TY - JOUR
T1 - Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis
AU - Rowe, Steven M.
AU - Daines, Cori
AU - Ringshausen, Felix C.
AU - Kerem, Eitan
AU - Wilson, John
AU - Tullis, Elizabeth
AU - Nair, Nitin
AU - Simard, Christopher
AU - Han, Linda
AU - Ingenito, Edward P.
AU - McKee, Charlotte
AU - Lekstrom-Himes, Julie
AU - Davies, Jane C.
N1 - Funding Information:
The trial sponsor (Vertex Pharmaceuticals) designed the protocol in collaboration with the authors. Local site investigators (listed in the Supplementary Appendix) collected the data, which were analyzed by the sponsor. All the authors had full access to the trial data after the data were unblinded and made the decision to submit the manuscript for publication. The manuscript was written with medical writing support, which was funded by the sponsor, with critical review and input from all the authors. The authors vouch for the accuracy and completeness of the data and analyses and for the adherence of the trial to the protocol. Confidentiality agreements were in place between the sponsor and all the investigators participating in this trial.
Funding Information:
Supported by Vertex Pharmaceuticals and in part by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Infrastructural support was provided in awards by the Cystic Fibrosis Foundation Therapeutics Development Network and the National Institutes of Health (P30DK072482, R35HL135816, and U54TR001005). No author received an honorarium or other form of financial support related to the development of this manuscript.
PY - 2017/11/23
Y1 - 2017/11/23
N2 - BACKGROUND: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor–ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS: The number of analyzed intervention periods was 162 for tezacaftor–ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor–ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor–ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS: CFTR modulator therapy with tezacaftor–ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation.
AB - BACKGROUND: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor–ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS: The number of analyzed intervention periods was 162 for tezacaftor–ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor–ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor–ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS: CFTR modulator therapy with tezacaftor–ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation.
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U2 - 10.1056/NEJMoa1709847
DO - 10.1056/NEJMoa1709847
M3 - Article
C2 - 29099333
AN - SCOPUS:85034732149
VL - 377
SP - 2024
EP - 2035
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 21
ER -