What Is ACE-031? Benefits, Research & Safety

The myostatin inhibition field began with Se-Jin Lee's discovery of myostatin in 1997 and the observation that myostatin-null animals developed massive muscle hypertrophy. This immediately suggested therapeutic potential for muscle wasting conditions. Multiple approaches to myostatin inhibition were developed, including antibodies, propeptides, and decoy receptors. The ActRIIB decoy approach was attractive because it could neutralise not only myostatin but also other inhibitory ligands like activins. Acceleron Pharma developed ACE-031 as a fusion of ActRIIB with an antibody Fc domain, providing good pharmacokinetic properties and allowing subcutaneous administration. Phase I trials in healthy volunteers showed ACE-031 increased lean body mass, confirming proof of concept. Phase II trials in Duchenne muscular dystrophy patients began with encouraging early results. However, in 2013, Acceleron announced discontinuation of ACE-031 development due to safety concerns. Patients experienced nosebleeds and telangiectasias, believed related to effects on BMP9, a ligand involved in blood vessel integrity that also binds to ActRIIB. Acceleron continued developing related compounds with different ligand binding profiles. ACE-083 (local muscle administration) and other agents are being explored. The company's experience with ACE-031 informed development of luspatercept (approved for anemia), which is related but has different activity.