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Myostatin inhibitors, is anything on the market yet that is legit?

Joined
Feb 10, 2008
Messages
1,045
I know it's thought to be on the market sometime soon, any research chems that work? Is this whole myostatin inhibitor shit legit?
 
aight im just gonna post this here again from the other myostain thread...
Whatever was on the market 5 yrs ago wasn't legit. The only legit inhibitor is in europe that was developed by a scientist looking for a cure to muscular dystrophy. Last year Wyte's pharmacuticals in New Jersey created their own form of myostatin inhibitor. The study fell through and the test results were never published. As for the pictures of the cow and rat. The cow has a genetic disorder where naturally his body inhibits myostatin. The rat was a subject from the european study and have yet to be tested on humans. Who knows if it's going to work in humans. 3 years ago science said that hyperplasia was far fetched and its just recently they discovered that some animals naturally under go hyperplasia, but still can't reproduce the effects in man. I know everyone thinks it will revolutionize body chemistry as we know it, and it's all good in theory, but until it's designed and tested on humans we just have to keep praying.
 
MyoBlast was supposed to be a myostatin inhibitor... It was on the market a few years back. I paid $90 or whatever it was for that junk. Did nothing lol
 
MYO-029 is the human anti-GDF-8(Growth Differentiation Factor 8), monoclonal antibody that is used in studies and 1mg is few thousand dollars.
 
MYO-029 is the human anti-GDF-8(Growth Differentiation Factor 8), monoclonal antibody that is used in studies and 1mg is few thousand dollars.
:eek: christ thats the most expensive thing i've ever heard of!!! that is wild!
 
Link is to the Clinical Trail Study I posted Below. It has some Diagram/Tables summarizing results and easier to read than below.

