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 = 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.

• Authors: Jerry R Mendell, Louise R Rodino-Klapac, Zarife Sahenk, Kandice Roush, Loren Bird, Linda P Lowes, Lindsay Alfano, Ann Maria Gomez, Sarah Lewis, Janaiah Kota, Vinod Malik, Kim Shontz, Christopher M Walker, Kevin M Flanigan, Marco Corridore, John R Kean, Hugh D Allen, Chris Shilling, Kathleen R Melia, Peter Sazani, Jay B Saoud, Edward M Kaye, Eteplirsen Study Group
• Journal: Annals of neurology (Ann Neurol) Vol. 74 Issue 5 Pg. 637-47 (Nov 2013) ISSN: 1531-8249 [Electronic] United States
• PMID: 23907995 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 American Neurological Association.

Chemical References

• Dystrophin
• Morpholinos
• Oligonucleotides
• eteplirsen

Topics

• Adolescent
• Child
• Double-Blind Method
• Dystrophin (genetics)
• Humans
• Male
• Morpholinos
• Muscle, Skeletal (pathology)
• Muscular Dystrophy, Duchenne (drug therapy, genetics, pathology)
• Mutation
• Oligonucleotides (therapeutic use)
• Treatment Outcome