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NEWS FROM THE AAN ANNUAL MEETING: Exon Skipping for Duchenne Muscular Dystrophy Moves Closer to the Clinic

Robinson, Richard

doi: 10.1097/01.NT.0000451837.80841.3b
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Investigators reported new data on two exon-skipping therapies for Duchenne muscular dystrophy (DMD), eteplirsen and drisapersen, which independent experts say is good news for the DMD community.

PHILADELPHIA—In what one expert is calling “the best news the Duchenne muscular dystrophy [DMD] field has ever had,” long-term results of exon-skipping therapy with eteplirsen indicate its potential to stabilize walking ability of boys with DMD over the course of 120 weeks of treatment. While the trial was in a small number of patients and the drug was given open-label for most of the time, the results are nonetheless encouraging enough that the Food and Drug Administration (FDA) has laid out a pathway for approval of eteplirsen, and its manufacturer is gearing up to provide enough drug for clinical use as early as 2015.



Results from long-term use of a second exon-skipping drug, drisapersen, suggest that it can slow decline of walking ability, and may be able to stabilize it in those who begin treatment by 7 years of age.

Both drugs are mutation-specific, and both induce the RNA editing machinery to skip exon 51 of the dystrophin gene, creating a truncated but still functional dystrophin protein. Mutations amenable to exon skipping with these drugs affect about 13 percent of boys with DMD. The RNA-like backbone structures of the two drugs differ, and may account for some differences in safety and adverse effects.

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In the eteplirsen trial, 12 boys with DMD, ages seven to 13 years old, were randomized 1:1:1 to 30 mg/kg, 50 mg/kg, or placebo, delivered once weekly by intravenous infusion over one hour. At 12 weeks, the high-dose patients and half the placebo patients underwent muscle biopsy to assess the production of dystrophin. At 24 weeks, the same occurred in the low-dose patients and the remaining placebo patients. Also at 24 weeks, the blind was broken and those receiving placebo were randomly assigned to one of the active treatment arms. All patients underwent muscle biopsy at 48 weeks. The primary clinical outcome was change in the 6-minute walk test (6MWT) distance from baseline compared to the placebo/delayed-treatment cohort.

Treatment has continued, and data out to 120 weeks was presented by Jerry Mendell, MD, FAAN, director of the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, OH, and a professor of pediatrics and neurology at Ohio State University.

Dystrophin production was seen in all patients in a time- and dose-dependent manner, with 47 percent of muscle fibers producing dystrophin after 48 weeks, with a dystrophin intensity of about 15 percent of normal. Dystrophin production was complemented by an increase in components of the dystrophin-glycoprotein complex, including sarcoglycan and neuronal nitric oxide synthase, proteins that are essential for normal muscle function.

Natural history studies have shown a progressive decline in the 6MWT distance, with a loss of roughly 1 meter per week after age seven. Boys treated from baseline with eteplirsen declined a mean of 16 meters during the first 36 weeks, and remained essentially stable for the next 84 weeks. Those initially on placebo declined by about 70 meters during the first 36 weeks, “and then reached a stable walk distance for the remainder of the study,” Dr. Mendell said.

Maximum inspiratory pressure and maximum expiratory pressure, highly sensitive measures of pulmonary function, decline annually by an average of 3.9 percent and 3.6 percent, respectively in DMD. In contrast, there was “remarkable stability” in these measures over the entire course of the trial, Dr. Mendell said, which represents a significant departure from the expected decline in Duchenne muscular dystrophy natural history.”

The drug was very well tolerated, with no differences in treatment-related adverse events between groups, except for slight elevations in urine protein in 5 samples, out of more than 100 taken.

Eteplirsen's manufacturer, Sarepta Therapeutics, has announced plans to submit a New Drug Application to the FDA by the end of 2014, based on guidance from the FDA. The company plans additional clinical trials, including ones in younger patients and those with more advanced disease. Under an Accelerated Approval pathway offered by the FDA, a decision on approval could come in early 2015. In preparation, the company recently purchased a manufacturing facility to scale up production of the drug.

While these were encouraging results, stabilization is not improvement, Dr. Mendell noted. The absence of improvement over baseline suggests these boys may not have enough regenerative potential to overcome their accumulated loss of muscle fibers. It may be, he said, that “without another adjunctive agent, that's the extent of what you are going to see. That's not a cure.” Higher dosing may be a possibility as well, though it remains to be seen whether that can boost dystrophin further.

On the other hand, he said, starting earlier may allow stabilizing at a much higher level of function. “If we can extrapolate these results back to newborns, we may have a winner.”

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Early treatment may be a key for the benefit from drisapersen, the second exon-skipping drug currently in trials. Nathalie Goemans, MD, head of the Neuromuscular Reference Center for Children at the University Hospitals of Leuven, Belgium, presented data from an open-label extension study that combined one phase 2 study, enrolling 53 boys, ages five to 11 years old, and one phase 3, study enrolling 186 boys, ages five to 16 years old. The drug was given at 6 mg/kg/week by subcutaneous injection. Results were available for treatment of up to 96 weeks.

The mean decline in the 6MWT distance from baseline for those receiving continuous treatment with drisapersen was 67 meters, versus 113 meters for those receiving placebo for the first 48 weeks. But when patients were stratified post-hoc by age, those 7 years old or younger at the beginning of treatment who received drisapersen for 96 weeks remained essentially stable over the course of treatment, and those receiving 48 weeks of drisapersen declined by about 20 meters. In contrast, the older boys in the study declined in both groups, although active treatment slowed the expected decline by about one third.

“This extension study suggests maintenance of a benefit in a subpopulation of boys with less severe disease,” Dr. Goemans said, “and a clinically meaningful benefit that is slower to emerge” in more severely affected boys.

The treatment was associated with injection-site reactions in about one-quarter of patients, proteinuria in about one-third, and thrombocytopenia in 6 percent. According to representatives of Prosensa, drisapersen's manufacturer, development of the drug will continue this year.

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“My feeling is that this is the best news the Duchenne muscular dystrophy community has ever had,” said Kathryn Wagner, MD, PhD, director of the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute in Baltimore, MD, and an associate professor of neurology at Johns Hopkins University. These results provide “a real reason to be optimistic.”

“The most prominent finding” from trials of both drugs “is the amount of time in which boys are staying relatively stable. That is extraordinary,” she said. “This is going to change this disease.” Whether either drug can ultimately improve function remains to be seen, although earlier treatment looks like it has the most promise. While these two drugs can treat only a fraction of DMD patients, about 60 percent of all patients are “skippable.” “These are just the first antisense drugs,” Dr. Wagner said, and both companies have drugs targeting other mutations in the pipeline.

The data were also convincing to Benjamin Rix Brooks, MD, a medical director of the Carolinas Neuromuscular Center in Charlotte, NC. “The risk-benefit analysis in my mind favors going ahead with therapy at this time,” he said. “I believe the FDA will have to look seriously at the data and decide that it's time for these agents to come into the clinic and be provided to patients.”

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•. AAN Annual Meeting Abstract: Safety profile and pharmacokinetic properties of eteplirsen in the treatment of boys with Duchenne muscular dystrophy [DMD]:
    •. Neurology Today archive on exon skipping for DMD:
      © 2014 American Academy of Neurology