Eteplirsen for the treatment of duchenne muscular dystrophy

Objective In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer (PMO), enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT). Methods DMD boys aged 7 to 13, with confirmed deletions correctable by skipping exon 51 and ability to walk 200-400 meters on 6-minute walk test (6MWT) were randomized to weekly intravenous infusions of 30 or 50 mg/kg/week eteplirsen or placebo for 24 weeks (n=4/group). Placebo-patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at Week 25; treatment was open-label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT. Results At Week 24, the 30-mg/kg eteplirsen patients were biopsied and percentage of dystrophin-positive fibers increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively) suggesting dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and nNOS at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3-meter benefit compared to placebo/delayed patients (p≤0.001). Interpretation Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.