Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles

Am J Respir Crit Care Med. 2022 Mar 1;205(5):540-549. doi: 10.1164/rccm.202110-2249OC.


Rationale: The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. Objectives: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. Methods: This prospective, observational, multicenter study assessed clinical outcomes including FEV1% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5-72.4; P < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; P < 0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl- secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; P < 0.001) in intestinal epithelia. Conclusions: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

Keywords: CFTR biomarker; cystic fibrosis; elexacaftor/tezacaftor/ivacaftor; intestinal current measurement; nasal potential difference.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Aminophenols / therapeutic use
  • Benzodioxoles / therapeutic use
  • Chloride Channel Agonists / therapeutic use
  • Chlorides
  • Cystic Fibrosis Transmembrane Conductance Regulator*
  • Cystic Fibrosis* / drug therapy
  • Cystic Fibrosis* / genetics
  • Humans
  • Indoles
  • Mutation
  • Prospective Studies
  • Pyrazoles
  • Pyridines
  • Pyrrolidines
  • Quinolones


  • Aminophenols
  • Benzodioxoles
  • CFTR protein, human
  • Chloride Channel Agonists
  • Chlorides
  • Indoles
  • Pyrazoles
  • Pyridines
  • Pyrrolidines
  • Quinolones
  • tezacaftor
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • elexacaftor

Associated data

  • ClinicalTrials.gov/NCT04732910