Ataluren in cystic fibrosis: development, clinical studies and where are we now?
Noreen Zainal Abidin1, Iram J Haq1,2, Aaron I Gardner2
1a Paediatric Respiratory Medicine , Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne , UK.
Insights
Ataluren, a drug designed to enable read-through of premature termination codons (PTCs) in cystic fibrosis (CF) patients, has shown limited clinical efficacy. Despite initial promise, high-quality evidence supporting its benefit in CF treatment is currently lacking.
Area of Science:
- Genetics and Molecular Biology
- Pharmacology
- Pulmonology
Background:
- Cystic Fibrosis (CF) is a genetic disorder caused by CFTR gene mutations.
- Class I nonsense mutations lead to premature termination codons (PTCs) and truncated CFTR protein.
- Approximately 10% of CF patients have PTCs.
Purpose of the Study:
- To review the discovery and clinical efficacy of ataluren for CF.
- To evaluate ataluren's ability to facilitate read-through of PTCs.
- To assess the clinical benefit of ataluren in CF patients with nonsense mutations.
Main Methods:
- Review of in vitro studies on ataluren's mechanism of action.
- Analysis of early-phase and Phase III clinical trials of ataluren in CF.
- Examination of subgroup analyses and ongoing clinical studies.
Main Results:
- Ataluren demonstrated in vitro ability to facilitate read-through of PTCs.
- Early studies showed improved nasal potential difference.
- Phase III trials did not meet primary lung function endpoints; post-hoc analyses suggested potential benefit in specific subgroups, but further trials have not confirmed efficacy.
Conclusions:
- Ataluren represents a small-molecule approach to address PTCs in CF.
- Current high-quality evidence does not support the clinical efficacy of ataluren in CF patients.
- Further research is needed to clarify the role of read-through therapies in CF treatment.
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.
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