Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved using the combination of a CFTR corrector and potentiator in people with CF (pwCF) homozygous for F508del . The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del . A phase 3, multi-centre, randomised, double-blind, active-controlled trial of ELX in triple combination with TEZ/IVA (ELX/TEZ/IVA) in pwCF homozygous for F508del was conducted. Eligible participants were aged ≥12 years with stable disease and percent predicted forced expiratory volume in 1 second (ppFEV 1 ) of 40 to 90, inclusive. After a four-week TEZ/IVA run-in, participants were randomised 1:1 to four weeks of ELX/TEZ/IVA versus TEZ/IVA alone. The primary endpoint was absolute change from baseline (measured at the end of the TEZ/IVA run-in) in ppFEV 1 at week 4. Key secondary endpoints were absolute change in sweat chloride and CF Questionnaire–Revised respiratory domain (CFQ-R RD) score. ClinicalTrials.gov , number NCT03525548 . Between August and December 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomised and completed the 4-week treatment period. The ELX/TEZ/IVA group had improvements in ppFEV 1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group. ELX/TEZ/IVA was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA. ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del .