Clinical Trials and Studies July-August 2005

Article Highlights:

The latest updates on clinical trials as of June 2005

by on July 1, 2005 - 9:54am

QUEST Vol. 12, No. 4

In this article: The latest news on clinical trials and studies related to Duchenne MD, spinal muscular atrophy, McArdle's disease, myotonic dystrophy, myasthenia gravis, Pompe's disease, diagnosis, translational research

MDA awards $1.5 million for PTC124 trial; drug safe in healthy subjects

A phase 1 study of the experimental Duchenne muscular dystrophy (DMD) drug PTC124 showed the compound was safe and reached adequate blood levels in healthy subjects.

Its developer, PTC Therapeutics of South Plainfield, N.J., announced the encouraging results April 11 at a meeting of the American Academy of Neurology. The next step will be testing the drug in boys with DMD who have a particular type of genetic flaw.

It’s been estimated that some 15 percent of boys with DMD have nonsense mutations, also called premature stop codons, which stop synthesis of dystrophin, a necessary muscle protein, before it’s complete and functional. PTC124 is designed to cause cells to "ignore" premature stop codons and make functional dystrophin molecules.

PTC124 coaxing cells into making full-length dystrophin
PTC124 is designed to coax cells to ignore genetic "stop signs" and to make full-length dystrophin.

(Testing is necessary to determine the type of mutation a person with DMD has. Families can inquire about such testing at an MDA clinic or via Search under "Laboratory Directory"; then "Duchenne"; then "Testing." Look at labs that offer "sequencing of entire coding region.")

MDA grantee H. Lee Sweeney at the University of Pennsylvania in Philadelphia contributed his expertise during the laboratory phase of PTC124’s development. In April, MDA authorized a $1.5 million award to PTC for further research with the compound.

See "Changing the Code: Running a Stop Sign," March-April 2005, for more about PTC124.

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DMD trials remain open

The Cooperative International Neuromuscular Research Group (CINRG), based at Children’s National Medical Center in Washington, has space remaining in two clinical trials in children with Duchenne muscular dystrophy (DMD).

Recruitment for participants in an MDA-supported trial of moderate-dose, daily prednisone versus high-dose, weekly prednisone, has been extended at multiple sites. Participants must be 4 to 10 years old and able to walk unassisted. Contact Lauren Morgenroth, project manager, at (412) 383-7207 or

Recruitment for a study of pentoxifylline, an anti-inflammatory drug that may also reduce scar tissue formation in muscles, remains open, probably through mid-summer, at several U.S. sites. The investigators are seeking boys 4 to 7 years old who have never taken steroids. Contact Angela Zimmerman, project manager, at (202) 884-4110 or

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SMA trials in California still recruiting

Two clinical trials of hydroxyurea, a compound that’s been found in laboratory studies to increase the amount of working SMN, a protein needed but missing or deficient in people with spinal muscular atrophy (SMA), remain open to new enrollees.

One is for children ages 16 months to 10 years with types 2 or 3 SMA. The other, with MDA funding, is for children less than a year old, with type 1 SMA. Participants must make regular visits to Stanford (Calif.) University Medical Center. Contact Tony Trela, study coordinator, at (650) 498-7658 or

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Moderate exercise good in McArdle’s, myotonic MD

Researchers at the Institute of Myology of the Pitie-Salpetriere Hospital in Paris asked 30 people with McArdle’s disease (myophosphorylase deficiency) and 87 people without muscle disease to keep a three-day record of daily physical activities. They found that daily energy (measured as kilocalories per kilogram of body weight) expended by the McArdle’s participants didn’t differ from that expended by the non-McArdle’s (control) group.

About half the participants in each group reported daily physical activities, such as "sport" or gardening. These activities seemed to improve exercise ability and reduce muscle pain.

The investigators, who published their results in the May issue of Muscle & Nerve, say that moderate physical activity may be beneficial in McArdle’s disease.

In the May issue of Annals of Neurology, researchers at National University Hospital in Copenhagen, Denmark, studied the effect of aerobic training in 12 adults with type 1 myotonic muscular dystrophy (MMD), and found that it was both safe and beneficial.

