RT Journal Article
SR Electronic
T1 Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP erj01209-2010
DO 10.1183/09031936.00120910
A1 M. Wilschanski
A1 L.L. Miller
A1 D. Shoseyov
A1 H. Blau
A1 J. Rivlin
A1 M. Aviram
A1 M. Cohen
A1 S. Armoni
A1 Y. Yaakov
A1 T. Pugatch
A1 M. Cohen-Cymberknoh
A1 N.L. Miller
A1 A. Reha
A1 V.J. Northcutt
A1 S. Hirawat
A1 K. Donnelly
A1 G.L. Elfring
A1 T. Ajayi
A1 E. Kerem
YR 2010
UL http://erj.ersjournals.com/content/early/2011/01/13/09031936.00120910.abstract
AB In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional cystic fibrosis 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 3 times daily (morning, midday, and evening) for 12 weeks at either a lower dose (4, 4, 8 mg·kg−1) or higher dose (10, 10, 20 mg·kg−1).The study enrolled 19 patients (males/females 10/9; ages 19 to 57 years; dose: lower 12, higher 7) with a classic CF phenotype, ≥1 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 hyperpolarizations (values more electrically negative than −5 mV) in 67% (p<0.001) and 59% (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.