CFTR pharmacological modulators: A great advance in Cystic Fibrosis management

Summary Cystic fibrosis is a severe monogenic disease that affects around 7300 patients in France. Mutations (>2000) in CFTR, the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate ions, lead to mucus dehydration and impaired bronchial clearance and pancreatic functions. Systematic neonatal screening in France has allowed early diagnosis since 2002. Although highly restrictive, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years of age. Ivacaftor was the first CFTR potentiator found to both reduce sweat chloride concentrations and improve pulmonary function in the rare so-called CFTR gating mutations. Then, combinations of a potentiator and various correctors such as lumacaftor + ivacaftor or tezacaftor + ivacaftor were found to improve pulmonary function in both F508del homozygous patients characterized by the lack of CFTR protein and heterozygous F508del/mutation with residual CFTR activity. Finally, the triple association ivacaftor + tezacaftor + elexacaftor was recently shown to normalize sweat chloride concentration, significantly improve pulmonary function testing, reduce the need for antibiotic treatments, and ultimately improve the quality of life in patients with at least one F508del mutation (83% in France). Those impressive data need, however, to be confirmed in the long-term range. Nevertheless, it is encouraging to hear the treated patients testify to their markedly improved quality of life and observe that the annual number of lung transplants for cystic fibrosis dramatically decreased in France from 2020, regardless of the Covid pandemic, with no increase in deaths without lung transplant. (c) 2022 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.