Study Results Show Long-term Safety and Efficacy for Eteplirsen

Boys with Duchenne muscular dystrophy (DMD) saw continued and significant clinical improvement in motor function tests after 96 weeks of administration of an investigational drug that allows production of a functional version of dystrophin, a protein they otherwise lack, according to Edward Kaye, MD, and coinvestigators. Kaye, a neurologist at Boston Children’s Hospital, presented his work with eteplirsen during a platform session at the American Academy of Neurology’s 2014 annual conference on April 29, 2014, in Philadelphia, PA.

Duchenne muscular dystrophy is caused by a defect in exons that code for dystrophin, resulting in initially proximal but progressive muscle atrophy and weakness, with many myocytes eventually being replaced by adipocytes in muscle tissue. Approximately 13 percent of sufferers of this rare and progressive neuromuscular disorder, which occurs in about one in 5000 male births, may be helped by eteplirsen, a drug that causes skipping of exon 51 during protein encoding. This allows a novel and functional (though not fully normal) version of dystrophin to be produced.

Eteplirsen is a phosphorodiamidate-linked morpholino oligomer (PMO). This type of molecule can allow for selective up- or down-regulation of gene expression. Eteplirsen is renally excreted and charge-neutral, an attribute that is believed to cause less immunogenicity.

In this placebo-controlled, double-blind study, 12 boys age 7-13 years were randomized to receive eteplirsen 30 mg/kg or 50 mg/kg, or placebo. All boys had DMD genotypes that would be amenable to the exon 51-skipping effect of eteplirsen. After completion of the initial 24-week treatment phase, the study was unblinded and all subjects received eteplirsen.

Improved motor function was measured by the primary endpoint of increased distance on the 6-Minute Walking Test (6MWT) for those study subjects able to ambulate and complete the test. The assessment during the open-label extension phase of the study was achieved by comparing those subjects who had been receiving eteplirsen for the full 96 weeks to those who had initially been on placebo but then placed on eteplirsen after 24 weeks (the placebo/delayed treatment cohort).

This portion of the study showed a significant difference between the full-treatment (n=6) and placebo/delayed treatment cohort (n=4). Full-treatment subjects walked an average 71 meters further than the placebo-delayed treatment subjects (p<0.001). For full-duration eteplirsen boys, an approximate overall 5% decline was seen in walking distance over the period studied. The placebo-delayed treatment children declined initially but then stabilized when placed on eteplirsen, showing less than 10 meters of decrease in walking distance on the 6MWT.

Though not the primary focus of this presentation, investigators also used muscle biopsy to document production and accretion of novel dystrophin. At week 48 of treatment, subjects on full-duration eteplirsen treatment demonstrated dystrophin-positive muscle fibers at a level 47.0% of normal (P<0.001), while the placebo-delayed treatment subjects also had increased presence of dystrophin-positive muscle fibers after 24 weeks of treatment at week 48 (38.3%, p</= 0.009).

The study drug was well tolerated with no significant adverse events reported over the nearly two years of administration. Subjects will be followed and 6MWT results and treatment-related adverse events collected and reported for 164 weeks of treatment.