Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Peter G Middleton1, Marcus A Mall1, Pavel Dřevínek1
1From the Department of Respiratory and Sleep Medicine, Westmead Hospital and CF Research Group, Ludwig Engel Centre for Respiratory Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia (P.G.M.); the Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, the Berlin Institute of Health, and the German Center for Lung Research, Berlin (M.A.M.); the Department of Medical Microbiology, Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic (P.D.); the Pediatric Respiratory Medicine and Pediatric Cystic Fibrosis Clinic, McGill University Health Centre, Montreal (L.C.L.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); the Department of Internal Medicine, University of Kansas Medical Center, Kansas City (D.P.); the Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle (B.W.R.); the Departments of Medicine and Pediatrics, National Jewish Health, Denver (J.L.T.-C.); the Division of Respirology, St. Michael's Hospital, University of Toronto, Toronto (E.T.); the Cystic Fibrosis Reference Center, Department of Pediatrics, Catholic University of Leuven, Leuven, Belgium (F.V.); Vertex Pharmaceuticals, Boston (G.M., C.M.M., S.M.M., N.N., J.S., C.S., S.T., D.W., F.X.); the Departments of Medicine, Pediatrics, and Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham (S.M.R.); and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (R.J.).
Insights
Elexacaftor-tezacaftor-ivacaftor significantly improved lung function and quality of life in cystic fibrosis patients with the Phe508del-minimal function genotype. This combination therapy demonstrated substantial clinical benefits and an acceptable safety profile in a phase 3 trial.
Area of Science:
- Pulmonology
- Genetics
- Pharmacology
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- The Phe508del mutation is the most common CFTR mutation, present in nearly 90% of patients.
- Previous CFTR modulator therapies showed limited efficacy in patients with specific CFTR mutation combinations.
Purpose of the Study:
- To evaluate the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis (CF) and Phe508del-minimal function genotypes.
- To confirm the benefits observed in phase 2 trials for this specific patient population.
- To assess the impact on lung function, pulmonary exacerbations, and quality of life.
Main Methods:
- A phase 3, randomized, double-blind, placebo-controlled trial was conducted.
- 403 patients aged 12 years or older with CF and Phe508del-minimal function genotypes were enrolled.
- Patients received either elexacaftor-tezacaftor-ivacaftor or a placebo for 24 weeks, with the primary endpoint being the change in FEV1 at week 4.
Main Results:
- Elexacaftor-tezacaftor-ivacaftor demonstrated a significant improvement in lung function, with a 13.8-point increase in percent predicted FEV1 at 4 weeks and 14.3 points at 24 weeks compared to placebo.
- The treatment group experienced a 63% reduction in pulmonary exacerbations and a 20.2-point increase in the CFQ-R respiratory domain score.
- Significant reductions in sweat chloride concentration (41.8 mmol/L lower) were observed, with a favorable safety profile and minimal treatment discontinuations due to adverse events.
Conclusions:
- Elexacaftor-tezacaftor-ivacaftor is an effective treatment for patients with cystic fibrosis and Phe508del-minimal function genotypes, including those unresponsive to prior CFTR modulators.
- The combination therapy offers significant clinical benefits, improving respiratory symptoms and overall quality of life.
- The drug combination is safe and well-tolerated, supporting its use in this patient population.
Background:
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.
Methods:
We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.
Results:
A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.
Conclusions:
Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
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