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Exon Skipping for Duchenne Muscular Dystrophy Clears Another Hurdle

Robinson, Richard

doi: 10.1097/01.NT.0000415804.34328.98
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An exon-skipping therapy for Duchenne muscular dystrophy showed six months of systemic therapy could increase the amount of dystrophin protein in muscle, and was safe, but functional benefits remained unproven.

NEW ORLEANS— Six months of systemic exon-skipping therapy for Duchenne muscular dystrophy (DMD) is safe and can increase the amount of dystrophin protein in muscle, but researchers are still waiting to see functional benefits, according to the results from a phase II double-blind trial. Whether longer-term treatment can lead to better mobility will be the major question as patients continue on therapy for an additional six months.

Exon skipping has been in development for DMD over the past decade. The goal is to prevent inclusion of the mutation-containing exon in the final messenger RNA. Mutations that cause DMD typically shift the reading frame, introducing premature stop codons and leading to a truncated protein. The exon-skipping strategy uses an antisense RNA-like molecule, called a morpholino, that binds to the RNA during the editing process, when introns are removed. The blockade of a splice site by the morpholino causes the editing machinery to skip over the downstream, mutation-containing exon, restoring the reading frame in the remaining RNA and leading to a shorter but still functional dystrophin protein.

The target of this trial, and previous open-label safety trials, has been exon 51. Mutations in exon 51 are the most common single cause of DMD, accounting for 13 percent of all patients. Those earlier trials demonstrated dose-dependent dystrophin expression over 12 weeks.

The purpose of the current trial, according to lead investigator Jerry Mendell, MD, director of the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, OH, was to test whether longer treatment led to more dystrophin. The trial is the first double-blind test of exon skipping in DMD.

Twelve patients between ages seven and 13 were randomized to receive either 30 mg/kg/week or 50 mg/kg/week of the antisense morpholino, called eteplirsen, or placebo, for 24 weeks. All patients were on stable doses of corticosteroids and could walk between 200 and 400 meters on the six-minute walk test. The drug was administered by intravenous infusion once weekly, a process lasting about an hour. Biopsies were performed at baseline in all patients, at 12 weeks in the high-dose and half of the placebo patients, and at 24 weeks in the low-dose and the other half of the placebo patients.

The biopsies were “intensively” analyzed, Dr. Mendell said, with each sample examined at multiple levels by blinded researchers. There was no change in the percentage of dystrophin positive fibers in those receiving placebo. Neither was there any change at 12 weeks in those receiving high-dose eteplirsen. But in those receiving low-dose treatment, the percent of dystrophin positive fibers increased by 23 percent after 24 weeks of treatment (p<0.002 compared with placebo), ranging from 15 percent to 30 percent. “This is unequivocal in terms of gene expression. The longer duration gave us better results that shorter duration. That's really the key issue,” he said.

“Systemic administration gives a very wide distribution, but it's not going to get into every muscle fiber initially. That's why duration may be so significant. Morpholinos have a very long half-life, so over time, you are going to get increased gene expression.”

Patients also underwent a walking test every four weeks during the trial, measuring how far they could walk in six minutes. Two patients in the low-dose group declined rapidly in their ability to walk shortly after the trial began, and were excluded from the functional analysis. Patients in the placebo group declined by 21 meters over the course of the trial, while as a whole, treated patients declined by 3 meters. The results suggest a trend of slower progression, Dr. Mendell said, but the patient numbers were too small to achieve statistical significance.

There were no safety concerns and no treatment-related adverse events at either dose level. If the treatment ultimately proves to be efficacious, Dr. Mendell said, subcutaneous administration may be possible, to ease the burden of weekly intravenous treatment. It may also be possible to deliver the treatment less frequently, given the long half-life of the morpholino.

“This is an extended study, and hopefully we will see a clearer functional difference as we go on,” he said. Each patient is now receiving open-label active treatment, which will continue through 48 weeks, with biopsies scheduled at the end of the treatment period. The difference between groups should manifest more strongly at that point, he said.

“We would hope to see more contiguous gene expression over time. We don't know what the expression level is that we would need, but most of us predict that we would need closer to 30 percent to 50 percent in order to have significant functional benefit. That's what we are shooting for.”

In parallel with the biopsy analysis, patients are also undergoing MRI imaging to look for changes in muscle size and amounts of fat and connective tissue. There are no results yet from this investigational endpoint.

According to Chris Garabedian, CEO of AVI BioPharma, which manufactures eteplirsen and supported the trial, the company is ready to scale up production should future trials demonstrate a functional benefit. “We are preparing for commercialization,” he said. He also suggested that expansion of this treatment strategy to other exons will likely be easier from a regulatory standpoint, given the safety data from this and previous trials.

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“This is not the ultimate cure, but it is a very exciting step,” said Yadollah Harati, MD, professor of neurology and head of the Neuromuscular Section of Baylor College of Medicine in Houston, TX, who was not involved in the study. “Dr. Mendell's team has done a careful study. But ultimately this treatment needs to be translated into a functional improvement, and I was somewhat disappointed that there was no indication of that. But still, I was encouraged by the increase in the number of fibers with new expression of dystrophin.”

Based on these results, he said, “I think we should go forward.” However, he cautioned, “What is going to happen is that, at best, we are turning patients with Duchenne muscular dystrophy into patients with Becker muscular dystrophy,” since Becker patients have a larger amount of functional dystrophin, but still less than normal. But that still constitutes meaningful improvement, he said.







Watch here as Neurology Today Editor-in-chief Steven P. Ringel, MD, and Associate Editor Robert Holloway, MD, provide commentary on the first double-blind trial of exon skipping in Duchenne muscular dystrophy. What do these inroads mean for clinicians? While the results are far from useful right now for clinical application, the promise of the therapy is exciting, they say:

©2012 American Academy of Neurology