ACE-083 was an experimental treatment for Charcot-Marie-Tooth (CMT) disease being developed by Acceleron Pharma. It aimed to treat CMT1 (the disease’s most common subtype) and CMTX (the X-linked form of the disease). 

The injectable therapy received fast-track and orphan drug designations from the U.S. Food and Drug Administration (FDA) but after ACE-083 failed to achieve statistically significant improvements in functional and quality of life measurements from their Phase 2 clinical trial, Acceleron decided to discontinue its development. 

How does ACE-083 work?

CMT is caused by mutations that affect the structure and function of peripheral nerves (those outside of the brain and spinal cord) that control movement and sensation. There are several types of CMT, depending on where in the genome the disease-causing mutation is located. Some forms affect the nerve fibers (called axons), while others affect the protein coat that protects and insulates these fibers (called myelin). CMT leads to poor nervous signal transmission from the brain to the muscles, which can cause muscles to weaken and atrophy (shrink). Many CMT patients have trouble with walking and balance as a result.

No cure or approved medications exist to date for CMT, but some types of treatment can help to manage its more debilitating symptoms.

ACE-083 was designed to block transforming growth factor-beta (TGF-beta) signaling in muscle cells.

TGF-beta is a receptor protein found on the surface of muscle cells. Cell-signaling molecules called cytokines bind to TGF-beta and initiate a cascade of signaling reactions that change gene expression in muscle cells, which causes muscle fibers to shrink in size.

Muscle tissues are constantly being remodeled according to a person’s needs. In people who exercise, muscle fibers increase in size and number. In people who are not exercising, muscle fibers decrease in size and number. In a similar way, muscles in people with CMT atrophy due to the absence of nerve signals from the brain.

ACE-083 binds to TGF-beta and prevents other cytokines from binding to the receptor, which blocks downstream signaling that would lead muscle fibers to shrink in size. By preventing muscle breakdown, ACE-083 did result in an increase in muscle volume but did not result in functional improvements.

ACE-083 was injected into muscles, where it acts locally.

ACE-083 in clinical trials

ACE-083 was tested in a Phase 1 clinical trial (NCT02257489), evaluating the safety and tolerability of single and multiple doses as a local injection into selected skeletal muscles of healthy volunteers. A total of 58 people received either 50, 100, 150, or 200 mg of ACE-083, or a placebo, as one or two injections into the muscles three weeks apart. Primary measures were safety and tolerability. Researchers also measured the treatment’s pharmacokinetics (where and how a drug is broken down in the body) and whether there was an increase in muscle strength or size following treatment.

Based on encouraging results from this trial, Acceleron enrolled CMT1 and CMTX patients for a two-part Phase 2 clinical trial (NCT03124459) to evaluate the safety and tolerability of ACE-083. 

The trial’s first part was an open-label study of 18 people. Three groups of six patients each were given multiple ascending doses of ACE-083 (150, 200, or 250 mg) injected into the leg muscle once every three weeks, for up to five doses. Adverse events and their frequency were recorded, as were changes in muscle volume or strength as evaluated by magnetic resonance imaging (MRI) and muscle strength tests, respectively.

Based on safety and efficacy results, Acceleron proceeded with the second half of the study. The aim was to establish the recommended dose of ACE-083.

In this second part, a new set of 44 patients received either ACE-083 or placebo injected into muscles in both legs once every three weeks for up to 17 doses. Part 2 ran for a six-month double-blind and placebo-controlled phase and then a six-month open-label phase. MRI scans and muscle strength tests were performed before the start of the trial and at each follow-up.

The results of the trial showed that the treatment was generally well tolerated with adverse events mostly due to the injections. Participants in the study receiving the treatment also had an increase in muscle volume compared to placebo. However, they did not show a significant improvement in quality of life measures or functional task performance. Due to these negative results, Acceleron decided to discontinue the development of ACE-083.

Other information

No serious adverse events were reported in the Phase 1 trial. The most common side effect was irritation at the injection site. One patient experienced muscle swelling in the lower leg, and recovered fully but left the study.

ACE-083 was evaluated as a potential treatment of facioscapulohumeral muscular dystrophy (FSHD) but failed to show effectiveness in a Phase 2 clinical trial and its development for that disease has been discontinued.


Last updated: March 11, 2020


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