Clinical Trials and Studies Spring 2009

Article Highlights:

Updates on the latest clinical trials and studies as of March 2009

by Quest Staff on April 1, 2009 - 4:12pm

QUEST Vol. 16, No. 2

This article contains items about: Duchenne muscular dystrophy and spinal muscular atrophy

Exon-skipping trial allowed dystrophin production in 10 boys with DMD

On Jan. 21, 2009, AVI BioPharma of Portland, Ore., announced that its experimental compound AVI4658 for the treatment of Duchenne muscular dystrophy (DMD) yielded promising results in a phase 1 clinical trial in the United Kingdom.

AVI4658 is a laboratory-engineered molecule that coaxes muscle cells to ignore, or “skip over,” a section (exon) of genetic instructions for the dystrophin protein, which is missing in DMD patients. The strategy, known as “exon skipping,” is designed to cause cells to make nearly normal dystrophin molecules.The AVI4658 construct, which specifically targets exon 51 of the dystrophin gene, 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, then at Leiden University in the Netherlands, working in collaboration with AVI BioPharma.

The study, which involved fewer than 10 DMD-affected boys between 12 and 17 years old, was conducted at Hammersmith Hospital in London and at the Institute of Human Genetics of the University of Newcastle Upon Tyne (U.K.).

Each boy received an injection of either 0.09 or 0.9 milligrams of AVI4658 into a foot muscle, and a salt solution into the corresponding muscle on the other foot. Three to four weeks later, each injected muscle was examined for evidence of dystrophin production.

Results showed the AVI4658-injected foot muscles produced dystrophin in all participants, and that the amount produced correlated with the injected dose. All participants tolerated the compound well, and there were no significant adverse events related to its administration.

The trial was funded by the U.K. Department of Health and led by Francesco Muntoni at Imperial College London, who has MDA support to study another muscle disease.

“As a clinician and scientist, I am very pleased by these findings and the prospects they offer for the potential treatment of this serious, lifethreatening condition,” Muntoni said in a Jan. 21 company press release. “Biopsies from muscles injected with the higher dose of test drug showed an unequivocal, widespread and robust response in terms of number of dystrophin positive muscle fibers. We will publish these exciting data in a peerreviewed journal in due course.”

The company says it will now study the effects of systemic (intravenous) delivery of AVI4658. It’s also developing four related exon-skipping compounds that target different dystrophin exons.

In December 2007, the Dutch biotechnology company Prosensa announced positive results for its exon-skipping compound, PRO051. In that study, conducted in the Netherlands and reported in the Dec. 27, 2007, issue of the New England Journal of Medicine, four boys with DMD between ages 10 and 13 began producing dystrophin after receiving injections into a leg muscle.

MDA is funding studies to develop exon skipping and related strategies to treat DMD and other diseases.

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Enrollment complete for phase 2b study of DMD drug

PTC Therapeutics of South Plainfield, N.J., developers of the experimental compound PTC124 for a subset of patients with Duchenne muscular dystrophy (DMD), announced in February that enrollment for its current clinical trial of this drug is complete. MDA has funded a portion of the drug’s development.

PTC124, recently given the generic name ataluren, is designed to coax muscle cells to ignore an erroneous molecular stop signal that keeps them from synthesizing dystrophin, the muscle protein needed but missing in DMD.

SMA is a major focus for MDA’s research program. See the special In Focus series.

If it leads to production of functional dystrophin, as early trials have suggested it does in some patients, it’s expected to be developed as a treatment for the 13 percent of boys with DMD estimated to have a stop-signal genetic flaw (mutation), known as a “premature stop codon” or “nonsense” mutation.

The one-year, multicenter trial of 174 boys will compare ataluren with a placebo (inert substance) on measures of safety and effectiveness. Results will likely be available in late 2010 or early 2011.

PTC has called this “phase 2b” trial (earlier phases were smaller, had no placebo group, and weren’t designed to detect efficacy) its “pivotal” study of ataluren.

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Valproic acid to be tested in walking adults with SMA3

A study at Ohio State University Medical Center in Columbus is seeking 36 adults with type 3 spinal muscular atrophy (SMA3) who can walk 30 feet independently and meet other study criteria to participate in a study of valproic acid. Laboratory studies have indicated that valproic acid increases levels of full-length SMN, the protein deficient in SMA, in patients’ cells. Contact Sharon Chelnick, clinical research manager, at (614) 293-4973 or

In January, researchers announced that a trial of valproic acid and carnitine showed the drugs were not beneficial in children with SMA ages 2 to 8 who were not walking. Results for children 3 to 17 years old who were able to stand or walk and who also were part of that study were not yet available.

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Researchers to determine SMA ‘biomarkers’

A study to compare functional, genetic and biochemical information in 120 children 2-12 years old with and without spinal muscular atrophy (SMA) is under way at some 20 institutions throughout North America. The goal of the study is to generate SMA-specific biochemical indicators (biomarkers) that can be used to track responses to experimental treatments in clinical trials. For information, go to the Clinical Trials website and enter “pilot study of biomarkers for spinal muscular atrophy” in the search box.

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Lisa Baumbach-Reardon
Lisa Baumbach-Reardon has MDA support to study SMA not linked to chromosome 5.

MDA grantee studying children with SMA not linked to chromosome 5

Lisa Baumbach-Reardon at the University of Miami has MDA support to extend studies of non-chromosome-5 spinal muscular atrophy (SMA). Mutations in the SMN1 gene on chromosome 5 are by far the most common form of SMA.

Baumbach-Reardon is interested in hearing from families with children who initially appeared to have infantile-onset, chromosome-5 SMA but whose DNA did not reveal any SMN1 gene abnormalities. She can be reached at (305) 243-3997, or

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