Muscular Dystrophy (MD) Therapeutics

GlobalData, the industry analysis specialist, has released its new report, "Muscular Dystrophy (MD)

Therapeutics - Pipeline Assessment and Market Forecasts to 2018". The report is an essential source of

information and analysis on the global MD therapeutics market. The report identifies the key trends

shaping and driving the global MD therapeutics market. The report also provides insights on the prevalent

competitive landscape and the emerging players expected to significantly alter the market positioning of

the current market leaders. Most importantly, the report provides valuable insights on the pipeline

products within the global MD therapeutics sector. This report is built using data and information sourced

from proprietary databases, primary and secondary research and in-house analysis by GlobalData's team of

industry experts.

GlobalData estimates that the global Muscular Dystrophy (MD) therapeutics market to grow at a

Compound Annual Growth Rate (CAGR) of 22.8%, from $33m in 2010 to $170.9m in 2018. The market

will show steady growth till 2010 and a steep increase in the market valuations will be seen after 2014.

This is primarily attributed to the expected launch of two molecules GSK2402968 in 2014 and

Catena/Sovrima (idebenone) in 2015 for the DuchenneMuscular Dystrophy/Becker Muscular Dystrophy

(DMD/BMD). The future market is set to witness significant high value growth mainly due to the high

cost of therapy of the pipeline molecules. The other factors that will contribute to the growth of the market

are high diagnosis and treatment rates and increasing disease awareness. Absence of approved drugs and

the high use of off-label generic drugs, such as prednisolone, deflazacort, mexiletine, naproxen and others

will act as a barrier to the MD therapeutics market.

his is a consecutive study on 28 patients who have been diagnosed as having congenital muscular

dystrophy at Jordan University Hospital in the period from January 1990 to February 1997. Of 75 patients

diagnosed as having muscle disease, 55 (73.3%) had muscular dystrophy. Of 55 muscular dystrophy

patients, 28 (50.9%) had congenital muscular dystrophy, 11 (20%) had Duchenne muscular dystrophy, 9

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(16.4%) had Becker muscular dystrophy, 9 (16.4%) had Becker muscular dystrophy, 4 (7.3%) had

myotonic dystrophy, 2 (3.6%) had limb-girdle dystrophy, and 1 (1.8%) patient had facioscapulohumeral

dystrophy. Age of onset of symptoms of congenital muscular dystrophy (hypotonia and weakness) was

documented antenatally or in the first few months in the majority (92.9%) of patients. Parental

consanguinity was documented in 21 (75%) of congenital muscular dystrophy cases, and family history of

possible similar cases in 15 (53.6%). Congenital muscular dystrophy patients with normal cognitive

milestones (n = 16; 57.1%) were slightly more common than patients with cognitive delay. In contrast to

previous reports, congenital muscular dystrophy is probably more common in communities with high rates

of parental consanguinity than other dystrophies. Our study adds significant support to the most recent

literature on this finding. (J Child Neurol 1998; 13:383386).

Muscle diseases are common causes of lower motor neuron unit disorders.1 Muscular dystrophies are the

most common muscle disease in children.2 Congenital muscular dystrophy is a heterogeneous uncommon

type of muscular dystrophy when compared to the most frequently reported form of muscular dystrophy,

the Duchenne muscular dystrophy, which has an incidence of 1 in 3000 to 1 in 8000 male births.2-3 All

congenital muscular dystrophy patients have autosomal recessive inheritance, except for few reports of

possible autosomal dominant inheritance and sporadic cases.3 The aim of the present study was to

evaluate the frequency and clinical patterns of congenital muscular dystrophy in Jordanian children

presenting with muscle disease.

PATIENTS AND METHODS

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This was a consecutive study, that included all children who had been diagnosed as having muscular

dystrophy with onset of their symptoms antenatally or in early infancy. All children were evaluated by the

first author in the pediatric neurology service at Jordan University Hospital in the period between January

1990 and February 1997. After clinical evaluation, nerve conduction study, electromyography, serum

creatine kinase enzyme study, and muscle biopsy were done on all of them.

