A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy.
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 1 mg/kg; Cohort 2 at 3 mg/kg; Cohort 3 at 10 mg/kg; Cohort 4 at 30 mg/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 30 mg/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.


CONCLUSIONS
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.
Wagner
Kathryn R
KR
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-7519, USA. kwagner@jhmi.edu
Fleckenstein
James L
JL
Amato
Anthony A
AA
Barohn
Richard J
RJ
Bushby
Katharine
K
Escolar
Diana M
DM
Flanigan
Kevin M
KM
Pestronk
Alan
A
Tawil
Rabi
R
Wolfe
Gil I
GI
Eagle
Michelle
M
Florence
Julaine M
JM
King
Wendy M
WM
Pandya
Shree
S
Straub
Volker
V
Juneau
Paul
P
Meyers
Kathleen
K
Csimma
Cristina
C
Araujo
Tracey
T
Allen
Robert
R
Parsons
Stephanie A
SA
Wozney
John M
JM
Lavallie
Edward R
ER
Mendell
Jerry R
JR
D000328:Adult; D000906:Antibodies / Q000627:therapeutic use*; D015331:Cohort Studies; D015897:Comorbidity; D004311:Double-Blind Method; D003875:Drug Eruptions / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D038622:Internationality; D008297:Male; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000453:epidemiology*; D015990:Placebo Effect; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D016896:Treatment Outcome
D000906:Antibodies; C506829:Stamulumab