Ataluren in cystic fibrosis: development, clinical studies and where are we now?
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.
['Zainal Abidin|Noreen|N|', 'Haq|Iram J|IJ|', 'Gardner|Aaron I|AI|', 'Brodlie|Malcolm|M|http://orcid.org/0000-0003-4591-8299']
D018389:Codon, Nonsense D003550:Cystic Fibrosis D019005:Cystic Fibrosis Transmembrane Conductance Regulator D055808:Drug Discovery D006801:Humans D010069:Oxadiazoles D016032:Randomized Controlled Trials as Topic D016896:Treatment Outcome
Ataluren cystic fibrosis CFTR nonsense mutation PTC 124 read-through agent