Hematoxylin and eosin stain was done on all muscle biopsies (Figure 1). Mason trichrome and periodic

acid-Schiff stains were occasionally done for further delineation of the abnormalities. No

immunohistochemistry was done on any of our patients because of lack of expertise and technical

limitations in our lab. Brain computed tomographic (CT) scans were requested for all cogitively delayed

patients; however, some patients refused the procedure because of financial reasons or they were not

convinced of the benefits from the procedure. Brain CT scans were done on a few non-cognitively delayed

patients to use as a control. Inclusion criteria were weakness and hypotonia documented by history from

the mother or from physician notations antenatally or in early infancy. Each patient had serum creatine

kinase evaluation done within 2 years from onset of symptoms, myopathic electromyography, normal

nerve conduction study, and muscle biopsy disclosing dystrophic changes.6 Patients were divided into two

major groups. Group A patients had normal cognitive developmental milestones and group B had

cognitive developmental delay. Patients were considered cognitively delayed if they had delay in language

milestones in the absence of hearing impairment, or problem-solving delay for age, or both.7-' Group A

patients were further divided into three subgroups: group Al had progressive course and high serum

creatine kinase level, group A2 had mild clin ical course with normal serum creatine kinase level, and

group A3 had mixed features.

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 RESULTS

Of 75 patients diagnosed to have muscle diseases, 55 (73.3%) patients had muscular dystrophy. Of the 55

muscular dystrophy patients, 28 (50.9%) had congenital muscular dystrophy, 11 (20%) had Duchenne

muscular dystrophy, 9 (16.4%) had Becker muscular dystrophy, 4 (7.3%) had myotonic dystrophy, 2

(3.6%) had limb-girdle muscular dystrophy, and 1 (1.8%) patient had facioscapulohumeral dystrophy9

(Table 1). Age of onset of patients with symptoms of congenital muscular dystrophy was documented

antenatally in 2 (7.1%) patients, neonatal period in 10 (33.7%) patients, at 1-3 months in 14 (50%)

patients, and at 4-9 months in 2 (7.1%) patients. There were 16 females and 12 males. Serum creatine

kinase levels did not correlate with the different groups. The serum creatine kinase range in group Al was

279-7730 U/L with a mean of 2324 U/L and the serum creatine kinase range in group B was 133-6405

U/L with a mean of 2123 U/L (normal value up to 110 U/L). Children with progressive clinical course

(mainly group Al) and children older than 3 years of age at the time of the biopsy tended to have greater

degree of muscle pathology in the form of excessive fibrosis and adipose tissue replacing muscle fibers.

Group A patients were the majority (n = 16, 57.1%). Seven patients belonged to group Al, another eight

patients belonged to group A2, and one patient belonged to group A3 (normal mental development,

progressive weakness, and normal serum creatine kinase level). Brain CT scans were done on four patients

of group A, which showed normal results. Group B included 12 (42.9%) patients with six of them having

normal serum creatine kinase levels. Seven patients of group B had brain CT scans, four of them were

abnormal. The first two patients had mild diffuse brain atrophy, one of them had a high serum creatine

kinase level. The third patient had cobblestone lissencephaly, DandyWalker cyst, dilated ventricles, and

occipital encephalocele. He had also a high serum creatine kinase level, retinal dysplasia,

microophthalmia, and cataracts, suggesting Walker-Warburg syndrome (Figure 2). The fourth patient had

periventricular cortical white-matter abnormalities with sparing of corpus callosum, internal capsule, and
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brain stem.10 He also had microcephaly, seizures, optic atrophy, and high serum creatine kinase level.

Consanguinity was documented in 21 (75%) patients. First cousin and second cousin marriages were

encountered in 10 patients of group A and eight patients of group B. Distant relation marriages were

encountered in two patients of group A and one patient of group B. Family history of possible similar

cases with autosomal recessive inheritance was documented in 15 (53.6%) patients (Table 2). No

particular correlation was noted between frequency of consanguinity and family history and specific

congenital muscular dystrophy groups.

DISCUSSION

Our study has shown that the most common muscle disease in Jordan is most probably congenital

muscular dystrophy, accounting for about one third of all muscle diseases and about one half of all

muscular dystrophies. This is in contrast to what has been reported in the literature.1-3,11-13 The high rate

(75%) of parental consanguinity and the family history of possible similar cases (53.6%) among

congenital muscular dystrophy patients may partially explain such a finding, despite the high incidence

(50%) of parental consanguinity in our community.14 The role of parental consanguinity in Arab

populations in increasing the incidence of autosomal recessive forms of neuromuscular disorders has been

recently emphasized.15 Donner et al reported 15 cases of congenital muscular dystrophy from Finland

accounting for 9% of neuromuscular cases and he suggested that congenital muscular dystrophy may be

more common in Finland than elsewhere.16

View Image - Figure 1 Figure 2

View Image - Table 1.

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Onset of symptoms (weakness and hypotonia) of congenital muscular dystrophy are reported antenatally,

at birth, or in the first few months.2,11,7 In our study, symptoms were documented before age 3 months in

92.9% of cases. The classification of congenital muscular dystrophy has long been a source of

uncertainty.2,3,17,18 Pa parano et ala proposed the most recent congenital muscular dystrophy

classification which included:

Classic congenital muscular dystrophy with merosin deficiency. These patients have normal mental

development, severe progressive symptoms and high serum creatine kinase levels. Group Al patients in

present study, fulfill the clinical diagnostic criteria of this entity.

