AVI-4658 Safe and Effective for Duchenne Muscular Dystrophy

Exon-51 skipping at all doses, dystrophin protein expression restored at doses above 2 mg/kg

TUESDAY, July 26 (HealthDay News) -- The phosphorodiamidate morpholino oligomer AVI-4658 has been found to safely induce new dystrophin protein expression in a significant dose-dependent manner in patients with Duchenne muscular dystrophy (DMD), according to a study published online July 25 in The Lancet.

Sebahattin Cirak, M.D., from University College of London Institute of Child Health, and colleagues evaluated the safety and efficacy of AVI-4658 in 19 male patients between the ages of 5 and 15 years with DMD who took part in a dose-escalation study (0.5, 1.0, 2.0, 4.0, 10.0, and 20.0 mg/kg bodyweight). A muscle biopsy was performed before starting AVI-4658 treatment and after 12 weekly intravenous infusions. The study objectives were the assessment of safety and tolerability and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration.

The investigators found that AVI-4658 caused no drug-related serious adverse events. Exon 51 skipping occurred in all cohorts, and new dystrophin protein expression significantly occurred from cohort 3 (dose 2 mg/kg) onward. Seven patients showed a significant response to the treatment, with an increase in mean dystrophin fluorescence intensity from 8.9 to 16.4 percent of normal control. Three of these patients showed the greatest responses with 21, 15, and 55 percent of dystrophin-positive fibers. These results were confirmed by western blot, which revealed an increase in post-treatment protein levels from 2 to 18 percent, from 0.9 to 17 percent, and from 0 to 7.7 percent of normal muscle, respectively. Two dystrophin-associated proteins, α-sarcoglycan and neuronal nitric oxide synthase, were restored at the sarcolemma.

"AVI-4658 induced restoration of dystrophin expression in [the] skeletal muscle of boys with DMD," the authors write.

Several authors disclosed financial relationships with the pharmaceutical industry, including AVI BioPharma, which partially funded the study.

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