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


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.