**broken link removed**

Ann Neurol 2008;63:561–571

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: [email protected]
ORIGINAL ARTICLES
© 2008 American Neurological Association 561
Published by Wiley-Liss, Inc., through Wiley Subscription Services
factor- superfamily, is an endogenous inhibitor of
muscle growth.7 The function of myostatin is conserved
in all animals examined, and the absence of
myostatin results in muscle growth approximately two
to three times greater than normal.7–11 Importantly,
the function of myostatin is also conserved in humans,
as was determined by the identification of a myostatin
splice-site mutation leading to the loss of myostatin
protein in a hypermuscular family.12
In the absence of myostatin, muscle regeneration has
been shown to occur earlier and more robustly after
acute and chronic injury. In the mdx mouse model of
muscular dystrophy, animals lacking myostatin had increased
muscle mass and strength and decreased fibrosis.
13,14 Furthermore, postnatal inhibition of myostatin
with a neutralizing monoclonal antibody to myostatin
also ameliorated disease features in the mdx mouse.15
Given these preclinical results, myostatin has been
considered a therapeutic target for the treatment of
muscular dystrophy. MYO-029 is a recombinant human
antibody that binds with a high affinity to myostatin
and inhibits its activity.16 This myostatinneutralizing
antibody has previously been shown to
increase muscle mass in immunodeficient mice by approximately
30% over 3 months, similar to the biological
response demonstrated for other myostatinneutralizing
antibodies.15–17 The primary objective of
this double-blind, placebo-controlled, multinational,
randomized trial was to evaluate the safety of ascending
doses of MYO-029 in adult subjects with Becker muscular
dystrophy (BMD), facioscapulohumeral dystrophy
(FSHD), and limb-girdle muscular dystrophy
(LGMD). A secondary goal was to assess exploratory
end points of clinical and biological activity of MYO-
029 through analysis of muscle strength, mass, and
composition. The prospective hypothesis was that
MYO-029 would be well tolerated.
Subjects and Methods
Study Design
The study was a randomized, double-blind, placebocontrolled,
ascending dose, safety study of MYO-029 approved
by regulatory agencies and the local institutional review
boards in 10 participating centers in the United States
and the United Kingdom. Subjects were randomly assigned
using a computerized randomization and enrollment system.
The randomization technology was provided through a centralized
telephone software system that provides sites with
the ability to perform various subject enrollment functions,
including screening, randomization, and emergency unblinding.
Sites were able to access the randomization system by
secure Internet access or by telephone.
Approximately 136 subjects were planned to be divided
into sequential dose cohorts, each compared with placebo.
There was an equal number of subjects with BMD, FSHD,
or LGMD in each cohort with MYO-029 dose escalation:
Cohort 1 received 1mg/kg; Cohort 2 received 3mg/kg; and
Cohort 3 received 10mg/kg. Within each cohort, subjects
were randomly assigned to receive the test drug or placebo in
a 3:1 ratio. Test article was administered intravenously every
2 weeks for 6 months (total of 13 doses). After the last dose,
subjects were followed for 3 months. After the start of the
study, safety data from a multiple ascending dose study in
healthy subjects became available, permitting an amendment
to add a fourth cohort, at 30mg/kg.
Subjects
Informed consent was given by all subjects before participation
in the trial. All subjects were at least 18 years old and
had a clinical and confirmed molecular diagnosis of BMD,
FSHD, or one of the following forms of LGMD: 2A, 2B,
2C, 2D, 2E, or 2I.18,19 Eligibility required independent ambulation;
muscle strength of 3 and 4 on manual
muscle testing (MMT) in at least 8 of 16 muscle groups2,3,20
on initial evaluation and confirmed at visit 2 by strength
within 2 steps (eg, 4 vs 5) in at least 10 of the 16 muscles;
a forced vital capacity 60% of the predicted value; and
ejection fraction greater than 40% by echocardiogram. A
negative urinary pregnancy test was required for women at
risk. All subjects of childbearing potential agreed to use two
reliable methods of birth control for the duration of the
study.
Exclusion criteria included heart disease related to ischemia,
congestive failure, or use of antiarrhythmic or anticoagulant
medication within 12 weeks before randomization,
glucocorticosteroids within 6 months before randomization
and for the duration of the study, and pharmacological treatment
potentially affecting muscle function within 4 weeks
before randomization and for the duration of the study.
Strengthening exercises and decline in endurance were not
permitted within 8 weeks before randomization, and
strengthening exercises were excluded during the study. Pregnant
or lactating women were disallowed. Also excluded were
subjects with a history of sensitivity to monoclonal antibodies
or protein pharmaceuticals.
Blinding
MYO-029 was provided in vials containing a lyophilized
form to be reconstituted with 1ml sterile water, USP. After
reconstitution with 1ml sterile water, each vial delivered
0.9ml MYO-029 at a concentration of 70mg/ml. Identical
placebo vials were provided, which contained a lyophilized
formulation containing only the excipients. At each participating
site, the responsibility for test article preparation was
assigned to an unblinded pharmacist who did not participate
in the evaluation of study subjects.
Assessments
SAFETY. Safety and tolerability of MYO-029 in adult subjects
with muscular dystrophy were the primary outcome
measures. Analyses included incidence and severity of adverse
