Eteplirsen for the treatment of Duchenne muscular dystrophy. Issue 5 (10th September 2013)

• Record Type: Journal Article
• Authors: Mendell, Jerry R.; Rodino‐Klapac, Louise R.; Sahenk, Zarife; Roush, Kandice; Bird, Loren; Lowes, Linda P.; Alfano, Lindsay; Gomez, Ann Maria; Lewis, Sarah; Kota, Janaiah; Malik, Vinod; Shontz, Kim; Walker, Christopher M.; Flanigan, Kevin M.; Corridore, Marco; Kean, John R.; Allen, Hugh D.; Shilling, Chris; Melia, Kathleen R.; Sazani, Peter; Saoud, Jay B.; Kaye, Edward M.
• Is Part Of: Annals of neurology. Volume 74:Issue 5(2013:Nov.)
• Page Start: 637
• Page End: 647
• Publication Date: 2013-09-10
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.23982
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana23982-sec-0001" sec-type="section"> <title>Objective</title> <p>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).</p> </sec> <sec id="ana23982-sec-0002" sec-type="section"> <title>Methods</title> <p>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 = 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.</p> </sec> <sec id="ana23982-sec-0003" sec-type="section"> <title>Results</title> <p>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 (<italic>p</italic> ≤ 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 (<italic>p</italic> ≤ 0.001).</p> </sec> <sec id="ana23982-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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. Ann Neurol 2013;74:637–647</p> </sec> </abstract>