ACE-031

What is ACE-031?

ACE-031, also known by the investigational name ramatercept, is a myostatin inhibitor. It's a soluble, recombinant fusion protein that functions as a "ligand trap." This means it's designed to bind to and neutralize specific proteins in the body that inhibit muscle growth.

Myostatin is a protein that negatively regulates muscle development. By binding to myostatin and other related signaling proteins like activin and GDF-11, ACE-031 prevents them from interacting with their natural receptors (Activin Receptor Type IIB or ActRIIB) on muscle cells. This action "removes the brakes" on muscle growth, leading to an increase in muscle mass.

ACE-031 was developed to treat muscle-wasting diseases such as Duchenne Muscular Dystrophy (DMD). While it showed promise in clinical trials by increasing lean body mass and muscle volume, its development was discontinued due to safety concerns.

Side Effects and Benefits

Benefits:

• Increased Lean Mass: Clinical trials demonstrated that ACE-031 treatment led to significant increases in total body lean mass and thigh muscle volume.

• Improved Bone Metabolism: Some studies suggested that ACE-031 could also improve bone mineral density (BMD), indicating potential benefits for bone health.

• Reduced Fat Mass: There were trends for a decrease in fat mass observed in some studies.

Side Effects:

• Bleeding Issues: The most significant and concerning side effects reported were epistaxis (nosebleeds) and telangiectasias (dilated blood vessels). This was a major reason for the termination of a Phase 2 trial in boys with DMD. This effect is thought to be due to ACE-031's binding to and inhibition of other proteins in the TGF-β superfamily, specifically BMP9 and BMP10, which are important for blood vessel integrity.

• Injection Site Reactions: Minor side effects like erythema (redness) at the injection site were also reported.

• Changes in Blood Hemoglobin: Some studies noted an undesired increase in hemoglobin levels.

• FSH Suppression: A decrease in Follicle-Stimulating Hormone (FSH) levels was observed in some participants.

Pros and Cons

Pros:

• Potent Anabolic Effect: ACE-031 has shown a strong ability to promote muscle growth and increase lean body mass.

• Potential for Multiple Benefits: Beyond muscle, it showed potential for improving bone health and reducing fat mass.

• Long Half-Life: Its long half-life allows for infrequent dosing, which could be a significant advantage for patient convenience.

Cons:

• Serious Safety Concerns: The risk of bleeding and other non-muscle-related adverse events, particularly in a pediatric population, led to the discontinuation of its development.

• Lack of Specificity: ACE-031's mechanism of action, which involves trapping a range of ligands in the TGF-β superfamily, resulted in off-target effects and the aforementioned side effects.

• No Steroid-like Effects: It does not operate on the same hormonal pathways as anabolic-androgenic steroids, so it does not have the same sterogenic, progestronic, or prolactin effects.

Dosage and Frequency

In clinical trials, ACE-031 was administered subcutaneously (SC). Dosage varied depending on the study and the population being tested. For example, in a study with healthy postmenopausal women, single doses ranging from 0.02 to 3 mg/kg were evaluated. In a study with boys with Duchenne Muscular Dystrophy, a dosing schedule of 0.5 to 2 mg/kg every 2-4 weeks was used.

Half-Life and Detection Time

• Half-Life: The mean half-life of ACE-031 was found to be approximately 10-15 days. This long half-life is due to its large molecular structure and is a characteristic of biologic drugs.

• Detection Time: The detection time for ACE-031 is not definitively established in humans for a doping context. In a study with rats, ACE-031 was detectable for up to 48 hours post-administration, but the researchers noted that the detection window would likely be different in humans. Given its long half-life, it would likely be detectable in human serum for an extended period, possibly weeks or even months.

Sterogenic, Progestronic, Prolactin, and Anabolic-Androgenic Ratio

• Sterogenic, Progestronic, and Prolactin Effects: ACE-031 is a myostatin inhibitor and does not act on androgen, estrogen, or progesterone receptors. It does not have any known sterogenic, progestronic, or prolactin-related effects. It is a biologic therapeutic, not a synthetic steroid.

• Anabolic-Androgenic Ratio: This ratio is a concept used to compare the anabolic (muscle-building) and androgenic (masculinizing) effects of anabolic-androgenic steroids (AAS). Since ACE-031 is not an AAS and does not act on androgen receptors, this ratio is not applicable. Its anabolic effects are mediated by a completely different mechanism—the inhibition of myostatin.