group on day 29, lean mass plus 3.3 percent (DXA) and thigh muscle volume plus 5.1 percent (MRI). No functional measurement.

Campbell et al., Muscle Nerve 2017 — phase 2 in Duchenne

24 ambulatory boys, 18 on ACE-031 subcutaneously every two to four weeks, 6 on placebo, 12 weeks. Primary endpoint safety — and it decided the study: termination after the second dosing regimen because of nosebleeds and telangiectasias. Secondary: lean mass plus 3.6 and 4.1 percent versus 2.6 percent, bone density plus 4.4 percent; muscle strength unchanged.

Cadena et al., J Appl Physiol 2010 — the mouse model

Eight-week-old C57BL/6 mice, 28 days of ACE-031 or vehicle. Body weight 16 percent above control, muscle wet weights plus 26 to 46 percent, fiber cross-sectional area in the soleus plus 22 percent (type I) and 28 percent (type II) with unchanged fiber distribution.

Reichel et al., Drug Test Anal 2025 — what is sold

Laboratory analysis of 14 black-market products. Only 12 contained a protein that responded to the activin receptor, and these 12 contained the complete activin receptor IIB instead of ACE-031. Main component about 58.4 kDa, alongside many other proteins.

Where the data stop

A functional gain is not established. Muscle strength measured by hand-held myometry did not change appreciably in any group in the Duchenne study, and the 6-minute walk test did not reach significance, with scatter larger than the differences. More mass did not mean more performance here — the same finding that has also held back other substances in this class.

The human basis is small and short: a single dose in 48 women, an unpublished multiple-dose study in 70 women and 12 weeks of treatment in 24 boys. There are no studies in healthy adults who train, and no data beyond one year either. The explanation of the side effects via BMP9 and BMP10 is an attribution from vascular biology, not a measurement in the study participants. And the program has been terminated since 2013.

Status, approval and legal

ACE-031 is not an approved medicine in Germany, the EU or the US; clinical development was suspended in 2011 and ended on May 2, 2013, and both Duchenne studies are listed in the registry as terminated. A related substance of the same design is approved for a different indication: luspatercept, in the EU since June 25, 2020, for anemia in myelodysplastic syndromes and beta-thalassemia. In sport, ACE-031 is prohibited at all times — the WADA Prohibited List 2026 explicitly names it in section S4.3 as an example of decoy receptors, and class S4.3 is non-specified, so it applies in and out of competition. In the German annex to Section 2(3) of the Anti-Doping Act, ACE-031 is not named; under the myostatin function modifiers, it lists only follistatin and its derivatives and stamulumab.

Safety

The safety profile is the reason this substance does not exist as a product. Dose-limiting are vascular side effects: nosebleeds, gum bleeding and telangiectasias, in the Duchenne study in the higher dosing regimen each in 5 of 9 boys, in none of 6 under placebo. They led to the termination of both studies, even though none was classified as serious. Also common were erythema at the injection site (6 of 9 in the higher regimen, 3 of 6 under placebo) and headaches (3 of 9). The half-life of 10 to 15 days means that an undesirable effect cannot be switched off quickly; as a fusion protein, the substance is also potentially immunogenic, and interactions have never been studied. For people with vascular diseases or a bleeding tendency, in pregnancy and breastfeeding, and for children and adolescents outside of studies, it is not an option; for tested athletes it means a ban.

Sources

• Attie et al., Muscle Nerve 2013 — phase 1 study in 48 healthy women
• Campbell et al., Muscle Nerve 2017 — phase 2 study in Duchenne muscular dystrophy
• ClinicalTrials.gov NCT01099761 — study data and adverse event tables of the Duchenne study
• Cadena et al., J Appl Physiol 2010 — ACE-031 in the mouse model, muscle mass and fiber types
• Cadena et al., PLoS One 2026 — ACE-031 in the marmoset
• Suh & Lee, J Bone Metab 2020 — review of myostatin inhibitors, attribution of the vascular side effects to BMP9 and BMP10
• Reichel et al., Drug Test Anal 2025 — analysis of 14 black-market products sold as ACE-031
• EMA — Reblozyl (luspatercept), fusion protein of a modified ActRIIB domain and IgG1 Fc
• Fierce Biotech, May 2, 2013 — Acceleron and Shire end their collaboration on ACE-031
• WADA — Prohibited List 2026, section S4.3 (decoy receptors, example ACE-031)