events (AEs) assessed by reported signs and symptoms, as
well as physical examinations, vital signs measurements, laboratory
results (excluding enzyme levels increased by muscle
disease),20 echocardiograms, electrocardiograms, and in subjects
with FSHD, fundoscopic and audiometry examinations.
562 Annals of Neurology Vol 63 No 5 May 2008
AEs were graded according to the World Health Organization
Toxicity Scale.
BIOLOGICAL ACTIVITY. Biological activity was assessed
through MMT, quantitative muscle testing (QMT), timed
function tests (TFTs), pulmonary function tests, and subjectreported
outcomes.
Muscle strength was assessed by MMT of 21 bilateral
limb muscles, as well as neck and abdominal muscles. A
modified MMT score was generated on each muscle group
using an 11-point system, as published previously.21 Composite
total MMT scores were calculated by averaging the
converted MMT scores across all muscle groups, as well as
composite upper body scores, which include neck muscles,
and lower body scores, which include abdominal muscles.
At 9 of the 10 participating centers, muscle strength was
also measured using QMT to assess maximum voluntary isometric
force of 12 limb-muscle groups.22 The maximum
force from three attempts was used in analysis. In addition to
total muscle strength assessments, separate analyses were conducted
for total upper and lower extremities.
TFTs included time to traverse 9m, climb four stairs, and
stand from a seated position. Pulmonary function tests included
sitting and supine forced vital capacity. Subjects with
FSHD were permitted to use a face mask during spirometry.
A direct assessment of a biological effect on muscle was
assessed via changes in muscle mass, myostatin levels, and
muscle histology. Changes in muscle mass were assessed
through dual-energy x-ray absorptiometry (DEXA) and magnetic
resonance imaging (MRI) scans. DEXA and MRI scans
were performed on all subjects at pretreatment baseline and
at week 26. Total body DEXA was performed to estimate
lean mass from the trunk, arms, and legs. For this study, lean
tissue was presumed to be muscle.
Proton-density MRI scans were performed on each upper
arm and on both thighs for three different image data sets,
using overlapping acquisitions. Volumes were calculated via
segmentation of the three-dimensional reconstructed MRI
data of the extremities by VirtualScopics® (Rochester, NY),
as shown in Figure 1. Muscle was automatically separated
from subcutaneous fat using the large signal differences of
muscle boundaries from fat tissue.23 A semiautomated system
was then used to separate intermuscular fat from subcutaneous
fat. Normal and abnormal muscle volumes were then
segmented from one another using a maximum likelihood
pixel classification algorithm.24 The algorithm was trained
using the signal intensities derived from selected tissue samples
of the normal muscle that determined well-defined
ranges for normal muscle and fat. The numbers of pixels of
each type were then summed across slices to determine the
total volume of normal and abnormal muscle; 13 cases were
excluded from analysis because of metal artifact, excessive
motion, or mispositioning of limbs.
SUBJECT-REPORTED OUTCOMES. Subject-reported outcomes
were assessed using Version 1.0 of the Short Form
(SF)-36, which has established validity as a measure of function
and well-being.25,26 Subjects self-administered the SF-36
during three visits. Scoring of the SF-36 Physical Health and
Mental Health components used a norm-based approach.27
MYOSTATIN LEVELS. Both free and total myostatin levels
were assessed in subject serum and muscle biopsy samples
using a validated enzyme-linked immunosorbent assay
(ELISA) that the Wyeth Biological Technologies group developed.
The ELISA capture antibody, RK35, is a mouse
monoclonal antibody that binds the putative receptor (activin
receptor IIB) binding site in myostatin.28 The detector
antibody, RK22, is a mouse monoclonal antibody specific for
myostatin that binds the ALK4/5 binding site near the
amino terminus (unpublished data). This assay detects free
myostatin but does not effectively measure latent myostatin
or myostatin bound to MYO-029. Therefore, an acid dissociation
step was incorporated into the assay to convert latent
myostatin to free myostatin and to dissociate MYO-029
from myostatin, thereby enabling the measurement of both
endogenous free and total myostatin in serum and muscle
samples. All clinical samples were analyzed in the Wyeth Biomarker
Laboratory (Collegeville, PA), which also conducted
a thorough analytical validation of the ELISA assay. Free and
total serum myostatin levels were assessed during three visits
(baseline, week 6, and week 36). Free and total myostatin
levels at the two later visits were compared with baseline to
determine whether alterations could be detected in myostatin
levels over time and in response to escalating doses of MYO-
029. Muscle myostatin levels were assessed before (baseline)
and after (week 26) dose administration to determine a response
to MYO-029. It should be noted that serum and
muscle biopsy samples were collected and stored at 70°C
Fig 1. Segmentation and three-dimensional reconstruction of proximal arm muscle by magnetic resonance imaging. Axially acquired
images (left) were obtained through the entire lengths of the extremities. Individual muscles were then segmented into cross-sectional
areas (center) and volumes summed from the segmented areas (right).
Wagner et al: MYO-029 in Muscular Dystrophy 563
for a period of up to 2 years in some cases. The long-term
stability of myostatin has not been characterized, and the effects
of long-term storage are therefore unknown.
MUSCLE HISTOLOGY. An open muscle biopsy was an optional
procedure, and specimens were obtained from 26 subjects
