ACE-031
Ramatercept (soluble activin receptor type IIB-Fc fusion protein, ActRIIB-IgG1 Fc)
ACE-031 (ramatercept) is an ActRIIB-IgG1 Fc ligand trap that increased lean mass in Phase 1 and Phase 2 human studies, but the Duchenne Phase 2 program was stopped after dose-related epistaxis and telangiectasia (PMID 23169607; PMID 27462804; NCT01099761; PMID 41686840).
Last updated: 2026-03-09
Safety Summary
In Phase 1, ACE-031 was 'generally well-tolerated' with adverse events limited to injection site erythema (PMID 23169607). In the Phase 2 Duchenne trial (NCT01099761), adverse event rates per arm were: injection site erythema 3/9 at 0.5 mg/kg q4wk, 6/9 at 1.0 mg/kg q2wk, 3/6 placebo; epistaxis 1/9 and 5/9 active vs 0/6 placebo; telangiectasia 5/9 at 1.0 mg/kg and 0/15 all others; headache 1/9, 3/9, and 1/6 respectively. No serious adverse events were reported in either trial (PMID 23169607; PMID 27462804; NCT01099761). The vascular adverse events (epistaxis, telangiectasia, gum bleeding) were later attributed to inhibition of BMP-9, a ligand critical for ALK1-dependent vascular maintenance; mutations in ALK1 or its ligands cause hereditary hemorrhagic telangiectasia (HHT) in humans, and ACE-031 effectively created a pharmacological phenocopy of this condition (PMID 41686840). The marmoset NHP study reported no adverse effects after 14 weeks of dosing: blood chemistries remained within normal ranges and no organ abnormalities were observed at necropsy (PMID 41686840). Biomarker changes in Phase 1 included statistically significant increases in bone-specific alkaline phosphatase and adiponectin, and decreases in leptin and C-terminal telopeptide (PMID 23169607).
Known Side Effects
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Who Should NOT Use This
ACE-031 inhibits BMP-9, critical for vascular maintenance through ALK1 signaling. The clinical program's vascular adverse events (epistaxis, telangiectasia, gum bleeding) were attributed to this mechanism. Individuals with HHT or related vascular fragility would face greatly increased risk (PMID 27462804; PMID 41686840).
Given dose-dependent epistaxis and telangiectasia in the Phase 2 trial (5/9 at 1.0 mg/kg), concurrent bleeding disorders or anticoagulant use would compound vascular risk (PMID 27462804; NCT01099761).
ACE-031 broadly inhibits activin signaling critical for reproductive hormone regulation and placental development. FSH suppression was observed in Phase 1 (PMID 23169607). No reproductive safety data exists.
ACE-031 is specifically prohibited by WADA under S4.3 (PMID 40312924).
A 2025 analytical study found that 12 of 14 tested internet products contained full-length ACVR2B and impurities rather than authentic ACE-031 Fc fusion protein; one contained follistatin 344 and another contained ipamorelin (PMID 40312924).
Talk to Your Doctor
Before considering ACE-031, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-7]
Evidence Assessment
Tier 3 is appropriate because ACE-031 has randomized Phase 1 and Phase 2 human data, including a placebo-controlled Duchenne trial (NCT01099761) with statistically significant lean mass results (P=0.023, P=0.012), and two completed Phase 1 studies (NCT00755638, NCT00952887), but no Phase 3 data and no approval. The Phase 2 program was terminated after the second dosing regimen for vascular safety reasons (PMID 23169607; PMID 27462804; NCT01099761). A terminated extension study (NCT01239758) also exists.
1A single ascending-dose study of muscle regulator ACE-031 in healthy volunteersNCT00755638PMID 23169607
Attie KM et al. - Muscle & Nerve (2013) - Phase 1 RCT (double-blind, placebo-controlled, single ascending dose) - N=48 healthy postmenopausal women (randomized 3:1 ACE-031:placebo across 6 dose cohorts)
Single SC doses of ACE-031 (0.02-3 mg/kg) were generally well-tolerated. At 3 mg/kg: 3.3% increase in total body lean mass (P=0.03, DXA), 5.1% increase in thigh muscle volume (P=0.03, MRI) at day 29. AUC and Cmax increased linearly. Mean half-life 10-15 days. Significant favorable changes in bone (increased BSAP, decreased CTX) and fat metabolism biomarkers (increased adiponectin, decreased leptin). Adverse events limited to injection site erythema.
Limitations: Single-dose study only; postmenopausal women may not represent broader populations; short follow-up; sponsor-led trial.
2Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trialNCT01099761PMID 27462804
Campbell C et al. - Muscle & Nerve (2017) - Phase 2 RCT (randomized, double-blind, placebo-controlled, ascending dose) - N=24 ambulatory boys with DMD (9 at 0.5 mg/kg, 9 at 1.0 mg/kg, 6 placebo)
Registry results showed statistically significant lean mass increases (3.6% at 0.5 mg/kg P=0.023, 4.1% at 1.0 mg/kg P=0.012 vs 2.6% placebo by ANCOVA) and lumbar spine BMD increase (4.4% at 1.0 mg/kg, P=0.039). Trends for maintenance of 6MWT distance. Study terminated after second cohort due to epistaxis (5/9 at high dose) and telangiectasia (5/9). No serious adverse events.
Limitations: Terminated prematurely; small sample; only two active regimens reached; pediatric DMD population limits generalizability; sponsor-led trial.
3Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber typePMID 20466801
Cadena SM et al. - Journal of Applied Physiology (2010) - Animal study (mouse) - C57BL/6 mice, 8 weeks old, treated for 28 days
First report that ACE-031 increases muscle mass independent of fiber-type expression. Mean body weight +16%. Individual muscle weights increased 26-46% (soleus +33%, plantaris +44%, gastrocnemius +46%, EDL +26%). Fiber CSA: soleus type I +22%, type II +28%; plantaris +57%. No change in fiber-type distribution.
Limitations: Mouse-only; short 28-day duration; species differences in myostatin/activin biology limit translatability.
4ACE-031, a soluble activin type IIB receptor, increases muscle mass and strength in the common marmoset (Callithrix jacchus)PMID 41686840
Cadena SM et al. - PLOS ONE (2026) - Animal study (non-human primate, marmoset) - N=12 marmosets (8 treated, 4 control; 6 male, 6 female)
14 weeks of weekly ACE-031 (3 mg/kg SC) produced: significant increase in lean body mass from baseline (weeks 2-14, time x treatment interaction P=0.0012); significant increase in arm lean mass (P=0.0225); biceps brachii type I fiber CSA +34%, type II +20%; significant increase in specific twitch and tetanic force of EDL. No fiber-type distribution changes. Well tolerated: normal blood chemistries, no organ abnormalities. Discussion attributes ACE-031 clinical vascular AEs to BMP-9 inhibition and notes KER-065 (next-gen chimera with 400-fold lower BMP-9 activity) completed Phase 1 without vascular AEs.
Limitations: Small sample (n=4 control, n=8 treated). One control animal showed unexplained weight gain. No main effect of treatment in ANOVA for body weight (P=0.68) or lean mass (P=0.75). Different muscles used for histology vs function. Co-authors were former Acceleron employees. Preprint version (PMID 41256654) originally used one-tailed t-tests; published version corrected to two-tailed.
5Gel Electrophoretic Detection of Black Market ACE-031PMID 40312924
Reichel C et al. - Drug Testing and Analysis (2025) - Analytical study with rat detection experiment - 14 black-market products analyzed; N=30 rats (10 per timepoint group) for detection study
None of 14 BM products contained authentic ACE-031. 12 contained full-length ACVR2B (not the Fc fusion); 1 contained follistatin 344; 1 contained ipamorelin. Products were produced in bacterial rather than mammalian expression systems (no glycosylation). Rat serum detection: positive at 24h (all), mostly positive at 48h, negative at 168h. Not detectable in urine. Confirms ACE-031 is WADA S4.3-prohibited.
Limitations: Not an efficacy study. Used mislabeled BM material, not authentic clinical-grade ACE-031. Rat detection window may not translate to humans due to high dose (10 mg/kg) and species differences.
6The relationship between myodural bridges, hyperplasia of the suboccipital musculature, and intracranial pressurePMID 36054096
Zheng N et al. - PLOS ONE (2022) - Animal study (rat) -- ACE-031 used as tool compound - N=36 rats (12 per group)
Used ACE-031 (5 mg/kg weekly x 16 weeks, local injection) for muscle hyperplasia model. 30% increase in suboccipital muscle fiber CSA; reduced atrophy markers; gastrocnemius +20% heavier and +25% contraction force.
Limitations: ACE-031 used as tool compound, not the study focus. Local injection differs from systemic clinical use. Small n for some analyses.
7The relationship between myodural bridge, atrophy and hyperplasia of the suboccipital musculature, and cerebrospinal fluid dynamicsPMID 37919345
Yang H et al. - Scientific Reports (2023) - Animal study (rat) -- ACE-031 used as tool compound - N=46 rats
Confirmed muscle hyperplasia with ACE-031. Increased CSF secretion rate (0.935 vs 0.711 uL/min, P<0.05) and reabsorption rate in ACE-031 group.
Limitations: ACE-031 used as tool compound. Local injection. Study focused on CSF dynamics.