Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis

This is the authors' abstract. We don't add key points for this paper.

BACKGROUND: Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a salt transporter. F508del, the most common CFTR mutation that causes CF, is found in up to 80% to 90% of people with CF. In people with this mutation, a full length of protein is transcribed, but recognised as misfolded by the cell and degraded before reaching the cell membrane, where it needs to be positioned to effect transepithelial salt transport. This severe mutation is associated with no meaningful CFTR function. A corrective therapy for this mutation could positively impact on an important proportion of the CF population. OBJECTIVES: To evaluate the effects of CFTR correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register. We also searched reference lists of relevant articles and online trials registries. Most recent search: 24 February 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to placebo in people with CF with class II mutations. We also included RCTs comparing CFTR correctors combined with CFTR potentiators to placebo. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and quality of the evidence using the GRADE criteria. Study authors were contacted for additional data. MAIN RESULTS: with tezacaftor-ivacaftor of 6.80% (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence).More participants receiving the lumacaftor-ivacaftor combination reported early transient breathlessness, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). In addition, participants allocated to the 400 mg twice-daily dose of lumacaftor-ivacaftor experienced a rise in blood pressure over the 120-week period of the initial studies and the follow-up study of 5.1 mmHg (systolic blood pressure) and 4.1 mmHg (diastolic blood pressure) (80 participants; high-quality evidence). These adverse effects were not reported in the tezacaftor-ivacaftor studies.The rate of pulmonary exacerbations decreased for participants receiving and additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation.Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.