A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation
Open accessAbstract
BACKGROUND: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).
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Ivacaftor and tezacaftor-ivacaftor are approved therapies with well-characterized safety profiles.
“Ivacaftor and tezacaftor–ivacaftor, two components of this triple combination, are approved therapies, with well-characterized safety profiles.10-12,30”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [10]
The Discussion reports that 48 weeks of ivacaftor was not associated with greater safety risk than placebo, supporting the ivacaftor safety portion. This paper does not establish approval status or address the safety of tezacaftor–ivacaftor; it describes ivacaftor as investigational at the time of the study. Page numbers were not supplied for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrior data with CFTR modulators show comparable safety data across numerous CF genotypes.
“prior data with CFTR modulators showing comparable safety data across numerous CF genotypes.7,8,28”
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 [7]
The Results (Safety and Adverse-Event Profile; page not provided) report similar adverse-event incidence with ivacaftor and placebo, supporting comparable safety in this trial. But the Results (Subjects; page not provided) identify a study population selected for the G551D mutation; the paper does not establish comparable safety across numerous CF genotypes. (LLM, conf=0.88)
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 [7]
The Methods (Study Oversight and Study Subjects; page unavailable) describe a phase 3 trial of the CFTR potentiator ivacaftor with a 48-week treatment period. This supports one example of a trial lasting at least 24 weeks, but the paper does not establish that a majority of phase 3 CFTR-modulator trials did so. (LLM, conf=0.88)
Experimental — accuracy not yet measuredShort-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”
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 [7]
The Results > Clinical Efficacy section reports a significant improvement in FEV1 by day 15 in a randomized, placebo-controlled trial of ivacaftor, supporting a lung-function change within four weeks. This paper reports one CFTR potentiator trial; it does not establish that such early changes were consistently demonstrated across previous trials of CFTR modulators. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCFTR 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 [10]
The current benchmark for highly effective CFTR modulator therapy is ivacaftor for patients with the Gly551Asp CFTR mutation, in whom disease modification has been shown with long-term use, including decreased lung-function decline and decreased mortality.
“The current benchmark for highly effective CFTR modulator therapy is ivacaftor for patients with the Gly551Asp CFTR mutation,10 in whom disease modification has been shown with long-term use, including decreased lung-function decline and decreased mortality.25-28”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [10]
The improvement in the primary end point of absolute change in percentage of predicted FEV1 was 10.6 points in patients with the Gly551Asp allele.
“The improvement in the primary end point of absolute change in percentage of predicted FEV1 was 10.6 points in patients with the Gly551Asp allele.10”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [10]
Following 24 weeks of IVA therapy, the 10.6 percentage point increase in ppFEV1 and a substantial reduction in pulmonary exacerbations compared with placebo were sustained in a 96-week trial.
“Following 24 weeks of IVA therapy, the 10.6 percentage point increase in ppFEV1 and a substantial reduction in pulmonary exacerbations compared with placebo7 were sustained in a 96-week trial.21”
The 10·0-percentage point improvement in lung function with ELX/TEZ/IVA compared with TEZ/IVA in pwCF homozygous for F508del observed in the current trial is similar to that seen with IVA in pwCF and the G551D mutation.
“The 10·0-percentage point improvement in lung function with ELX/TEZ/IVA compared with TEZ/IVA in pwCF homozygous for F508del observed in the current trial is similar to that seen with IVA in pwCF and the G551D mutation.7”
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”
Based on the known impact of IVA in a small subset of pwCF, the introduction of ELX/TEZ/IVA is likely to lead to meaningful improvements in the lives of pwCF homozygous for F508del.
“Based on the known impact of the benchmark therapy IVA in a small subset of pwCF, the introduction of ELX/TEZ/IVA is likely to lead to meaningful improvements in the lives of pwCF homozygous for F508del.”
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 [7]
The Methods (Study Subjects; page not provided) describe a 48-week trial, and the Discussion reports outcomes through 48 weeks. Our copy does not assess whether the citing authors’ 4-week trial duration is a limitation (searched: “4-week duration,” “short-term trial,” and “study duration”). (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Research works printed but not linked: 25
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- Authors
- Ramsey, B. W., Davies, J., McElvaney, N. G., Tullis, E., Bell, S. C., Dřevínek, P., Griese, M., McKone, E. F., Wainwright, C. E., Konstan, M. W., Moss, R., Ratjen, F., Sermet-Gaudelus, I., Rowe, S. M., Dong, Q., Rodriguez, S., Yen, K., Ordoñez, C., & Elborn, J. S.
- Affiliations
- Seattle Children's Hospital (US)
- National Health Service (GB)
- Royal College of Surgeons in Ireland (IE)
- St. Michael's Hospital (CA)
- The University of Queensland (AU)
- Ludwig-Maximilians-Universität München (DE)
- St. Vincent's University Hospital (IE)
- Rainbow Babies & Children's Hospital (US)
- Stanford Medicine (US)
- Great Ormond Street Hospital (GB)
- University of Alabama at Birmingham (US)
- Vertex Pharmaceuticals (United States) (US)
- Queen's University Belfast (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-11-03
- Volume
- 365
- Issue
- 18
- Pages
- 1663-1672
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3230303
- OpenAlex
- W2140868856
- Cited by
- 2,195
- References
- 0
- Citations by year
- 2026: 66 · 2025: 101 · 2024: 133 · 2023: 139 · 2022: 145 · 2021: 171 · 2020: 219 · 2019: 177 · 2018: 156 · 2017: 166 · 2016: 157 · 2015: 174 · 2014: 147 · 2013: 144 · 2012: 93
- FWCI
- 100.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- New England Journal of Medicine (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
- Funders
- Cystic Fibrosis Foundation (P30 DK27651)
- Children's Hospital of Philadelphia
- Cystic Fibrosis Foundation Therapeutics
- University of Pennsylvania (UL1 RR024134)
- University of Washington (UL1 RR025014)
- Johns Hopkins University
- University of Pittsburgh (UL1RR024153, RR024153)
- Case Western Reserve University (UL1RR024989)
- University of Alabama at Birmingham (RR025777)
- Seattle Children's Research Institute
- Vertex Pharmaceuticals
- University of Alabama
- National Institute for Health and Care Research
- Imperial College London
- National Institutes of Health (5ul1rr025777-04, DK2765 1, RR025014, RR025777, 5UL1 RR025777, RR024153, RR024989)
- Medical Center, University of Pittsburgh
- National Heart, Lung, and Blood Institute (R01HL105487)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK027651, K23DK075788, P30DK072482, P30DK089507)
- National Center for Research Resources (5UL 1RR025777, RR 024989, UL1RR024989, RR-024153, UL1RR025005, UL1RR025744, UL1-RR-025777, RR025005, UL1RR025758, UL1RR024153, UL1RR025014, UL1RR024134)
- Children's Hospital of Pittsburgh
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Keywords
- cystic fibrosis, CFTR potentiators, ivacaftor, G551D mutation, CFTR modulator therapy, lung function, FEV1, pulmonary exacerbations, sweat chloride, quality of life, weight gain, adverse events, children and adolescents, drug safety and efficacy, respiratory symptoms
- MeSH terms
- Administration, Oral, Adolescent, Adult, Aminophenols, Child, Cystic Fibrosis, Drug Synergism, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, Mutation, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Young Adult
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