ACE-031 (ramatercept) is the ligand-binding part of activin receptor type IIB (ActRIIB) fused to human IgG1 Fc. As a ligand trap, it soaks up growth factors before they reach muscle receptors, which explains both the muscle effects and the bleeding seen in its clinical trials.
| Component |
Role |
| ActRIIB |
Type II cell surface receptor |
| Myostatin (GDF-8) |
Primary ligand, limits muscle |
| Activins A and B |
Additional ligands |
| GDF11 |
Related factor |
| BMP9, BMP10 |
Vascular ligands |
| Step |
Event |
Outcome |
| 1 |
Myostatin binds ActRIIB |
Pairs with ALK4 or ALK5 |
| 2 |
Smad2/3 phosphorylation |
Signal transduction |
| 3 |
Nuclear translocation |
Gene regulation |
| 4 |
Muscle-limiting genes |
Growth restriction |
| Aspect |
Explanation |
| Structure |
ActRIIB extracellular domain + IgG1 Fc |
| Function |
Binds myostatin and related ligands in circulation |
| Effect |
Prevents cellular receptor activation |
| Result |
Removes growth inhibition |
| Step |
Event |
| 1 |
ACE-031 injected |
| 2 |
Circulates in bloodstream |
| 3 |
Binds free myostatin and related ligands |
| 4 |
Ligands neutralized |
| 5 |
Muscle ActRIIB not activated |
| 6 |
Growth inhibition removed |
| Ligand |
ACE-031 Binding |
Normal Role |
| Myostatin |
Yes |
Muscle limitation |
| Activin A |
Yes |
Multiple functions |
| Activin B |
Yes |
Reproductive, other |
| GDF11 |
Yes |
Multiple roles |
| BMP9 |
Yes |
Vascular |
| BMP10 |
Probably |
Vascular |
In the developer's lab studies, ActRIIB-Fc bound all of these tightly, BMP9 included (about 116 pM). We found no BMP10 measurement for ACE-031 itself, though BMP10 binds ActRIIB readily.
| Issue |
Consequence |
| Activin inhibition |
Reproductive, other effects |
| GDF11 inhibition |
Unknown full impact |
| BMP9/BMP10 inhibition |
Vascular concerns |
| Factor |
Relationship |
| BMP9 |
Vascular integrity factor |
| ALK1 |
Endothelial receptor activated by BMP9 and BMP10 |
| ActRIIB |
Type II partner in the BMP9-ALK1 complex |
| ACE-031 |
Traps BMP9 |
ALK1 mutations cause hereditary hemorrhagic telangiectasia (HHT) type 2, with fragile, dilated small vessels and nosebleeds. ACE-031's Duchenne trial was stopped over nosebleeds and telangiectasias, which resolved after treatment ended. The BMP9 link is inferred from mouse work: ActRIIB-Fc blocked BMP9-dependent retinal vessel growth, and a modified trap that doesn't hold BMP9 did not.
| Component |
Role |
| Blood vessel stability |
Requires BMP9/ALK1 signaling |
| ACE-031 interference |
Reduces available BMP9 |
| Clinical presentation |
Nosebleeds, gum bleeding, vessel dilation |
Follistatin is a natural binding protein for myostatin, activins and GDF11.
| Factor |
ACE-031 |
Follistatin |
| Mechanism |
Decoy receptor |
Direct binding |
| Selectivity |
Lower |
Variable |
| Vascular concern |
Yes |
Less documented |
| Development status |
Discontinued May 2013 |
Small gene-therapy trials |
| Direction |
Rationale |
| More selective agents |
Avoid trapping BMP9 |
| Different mechanisms |
Antibodies, engineered traps |
| Careful monitoring |
Vascular surveillance |
As of October 2026, newer agents hit fewer targets. Apitegromab (Isembyld), which binds promyostatin and latent myostatin, was FDA-approved for spinal muscular atrophy on September 11, 2026. In Phase 2 obesity trials, the antibodies bimagrumab (against ActRII) and trevogrumab (against myostatin) reduced lean-mass loss alongside semaglutide.
