Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

Abstract

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.).

• Authors: Peter G Middleton, Marcus A Mall, Pavel Dřevínek, Larry C Lands, Edward F McKone, Deepika Polineni, Bonnie W Ramsey, Jennifer L Taylor-Cousar, Elizabeth Tullis, François Vermeulen, Gautham Marigowda, Charlotte M McKee, Samuel M Moskowitz, Nitin Nair, Jessica Savage, Christopher Simard, Simon Tian, David Waltz, Fengjuan Xuan, Steven M Rowe, Raksha Jain, VX17-445-102 Study Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 381 Issue 19 Pg. 1809-1819 (11 07 2019) ISSN: 1533-4406 [Electronic] United States
• PMID: 31697873 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Massachusetts Medical Society.

Chemical References

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

Topics

• Adolescent
• Adult
• Aminophenols (administration & dosage, adverse effects)
• Benzodioxoles (administration & dosage, adverse effects)
• Child
• Chloride Channel Agonists (administration & dosage, adverse effects)
• Chlorides (analysis)
• Cystic Fibrosis (drug therapy, genetics, physiopathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics)
• Double-Blind Method
• Drug Combinations
• Female
• Forced Expiratory Volume
• Genotype
• Humans
• Indoles (administration & dosage, adverse effects)
• Male
• Mutation
• Pyrazoles (administration & dosage, adverse effects)
• Pyridines (administration & dosage, adverse effects)
• Pyrrolidines (administration & dosage, adverse effects)
• Quinolones (administration & dosage, adverse effects)
• Sweat (chemistry)
• Young Adult