Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis

Background Cystic fibrosis (CF) is a common, life‐shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces, and the mutation most notably affects the airways. In the lungs of people with CF, the defective protein compromises mucociliary clearance and makes the airway prone to chronic infection and inflammation, damaging the structure of the airways and eventually leading to respiratory failure. In addition, abnormalities in the truncated CFTR protein lead to other systemic complications, including malnutrition, diabetes and subfertility. Five classes of mutation have been described, depending on the impact of the mutation on the processing of the CFTR protein in the cell. In class I mutations, premature termination codons prevent the production of any functional protein, resulting in severe CF. Therapies targeting class I mutations aim to enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the CFTR protein. This could, in turn, normalise salt transport in the cells and decrease the chronic infection and inflammation that characterises lung disease in people with CF. This is an update of a previously published review. Objectives To evaluate the benefits and harms of ataluren and similar compounds on clinically important outcomes in people with CF with class I mutations (premature termination codons). Search methods We searched the Cochrane Cystic Fibrosis Trials Register, which is compiled from electronic database searches and handsearching of journals and conference books. We also searched the reference lists of relevant articles. The last search of the Cochrane Cystic Fibrosis Trials Register was conducted on 7 March 2022. We searched clinical trial registries maintained by the European Medicines Agency, the US National Institutes of Health and the World Health Organization. The last search of the clinical trials registries was conducted on 4 October 2022. Selection criteria Randomised controlled trials (RCTs) of parallel design comparing ataluren and similar compounds (specific therapies for class I mutations) with placebo in people with CF who have at least one class I mutation. Data collection and analysis For the included trials, the review authors indepe