Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis

M. Wilschanski, L. L. Miller, D. Shoseyov, H. Blau, J. Rivlin, M. Aviram, M. Cohen, S. Armoni, Y. Yaakov, T. Pugatch, M. Cohen-Cymberknoh, N. L. Miller, A. Reha, V. J. Northcutt, S. Hirawat, K. Donnelly, G. L. Elfring, T. Ajayi, E. Kerem

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg-1) or higher dose (10, 10 and 20 mg·kg-1). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p=0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability. Copyright

Original languageEnglish
Pages (from-to)59-69
Number of pages11
JournalEuropean Respiratory Journal
Volume38
Issue number1
DOIs
StatePublished - 1 Jul 2011
Externally publishedYes

Keywords

  • Adult
  • Cough
  • Cystic fibrosis transmembrane conductance regulator
  • Investigational drug
  • Nasal potential difference
  • Nonsense mutation

Fingerprint

Dive into the research topics of 'Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis'. Together they form a unique fingerprint.

Cite this