ACE-031 dosage protocol

What the compound is

ACE-031, also known as Ramatercept, is a dimeric fusion protein. It consists of an extracellular fragment from the human activin receptor type IIB (ACVR2B, or ActRIIB) linked to the Fc-part of human immunoglobulin G1 (IgG1) (PMID 40312924, PMID 41686840). This structure makes it a 'soluble trap' for certain signaling molecules.

A similar therapeutic protein, luspatercept, is also an activin receptor type IIB ligand trap (PMID 40424086).

How it is thought to work

ACE-031 functions by blocking ligands (signaling molecules) that normally bind to the activin receptor type IIB (ActRIIB). These ligands include myostatin, GDF11 (growth and differentiation factor 11), and activins, which are part of the TGF-β family and typically act as negative regulators of skeletal muscle mass (PMID 41686840, PMID 29109273).

By acting as a 'trap,' ACE-031 prevents these ligands from binding to and activating the natural ActRIIB receptor on muscle cells, thereby inhibiting their signaling pathway and potentially promoting muscle growth or preventing muscle loss (PMID 29109273, PMID 41686840). Blockade of ActRIIB signaling by a fusion protein was shown to inhibit myostatin pathway signaling (PMID 29109273).

In the context of anemia in myelodysplastic syndromes (MDS), GDF11 (an ActRIIB ligand) was found to inhibit human red blood cell formation in laboratory cell cultures and cause anemia in zebrafish. Luspatercept, a similar ActRIIB ligand trap, abrogated these effects. The mechanism involved GDF11-mediated activation of SMAD2, leading to the production of a less functional GATA1 protein isoform, which contributed to anemia (PMID 40424086).

What laboratory and animal studies report

In mice, treatment with ActRIIB-Fc (the fusion protein) prevented muscle loss in cachectic mice and induced hypertrophy (muscle growth) in normal mice (PMID 29109273). Short-term treatment (3 days) with ActRIIB-Fc in adult, 18-month-old, and orchidectomized mice led to significant muscle growth and enhanced muscle function, particularly fast fatigable muscle function (PMID 23525481). It also increased bone mineral density and markers of bone formation in these rodents (PMID 23525481).

A related compound, ActRIIB:ALK4-Fc (a heterodimeric fusion protein with a different ligand binding profile), increased muscle mass and function in wild-type mice and murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. It also improved neuromuscular junction abnormalities in DMD and pre-symptomatic ALS models, and alleviated acute muscle fibrosis in a DMD model (PMID 33586684).

In common marmosets (non-human primates), ACE-031 administration for 14 weeks significantly increased lean body mass and body weight compared to baseline. Marmosets treated with ACE-031 also showed increased cross-sectional area of both type I and type II muscle fibers in the biceps brachii, and improved absolute and specific force production in skeletal muscle (PMID 41686840, PMID 41256654).

In a mouse model, a murine ActRIIB-Fc (RAP-536) rescued anemia caused by the expression of a shorter, hypomorphic GATA1 isoform (PMID 40424086). Also in mice, ActRIIB:Fc treatment was shown to restore most oocyte maturation that was inhibited by high FSH activity (PMID 38711160).

Human evidence so far

ACE-031 has not yet been pharmaceutically approved, but is sold as a research chemical on the 'black market' (PMID 40312924).

Regarding the related compound luspatercept, analysis of human patient samples from the phase 3 MEDALIST trial (for myelodysplastic syndromes) showed that responders to luspatercept had a higher proportion of a less functional GATA1 protein isoform compared to non-responders. An increase in red blood cells after luspatercept treatment was linked to a relative decrease in these GATA1 isoforms (PMID 40424086).

Open questions and limitations

The World Anti-Doping Agency (WADA) has banned ACE-031 due to its potential performance-enhancing properties (PMID 40312924).

Studies on 'black market' ACE-031 products revealed inconsistencies: only 12 out of 14 tested products contained an ACVR2B-immunoreactive protein, and these products contained the full-length human activin receptor IIB instead of the fusion protein ACE-031, with many other proteins also present (PMID 40312924). These findings highlight concerns about the purity and authenticity of unapproved compounds.

While 'black market' ACE-031 was detectable in rat serum for up to 48 hours post-administration, differences in metabolism and the high dose used (10 mg/kg body weight) mean the detection window in humans may vary (PMID 40312924).

A study on ActRIIB:ALK4-Fc noted its ligand binding profile was different from ActRIIB-Fc, as it did not trap bone morphogenetic protein 9 (BMP9), which is a vascular regulatory ligand (PMID 33586684). This suggests differences in how related activin receptor modulators might impact different biological pathways.

Key terms explained

ActRIIB (Activin Receptor Type IIB): A receptor on cell surfaces that binds to certain signaling molecules (ligands) and plays a role in regulating processes like muscle growth (PMID 29109273).

Fc-part: The fragment crystallizable region of an antibody, often used in fusion proteins to increase stability and half-life (PMID 40312924).

Ligand: A molecule that binds to a specific receptor, initiating a biological signal or response (PMID 29109273).

Myostatin: A protein that typically acts as a negative regulator of muscle growth (PMID 29109273).

GDF11 (Growth Differentiation Factor 11): A protein similar to myostatin, also a negative regulator of muscle mass and implicated in erythropoiesis (red blood cell formation) (PMID 29109273, PMID 40424086).

Activins: A family of proteins involved in various biological processes, including regulation of muscle mass (PMID 29109273).

Hypertrophy: The enlargement of an organ or tissue from the increase in size of its cells, such as muscle growth (PMID 29109273).

Cachexia: Muscle wasting, a condition characterized by loss of muscle mass (PMID 29109273).