Participants trained at home on a cycle ergometer, a stationary bicycle equipped with devices to measure heart rate, oxygen levels and workload, for 12 weeks in sessions of 35 minutes each.

After the training period, seven people reported feeling stronger, with better endurance and increased activity levels. The training didn’t increase creatine kinase (CK) levels in the blood, which would have indicated muscle damage.

A caveat is that the original study contained 17 people, five of whom dropped out; and of the remaining 12, only nine completed the 50 planned training sessions. Those who stayed in the study may therefore have been those most likely to report improvement.

Nevertheless, the investigators conclude that "aerobic training is safe and can improve fitness effectively in patients with myotonic dystrophy.

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Tacrolimus holds up in long-term MG trials

Tacrolimus (FK506, or Prograf) continues to show promise in the treatment of myasthenia gravis (MG).

Tacrolimus is a potent immune system suppressant, which is the basis of its usage in MG, a disorder in which the immune system attacks specialized areas of muscle cells and prevents them from receiving signals from nerve cells.

A Japanese research group reported in the March issue of the Journal of Neurology, Neurosurgery, and Psychiatry that a small, long-term study of tacrolimus confirmed the drug’s benefit in a shorter study.

The researchers studied 12 people with MG for two years, administering 2 milligrams to 4.5 milligrams per day of oral tacrolimus. Eight participants (67 percent) showed improvement in either an MG muscle-strength score or an activities-of-daily-living score. Dosage levels of prednisolone (a corticosteroid drug similar to prednisone), which has many undesirable side effects, could be reduced in seven (58 percent) of the participants.

The investigators concluded that "long-term use of FK506 for MG can be more effective than short-term administration, with no serious side effects."

A larger study of tacrolimus in MG, at Hospital General Universitari Vall d’Hebron in Barcelona, Spain, also showed the drug was effective and well tolerated.

In this study, 79 patients with MG took tacrolimus for at least a year, with 76 participants (95 percent) taking the drug for more than three years.

Of the 79 people who took tacrolimus for an average of 2.5 years, all but two were able to stop taking prednisone. Their undesirable immune system activity and disease severity scores decreased significantly, and strength increased by an average of 39 percent. All resumed full activities of daily living.

"Tacrolimus was well tolerated," the investigators write, "without [the] adverse effects related to long-term treatment with prednisone and cyclosporine, and might replace these drugs as a sole immunosuppressive agent for the treatment of MG."

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Childhood myasthenia likely to remain limited

Investigators in Ankara, Turkey, followed the progress of 30 patients with childhood-onset myasthenia for at least two years, and they found that the condition tends to remain confined to the ocular (eye) muscles when it begins there, even though changes in immune system proteins (antibodies) can occur after a few years.

Childhood myasthenia involves weakness caused by a disruption of the signals that normally go from nerve to muscle cells. It can result from a genetic flaw — a congenital myasthenic syndrome (CMS) — or an immunologic disorder. None of the children in this study had CMS, and all were therefore presumed to have an immunologic problem.

In the May issue of Neuromuscular Disorders, the investigators say that, contrary to earlier reports, disease severity didn’t increase in patients who developed antibodies.

In 15 of the 30 children and teens, the disease started as ocular muscle weakness (drooping eyes or difficulty moving the eyes) alone. Only one patient experienced weakness spreading to other muscles after two or more years.

"While change in [antibody] status is not rare in juvenile myasthenia, generalization of initially ocular disease is uncommon," the authors write.

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Treatment looks good in infantile Pompe disease

Genzyme, a Cambridge, Mass., biotechnology company, announced April 26 that an interim analysis of a trial of its experimental Pompe’s treatment, Myozyme, is "extremely encouraging."

Yuan-Tsong Cheng
Research by Yuan-Tsong Chen, an MDA grantee, underlies the Pompe trials.

Pompe disease, also known as acid maltase deficiency (AMD), is a metabolic muscle disorder that results from a lack of the acid maltase enzyme. The infantile-onset form of the disease has severe effects on the cardiac and respiratory muscles and usually leads to death early in childhood.