at baseline and at week 26. Baseline biopsies were obtained
from muscles having MMT grades of 4 or 4, and
the same or contralateral muscle underwent biopsy at week
26. Fiber necrosis, inflammation, and regeneration were
qualitatively scored as none/minimal, mild, moderate, or severe
by a muscle pathologist blinded to prestudy/poststudy
status, diagnosis, and treatment group. Central nucleated fibers
and fiber diameter were quantitatively determined on all
muscle fibers up to 500 fibers per biopsy using OpenLab
software (Improvision®, Lexington, MA).
Statistical Analysis
Statistical analysis of safety end points is reported using the
intent-to-treat population, defined as all randomly assigned
subjects who received at least one dose of placebo or MYO-
029. Analysis of biological activity was based on a modified
intent-to-treat analysis, which included all subjects who had
results from baseline and visit 15 for a particular end point.
Because the primary objective of the study was assessment of
safety and tolerability, sample sizes were determined by clinical
rather than statistical considerations. However, for 9 (or
6 BMD subjects in Cohorts 3 and 4) MYO-029 subjects
with 1 dystrophy in 1 cohort, the probabilities of detecting
at least 1 AE were calculated to be 0.09 (0.06), 0.61 (0.47),
0.77 (0.62), 0.87 (0.74), and 0.96 (0.88) when the rates are
1, 10, 15, 20, and 30, respectively.
The MMT, QMT, TFT, DEXA, and SF-36 percentage
changes from baseline measurements were summarized by
treatment group using mean and standard errors within a
disease cohort by week. The mean percentage change from
baseline response of subjects treated in each dose cohort was
compared with the mean percentage change from baseline of
the placebo group at week 26 via Dunnett’s Multiple-
Comparisons Procedure. The adjusted p values of these comparisons
were reported and considered to be statistically significant
if less than 0.05.
The MRI percentage changes from baseline measurements
were evaluated for adequacy of statistical assumptions (ie,
symmetry of the response about the group mean). Because
skewness was observed among the MRI responses, the percentage
changes from baseline measurements were summarized
via the treatment group medians within disease cohort
by week. The median percentage changes from baseline response
of subjects treated with either 1.0, 3.0, or 10.0mg/kg
MYO-029 were compared with the median percentage
change from baseline of the placebo group at week 26, via
Dunn’s Multiple-Comparisons Procedure. The adjusted p
values of these comparisons were reported and considered to
be statistically significant if less than 0.05.
Mean muscle fiber diameters pretreatment and posttreatment
were compared using a paired t test for each dosing
cohort. Analysis of variance was used to evaluate the effect of
dose on the percentage change in mean fiber diameter between
the pretreatment and posttreatment samples. Myostatin
levels were compared using a paired t test. Significance
was set at p 0.05 for both analyses.
Results
A total of 116 subjects in 4 dosing cohorts with muscular
dystrophies (36 with BMD, 42 with FSHD, and
38 with LGMD) were included in the study. Enrollment
in Cohort 4 (30mg/kg) was discontinued during
the study. There were no significant differences between
groups in any demographic characteristic, as
shown in Table 1. Figure 2 depicts subject disposition.
Safety
Safety assessments, including vital signs, laboratory
tests, and physical examination showed no significant
differences between treatment and placebo groups, and
were not dose limiting. Twenty-seven subjects discontinued
from the study as depicted in Figure 2. This
included four subjects who were withdrawn after experiencing
hypersensitivity reactions (three with urticaria).
Two of the subjects experiencing hypersensitivity
reactions were in the 10mg/kg cohort and two were
in the 30mg/kg cohort. A decision was made to terminate
Cohort 4 (30mg/kg) after the occurrence of hypersensitivity
reactions and a case of unconfirmed aseptic
meningitis in the 10mg/kg group. In the one
unconfirmed case of “aseptic meningitis” in a subject
in the 10mg/kg cohort, symptoms included diplopia
and headache. Cerebrospinal fluid showed increased
protein without cells. MRI showed an area of meningeal
enhancement. This subject’s symptoms resolved
and cerebrospinal fluid findings normalized on repeat
study without treatment.
A total of 109 subjects reported AEs, of which 104
were considered to be treatment-emergent adverse
events. Table 2 shows treatment-emergent adverse
events that occurred in at least 5% of any group and
were more common in any treatment cohort than in
the placebo group. The only treatment-emergent adverse
event more common in the treatment groups
than placebo that was statistically significant was accidental
injury ( p 0.026).
Rash, with or without pruritus, and urticaria were
seen in 12 subjects. Three of the 12 had urticaria only
(all occurring in the 10mg/kg cohort), believed to be
drug related. Other rashes were also considered to be
forms of cutaneous hypersensitivity reactions, based on
the temporal relation to drug infusion. The number of
these skin reactions according to treatment regimen
was as follows: placebo group had 2 reactions in 29
placebo-treated subjects, 1mg/kg cohort had 3 in 27
subjects, 3mg/kg cohort had 1 in 27 subjects, 10mg/kg
cohort had 4 in 27 subjects, and 30mg/kg cohort had
2 in 6 subjects.
A total of 7 (6%) subjects reported serious AEs, including
2 of 29 (6.9%) in the placebo group (dyspnea
564 Annals of Neurology Vol 63 No 5 May 2008
and upper respiratory infection in 1 and unintended
pregnancy in 1), 2 of 27 (7.4%) in the 3mg/kg group
(1 with dementia and 1 with depression followed by a
suicide attempt), and 3 of 27 (11.1%) in the 10mg/kg
cohort (1 with diplopia and unconfirmed aseptic meningitis,
