Clinical Trials January-February 2008

Article Highlights:

Updates on clinical trails and studies as of December 2007

by Quest Staff on January 1, 2008 - 11:16am

QUEST Vol. 15, No. 1

This article reports on clinical trials in: Duchenne muscular dystrophy, Friedreich's ataxia and myotonic dystrophy.

Bone development in DMD under study

MDA-supported researchers at Ohio State University Medical Center in Columbus have begun a new study of bone development in boys with Duchenne muscular dystrophy (DMD), which earlier observations have suggested may be abnormal.

The investigators are seeking 120 boys with DMD who are at least 5 years old and 120 who are at least 5 and don’t have DMD. For details, click on Clinical Trials at; or contact John Landoll at (614) 293-3838 or

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PTC124 allowed dystrophin production in half of DMD-affected trial participants

An oral medication called PTC124 that changes the way muscle cells interpret genetic information holds promise as a treatment for some patients with Duchenne muscular dystrophy (DMD).

The drug was developed by PTC Therapeutics of South Plainfield, N.J., with support from MDA and other sources.

Carsten Bonnemann, of the University of Pennsylvania and Children’s Hospital of Philadelphia, announced Oct. 18 at the World Muscle Society International Congress in Italy that production of the needed dystrophin protein was restored in about half of 12 boys with DMD who took PTC124 for a month.

This group received a higher dose than did 26 boys in two earlier groups. About half of them also began making dystrophin.

The new results show that the drug was well tolerated at all three dose levels and that target concentrations in the blood were achieved at the mid- and high-dose levels.

The studies also suggest that the middle dose of PTC124 is as effective as the highest dose, at least over the course of a month’s treatment.

PTC124 tells cells to ignore a type of genetic mutation known as a premature stop codon, which is the cause of DMD in an estimated 13 percent of cases. Premature stop codons, also called nonsense mutations, interrupt protein synthesis from genetic instructions before the full protein molecule has been constructed.

“DMD is a disorder with a significant need for better treatment options and we are encouraged by the results we have seen to date with PTC124,” said Brenda Wong, associate professor of Pediatrics and Neurology at Cincinnati (Ohio) Children’s Hospital Medical Center and one of the trial’s lead investigators. “Based on the findings from this study, we believe that the safety profile of PTC124 supports continued testing in longer-term studies.”

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Trial of exon skipping in DMD opens in UK

A trial of a synthetic compound that coaxes muscle cells to ignore a genetic mutation (abnormality) in the gene for dystrophin, the protein needed but missing in Duchenne muscular dystrophy (DMD), has opened in London.

The trial, which will include up to nine boys with DMD, will test at least two and possibly three dosage levels of AVI-4658, a so-called antisense oligonucleotide (AO) that tells cells to ignore mutations in and around a section of the dystrophin gene known as exon 51 and splice together the genetic instructions surrounding the abnormality.

The hoped-for result is production of a functional dystrophin protein molecule, although this phase 1 trial is not expected to have any clinical benefit for the participants.

AVI-4658 was developed by an international team of investigators that included MDA-supported Stephen Wilton at the University of Western Australia in Perth and Judith van Deutekom of Leiden University in the Netherlands, working in collaboration with AVI BioPharma ( of Portland, Ore.

The AO strategy has recently shown promise in a small trial of a similar compound that was conducted in the Netherlands. In that trial, four out of four boys with DMD began making what appeared to be nearly normal dystrophin in an injected leg muscle. (See "Tackling DMD on Many Fronts," Quest, July-August 2007.)

The British clinical trial is funded by the United Kingdom Department of Health. The trial investigators, coordinated by Francesco Muntoni and colleagues at Imperial College London, are mainly seeking trial participants who are U.K. residents.

“Ideally, we would like not to put excessive burden on families for a proof-of-concept study that will not be personally beneficial to participants,” Muntoni said. “We would rather recruit families from the U.K. because of the practicalities.”

For details about the trial, see (Enter “Duchenne muscular dystrophy” in the search box, and then select “Safety and Efficacy Study of Antisense Oliogonucleotides in DMD.”)

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Santhera drug may help DMD-affected hearts, respiratory muscles

Santhera Pharmaceuticals ( of Liestal, Switzerland, has announced that its phase 2a trial of SNT-MC17 (idebenone) in 21 patients wit Duchenne muscular dystrophy (DMD) shows that the drug is safe and well tolerated and that it may slow the decline in cardiac function and actually improve respiratory function.

The trial, conducted at the University of Leuven (Belgium), included 21 boys with DMD who were between 8 and 16 years old and received either 450 milligrams per day of SNT-MC17 or a placebo (inert, look-alike substance) for a year.

The investigators, who announced their findings in a press release Oct. 29, said there was a trend toward improvement in cardiac function in the idebenone-treated group, as measured by heart-wall function in the left ventricle (lower chamber of the heart).

The idebenone-treated patients also showed improvement on certain respiratory tests, particularly one that measures how fast a person can exhale (peak flow). Santhera says the treated boys improved on this measurement, while those on the placebo deteriorated.

The company says it intends to seek advice from the European Medicines Agency and the U.S. Food and Drug Administration in preparation for further development of SNT-MC17.

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Santhera drug also may help in Friedreich’s ataxia>

Santhera also is planning to open a phase 3 trial of SNT-MC17 in Friedreich’s ataxia, where preliminary studies have shown that the compound may have beneficial effects on cardiac and possibly neurologic functions. Contact Susan Perlman, principal investigator at the University of California Los Angeles, at (310) 794-1225 or; or David Lynch, principal investigator at Children’s Hospital of Philadelphia, at (215) 265-0412, or

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Brain involvement appears less serious in MMD2 than MMD1

A recent review of several studies of cognitive and behavioral aspects of type 1 and type 2 myotonic dystrophy (MMD1 and MMD2) shows that, in general, these aspects of the disease are present in MMD2 but to a lesser extent than they are in MMD1.

MMD1 is a disease of varying severity caused by an expanded section of DNA on chromosome 19, and MMD2 is a more recently identified and usually less severe disease resulting from an expanded DNA section on chromosome 3.

In the September issue of Muscle & Nerve, Giovanni Meola and Valeria Sansone at the University of Milan (Italy) and San Donato Hospital in Milan review their and others’ studies of cognitive and behavioral aspects of MMD1 and MMD2.

Deficits in visual-spatial skills (as shown by putting together puzzles, reading maps, etc.) and deficits in attention were noted in both diseases, but they were less severe in MMD2 than in MMD1.

Excessive daytime sleepiness is a prominent feature in MMD1, but it’s less frequently found in MMD2.

However, difficulty with planning and executing tasks has been noted in both MMD1 and MMD2, and both groups of patients have been described as having “avoidant” personalities.

Recent studies have shown that some atrophy (shrinkage) of the brain’s cerebral cortex occurs in both diseases, but to a lesser degree in MMD2 than in MMD1. Some impairment of blood flow to parts of the brain appears to be similar in MMD1 and MMD2. However, studies using magnetic resonance spectroscopy have suggested that brain metabolic activities are different in the two diseases.

Meola said that taking into account the possibility of cerebral involvement in the myotonic dystrophies could help patients manage their daily lives better.

In their paper, the investigators also note that “it may help physicians, family members, and employers to understand why, despite mild muscle disability, patients with DM [MMD] may not function as well as expected by their muscle strength and status.”

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