ACE-083 is an experimental treatment for Charcot-Marie-Tooth (CMT) disease being developed by Acceleron Pharma. It aims to treat CMT1 (the disease’s most common subtype) and CMTX (the X-linked form of the disease).
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.
ACE-083 is 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 may increase muscle strength and delay CMT progression.
ACE-083 is 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, but 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.
The trial’s first part is open-label study in 18 people. Three groups of six patients each will be 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 will be recorded, as will 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 will proceed with the second half of the study, which will establish the recommended dose of ACE-083.
In this second part, a new set of up to 40 patients will receive either ACE-083 or placebo injected into muscles in both legs once every three weeks for up to 17 doses. Part 2 will run for 15 months, and include a four-week screening period, a six-month double-blind and placebo-controlled phase, a six-month open-label phase, and an eight-week follow-up. MRI scans and muscle strength tests will be performed before the start of the trial and at each follow-up.
This Phase 2 study is being conducted at sites across the U.S., and contact information is available here.
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: Sept. 29, 2019
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