Ataluren (PTC124) Induces Cystic Fibrosis Transmembrane Conductance Regulator Protein Expression and Activity in Children with Nonsense Mutation Cystic Fibrosis

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 Clinical trial registered with www clinicaltrials gov (NCT 00458341)