A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy

Kathryn Rae Wagner, James L. Fleckenstein, Anthony A. Amato, Richard J. Barohn, Katharine Bushby, Diana M. Escolar, Kevin M. Flanigan, Alan Pestronk, Rabi Tawil, Gil I. Wolfe, Michelle Eagle, Julaine M. Florence, Wendy M. King, Shree Pandya, Volker Straub, Paul Juneau, Kathleen Meyers, Cristina Csimma, Tracey Araujo, Robert Allen & 4 others Stephanie A. Parsons, John M. Wozney, Edward R. LaVallie, Jerry R. Mendell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)561-571
Number of pages11
JournalAnnals of Neurology
Volume63
Issue number5
DOIs
StatePublished - May 2008

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Muscular Dystrophies
Myostatin
Muscles
Safety
Photon Absorptiometry
Placebos
Limb-Girdle Muscular Dystrophies
Audiometry
Duchenne Muscular Dystrophy
Stamulumab
Muscle Strength
Growth
Neutralizing Antibodies
Double-Blind Method
Signs and Symptoms
Physical Examination
Histology
Hypersensitivity
Electrocardiography
Magnetic Resonance Imaging

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Neuroscience(all)

Cite this

Wagner, K. R., Fleckenstein, J. L., Amato, A. A., Barohn, R. J., Bushby, K., Escolar, D. M., ... Mendell, J. R. (2008). A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Annals of Neurology, 63(5), 561-571. https://doi.org/10.1002/ana.21338

A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. / Wagner, Kathryn Rae; Fleckenstein, James L.; Amato, Anthony A.; Barohn, Richard J.; Bushby, Katharine; Escolar, Diana M.; Flanigan, Kevin M.; Pestronk, Alan; Tawil, Rabi; Wolfe, Gil I.; Eagle, Michelle; Florence, Julaine M.; King, Wendy M.; Pandya, Shree; Straub, Volker; Juneau, Paul; Meyers, Kathleen; Csimma, Cristina; Araujo, Tracey; Allen, Robert; Parsons, Stephanie A.; Wozney, John M.; LaVallie, Edward R.; Mendell, Jerry R.

In: Annals of Neurology, Vol. 63, No. 5, 05.2008, p. 561-571.

Research output: Contribution to journalArticle

Wagner, KR, Fleckenstein, JL, Amato, AA, Barohn, RJ, Bushby, K, Escolar, DM, Flanigan, KM, Pestronk, A, Tawil, R, Wolfe, GI, Eagle, M, Florence, JM, King, WM, Pandya, S, Straub, V, Juneau, P, Meyers, K, Csimma, C, Araujo, T, Allen, R, Parsons, SA, Wozney, JM, LaVallie, ER & Mendell, JR 2008, 'A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy', Annals of Neurology, vol. 63, no. 5, pp. 561-571. https://doi.org/10.1002/ana.21338
Wagner KR, Fleckenstein JL, Amato AA, Barohn RJ, Bushby K, Escolar DM et al. A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Annals of Neurology. 2008 May;63(5):561-571. https://doi.org/10.1002/ana.21338
Wagner, Kathryn Rae ; Fleckenstein, James L. ; Amato, Anthony A. ; Barohn, Richard J. ; Bushby, Katharine ; Escolar, Diana M. ; Flanigan, Kevin M. ; Pestronk, Alan ; Tawil, Rabi ; Wolfe, Gil I. ; Eagle, Michelle ; Florence, Julaine M. ; King, Wendy M. ; Pandya, Shree ; Straub, Volker ; Juneau, Paul ; Meyers, Kathleen ; Csimma, Cristina ; Araujo, Tracey ; Allen, Robert ; Parsons, Stephanie A. ; Wozney, John M. ; LaVallie, Edward R. ; Mendell, Jerry R. / A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. In: Annals of Neurology. 2008 ; Vol. 63, No. 5. pp. 561-571.
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abstract = "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.",
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AU - Wagner, Kathryn Rae

AU - Fleckenstein, James L.

AU - Amato, Anthony A.

AU - Barohn, Richard J.

AU - Bushby, Katharine

AU - Escolar, Diana M.

AU - Flanigan, Kevin M.

AU - Pestronk, Alan

AU - Tawil, Rabi

AU - Wolfe, Gil I.

AU - Eagle, Michelle

AU - Florence, Julaine M.

AU - King, Wendy M.

AU - Pandya, Shree

AU - Straub, Volker

AU - Juneau, Paul

AU - Meyers, Kathleen

AU - Csimma, Cristina

AU - Araujo, Tracey

AU - Allen, Robert

AU - Parsons, Stephanie A.

AU - Wozney, John M.

AU - LaVallie, Edward R.

AU - Mendell, Jerry R.

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N2 - 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.

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