Eteplirsen for the treatment of Duchenne muscular dystrophy

Abstract

Objective:In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, 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 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n 5 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n 5 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 was 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 that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m 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.

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

“…Eteplirsen has been previously demonstrated to reliably induce the production of functional dystrophin in patients with DMD,1, 10, 11, 12 and in so doing, significantly slowed the rate of progression of this devastating disease as demonstrated here by comparison of longitudinal 6MWT results to untreated, matched historical controls over 36 months. This was evidenced by a slower decline in walking ability in eteplirsen‐treated patients compared to age‐matched historical controls amenable to exon 51 skipping, with a clinically relevant 75m difference by 24 months, and a statistically significant and clinically relevant difference of 151m by 36 months.…”

“…This is supported by the finding that internally deleted dystrophin proteins occur in patients with Becker muscular dystrophy, a dystrophinopathy allelic to DMD, but with a less severe phenotype 9. The ability of eteplirsen to induce expression of dystrophin in DMD patients was demonstrated by an observed increase of dystrophin‐positive fibers in skeletal muscle, observed increases in dystrophin intensity in this1 and other studies,10, 11 and by the observed restoration of the dystroglycan complex, as evidenced by localization of neuronal nitric oxide synthase and B‐dystroglycan to the sarcolemma 12…”

“…As described previously,1 patients were randomly assigned to 3 cohorts (n = 4 each) in a double‐blind fashion and received weekly intravenous (IV) eteplirsen 30mg/kg or 50mg/kg or placebo for 24 weeks (Fig 1). Thereafter, patients who had received eteplirsen continued at the same dose on an open‐label basis, whereas those patients who had received placebo were randomized 1:1 to weekly 30mg/kg or 50mg/kg eteplirsen on an open‐label basis.…”

“…Functional clinical assessments including the 6‐Minute Walk Test and pulmonary function tests were performed at each week shown on the time axis. Muscle biopsies for evaluation of dystrophin were obtained from the upper arm at the time points specified; data reported elsewhere 1. BL = baseline.…”

“…The etiology of this rare but devastating disease, the eteplirsen mode of action, and the course of the clinical studies (studies 201/202) have been described in detail in an earlier publication1 and in several reviews 2, 3, 4. Briefly, DMD is caused by deletions and other mutations in the dystrophin (also known as DMD ) gene that abrogate the mRNA reading frame and prevent expression of dystrophin protein.…”