Ataluren in cystic fibrosis: development, clinical studies and where are we now?
Open Access
- 1 August 2017
- journal article
- review article
- Published by Taylor & Francis Ltd in Expert Opinion on Pharmacotherapy
- Vol. 18 (13), 1363-1371
- https://doi.org/10.1080/14656566.2017.1359255
Abstract
Introduction: Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC). Areas covered: We discuss the discovery of the small-molecule drug ataluren, which in vitro has been shown to allow read-through of PTCs and facilitate synthesis of full-length protein. We review clinical studies that have been performed involving ataluren in CF. Early-phase short-term cross-over studies showed improvement in nasal potential difference. A follow-up phase III randomised controlled trial did not show a significant difference for the primary outcome of lung function, however a post-hoc analysis suggested possible benefit in patients not receiving tobramycin. A further randomised controlled trial in patients not receiving tobramycin has been reported as showing no benefit but has not yet been published in full peer-reviewed form. Expert opinion: A small-molecule approach to facilitate read-through of PTCs in nonsense mutations makes intuitive sense. However, at present there is no high-quality evidence of clinical efficacy for ataluren in people with CF.Keywords
Funding Information
- Medical Research Council (MR/M008797/1)
- Wellcome Trust (Clinical Research Training Fellowship to IH)
This publication has 42 references indexed in Scilit:
- Cystic fibrosisThe Lancet, 2016
- Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targetsThorax, 2015
- Translating the genetics of cystic fibrosis to personalized medicineTranslational Research, 2015
- Future trends in cystic fibrosis demography in 34 European countriesEuropean Respiratory Journal, 2015
- The relative frequency of CFTR mutation classes in European patients with cystic fibrosisJournal of Cystic Fibrosis, 2014
- Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770Proceedings of the National Academy of Sciences of the United States of America, 2009
- Cystic Fibrosis Since 1938American Journal of Respiratory and Critical Care Medicine, 2006
- Clinical outcome in relation to care in centres specialising in cystic fibrosis: cross sectional study Commentary: Management in paediatric and adult cystic fibrosis centres improves clinical outcomeBMJ, 1998
- Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNAScience, 1989
- CYSTIC FIBROSIS OF THE PANCREAS AND ITS RELATION TO CELIAC DISEASEAmerican Journal of Diseases of Children, 1938