Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.
Middleton, Peter G. M.D.; Mall, Marcus A. M.D.; Drevinek, Pavel M.D.; Lands, Larry C. M.D.; McKone, Edward F. M.D.; Polineni, Deepika M.D.; Ramsey, Bonnie W. M.D.; Taylor-Cousar, Jennifer L. M.D.; Tullis, Elizabeth M.D.; Vermeulen, Francois M.D.; Marigowda, Gautham M.D.; McKee, Charlotte M. M.D.; Moskowitz, Samuel M. M.D.; Nair, Nitin Ph.D.; Savage, Jessica M.D.; Simard, Christopher M.D.; Tian, Simon M.D.; Waltz, David M.D.; Xuan, Fengjuan Ph.D.; Rowe, Steven M. M.D.; Jain, Raksha M.D.; the VX17-445-102 Study Group
[Article]
New England Journal of Medicine.
381(19):1809-1819, November 7, 2019.
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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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