Ramatercept, ACVR2B-Fc
Evidence Grade C — Moderate human evidence. 12 published studies, 10 human. 4 registered clinical trials.
ACE-031 is a fusion protein — not a peptide — that was developed to intercept the signals that limit muscle growth, intended as a treatment for Duchenne muscular dystrophy (DMD). It was discontinued after clinical trials revealed bleeding-related safety concerns caused by the drug inadvertently trapping signals important for blood vessel health.
12 published studies: 10 human, 1 animal, 1 in-vitro, 0 reviews
ACE-031 has no marketing authorisation. A Phase I trial in healthy women showed increased lean mass and decreased fat mass. A Phase II trial in DMD (24 patients) showed lean body mass increases but was discontinued due to bleeding-related safety concerns (epistaxis, telangiectasias, and gum bleeding), likely caused by inhibition of BMP-9/10 vascular signalling.
ACE-031 is a large fusion protein (~90 kDa), not a peptide. Its clinical development was halted. The non-selective ligand-trapping profile — capturing beneficial vascular signalling molecules alongside the intended muscle-growth targets — illustrates the challenge of targeting the TGF-beta superfamily. Acceleron subsequently developed more selective agents.
ACE-031 functions as a soluble decoy version of the activin type IIB receptor. It circulates in the bloodstream and captures myostatin, activin, and related signalling molecules before they can reach cell-surface receptors, preventing the 'stop growing' signals they normally deliver to muscle. However, it also captures BMP-9 and BMP-10, which regulate blood vessel formation — a non-selectivity that likely caused the bleeding side effects.
Research suggests a Phase I trial in healthy women showed meaningful increases in lean mass and decreases in fat mass, and a Phase II DMD trial (24 patients) showed lean body mass increases. However, nosebleeds, skin blood vessel changes, and gum bleeding emerged — likely caused by the drug capturing vascular signalling molecules (BMP-9/BMP-10) alongside its intended muscle targets. The safety profile was considered unmanageable, and the developer (Acceleron Pharma) pivoted to more selective agents, eventually developing luspatercept (Reblozyl), which received FDA approval for a different condition. ACE-031 illustrates the challenge of targeting the TGF-beta superfamily, where many related signals share the same receptors.
Extension Study of ACE-031 in Subjects With Duchenne Muscular Dystrophy
Study of ACE-031 in Subjects With Duchenne Muscular Dystrophy
A Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of ACE-031 in Healthy Postmenopausal Women
A Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of ACE-031 (ActRIIB-IgG1)in Healthy Postmenopausal Volunteers
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Somatropin has been available since the mid-1980s and is one of the most established peptide therapies. It is sold under numerous brand names including Genotropin, Humatrope, Norditropin, and Omnitrope (the first biosimilar approved in the US, 2006). Approved indications include childhood and adult growth hormone deficiency, Turner syndrome, children born small for gestational age, Prader-Willi syndrome, idiopathic short stature, and short stature from chronic kidney disease. Daily injection has been the main burden of somatropin therapy, particularly for paediatric patients who may require years of treatment. This has driven the development of once-weekly alternatives (somatrogon and somapacitan), which are gradually changing the treatment landscape. Annual treatment costs remain substantial, and concerns about misuse in anti-ageing and performance enhancement contexts are ongoing.
Tesamorelin is marketed as Egrifta SV (approved November 2010) for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. In clinical trials, it reduced visceral fat by approximately 15% compared to a 5% increase with placebo, and this reduction was sustained with continued treatment. Tesamorelin occupies a unique niche — it is the only approved GHRH analogue and the only medication specifically approved for HIV-associated lipodystrophy. Beyond its approved indication, it has attracted research interest for potential effects on liver fat, cognitive function, and peripheral neuropathy. Fat reduction reverses when treatment stops, and it is not approved for general weight loss or body composition purposes.
Somatrogon is marketed as Ngenla (approved June 2023) for paediatric growth hormone deficiency in children aged 3 years and older. In the pivotal trial, once-weekly somatrogon produced growth rates equivalent to daily somatropin injections (10.1 cm/year versus 9.8 cm/year), confirming that reducing injection frequency does not compromise growth outcomes. Ngenla represents a meaningful advance for paediatric patients and their families, reducing injections from 365 to 52 per year. Treatment adherence has been a persistent challenge with daily growth hormone, and weekly dosing is expected to improve long-term outcomes through better compliance. Somatrogon competes directly with somapacitan (Sogroya), the other approved weekly growth hormone, creating a new generation of less burdensome treatment options.
