Drug Passes Phase 2 Test in Duchenne Muscular Dystrophy

Pauline Anderson

April 27, 2012

April 27, 2012 (New Orleans, Louisiana) — More emerging research supports the safety and efficacy of eteplirsen, the first in class phosphorodiamidate morpholino oligomer (PMO), in patients with Duchenne muscular dystrophy (DMD).

Results of a phase 2b study released here during the American Academy of Neurology's 64th Annual Meeting showed that the drug produced significant levels of the protein dystrophin in DMD patients after 24 weeks of treatment.

Topline results of the trial were released earlier this month and were reported by Medscape Medical News at that time.

Children affected by DMD are unable to produce more than 5% of usual dystrophin levels, which results in progressive muscle deterioration and death. Eteplirsen skips exon 51 of the dystrophin gene and by doing so, restores the gene's ability to make a shorter but functional form of dystrophin.

Earlier proof of concept studies carried out in rodents and canines showed that the drug was well tolerated and safe. A phase 1b intramuscular study and a 2-week phase 2a systemic delivery study in 19 DMD patients showed that eteplirsen converted specific out-of-frame DMD mutations to in-frame deletions, leading to new expression of truncated dystrophin protein.

Exon Skipping

The results of the current randomized, single-center, double-blind phase 2b study were released during an Emerging Science Session highlighting important abstracts at the meeting. The results were the first to be presented from a placebo-controlled study of an exon-skipping therapy for DMD.

The study enrolled 12 children with DMD aged 7 to 13 years with genetically confirmed exon 51 amenable mutations. The patients were receiving oral corticosteroids at a stable dose for at least 24 weeks. These children were randomly assigned to receive either placebo or the intravenous treatment drug in 1 of 2 doses, 30 mg/kg or 50 mg/kg.

Biopsy results at 24 weeks showed that the children in the 30 mg/kg dose group had significantly increased dystrophin levels compared with the children receiving placebo (P ≤ .002). This treatment group had a 23% mean change in dystrophin positive fibers as measured by immunohistochemistry.

The drug induced production of dystrophin at consistent levels. The range observed (from 15% to 30% dystrophic positive fibers) is likely to produce a clinical benefit if maintained over time, said lead investigator Jerry R. Mendell, MD, Director, Center for Disease Therapy and Neuromuscular Disorders, Nationwide Children's Hospital, Columbus, Ohio.

Dr. Jerry R. Mendell

On the 6-minute walk test, 2 patients on the 30 mg/kg dose were excluded from the analysis because they exhibited a rapidly progressive decline on this test (greater than 50 meters by week 12). A trend of slower progression was demonstrated in the remaining treated patients, with a benefit over placebo of 17.8 meters.

The study showed that eteplirsen is safe at both doses, with no treatment-related adverse events. The current treatment for DMD, glucocorticoids, carries significant side effects.

The study was funded by AVIBioPharma.

American Academy of Neurology 64th Annual Meeting. Emerging Science Abstract #004. Presented April 25, 2012.

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