1 with diarrhea, and 1 with chest pain). No
serious AEs were reported in the 1 (n 27) and
30mg/kg (n 6) cohorts. No deaths were reported in
this study.
There were no clinically significant changes in electrocardiograms,
echocardiograms, audiometry, and eye
examinations in the review of changes from baseline in
treatment groups compared with placebo groups.
Biological Activity
Results of strength, as measured by MMT, at baseline
and end of treatment (week 26), together with the percentage
change from baseline, are provided in Table 3.
No improvement in total, upper body, or lower body
strength was seen for any dystrophy subgroup at any
dose. Note that there were fewer subjects completing
testing at week 26 in the 10mg/kg dose cohort as a
result of the subject discontinuations described in the
safety section. Based on several analyses, QMT followed
a pattern similar to MMT, without demonstrable
improvement. No improvement in QMT was seen
for any of the subgroups with muscular dystrophy.
Based on the hypothesis that stronger muscle groups
might respond better to MYO-029, the QMT scores of
muscle groups with MMT scores of grade 4 (4, 4,
4) were evaluated in each of the dystrophy subgroups
at each dosing level. This approach also failed to demonstrate
any improvement in QMT for any of the diseases
under study (data not shown).
No improvement in TFTs was seen for any of the
groups at any dosing regimen (data not shown). There
was also no evidence of perceived improvement via
analysis of the SF-36 Physical Health or Mental Health
component in the total subject population or in individual
disease states.
Percentage change in lean body mass, as measured
by DEXA, was 0.07 0.7 in control subjects during
the study period. Changes in the 1.0, 3.0, and
10mg/kg cohorts were 0.9 0.9, 2.4 0.7, and
1.4 0.7, respectively. The changes were not significantly
different in treatment groups versus placebo
groups at the 1.0 and 10mg/kg doses ( p 0.6427 and
0.4863, respectively), and approached significance in
the 3.0mg/kg group ( p 0.0514).
Percentage change in muscle volume of the arms and
legs, as measured by MRI, was 0.7 0.8 in control
subjects during the study period. Changes in the 1.0,
3.0, and 10mg/kg cohorts were 0.6 0.9, 2.1
1.0, and 1.2 1.1, respectively. These changes were
Table 1. Demographic and Baseline Characteristics
Characteristics Treatment Group
Placebo
(n 29)
MYO-029 Total
(n 116)
1mg/kg
(n 27)
3mg/kg
(n 27)
10mg/kg
(n 27)
30mg/kg
(n 6)
Mean age, yr (SD) 39.3 (13.3) 37.2 (9.5) 37.1 (13.6) 40.2 (11.5) 44.3 (10.2) 38.8 (12.0)
Sex, n (%)
Female 8 (27.6) 7 (25.9) 5 (18.5) 7 (25.9) 1 (16.7) 28 (24.1)
Male 21 (72.4) 20 (74.1) 22 (81.5) 20 (74.1) 5 (83.3) 88 (75.9)
Race, n (%)
White 26 (89.7) 25 (92.6) 25 (92.6) 27 (100) 6 (100) 109 (94.0)
American Indian 0 1 (3.7) 0 0 0 1 (0.9)
Asian 1 (3.4) 0 0 0 0 1 (0.9)
Black 2 (6.9) 1 (3.7) 1 (3.7) 0 0 4 (3.4)
Hispanic 0 0 1 (3.7) 0 0 1 (0.9)
Mean weight, kg
(SD)
73.4 (18.0) 82.5 (20.3) 75.6 (19.8) 79.0 (17.6) 87.2 (19.4) 78.0 (19.1)
Mean height, cm
(SD)
174.2 (10.9) 174.4 (9.6) 173.2 (8.6) 173.1 (8.9) 179.7 (13.1) 174.0 (9.7)
Mean body mass
index, kg/m2
(SD)
23.9 (3.7) 26.9 (5.4) 25.0 (5.0) 26.3 (4.9) 26.9 (5.0) 25.6 (4.9)
Mean body surface
area (SD)
1.9 (0.3) 2.0 (0.3) 1.9 (0.3) 1.9 (0.2) 2.1 (0.3) 1.9 (0.3)
SD standard deviation.
Wagner et al: MYO-029 in Muscular Dystrophy 565
not significantly different from control subjects in any
treatment group.
Of the 296 serum myostatin samples received for
testing (representing baseline, week 6, and week 36)
from 119 subjects, all had a total myostatin concentration
within the limits of quantitation (0.147–37.5ng/
ml) by the ELISA, whereas 189 samples (64%) had a
free myostatin concentration below the lower limit of
quantitation reflecting interference in the assay from
specific binding of MYO-029 to myostatin in those
samples. No observable changes could be detected in
total myostatin levels or measurable free myostatin levels
in serum (data not shown) at either week 6 or 36
compared with baseline in any group.
Determination of changes in muscle myostatin levels
was limited by the number of biopsies received and the
level of sensitivity of the ELISA assay. Of the 59 biopsy
samples received from 33 subjects, 12 had a total
myostatin concentration below the lower limit of quantitation
(44pg/ml), and 42 samples had a free myostatin
concentration below the lower limit of quantitation.
In subjects for whom total myostatin levels were
Fig 2. Trial profile shows the breakdown of enrolled subjects by disease, including the total number per group and the number
completing the trial. AE adverse event; BMD Becker’s muscular dystrophy; FSHD facioscapulohumeral dystrophy;
LGMD limb-girdle muscular dystrophy.
566 Annals of Neurology Vol 63 No 5 May 2008
detectable in both predose and postdose samples, the
high variability and low sample number precluded detection
of meaningful changes in myostatin levels relative
to baseline for all treatment groups.
Based on 26 available pairs of biopsy specimens,
treatment with MYO-029 had no observable adverse
effect on muscle pathology as assessed by standard histological
analysis. Specifically, there was no change in
inflammation or fiber necrosis in treated versus untreated
subjects. There was also no significant change
in fibrosis, fiber regeneration, or the percentage of central
nucleated fibers, a marker of degeneration and subsequent
regeneration of muscle fibers.
Morphometric analysis demonstrated a dosedependent
increase in fiber size diameter. Muscle fiber
diameter after treatment, expressed as percentage of
baseline, is shown in Figure 3. Increased muscle fiber
diameters were seen in the 10 (median 15.2%
Table 2. Number (%) of subjects experiencing adverse events in descending order of incidence for events
