• Open Access

Eteplirsen for the treatment of Duchenne muscular dystrophy

Authors

  • Jerry R. Mendell MD,

    Corresponding author
    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Neurology the Ohio State University, Ohio State University, Columbus, OH
    3. Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    4. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    • Address correspondence to Dr Mendell, Center for Gene Therapy, the Research Institute at Nationwide Children's Hospital, Rm WA301, 700 Children's Dr, Columbus, OH 43205. E-mail: Jerry.mendell@nationwidechildrens.org

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  • Louise R. Rodino-Klapac PhD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Zarife Sahenk MD, PhD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Neurology the Ohio State University, Ohio State University, Columbus, OH
    3. Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    4. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Kandice Roush RN,

    1. Department of Pediatrics Clinical Research Services, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Loren Bird RN,

    1. Department of Pediatrics Clinical Research Services, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Linda P. Lowes PhD,

    1. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Lindsay Alfano PT,

    1. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Ann Maria Gomez MD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Sarah Lewis HT, ASCP,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Janaiah Kota PhD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Vinod Malik PhD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Kim Shontz BA, MS,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Christopher M. Walker PhD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    3. Center for Vaccines and Immunity, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Kevin M. Flanigan MD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Neurology the Ohio State University, Ohio State University, Columbus, OH
    3. Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    4. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Marco Corridore MD,

    1. Departments of Surgery and Anesthesiology, Nationwide Children's Hospital, Columbus, OH
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  • John R. Kean MD,

    1. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    2. Departments of Surgery and Anesthesiology, Nationwide Children's Hospital, Columbus, OH
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  • Hugh D. Allen MD,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Chris Shilling MS,

    1. Departments of Pediatrics, Ohio State University, Columbus, OH
    2. Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
    3. Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH
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  • Kathleen R. Melia PhD,

    1. Sarepta Therapeutics, Cambridge, MA
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  • Peter Sazani PhD,

    1. Sarepta Therapeutics, Cambridge, MA
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  • Jay B. Saoud PhD,

    1. Sarepta Therapeutics, Cambridge, MA
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  • Edward M. Kaye MD,

    1. Sarepta Therapeutics, Cambridge, MA
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  • the Eteplirsen Study Group


  • Members of the Eteplirsen Study Group are listed in the Appendix on page 10.

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 = 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 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. Ann Neurol 2013;74:637–647

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