FSHD is one of the most common forms of muscular dystrophyacross populations. The progressive loss of skeletal muscle strength in FSHD causes patients to losephysical function and quality of life. Despite this heavy public health burden, there has been a paucity ofclinical 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 notimminent. However, more general targets, such as those involved in muscle regeneration, may provebeneficial. We have found that inhibition of an endogenous growth factor, myostatin, stimulates muscleregeneration from acute and chronic injury and ameliorates disease features in the mdx mouse model ofmuscular dystrophy. Several inhibitors of myostatin have been recently developed by industry. ACE-031 isa novel protein therapeutic developed by Acceleron Pharma, Inc. (Cambridge, MA) comprised of theextracellular domain of ActRIIB fused to human IgG that binds avidly to myostatin and other negativeregulators of muscle mass and inhibits their biological effect. ACE-031 rapidly produces muscle growth inwild-type animals and stimulates muscle regeneration in models of muscular dystrophy. Acceleron hasdeveloped GMP-grade ACE-031 drug product for clinical trials in muscle disease. Animal Pharmacologyand Toxicology Studies are currently underway to support the initial human studies of ACE-031. Accerelonanticipates submitting an IND application to the FDA in early 2008. The goal of Project 1 of the FSHDWellstone is to generate all the necessary data and protocols for a successful efficacy trial of ACE-031 inFSHD.
Three specific aims will be addressed to meet this goal.
In Aim 1, we will collaborate with Acceleronto conduct a randomized, double-blind, placebo-controlled, multiple-dose, dose escalating clinical trial toevaluate 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 amolecular 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 aPhase l/ll trial of ACE-031 in adult FSHD. During the award period, this trial will be designed to examine ifadministration of ACE-031 can lead to an increase in muscle strength and muscle
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