A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy
Article first published online: 11 MAR 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 63, Issue 5, pages 561–571, May 2008
How to Cite
Wagner, K. R., Fleckenstein, J. L., Amato, A. A., Barohn, R. J., Bushby, K., Escolar, D. M., Flanigan, K. M., Pestronk, A., Tawil, R., Wolfe, G. I., Eagle, M., Florence, J. M., King, W. M., Pandya, S., Straub, V., Juneau, P., Meyers, K., Csimma, C., Araujo, T., Allen, R., Parsons, S. A., Wozney, J. M., LaVallie, E. R. and Mendell, J. R. (2008), A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol., 63: 561–571. doi: 10.1002/ana.21338
- Issue published online: 14 MAY 2008
- Article first published online: 11 MAR 2008
- Manuscript Accepted: 21 DEC 2007
- Manuscript Revised: 18 DEC 2007
- Manuscript Received: 31 OCT 2007
- Wyeth Pharmaceuticals
- Muscular Dystrophy Association. Grant Numbers: 4020, 4018
- KUMC GCRC
- NIH/NCRR. Grant Numbers: M01-RR023940, M01-RR000052
- JHH GCRC
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).
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.
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.
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