A Phase I/II trial of MYO-029 in Adult
Subjects with Muscular Dystrophy
Kathryn R. Wagner, MD, PhD,1 James L. Fleckenstein, MD,2 Anthony A. Amato, MD,3
Richard J. Barohn, MD,4 Katharine Bushby, MD,5 Diana M. Escolar, MD,6 Kevin M. Flanigan, MD,7
Alan Pestronk, MD,8 Rabi Tawil, MD,9 Gil I. Wolfe, MD,10 Michelle Eagle, PhD, MSc, MCSP, SRP,5
Julaine M. Florence, PT, DPT,8 Wendy M. King, PT,11 Shree Pandya, MS, PT,9 Volker Straub, MD,5
Paul Juneau, MS,12 Kathleen Meyers, RN, BSN,13 Cristina Csimma, PharmD, MHP,14
Tracey Araujo, MSPharm,14 Robert Allen, MD,13 Stephanie A. Parsons, PhD,13 John M. Wozney, PhD,14
Edward R. LaVallie, PhD,14 and Jerry R. Mendell, MD11
Objective: Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted
a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy,
facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy).
Methods: This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential
dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1mg/kg; Cohort 2 at 3mg/kg; Cohort 3 at 10mg/kg;
Cohort 4 at 30mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations,
laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic
and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative
muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic
absorptiometry studies, and muscle biopsy.
Results: MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30mg/kg
doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not
powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects
toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology.
Interpretation: This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate
safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in
muscular dystrophy should be considered.
Ann Neurol 2008;63:561–571
Muscular dystrophies are a diverse set of distinct, inherited
disorders that commonly manifest with progressive
skeletal muscle weakness and wasting. Despite
substantial progress in understanding the pathophysiological
basis of these diseases, no pharmacological therapies
have been identified that increase muscle
strength, other than corticosteroids, which provide a
modest benefit to some patients with these disorders.1
For muscular dystrophies that present in adulthood,
there have been only a few small clinical trials, and
none involved a novel therapeutic agent.2–6 This article
describes a clinical trial of a novel agent, an inhibitor
of myostatin, designed to increase muscle mass and
strength in several of the most common forms of adult
muscular dystrophy.
Myostatin, a member of the transforming growth
From the 1Departments of Neurology and Neuroscience, The Johns
Hopkins University School of Medicine, Baltimore, MD; 2Department
of Internal Medicine, University of Oklahoma College of
Medicine at Tulsa, Tulsa, OK; 3Department of Neurology, Brigham
and Women’s Hospital, Boston, MA; 4Department of Neurology,
University of Kansas Medical Center, Kansas City, KS; 5University
of Newcastle Upon Tyne, Institute of Human Genetics, Newcastle
Upon Tyne, United Kingdom; 6Children’s National Medical Center,
Research Center Genetic Medicine, Washington, DC; 7University
of Utah School of Medicine, Departments of Neurology, Human
Genetics, and Pathology, Salt Lake City, UT; 8Neuromuscular
Division, Washington University School of Medicine, St. Louis,
MO; 9Neuromuscular Disease Center, University of Rochester
Medical Center, Rochester, NY; 10University of Texas Southwestern
Medical Center, Dallas, TX; 11Department of Pediatrics and Neurology,
Columbus Children’s Research Institute, Ohio State University,
Columbus, OH; 12Senior Statistician, MMS Holdings, Inc.,
Canton, MI; 13Wyeth Research, Collegeville, PA; and 14Wyeth Research,
Cambridge, MA.
Received Oct 31, 2007, and in revised form Dec 18. Accepted for
publication Dec 21, 2007.
Current address for Dr Csimma: Clarus Ventures, Cambridge, MA.
Published online Mar 11, 2008, in Wiley InterScience
(
www.interscience.wiley.com). DOI: 10.1002/ana.21338
Address correspondence to Dr Wagner, The Johns Hopkins University
School of Medicine, Department of Neurology, Meyer
5-119, 600 North Wolfe Street, Baltimore, MD 21287-7519.
E-mail:
kwagner@jhmi.eduORIGINAL ARTICLES
© 2008 American Neurological Association 561
Published by Wiley-Liss, Inc., through Wiley Subscription Services
