title: 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).
  
  
  CONCLUSIONS
  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.affiliation: Departments of Pediatrics, Ohio State University, Columbus, OH; Neurology the Ohio State University, Ohio State University, Columbus, OH; Gene Therapy Center, Nationwide Children's Hospital Ohio State University, Columbus, OH; Paul D. Wellstone Center, Nationwide Children's Hospital Ohio State University, Columbus, OH.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Louise R
authors.initials: LR
authors.lastname: Rodino-Klapac
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.forename: Kandice
authors.initials: K
authors.lastname: Roush
authors.forename: Loren
authors.initials: L
authors.lastname: Bird
authors.forename: Linda P
authors.initials: LP
authors.lastname: Lowes
authors.forename: Lindsay
authors.initials: L
authors.lastname: Alfano
authors.forename: Ann Maria
authors.initials: AM
authors.lastname: Gomez
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.forename: Janaiah
authors.initials: J
authors.lastname: Kota
authors.forename: Vinod
authors.initials: V
authors.lastname: Malik
authors.forename: Kim
authors.initials: K
authors.lastname: Shontz
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Marco
authors.initials: M
authors.lastname: Corridore
authors.forename: John R
authors.initials: JR
authors.lastname: Kean
authors.forename: Hugh D
authors.initials: HD
authors.lastname: Allen
authors.forename: Chris
authors.initials: C
authors.lastname: Shilling
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Melia
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
authors.forename: Jay B
authors.initials: JB
authors.lastname: Saoud
authors.forename: Edward M
authors.initials: EM
authors.lastname: Kaye
mesh_terms: D000293:Adolescent; D002648:Child; D004311:Double-Blind Method; D016189:Dystrophin / Q000235:genetics; D006801:Humans; D008297:Male; D060172:Morpholinos; D018482:Muscle, Skeletal / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009841:Oligonucleotides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016189:Dystrophin; D060172:Morpholinos; D009841:Oligonucleotides; C000611335:eteplirsen