title: Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis.
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.
authors.affiliation: Paediatric Gastroenterology, Hadassah University Hospital, Mount Scopus POB 24035, Jerusalem, 91240, Israel. michaelwil@hadassah.org.il
authors.forename: M
authors.initials: M
authors.lastname: Wilschanski
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
authors.forename: D
authors.initials: D
authors.lastname: Shoseyov
authors.forename: H
authors.initials: H
authors.lastname: Blau
authors.forename: J
authors.initials: J
authors.lastname: Rivlin
authors.forename: M
authors.initials: M
authors.lastname: Aviram
authors.forename: M
authors.initials: M
authors.lastname: Cohen
authors.forename: S
authors.initials: S
authors.lastname: Armoni
authors.forename: Y
authors.initials: Y
authors.lastname: Yaakov
authors.forename: T
authors.initials: T
authors.lastname: Pugatsch
authors.forename: T
authors.initials: T
authors.lastname: Pugatch
authors.forename: M
authors.initials: M
authors.lastname: Cohen-Cymberknoh
authors.forename: N L
authors.initials: NL
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Reha
authors.forename: V J
authors.initials: VJ
authors.lastname: Northcutt
authors.forename: S
authors.initials: S
authors.lastname: Hirawat
authors.forename: K
authors.initials: K
authors.lastname: Donnelly
authors.forename: G L
authors.initials: GL
authors.lastname: Elfring
authors.forename: T
authors.initials: T
authors.lastname: Ajayi
authors.forename: E
authors.initials: E
authors.lastname: Kerem
mesh_terms: D000328:Adult; D018389:Codon, Nonsense; D018388:Codon, Terminator; D003371:Cough; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000627:therapeutic use*; D011379:Prognosis; D012270:Ribosomes / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D010069:Oxadiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C515878:ataluren