Progress Now Summer 2014

Research and Clinical Trial Updates

by Quest Staff on July 7, 2014 - 9:03am

Quest Summer 2014

Readers sometimes wonder what’s happening with research for their diseases when they don’t see news about them for a while in the pages of Quest. But keep in mind: Research that seems to be for one disorder often has spillover implications for others.

In this issue: Understanding how the CoughAssist affects clearance of secretions in congenital muscular dystrophy and limb-girdle muscular dystrophy may have implications for its use in other muscle diseases. And developing exon skipping for Duchenne muscular dystrophy is likely to provide a foundation for moving this strategy forward in other genetic disorders.

To learn more about the diseases in MDA’s program, go to the online disease directory.

Progress Through Research: Funding for new MDA research projects underway

MDA recently approved funding for 38 new research grants for projects focused on a number of diseases under MDA’s umbrella, including: 

Some of the new grants, such as a three-year, $253,800 grant given to Jocelyn Laporte, a team leader at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, have implications for several of the disorders in MDA’s program. Laporte’s group will investigate whether drugs that affect the flow of calcium in cells have the potential to treat congenital myasthenic syndromes, limb-girdle muscular dystrophy, periodic paralysis or muscle aging, using cells taken from patients and animals with conditions mimicking various muscle disorders.

Others, like the three-year, $253,800 grant given to Howard Worman, professor of medicine, pathology and cell biology at Columbia University in New York, are highly specific. Worman’s team will test a potential new treatment for the X-linked form of Emery-Dreifuss muscular dystrophy by assessing its effects in mice developed in his lab that have a disorder closely mimicking the human form of this disease.

The grants began May 1 and will last for two to three years totaling $10.7 million in new funding. The new grants are in addition to the more than 200 MDA-funded research projects underway in 2014 across 12 countries.

“Our mission is to save and improve lives,” said neurologist Valerie Cwik, MDA’s chief medical and scientific officer, “and these new grants represent the best in current possibilities to help lead us to treatments and cures.”

Better Breathing? Tirasemtiv may slow respiratory decline

The experimental, orally administered drug tirasemtiv, in development by Cytokinetics, may have some benefit for respiratory function in ALS but does not seem to help motor function in general. The company announced these findings in April, based on a large-scale ALS trial. The investigators will continue to analyze the results, and MDA will publicize these when they become available.

Do Calories Count? High-calorie diet may help in ALS

An MDA-supported study of 24 people with ALS has shown that those on high-calorie, high-carbohydrate tube feedings fared better than those on a regular or high-calorie, high-fat formula. Those in the high-carbohydrate, high-calorie group gained more weight and experienced fewer adverse events, including deaths, than those on tube feedings designed to replace expended calories and maintain weight (“control” group) or those on a high-fat, high-calorie formula, which may not have been well-absorbed. 

Neurologist Anne-Marie Wills, an MDA research grantee at Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues, published their findings Feb. 28, 2014, in The Lancet.

The results suggest that increasing calories is safe and may be beneficial in ALS, and that larger, longer studies should be conducted to further test this hypothesis.

If you have specific questions, ask your MDA clinic team for a referral to a dietitian or nutritionist. Go to to get started.

Exon-Skipping Drugs Forge Ahead: Developers of eteplirsen and drisapersen will seek accelerated approvals

Eteplirsen to be considered for accelerated approval

In January, Sarepta Therapeutics, developer of the experimental “exon-skipping” drug eteplirsen to treat Duchenne muscular dystrophy (DMD) patients with mutations near exon (section) 51 of the dystrophin gene, announced encouraging results of an extension of a 12-person, phase 2b trial of the drug.

DMD-affected participants who received the drug for 120 weeks showed a decline in the distance they walked in six minutes of only about 46 feet from baseline, much less than the 400–410 feet seen at 104 weeks in natural history studies.

In April, Sarepta announced that the U.S. Food and Drug Administration (FDA) will consider an “accelerated approval” application for eteplirsen, which, if accepted, would mean the drug could become available to patients before completion of a confirmatory trial. (See The FDA Approval Progress: Can We Have This Drug Now?) In November 2013, the FDA had said it considered a new drug application for eteplirsen via the accelerated approval pathway to be premature.

Sarepta said it plans to open a confirmatory study of eteplirsen in boys with DMD who can walk and have dystrophin gene mutations near exon 51 during the third quarter of 2014. Trial sites in the U.S. and Canada are anticipated, and a historical control group, instead of a placebo group, will likely be used to measure drug effects.

In addition to this confirmatory study, Sarepta plans to study eteplirsen in patients who are younger than age 7 and in those who cannot walk a minimum distance or have lost the ability to walk entirely. Plans are to open those trials in 2014 as well. The company also plans a placebo-controlled study of one or more of its experimental drugs targeting dystrophin exons other than 51 by the end of 2014.

