title: Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy.
abstract: BACKGROUND
  Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins.
  
  
  METHODS
  This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint.
  
  
  RESULTS
  Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated.
  
  
  CONCLUSIONS
  Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00264888.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America ; Nemours Children's Hospital, Orlando, Florida, United States of America.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Brenda
authors.initials: B
authors.lastname: Wong
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bönnemann
authors.affiliation: University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Jacinda
authors.initials: J
authors.lastname: Sampson
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
authors.forename: Allen
authors.initials: A
authors.lastname: Reha
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Northcutt
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Elfring
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
authors.forename: Jay
authors.initials: J
authors.lastname: Barth
authors.affiliation: PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Peltz
mesh_terms: D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D016189:Dystrophin / Q000378:metabolism*; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism*; D010069:Oxadiazoles / Q000627:therapeutic use*
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin; D010069:Oxadiazoles; C515878:ataluren