FSHD is one of the most common forms of muscular dystrophy across populations. The progressive loss of skeletal muscle strength in FSHD causes patients to lose physical function and quality of life. Despite this heavy public health burden, there has been a paucity of clinical trials in FSHD, and no effective therapeutic agents have been identified or developed for FSHD. Since the basic pathophysiology of FSHD is unknown, a disease specific approach to therapy is not imminent. However, more general targets, such as those involved in muscle regeneration, may prove beneficial. We have found that inhibition of an endogenous growth factor, myostatin, stimulates muscle regeneration from acute and chronic injury and ameliorates disease features in the mdx mouse model of muscular dystrophy. Several inhibitors of myostatin have been recently developed by industry. ACE-031 is a novel protein therapeutic developed by Acceleron Pharma, Inc. (Cambridge, MA) comprised of the extracellular domain of ActRIIB fused to human IgG that binds avidly to myostatin and other negative regulators of muscle mass and inhibits their biological effect. ACE-031 rapidly produces muscle growth in wild-type animals and stimulates muscle regeneration in models of muscular dystrophy. Acceleron has developed GMP-grade ACE-031 drug product for clinical trials in muscle disease. Animal Pharmacology and Toxicology Studies are currently underway to support the initial human studies of ACE-031. Accerelon anticipates submitting an IND application to the FDA in early 2008. The goal of Project 1 of the FSHD Wellstone is to generate all the necessary data and protocols for a successful efficacy trial of ACE-031 in FSHD.
Three specific aims will be addressed to meet this goal.
In Aim 1, we will collaborate with Acceleron to conduct a randomized, double-blind, placebo-controlled, multiple-dose, dose escalating clinical trial to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects of ACE-031 (ActRIIB-lgG1) in healthy volunteers. Biological material from this healthy volunteer trial will be studied to determine a molecular signature of myostatin inhibition in the laboratory of Lou Kunkel in Aim 2. Pharmacokinetic, pharmacodynamic and biomarker data from Aims 1 and 2 will be used for Aim 3: the development of a Phase l/ll trial of ACE-031 in adult FSHD. During the award period, this trial will be designed to examine if administration of ACE-031 can lead to an increase in muscle strength and muscle

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAR1)
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Boston Biomedical Research Institute
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