Genzyme, with support from MDA, tested Myozyme, a laboratory-engineered compound to replace the missing acid maltase enzyme, in 18 babies with Pompe. Their disease courses were compared to those of babies with Pompe not treated with Myozyme in the past (a "historical cohort").

The babies in the trial began receiving Myozyme by 6 months of age. By 12 months of age, 89 percent of those treated (16 of the 18) were alive and free of invasive ventilator support, compared with 17 percent in the historical cohort at 12 months.

The interim analysis also showed that:

  • All patients treated with Myozyme showed a reversal in cardiomyopathy, a condition in which the heart muscle becomes enlarged and heart function is impaired.
  • When the Alberta Infant Motor Scale was used as a measurement, 72 percent of those treated with Myozyme showed gains in motor (movement) development.
  • All patients evaluated showed gains in cognitive (thinking), language, and personal and social skills.
  • Antibodies (immune system proteins) to Myozyme developed in 83 percent of treated patients, and reactions to the Myozyme infusions occurred in 44 percent.

Genzyme plans to submit a license application for Myozyme as a treatment for Pompe disease to the U.S. Food and Drug Administration this summer. The company submitted a similar application to the European Medicines Agency in December.

In addition to supplemental funds for Genzyme’s Myozyme program, MDA has provided support to Yuan-Tsong Chen at Duke University, whose work in the 1990s laid the foundation for Myozyme’s development.

Genzyme is also studying the natural course of late-onset Pompe disease and will soon begin a trial of Myozyme in those patients.

For information about the Myozyme program, contact Genzyme’s Medical Information Department at (800) 745-4447, (617) 768-9000 or

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Noninvasive ventilation helps 8 with Pompe

German researchers reported in the April 26 issue of Neurology that noninvasive ventilation (NIV) was decidedly helpful in acid maltase deficiency (AMD, or Pompe disease) in the eight people they studied.

The investigators at the University of Essen studied seven adults and one teenager with Pompe disease that began in childhood or adulthood (not in infancy). All showed severe deterioration of respiration, low oxygen levels during sleep and weakness of the respiratory diaphragm. All but one were able to walk.

All participants began using air (not oxygen) under pressure delivered by face mask, and all reported that they used the NIV device regularly during nighttime sleep and sometimes during the day.

The investigators assessed participants’ symptoms and lab values at the start of the study, three months later, and then every six months for up to five years.

They found that NIV use corrected nighttime blood oxygen to normal or nearly normal levels, improved daytime blood levels of oxygen and carbon dioxide, and, in four people, reversed cardiac changes.

Participants reported that NIV reduced nighttime sleep disturbances, reduced daytime sleepiness and fatigue, and decreased shortness of breath.

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MD diagnoses sometimes warrant closer look

Danish researchers screened DNA samples from 102 male patients who were given a diagnosis of Duchenne or Becker muscular dystrophy (DMD or BMD) between 1988 and 2004 but in whom no missing or duplicated parts of the dystrophin gene had been identified.

Missing parts of this muscle protein gene (deletion mutations) or duplicated parts (duplication mutations) are found in approximately 60 percent of DNA samples in boys with signs and symptoms of DMD or BMD. Small flaws (point mutations) in the dystrophin gene are thought to be responsible for most of the remaining 40 percent. But, as a paper in the May 10 issue of Neurology demonstrates, sometimes the flaw is in another gene.

Of the 102 samples, 13 had disease-causing mutations in a gene that gives rise to fukutin-related protein (FKRP), on chromosome 19. Their diagnoses have been revised to type 2I limb-girdle muscular dystrophy (LGMD).

In a study conducted at the University of Connecticut School of Medicine in Farmington and published in the March issue of the Journal of Clinical Neuromuscular Disease, investigators found that facioscapulohumeral muscular dystrophy (FSHD) can, at the less severe end of its spectrum, be misdiagnosed as LGMD, distal MD or other muscle disorders.

FSHD results from a shorter than average DNA segment on chromosome 4. In the study, those with chromosome 4 segments near the normal range had "classic" FSHD symptoms only 18 percent of the time.

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