title: Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial.
abstract: BACKGROUND
  In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR.
  
  
  METHODS
  This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380.
  
  
  RESULTS
  Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded.
  
  
  CONCLUSIONS
  In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.
authors: Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors: Eitan
authors: E
authors: Kerem
authors: Samit
authors: S
authors: Hirawat
authors: Shoshana
authors: S
authors: Armoni
authors: Yasmin
authors: Y
authors: Yaakov
authors: David
authors: D
authors: Shoseyov
authors: Michael
authors: M
authors: Cohen
authors: Malka
authors: M
authors: Nissim-Rafinia
authors: Hannah
authors: H
authors: Blau
authors: Joseph
authors: J
authors: Rivlin
authors: Micha
authors: M
authors: Aviram
authors: Gary L
authors: GL
authors: Elfring
authors: Valerie J
authors: VJ
authors: Northcutt
authors: Langdon L
authors: LL
authors: Miller
authors: Batsheva
authors: B
authors: Kerem
authors: Michael
authors: M
authors: Wilschanski
mesh_terms: D000293:Adolescent; D000328:Adult; D002712:Chlorides / Q000378:metabolism; D018389:Codon, Nonsense / Q000187:drug effects / Q000235:genetics; D018388:Codon, Terminator / Q000187:drug effects*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002712:Chlorides; D018389:Codon, Nonsense; D018388:Codon, Terminator; D010069:Oxadiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C515878:ataluren