ACE-031 — Research, Dosing & Price Guide

ACE-031 is a recombinant fusion protein consisting of the extracellular domain of the activin receptor type IIB (ActRIIB) fused to a human IgG1 Fc domain. It functions as a soluble decoy receptor or 'myostatin trap,' intercepting myostatin and other TGF-β superfamily ligands before they can bind to muscle cells and inhibit growth. Originally developed by Acceleron Pharma for Duchenne muscular dystrophy, it produced remarkable muscle-building effects in early clinical trials before development was paused due to minor vascular side effects.

ACE-031 circulates in the bloodstream as a decoy receptor, binding with high affinity to multiple TGF-β superfamily ligands that normally suppress muscle growth. Its primary targets include myostatin (GDF-8), activin A, activin B, and GDF-11 — all of which signal through the endogenous ActRIIB receptor to activate Smad2/3 phosphorylation and suppress muscle protein synthesis. By sequestering these negative regulators, ACE-031 effectively removes the biological brake on skeletal muscle hypertrophy. When myostatin and activins are trapped, the Smad2/3 inhibitory pathway is deactivated, allowing the mTOR and Akt/PKB pathways to proceed unchecked. This results in increased muscle protein synthesis, enhanced satellite cell activation and fusion, and muscle fiber hypertrophy — predominantly in fast-twitch (type II) fibers. The IgG1 Fc domain extends the compound's half-life through FcRn-mediated recycling, enabling bi-weekly dosing. Notably, ACE-031's broad ligand capture means it affects more than just myostatin. The trapping of activin A may contribute to both its potent muscle effects and some of its side effects, as activins play roles in vascular homeostasis. This broad activity profile distinguishes it from selective myostatin antibodies and explains both its dramatic efficacy and its clinical challenges.

• A Phase I trial in 48 healthy postmenopausal women demonstrated dose-dependent increases in lean body mass of up to 3.3% in just 29 days after a single dose — an unprecedented rate of muscle gain for a pharmaceutical agent.
• At the 3 mg/kg dose, thigh muscle volume increased by 5.1% as measured by MRI, confirming true muscle hypertrophy rather than water retention.
• Total lean mass increased significantly at doses ≥0.3 mg/kg, with a clear dose-response relationship.
• Preclinical studies in mdx mice (the standard Duchenne muscular dystrophy model) showed >20% increases in skeletal muscle mass with improvements in grip strength and functional measures.
• Bone mineral density also increased in clinical trials, likely due to the trapping of activin A which has catabolic effects on bone.
• The compound was generally well-tolerated up to 1 mg/kg. At 3 mg/kg, minor vascular events (nosebleeds, telangiectasias) were observed, leading to dose-limiting concerns.
• Acceleron's related compound ACE-083 (a locally-acting version) was also studied but ultimately discontinued, while luspatercept (ACE-536, targeting a different receptor) was successfully developed for anemia.

• Phase I clinical trial doses ranged from 0.02 to 3 mg/kg administered subcutaneously every 2 weeks. The 1–3 mg/kg range showed the most significant muscle effects.
• Preclinical doses in mouse models: 10 mg/kg intraperitoneal, twice weekly, produced >20% increases in lean mass over 4 weeks.
• No established off-label human protocol exists. Researchers typically extrapolate from the 1 mg/kg clinical dose, administered every 14 days.
• The compound has a long half-life due to its Fc domain (estimated 10–14 days), supporting every-other-week dosing.
• Development was paused after Phase II for Duchenne muscular dystrophy due to minor vascular events (epistaxis, telangiectasias, gum bleeding) at higher doses.
• If used in research settings, baseline and periodic monitoring of platelet counts, coagulation parameters, and vascular markers is recommended.
• Subcutaneous injection is the standard route. Reconstitute lyophilized powder with sterile water per vial instructions.

Known Side Effects

• Epistaxis (nosebleeds) — reported at higher doses (≥3 mg/kg), related to activin A's role in vascular integrity. This was the primary dose-limiting side effect.
• Telangiectasias — small dilated blood vessels near the skin surface, observed in clinical trials at higher doses.
• Gum bleeding — minor mucosal bleeding events reported alongside other vascular effects.
• Potential impact on reproductive hormones — activin A and B play important roles in the hypothalamic-pituitary-gonadal axis. Trapping these ligands could theoretically affect FSH levels and fertility.
• Muscle soreness/tightness — anecdotally reported, likely related to rapid muscle growth exceeding the adaptation rate of surrounding connective tissue.
• Long-term safety is unknown — clinical development was halted early, and no long-term human exposure data exists.

Safety Profile

ACE-031's safety profile is incompletely characterized due to early termination of clinical development. The primary concern is its broad ligand-trapping activity — by capturing not only myostatin but also activins and other TGF-β ligands, it affects multiple physiological systems beyond muscle. The vascular events observed at higher doses (epistaxis, telangiectasias) are attributed to activin A's role in maintaining vascular integrity and angiogenesis. Contraindications would include any bleeding disorder, use of anticoagulant therapy, and active vascular disease. Given activin's role in reproductive biology, it should be considered contraindicated in women of childbearing potential without adequate contraception. There is no reproductive toxicity data available. The compound's effects on the heart, liver, and other organs with ActRIIB expression are not fully characterized. Anyone considering research use should understand this is an experimental compound with incomplete safety data and proceed with appropriate caution and medical oversight.

Week 1–2: After the first injection, initial changes are occurring at the molecular level — Smad2/3 signaling is being suppressed and satellite cells are activating. No visible changes yet, but some users report mild muscle fullness. Weeks 3–4: Measurable increases in lean mass begin to appear. Clinical trial data showed up to 3.3% lean mass increase within 29 days of a single dose. Muscles may feel fuller and slightly pumped. Weeks 5–8: With continued bi-weekly dosing, muscle hypertrophy becomes visually noticeable. Strength gains typically accompany the size increases. This is the primary window where clinical trial data showed the most dramatic body composition changes. Weeks 9–12: Continued gains, though the rate may begin to plateau. Monitor for any vascular side effects. Long-term data beyond 12 weeks is extremely limited in humans.

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