Classic congenital muscular dystrophy with normal merosin. Patients have normal mental development,

mild weakness and hypotonia, and usually normal serum creatine kinase levels. Group A2 patients fulfill

clinical diagnostic criteria of this entity.

Congenital muscular dystrophy with mental retardation. Eleven of 12 patients of group B probably

correspond to this entity. One of these patients had brain CT with whitematter changes similar to Saudi

cases reported by Cook et al.10

Cobblestone lissencephaly syndrome such as Fukuyama congenital muscular dystrophy, muscle-eye-brain

disease and Walker-Warburg syndrome. The twelfth patient of group B fulfilled the diagnostic criteria of

Walker Warburg syndrome, which has world wide distribution, in contrast to Fukuyama congenital

muscular dystrophy which occurs mainly in Japan and muscle-eye-brain disease which has been reported

primarily from Finland.13,17,19

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Congenital muscular dystrophy with occipital pachygyria and atypical congenital muscular dystrophy

syndrome. None of our patients belong to these two entities. One patient (group A3) probably belongs to

the first entity in the Parano et al classification (classic congenital muscular dystrophy with merosin

deficiency) ie, group Al in our study.3 The normal serum creatine kinase level in this patient is most likely

due to the severe muscle atrophy he had.

To conclude, congenital muscular dystrophy is a common muscular dystrophy in Jordan. It is probably

more common in communities with high rates of parental consanguinity than other dystrophies. Our study

adds significant support to the scant literature on this finding, considering the relatively large number of

our patients compared to other studies. Immunohistochemical studies are definitely helpful in defining

accurately the various congenital muscular dystrophy entities.

Advocates in Muscular Dystrophy Community Press Congress for Fast Action on Muscle Disease

Research and Treatment

TUCSON, Ariz., Feb. 14, 2013 /PRNewswire-USNewswire/ -- The Muscular Dystrophy Association,

Parent Project Muscular Dystrophy and the Foundation to Eradicate

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Duchenne today called on the U.S. Senate and the U.S. House of Representatives to reauthorize the MD

CARE Act of 2001, and to continue federal support for the accelerated pace of research and treatment

development for muscular dystrophy. The nonprofits also are urging the public to contact their U.S.

Senators and ask them to vote for reauthorization of The Paul D. Wellstone Muscular Dystrophy

Community Assistance, Research and Education (MD CARE) Amendments of 2013. The Senate

introduced the bill last night (S. 315), and the House introduced the bill (H.R. 594) Feb. 8.

Since 2001, federal funding and coordination of muscular dystrophy research has dramatically enhanced

discovery and development of potential treatments for the muscular dystrophies, including: Duchenne and

Becker muscular dystrophies (DMD/BMD, or also known as DBMD); congenital muscular dystrophy

(CMD); facioscapulohumeral muscular dystrophy (FSHD); limb-girdle muscular dystrophy (LGMD); and

myotonic muscular dystrophy (MMD).

"Progress in muscle disease research since the MD CARE Act was passed has been extraordinary," said

MDA President and Chief Executive Officer Steven M. Derks. "Sixty-seven clinical trials for drugs or

therapies have been conducted since 2001, with 37 clinical trials currently under way. Additionally, new

clinical care guidelines will be valuable tools to improve standards of care for those living with muscle

diseases. We are counting on the unparalleled strength of our nationwide muscular dystrophy community

to ensure that Congress understands the importance of this reauthorization. We must build on the success

of the MD CARE Act and deliver effective treatments to those affected."

Senator Roger Wicker of Mississippi, author of the MD CARE Act of 2001, and Senator Amy Klobuchar

of Minnesota, sponsor of the 2008 reauthorization, are lead Senate sponsors of the bill. In the House, Eliot

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Engel of New York and Dr. Michael Burgess of Texas are leading the effort for reauthorization of the MD

CARE Act as they did in 2008.

"In 2001, as we celebrated the signing of the MD CARE Act, we could not imagine its impact," said

Parent Project Muscular Dystrophy President and CEO Pat Furlong. "Over the years, we have seen

scientific breakthroughs across the muscular dystrophies, which have led to the expansion and

intensification of muscular dystrophy research, including the leveraging of significant non-federal sources

of funding. Today, people with muscular dystrophy are living longer, more clinical trials are in progress,

and the hope of treatments is palpable within our community."

