Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial

Eitan Kerem*, Samit Hirawat, Shoshana Armoni, Yasmin Yaakov, David Shoseyov, Michael Cohen, Malka Nissim-Rafinia, Hannah Blau, Joseph Rivlin, Micha Aviram, Gary L. Elfring, Valerie J. Northcutt, Langdon L. Miller, Batsheva Kerem, Michael Wilschanski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

356 Scopus citations


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. Findings: 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. Interpretation: 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. Funding: PTC Therapeutics, Cystic Fibrosis Foundation Therapeutics.

Original languageAmerican English
Pages (from-to)719-727
Number of pages9
JournalThe Lancet
Issue number9640
StatePublished - 2008

Bibliographical note

Funding Information:
This study was sponsored by PTC Therapeutics, and funded in part by a grant from the Cystic Fibrosis Foundation Therapeutics. We thank the patients who committed their time and effort despite the uncertainties of testing a new medication; Martin Sinaasappel for his expert review of the nasal potential difference tracings; Greg Elfring and James Dancy, Innovative Analytics, for their expertise in data management; Erella Kenoshi for capable monitoring of the conduct of this study; Elizabeth Colacino and Allen Reha for data review; and Peter Riebling for support with the submission process.


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