Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR
Open accessAbstract
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: through week 24 (calculated as a percentage) was a key secondary end point. RESULTS: 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 .).
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A potential limitation of this trial is the 4-week duration.
“a potential limitation of this trial is the 4-week duration.7,11,12”
From Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial (2019) · cites this paper as [11]
The Methods (Study Design and Oversight) state that the cited TRAFFIC and TRANSPORT trials administered treatment for 24 weeks, not 4 weeks. The ≤4-week interval in Methods (Study Participants) was between screening and baseline, not the trial duration. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredThe majority of phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer.
“The majority of phase 3 trials assessing the efficacy of CFTR modulators have used treatment periods of 24 weeks or longer”
From Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial (2019) · cites this paper as [11]
The Methods (Study Design and Oversight; page unavailable) describe two phase 3 CFTR-modulator efficacy trials with 24-week treatment periods. The paper does not establish that a majority of phase 3 CFTR-modulator trials used treatment periods of 24 weeks or longer. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFor persons homozygous for the Phe508del CFTR mutation, the combination of a single corrector, either lumacaftor or tezacaftor, with the potentiator ivacaftor improves clinical outcomes, including lung function and the rate of pulmonary exacerbations.
“For persons with cystic fibrosis who are homozygous for the Phe508del CFTR mutation, the combination of a single corrector, either lumacaftor or tezacaftor, with the potentiator ivacaftor improves clinical outcomes, including lung function and the rate of pulmonary exacerbations.9,11”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [9]
CFTR modulators treat the underlying cause of disease and improve clinical outcomes in persons with specific CFTR mutations.
“CFTR modulators treat the underlying cause of disease and have improved clinical outcomes in persons with specific CFTR mutations.9-12”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [9]
Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2.6-4.0 percentage points of ppFEV1) in people with cystic fibrosis homozygous for F508del.
“Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2·6–4·0 percentage points of the percentage of predicted forced expiratory volume in 1 second [ppFEV1]) and decreases in the rate of pulmonary exacerbations (a 35%–39% reduction) in pwCF homozygous for F508del.11,12”
Studies of lumacaftor/IVA and TEZ/IVA showed decreases in the rate of pulmonary exacerbations (a 35%-39% reduction) in people with cystic fibrosis homozygous for F508del.
“Studies of lumacaftor/IVA and TEZ/IVA showed improvements in lung function (2·6–4·0 percentage points of the percentage of predicted forced expiratory volume in 1 second [ppFEV1]) and decreases in the rate of pulmonary exacerbations (a 35%–39% reduction) in pwCF homozygous for F508del.11,12”
Short-term changes in lung function have consistently been demonstrated within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials.
“observations that short-term changes in lung function have consistently been demonstrated within 4 weeks of treatment with CFTR modulators in previous randomised controlled trials”
Short-term improvements in lung function have been sustained through 24 weeks of treatment.
“these short-term improvements in lung function have been sustained through 24 weeks of treatment, 7,11,12”
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- Authors
- Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J. C., De Boeck, K., Flume, P. A., Konstan, M. W., McColley, S. A., McCoy, K., McKone, E. F., Munck, A., Ratjen, F., Rowe, S. M., Waltz, D., & Boyle, M. P.
- Affiliations
- Queen's University Belfast (GB)
- Seattle Children's Hospital (US)
- Vertex Pharmaceuticals (United States) (US)
- Azienda Ospedaliera Universitaria Integrata Verona (IT)
- University of Milan (IT)
- Royal Brompton & Harefield NHS Foundation Trust (GB)
- Medical University of South Carolina (US)
- Rainbow Babies & Children's Hospital (US)
- Northwestern University (US)
- Nationwide Children's Hospital (US)
- University College Dublin (IE)
- University of Toronto (CA)
- University of Alabama at Birmingham (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-07-16
- Volume
- 373
- Issue
- 3
- Pages
- 220-231
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4764353
- OpenAlex
- W1589654967
- Cited by
- 1,622
- References
- 2
- Citations by year
- 2026: 44 · 2025: 79 · 2024: 103 · 2023: 124 · 2022: 149 · 2021: 174 · 2020: 210 · 2019: 185 · 2018: 169 · 2017: 156 · 2016: 153 · 2015: 72 · 2014: 4
- FWCI
- 134.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000423, UL1TR000062, UL1TR000427, UL1TR001079, UL1TR000165, UL1TR000439)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072482, P30DK027651, DK-027651, P30DK072482, P30DK089507)
- National Center for Research Resources (UL1RR025741)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- cystic fibrosis, CFTR modulators, tezacaftor/ivacaftor, lumacaftor/ivacaftor, CFTR, pulmonary exacerbations, lung function, adverse events, drug safety, combination therapy
- MeSH terms
- Adolescent, Adult, Aminophenols, Aminopyridines, Child, Cystic Fibrosis, Double-Blind Method, Drug Therapy, Combination, Female, Forced Expiratory Volume, Homozygote, Hospitalization, Humans, Male, Middle Aged, Mutation, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, Young Adult
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