When available, details about Sarepta’s trials will be posted on and on Sarepta’s site. Sarepta urges families to register for updates on Sarepta at or (855) 363-7547.

Drisapersen extension study shows encouraging results

Also in April, Dutch biotechnology company Prosensa announced encouraging results from an extension study of its exon-skipping drug drisapersen, which targets the same part of the dystrophin gene as eteplirsen but has a different chemical structure.

Administration of drisapersen in clinical trials was halted in September 2013 after a phase 3 trial found no significant differences in walking distance or motor function between the drisapersen and placebo groups. However, a 48-week extension study that included boys with DMD who had formerly participated in the phase 3 trial or a phase 2 trial of the drug found boys who were 7 years old or younger and received continuous drisapersen treatment for 96 weeks actually increased the distance they walked in six minutes.

Prosensa has said it plans to resume administering drisapersen to previously enrolled trial participants in the third quarter of 2014. And in a surprise announcement in June, the company said the FDA will consider an application for accelerated approval of drisapersen. Prosensa plans to submit an accelerated approval file later this year based on existing data and will commit to conducting two confirmatory post-approval studies.

“Thanks to our supporters, MDA has had a rich and unparalleled role in funding the foundational research that has made the progress we’re seeing today possible.” — Valerie Cwik, neurologist and MDA’s chief medical and scientific officer

When available, updated information about clinical trials of drisapersen and other exon-skipping drugs in Prosensa’s pipeline will be posted on and at For a June 3 webcast and other archived presentations from Prosensa, go to

To see a timeline of MDA’s involvement in the development of exon skipping for DMD, go to Test Tubes to Trials.

Better Blood Flow: PDE5 inhibitors helped in DMD; large trial underway

A pilot study involving 10 boys with DMD has found that blood flow to exercising muscles is inadequate and that treatment with either tadalafil (Cialis) or sildenafil (Viagra) normalizes it, at least in the short term (after one dose of either oral drug). A large-scale, 48-week trial of tadalafil in DMD is underway at more than 60 sites in the U.S. and other countries.

Tadalafil and sildenafil, both PDE5 inhibitors, are approved by the U.S. Food and Drug Administration to treat erectile dysfunction.

Michael Nelson and colleagues at Cedars-Sinai Medical Center in Los Angeles published the new PDE5 inhibitor findings on DMD online May 7, in Neurology. Ronald Victor, a physician specializing in cardiovascular disorders at Cedars-Sinai and the senior author on the new study, has received MDA support for closely related research in men with Becker muscular dystrophy (BMD). The underlying cause of DMD/BMD is any of a large number of mutations in the gene for the muscle protein known as dystrophin.

“We do not know whether the improved blood flow regulation will be sustained with chronic administration [of PDE5 inhibitors],” the study authors write. They also note that this “proof of concept” study does not address the crucial question of whether restoring normal blood flow to muscles will protect DMD-affected muscles from damage or slow overall disease progression.

However, they indicate that the data from this and other studies “have informed the design of a pivotal, multicenter clinical trial to determine whether chronic daily tadalafil can preserve muscle function in boys with DMD.”

Participants in the large-scale trial of tadalafil in DMD must be 7–14 years old, be able to walk and meet many other study criteria. Contact Eli Lilly at (877) 285-4559 between 9 a.m. and 5 p.m. Eastern time, Monday through Friday. For details and locations, go to

Airway Clearance: Researchers study the effects of a respiratory device for young people with specific muscular diseases

A study of the effects of the CoughAssist, a device by Philips Respironics designed to clear secretions from the respiratory tract, is being conducted in Cincinnati and Philadelphia for children and teens ages 5–20 with Ullrich congenital muscular dystrophy (CMD) or Bethlem myopathy, which MDA classifies as a limb-girdle muscular dystrophy (LGMD). (Both disorders are caused by genetic mutations affecting a protein called collagen 6.)

For details, contact Katie Fields in Cincinnati at (513) 636-0736 or; or Anne Rutkowski in Los Angeles at (424) 210-7749 or

A Major Mouse Advance: New mouse model had muscle tissue transplanted from FSHD patients

An MDA-supported research group has created a new research mouse (mouse model) that is likely to speed studies of and therapy development for facioscapulohumeral muscular dystrophy (FSHD), a form of MD that first affects the muscles of the face, shoulder blade (scapula) area and upper arms. It’s expected to complement an existing FSHD mouse model, created last year by other MDA-supported investigators, with the two models providing different kinds of information.

