Entering the era of highly effective CFTR modulator therapy

Abstract

Cystic fibrosis is a chronic, progressive, genetic disease caused by absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which leads to chronic sinopulmonary disease and gastrointestinal abnormalities. 1 Elborn JS Cystic fibrosis. Lancet. 2016; 388: 2519-2531 Summary Full Text Full Text PDF PubMed Scopus (807) Google Scholar Approximately 50% of individuals with cystic fibrosis are homozygous for the F508del-CFTR mutation. 2 Zolin A Orenti A Naehrlich L et al. European Cystic Fibrosis Society Patient Registry Report Annual Report 2017. https://www.ecfs.eu/projects/ecfs-patient-registry/annual-reportsDate: 2019 Date accessed: October 23, 2019 Google Scholar Over the past decade, CFTR protein modulators have been developed, which improve CFTR function either through potentiation of the abnormal protein channel at the cell surface (eg, ivacaftor) or through correction of protein transport to the cell surface (eg, lumacaftor and tezacaftor); these treatments have now been approved by the European Medicines Agency and US Food and Drug Administration for use in people with cystic fibrosis and certain genotypes. Ivacaftor has been shown to be effective in people with CFTR gating or residual function mutations (weighted absolute mean difference in percentage predicted forced expiratory volume in 1 s [ppFEV1] of 10·8 [95% CI 9·0–12·7] across two randomised placebo-controlled studies of ivacaftor in patients with one G551D mutation over 48 weeks), whereas the combination treatments of lumacaftor plus ivacaftor and tezacaftor plus ivacaftor appear to have more modest effects compared with placebo in those homozygous for the F508del mutation (weighted absolute mean difference in ppFEV1 of 3·4 [95% CI 2·4–4·4] over 24 weeks of lumacaftor plus ivacaftor and 4·0 [3·2–4·8] over 24 weeks of tezacaftor plus ivacaftor). 3 Habib AR Kajbafzadeh M Desai S Yang CL Skolnik K Quon BS A systematic review of the clinical efficacy and safety of CFTR modulators in cystic fibrosis. Sci Rep. 2019; 97234 Crossref PubMed Scopus (41) Google Scholar Developing effective modulator therapy for those homozygous for F508del, and for the approximately 40% of the cystic fibrosis population heterozygous for F508del, 2 Zolin A Orenti A Naehrlich L et al. European Cystic Fibrosis Society Patient Registry Report Annual Report 2017. https://www.ecfs.eu/projects/ecfs-patient-registry/annual-reportsDate: 2019 Date accessed: October 23, 2019 Google Scholar has been a key research priority for the cystic fibrosis community and a cornerstone to improving the lives of those with cystic fibrosis. 4 Clancy JP Rapid therapeutic advances in CFTR modulator science. Pediatr Pulmonol. 2018; 53: S4-S11 Crossref PubMed Scopus (24) Google Scholar Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trialElexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Full-Text PDF