Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del.

Abstract

BACKGROUND:

Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis.

METHODS:

In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, we evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV1) through week 24 (calculated in percentage points); relative change in the percentage of the predicted FEV1 through week 24 (calculated as a percentage) was a key secondary end point.

RESULTS:

Of the 510 patients who underwent randomization, 509 received tezacaftor-ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV1 at baseline was 60.0% of the predicted value. The effects on the absolute and relative changes in the percentage of the predicted FEV1 in favor of tezacaftor-ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (P<0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group (P=0.005). The incidence of adverse events was similar in the two groups. Most adverse events were of mild severity (in 41.8% of patients overall) or moderate severity (in 40.9% overall), and serious adverse events were less frequent with tezacaftor-ivacaftor (12.4%) than with placebo (18.2%). A total of 2.9% of patients discontinued the assigned regimen owing to adverse events. Fewer patients in the tezacaftor-ivacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation.

CONCLUSIONS:

The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. (Funded by Vertex Pharmaceuticals; EVOLVE ClinicalTrials.gov number, NCT02347657 .).

• Authors: Jennifer L Taylor-Cousar, Anne Munck, Edward F McKone, Cornelis K van der Ent, Alexander Moeller, Christopher Simard, Linda T Wang, Edward P Ingenito, Charlotte McKee, Yimeng Lu, Julie Lekstrom-Himes, J Stuart Elborn
• Journal: The New England journal of medicine (N Engl J Med) Vol. 377 Issue 21 Pg. 2013-2023 (11 23 2017) ISSN: 1533-4406 [Electronic] United States
• PMID: 29099344 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Aminophenols
• Benzodioxoles
• CFTR protein, human
• Drug Combinations
• Indoles
• Quinolones
• tezacaftor
• Cystic Fibrosis Transmembrane Conductance Regulator
• ivacaftor

Topics

• Adolescent
• Adult
• Aminophenols (adverse effects, pharmacology, therapeutic use)
• Benzodioxoles (adverse effects, pharmacology, therapeutic use)
• Body Mass Index
• Child
• Cystic Fibrosis (drug therapy, genetics, physiopathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (adverse effects, genetics, pharmacology, therapeutic use)
• Double-Blind Method
• Drug Combinations
• Female
• Forced Expiratory Volume (drug effects)
• Homozygote
• Humans
• Indoles (adverse effects, pharmacology, therapeutic use)
• Male
• Mutation
• Quality of Life
• Quinolones (adverse effects, pharmacology, therapeutic use)
• Young Adult