The new FSHD mouse utilizes a xenograft strategy, a technology involving transplanting tissue from one species to another. In this case, small pieces of muscle taken from FSHD patients were successfully transplanted to the leg muscles of mice. The researchers say the muscle xenograft strategy used for the FSHD mouse model has potential usefulness in the study of other muscle diseases and studies of muscle aging.

MDA supported Fedik Rahimov at Harvard Medical School and Boston Children’s Hospital and Charles Emerson at the University of Massachusetts Medical School in Worcester on this study, results of which were published online Jan. 22, in Human Molecular Genetics. Study team leader Kathryn Wagner has MDA support at the Kennedy Krieger Institute in Baltimore for research on muscle regeneration and muscle scarring.

The investigators say the xenograft FSHD model will allow the study of human FSHD-affected muscle over time, including its response to experimental therapies, “with a degree of access and invasive experimental scrutiny that is not available in human subjects.”

Tracking MTM: Investigators to review natural history of MTM to help with clinical trial design

A study to track the usual disease progression in patients with the muscle disease myotubular myopathy (MTM), a form of centronuclear myopathy (CNM), is seeking participants of any age, including newborns. So far, there are three North American sites — Boston; Bethesda, Md; and Toronto — and a site in Paris. MTM often takes the lives of infants and young children.

The investigators, sponsored by Massachusetts-based Valerion Therapeutics and the French nonprofit group Genethon, will follow study participants for three years, during which time they will perform functional assessments, analyze blood and urine samples, and administer questionnaires. They intend to observe changes over time in motor and respiratory function, quality of life and disability in patients with MTM.

Data from the study will be used to understand the usual disease course of MTM and decide which outcome measures would be best to use in testing potential therapies in future trials.

Valerion received a $1.2 million grant from MDA in 2013 to help move an experimental cell-penetrating treatment for MTM toward human testing. And, an MDA-supported research team reported in early 2014 that dogs with an MTM-like disorder benefited from gene-transfer therapy.

To participate in the MTM natural history study, go to and enter NCT02057705 in the search box. Or, contact Michelle Nelken in the Boston area at (617) 755-4149 or For the French site, contact Melanie Annoussamy at +33 1 42 16 66 49 or

Dialing Down Dynamin 2: Reducing levels of the protein increased survival time in mice

A French research team has found that reducing levels of a protein called dynamin 2 has potential as a strategy to treat MTM. The findings shed light on the underlying cause of MTM, a disorder in which the myotubularin protein is deficient, and suggest a possible new therapeutic target. Belinda Cowling and colleagues, who published their findings March 3 in the Journal of Clinical Investigation, found that reducing dynamin 2 levels in myotubularin-deficient mice increased life span and improved motor function.

Steady Progress: An experimental, antisense-based drug will move to phase 3 trials

Treatment with the experimental drug ISIS-SMNRx, in development by Isis Pharmaceuticals, was correlated with functional improvement in two phase 2 studies in infants and children with spinal muscular atrophy (SMA), based on standardized tests of strength and motor function. SMA is a disorder of the motor neurons (nerve cells that control muscle activity).

Isis announced the encouraging results at the spring 2014 meeting of the American Academy of Neurology. The results should be interpreted with caution, since the studies were small and did not include placebo groups. 

The company plans to open two phase 3 studies of ISIS-SMNRx in infants and children during 2014.

The drug was created using a technology called antisense, a method of altering genetic instructions. In SMA, the goal is to alter genetic instructions for the SMN protein in order to increase levels of the needed, full-length protein.

MDA supported laboratory development of ISIS-SMNRx through a 2007–2010 grant to molecular biologist Adrian Krainer at Cold Spring Harbor (New York) Laboratory.

Gene Therapy Trial: In a first-of-its-kind human trial, nine infants will receive SMN gene-transfer therapy

A phase 1 trial to test the safety and efficacy of gene-transfer therapy in nine infants with type 1 SMA is open at Nationwide Children’s Hospital in Columbus, Ohio, under neurologist Jerry Mendell. Mendell, who directs the Center for Gene Therapy at Nationwide, also co-directs the MDA clinic at that institution and is a longtime MDA research grantee.

Trial participants will be randomly assigned to receive either a low or high dose of genes for the SMN protein, which is deficient in SMA, encased in type AAV9 viral shells and delivered as a one-time intravenous injection.

Since the 1990s, MDA has funded investigations of SMN1 and SMN2 genes and other research leading to this first clinical trial of gene transfer therapy in SMA.

Participants must be 9 months old or younger, must not be using tracheostomy ventilation and must meet other study criteria. Contact study coordinator Sohyun McElroy at (614) 355-2606 or Orenter NCT02122952 in the search box at

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