occurring in >5% of subjects in any group, including the total group (intent-to-treat population)
Wagner et al: MYO-029 in Muscular Dystrophy 567
change from baseline) and 3mg/kg groups (14.4%)
compared with the 1mg/kg treatment (0. 93%) and
placebo groups (2.7%). The sample sizes in each
group are small (see Fig 3), and these differences did
not reach statistical significance.
Discussion
Few therapeutic trials have been conducted in adults
with muscular dystrophy. Small clinical trials in FSHD
have included glucocorticoid steroids (prednisone),24
-adrenergic agonists (albuterol),3,29 and most recently,
calcium-channel blockade (diltiazem).2 Therapeutic
studies of adult BMD have been limited to inclusion
of a few subjects in a Phase I study of
dystrophin plasmid-based gene therapy in DMD/
BMD31 and in a study of creatine monohydrate in
multiple muscular dystrophies.5 LGMD includes more
than 15 distinct diseases, some of which have been
studied with glucocorticoid steroids and creatine.5,31–33
None of these studies has resulted in the accepted use
of a therapeutic agent in adult muscular dystrophy.
In this first-ever study of a myostatin inhibitor, the
primary objective was safety. MYO-029 was well tolerated
in a diverse group of muscular dystrophies with
varying pathogenic mechanisms. No target-related side
effects were identified; that is, no side effects to skeletal,
smooth, or cardiac muscle were found. The most
significant agent-related AEs were hypersensitivity skin
reactions. Urticaria was seen in three subjects in the
10mg/kg cohort. Immune-mediated side effects, such
as hypersensitivity reactions, are anticipated in biological
agents and account for the majority of type B reactions,
unrelated to pharmacological activity of the
drug.34 Hypersensitivity reactions to MYO-029 limited
dose escalation to more than 10mg/kg and represent a
potential restrictive factor in achieving efficacy with
MYO-029.
This trial also examined muscle mass and strength as
measures of biological activity of MYO-029, without
intent to address the specific pathophysiology of the
various muscular dystrophies. These exploratory outcome
measures were found to be feasible in all disease
populations studied. No increase in strength by MMT
or QMT or improvement in function by TFTs could
be demonstrated in this 9-month trial of MYO-029 (6
months of dosing, 3 months of follow-up).
Because statistically significant changes were not observed
for MMT or QMT, the investigators performed
a retrospective power analysis for a small subset (n
24) of MMT and QMT measurement by disease co-
Table 3. Strength by Manual Muscle Testing (Average of All Muscles Tested)
Diagnosis Treatment Baseline
Mean (SE)
Week 26
Mean (SE)
Week 26
Mean
Percentage
Change (SE)
Adjusted
pa
BMD Placebo 8, 3.29 (0.29) 8, 3.59 (0.17) 8, 0.66 (1.41)
MYO-029 1.0mg/kg 8, 3.90 (0.10) 8, 3.97 (0.11) 8, 3.67 (1.23) 0.5503
MYO-029 3.0mg/kg 9, 3.81 (0.12) 9, 3.89 (0.15) 9, 3.99 (2.54) 0.4490
MYO-029 10.0mg/kg 5, 3.77 (0.15) 5, 3.84 (0.20) 5, 2.45 (1.97) 0.8871
FSHD Placebo 8, 3.70 (0.05) 8, 3.74 (0.07) 8, 2.87 (1.33)
MYO-029 1.0mg/kg 9, 3.70 (0.08) 9, 3.73 (0.13) 9, 1.99 (2.71) 0.9894
MYO-029 3.0mg/kg 8, 3.88 (0.12) 8, 3.91 (0.14) 8, 2.22 (1.67) 0.9959
MYO-029 10.0mg/kg 5, 3.87 (0.15) 5, 3.99 (0.20) 5, 5.28 (5.31) 0.8896
LGMD Placebo 8, 3.15 (0.32) 8, 3.43 (0.12) 8, 2.25 (2.77)
MYO-029 1.0mg/kg 8, 3.74 (0.13) 8, 3.75 (0.10) 8, 2.00 (1.87) 0.9997
MYO-029 3.0mg/kg 9, 3.30 (0.17) 9, 3.25 (0.15) 9, 0.40 (1.86) 0.7325
MYO-029 10.0mg/kg 5, 3.44 (0.27) 5, 3.45 (0.34) 5, 0.09 (2.93) 0.8847
Total Placebo 24, 3.38 (0.15) 24, 3.59 (0.07) 24, 1.93 (1.09)
MYO-029 1.0mg/kg 25, 3.78 (0.06) 25, 3.81 (0.07) 25, 2.53 (1.17) 0.9746
MYO-029 3.0mg/kg 26, 3.65 (0.09) 26, 3.67 (0.10) 26, 1.93 (1.21) 1.0000
MYO-029 10.0mg/kg 15, 3.69 (0.12) 15, 3.76 (0.15) 15, 2.61 (2.05) 0.9763
ap values represent the comparison of group means with the placebo group mean via Dunnett’s test. The resultant p values reflect an
adjustment for multiple comparisons of means with the placebo group mean.
SE standard error; BMD Becker muscular dystrophy; FSHD facioscapulohumeral muscular dystrophy; LGMD limb-girdle
muscular dystrophy.
568 Annals of Neurology Vol 63 No 5 May 2008
hort combinations (eg, the MMT measurement for upper
muscles in BMD, FSHD, LGMD, and combined
cohorts) to develop some intuition about the optimal
statistical testing conditions for comparing various
groups. Statistical power was calculated based on the
differences observed between the three MYO-029 dose
group means and the placebo-treated patients’ mean response,
and at the same level of overall statistical significance
as used in the analysis of the MMT and
QMT data. Amongst these calculations, the maximum
power for any comparison (adjusted for multiplicity of
testing) was approximately 47%. Typically, the power
for efficacy in a clinical trial is at least 80%. The results
of these calculations are not surprising as a previously
published report of a prospective, quantitative study of
the natural history of FSHD estimated that a twoarmed
clinical trial with a power of 80% to detect arrest
of disease progression after 1 year would require
160 subjects in each arm.21
Although an improvement in strength and function
were not demonstrated, biological activity in another
sphere was suggested by findings in some subjects.
Muscle mass, as estimated by lean mass by DEXA, was
found to increase by approximately 2.4% in the
3mg/kg cohort, which was statistically significant from
control subjects in BMD subjects and approached significance
in all treated subjects. Muscle mass alterations
during the study period, as determined by MRI, were
not significant in treated subjects versus control subjects.
Muscle from placebo-treated subjects had stable
fiber diameters in the pretreatment and posttreatment
