Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis

Am J Respir Crit Care Med. 2010 Nov 15;182(10):1262-72. doi: 10.1164/rccm.201001-0137OC. Epub 2010 Jul 9.


Rationale: Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein.

Objectives: To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF.

Methods: Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles.

Measurements and main results: The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults.

Conclusions: In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

Trial registration: NCT00458341.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Codon, Nonsense / drug effects*
  • Codon, Nonsense / genetics
  • Codon, Nonsense / physiology
  • Cross-Over Studies
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / physiopathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / biosynthesis*
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Humans
  • Male
  • Nasal Mucosa / metabolism
  • Nasal Mucosa / physiopathology
  • Oxadiazoles / administration & dosage
  • Oxadiazoles / pharmacology
  • Oxadiazoles / therapeutic use*


  • Codon, Nonsense
  • Oxadiazoles
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ataluren

Associated data