As a result of the accelerated pace of discovery and development of therapeutic treatments, more young

people with muscle disease are living longer and making the transition into adulthood. This year's

Amendment addresses that progress by requiring studies to develop optimal clinical care interventions for

young adults with Duchenne and Becker muscular dystrophies (DMD/BMD).

"We are extremely grateful to members of Congress that have recognized the vital importance of this

legislation to advance Duchenne muscular dystrophy research and produce real therapeutic approaches

that are extending the lives of young men living with the devastating impact of Duchenne muscular

dystrophy every day," said Joel Wood, president of the Foundation to Eradicate Duchenne. "This

legislation and the research and therapeutics it produces are bringing us closer to our goal of finding a cure

for this generation of Duchenne men."

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The proposed legislation also mandates studies to demonstrate the cost effectiveness of providing

independent living resources and support services for young adults with all forms of muscular dystrophy.

"When I was first diagnosed with Becker muscular dystrophy 36 years ago, I'm not sure that anyone would

have envisioned I would be a 44-year-old man with a passion for the Mets, Bruce Springsteen and serving

as the University Dean for Student Affairs at City University of New York," said Chris Rosa, Ph.D. "I've

had to overcome many obstacles along the way, and all too often the resources I needed to overcome those

obstacles did not exist. It's very encouraging to see this included in the Amendment so that we can create

smarter policies and clear away some of the hurdles."

The 2013 MD CARE Amendment also:

directs the Muscular Dystrophy Coordinating Committee to consider a plan to expedite approval of

emerging therapies and personalized medicines with the potential to treat people with muscular dystrophy;

expands areas of research focus within the NIH-funded Paul D. Wellstone Muscular Dystrophy Centers of

Excellence to include heart and lung function;

directs the CDC to develop and disseminate care considerations for adults with Duchenne and Becker

muscular dystrophies (DMD/BMD, or DBMD); and

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directs the CDC to develop and disseminate acute care considerations for adults with all muscular

dystrophies.

MDA, PPMD and FED were instrumental in passage of the original act in 2001.

About Parent Project Muscular DystrophyDuchenne is a fatal genetic disorder that slowly robs young men

of their muscle strength. Parent Project Muscular Dystrophy (PPMD) is the largest most comprehensive

nonprofit organization in the United States focused on finding a cure for Duchenne muscular dystrophy --

our mission is to end Duchenne.

We invest deeply in treatments for this generation of young men affected by Duchenne and in research

that will benefit future generations. We advocate in Washington, D.C., and have secured hundreds of

millions of dollars in funding. We demand optimal care, and we strengthen, unite and educate the global

Duchenne community.

Everything we do -- and everything we have done since our founding in 1994 -- helps boys with Duchenne

live longer, stronger lives. We will not rest until every young man has a treatment to end Duchenne. Go to

ParentProjectMD.org for more information, or to learn how you can support our efforts and help families

affected by Duchenne.

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About the Foundation to Eradicate DuchenneThe Foundation to Eradicate Duchenne is a 501c(3)

organization established in 2002 with the goal of finding treatments and an ultimate cure for Duchenne

muscular dystrophy, the world's leading lethal childhood genetic disease.

The Foundation to Eradicate Duchenne was established by Dana and Joel Wood of Alexandria, Va. Their

son James Wood, now 15, was diagnosed in May 2000 with Duchenne muscular dystrophy. The Woods

are both lobbyists in Washington, D.C., and have devoted much of their time and energies to this cause,

working with others to attain millions of dollars in federal earmarks for Duchenne muscular dystrophy

research and a significant increase in the attention devoted to DMD at the National Institutes of Health.

Additionally, through the FED and other fundraising efforts, they have raised approximately $10 million

in private donations since James was diagnosed.

About MDAMDA is the nonprofit health agency dedicated to finding treatments and cures for muscular

dystrophy, ALS and related diseases by funding worldwide research. The Association also provides

comprehensive health care and support services, advocacy and education.

In addition to funding more than 250 research projects worldwide, MDA maintains a national network of

200 medical clinics; facilitates hundreds of support groups for families affected by neuromuscular

diseases; and provides local summer camp opportunities for thousands of youngsters living with

progressive muscle diseases.

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Contenido
Muscular Dystrophy (MD) Therapeutics.......................................................................................................i
PATIENTS AND METHODS.....................................................................................................................ii
RESULTS...............................................................................................................................................iii
DISCUSSION.........................................................................................................................................iv
Advocates in Muscular Dystrophy Community Press Congress for Fast Action on Muscle Disease
Research and Treatment...............................................................................................................................v
Foto.............................................................................................................................................................. 5