periods, whereas there was a dose-dependent increase
in fiber diameter in the 3 and 10mg/kg cohorts. Sample
sizes were small in all of the above analyses, and
differences between populations did not reach statistical
significance. However, the consistency of the response
to treatment in the various measures of effects
on muscle tissue suggest that MYO-029 reached its intended
target, producing a modest degree of muscle fiber
hypertrophy and increased muscle mass in some
treated subjects.
Considering the duration of this treatment trial, it is
not unexpected that strength is stable in adults with
muscular dystrophy. As stated previously, the ability to
detect arrest of disease progression or minimal improvements
in strength would require larger sample
sizes in a study designed to look at efficacy. The MYO-
029 study was a safety trial, not originally designed to
detect efficacy: The sample sizes chosen are not optimal
for detecting statistically significant changes between
MYO-029– and placebo-treated patients.
In conclusion, MYO-029 is a neutralizing antibody
to myostatin that had good safety and tolerability with
the exception of cutaneous hypersensitivity, especially
in higher dose cohorts. This trial supports the hypothesis
that systemic administration of myostatin inhibitors
provides an adequate safety margin for clinical
studies, and these inhibitors should be evaluated for
Fig 3. Muscle fiber diameters show the percentage change in muscle fiber diameter before and after treatment. Each vertical bar
represents one patient. There was an increase in muscle fiber diameters in the 10 (median 15.2% change from baseline) and
3mg/kg groups (14.4%) compared with the 1mg/kg treatment (0.93%) and placebo groups (2.7%). A trend toward larger
fibers with increasing dose (differences did not reach statistical significance) is shown; only two patients in the 10mg/kg group had
muscle biopsies.
Wagner et al: MYO-029 in Muscular Dystrophy 569
stimulating muscle growth in muscular dystrophy.
Multiple pharmaceutical companies are evaluating
other myostatin inhibitors for a variety of disorders including
cachexia and sarcopenia. Further evaluation of
more potent myostatin inhibitors for primary muscle
disorders should be considered.
Disclosure
A.P. received compensation from Wyeth Pharmaceuticals
(Collegeville, PA) to his laboratory for histological
analysis. T.A., E.R.L., and J.M.W. are employed by
Wyeth Pharmaceuticals (Cambridge, MA). R.A. and
S.A.P. are employed by Wyeth Pharmaceuticals (Collegeville,
PA). K.M. is a consultant for Wyeth Pharmaceuticals
(Collegeville, PA). Under a licensing agreement
between MetaMorphix and Johns Hopkins
University, the university is entitled to royalty payments
on sales of the growth factor, myostatin, described
in this article. The university also is entitled to
a share of sublicensing income from arrangements between
MetaMorphix and Wyeth. The university owns
MetaMorphix stock, which is subject to certain restrictions
under university policy. The terms of this arrangement
are being managed by Johns Hopkins University
in accordance with its conflict of interest
policies.
Appendix
The following people participated in this study (by site):
Brigham and Women’s Hospital—Ronan Walsh, MD,
Lisa Krivickas, MD, Kristen McIntosh, MPH, Kristen
Whiteside (Study Coordinator), and Merideth Donlan,
DPT; Children’s National Medical Center—Robert
Leshner, MD, Paola Canelos (Study Coordinator),
Katherina Parker, MSPT, PCS, and Marissa Bartczak,
MSPT; Columbus Children’s Research Institute—Roula
al-Dahhak, MD, Karen Downing, and Cheryl Wall,
RN; Johns Hopkins University School of Medicine—
Leigh Warsing (Senior Laboratory Technician), Ronald
Cohn, MD, PhD, Daniel B. Drachman, MD, Regina
Brock-Simmons (Study Coordinator), Molly Sprung
(Study Coordinator), and Hejab Imteyaz (Clinical Evaluator);
University of Kansas Medical Center—April
McVey, MD, Arthur Dick, MD, Victoria Watts, RN
(Study Coordinator), and Laura Herbelin, BS; University
of Newcastle Upon Tyne—Jane Barnes, SRN,
Penny Garrood, MBChB, Michelle McCallum, and
Sarah Russell, SRN; University of Rochester Medical
Center–Colleen Donlin-Smith, MA (Study Coordinator),
and Deborah Whalen PT, DPT, MHS; University
of Texas Southwestern Medical Center—Sharon Nations,
MD, Nina Gorham, MA, CCRP, Cindy Wynne-
Jones, RN, and Rhonda McLin, PTA; University of
Utah Hospital—Jacinda Sampson, MD, PhD, Cade
Walker (Study Coordinator), Kim Hart, MS (Study Coordinator),
Justine Bagley (Study Coordinator), and
Eduard Gappmaier, PT, PhD; Washington University
School of Medicine—Charlie Wulf, BA (Study Coordinator),
Jeanine Schierbecker, PT, MHS (Study Coordinator),
Betsy Malkus, PT, MHS, and Catherine Seiner,
PT, MHS, GCS; Wyeth Pharmaceuticals—Christopher
Corcoran, BS, Lisa A. Collins-Racie, MS, Stephen Bradley
Forlow, PhD, Riyez Karim, BSc, and Lioudmila
Tchistiakova, PhD.
This study was funded by Wyeth Pharmaceuticals and the Muscular
Dystrophy Association specifically for genotyping of prospective
subjects (4020, R.B.; 4018, R.T.) Study conducted in part within
the KUMC GCRC, which is funded by NIH/NCRR (M01-
RR023940) and the JHH GCRC, which is funded by NIH/NCRR
(M01-RR000052).
We thank Dr J. Ryan for his leadership in initiating the program, I.
Wyglendowski for overall study management, Dr R. Li for coordinating
the biopsy and imaging protocol development and outcomes
assessment, A. Holbrook for clinical operations support, Dr K. Fischbeck
for clinical trial protocol development, Dr M. McDermott
for statistical advice, and M. Gayari for her work in performing the
statistical calculations and table generation. We also thank L.
Dubach for professional writing support, which was funded by
Wyeth Pharmaceuticals.
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Wagner
 
Last edited:
Summary/Conclusions of Above Study

Although an improvement in strength and function
were not demonstrated, biological activity in another
sphere was suggested by findings in some subjects.
Muscle mass, as estimated by lean mass by DEXA, was
found to increase by approximately 2.4% in the
3mg/kg cohort, which was statistically significant from
control subjects in BMD subjects and approached significance
in all treated subjects. Muscle mass alterations
during the study period, as determined by MRI, were
not significant in treated subjects versus control subjects.
Muscle from placebo-treated subjects had stable
fiber diameters in the pretreatment and posttreatment
periods, whereas there was a dose-dependent increase
in fiber diameter in the 3 and 10mg/kg cohorts. Sample
sizes were small in all of the above analyses, and
differences between populations did not reach statistical
significance. However, the consistency of the response
to treatment in the various measures of effects
on muscle tissue suggest that MYO-029 reached its intended
target, producing a modest degree of muscle fiber
hypertrophy and increased muscle mass in some
treated subjects.

Considering the duration of this treatment trial, it is
not unexpected that strength is stable in adults with
muscular dystrophy. As stated previously, the ability to
detect arrest of disease progression or minimal improvements
in strength would require larger sample
sizes in a study designed to look at efficacy. The MYO-
029 study was a safety trial, not originally designed to
detect efficacy: The sample sizes chosen are not optimal
for detecting statistically significant changes between
MYO-029– and placebo-treated patients.
In conclusion, MYO-029 is a neutralizing antibody
to myostatin that had good safety and tolerability with
the exception of cutaneous hypersensitivity, especially
in higher dose cohorts. This trial supports the hypothesis
that systemic administration of myostatin inhibitors
provides an adequate safety margin for clinical
studies, and these inhibitors should be evaluated for
stimulating muscle growth in muscular dystrophy.

Multiple pharmaceutical companies are evaluating
other myostatin inhibitors for a variety of disorders including
cachexia and sarcopenia. Further evaluation of
more potent myostatin inhibitors for primary muscle
disorders should be considered.
 
i can think of one or two ways id rather spend a grand, and those dont even involve hookers haha...
 

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