Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del
Open accessAbstract
modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis.
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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 [11]
For 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 [11]
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 [11]
The baseline sweat chloride concentration in the current trial is comparable to that observed at the end of the TEZ/IVA versus placebo trial.
“which is comparable to that observed at the end of the TEZ/IVA versus placebo trial,12”
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”
pwCF homozygous for F508del treated with TEZ/IVA experienced a 4-percentage point increase in ppFEV1 compared with placebo.
“Comparatively, pwCF homozygous for F508del treated with TEZ/IVA experienced a 4-percentage point increase in ppFEV1 compared with placebo.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”
TEZ/IVA improved ppFEV1 by 4 percentage points compared with placebo in this population.
“the demonstrated impact of TEZ/IVA in this population (a 4-percentage point improvement in ppFEV1 compared with placebo).12”
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”
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”
Improvements in weight and BMI were not observed in a 24-week study of TEZ/IVA in the same population.
“Improvements in weight and BMI were not observed in a 24-week study of TEZ/IVA in the same population.12”
The 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”
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”
Cites
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Van Goor, F., Hadida, S., Grootenhuis, P. D. J., Burton, B., Stack, J. H., Straley, K. S., Decker, C. J., Miller, M., McCartney, J., Olson, E. R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105787108 · Cited by 1,088 · see citing works
Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis
de Boer, K., Vandemheen, K. L., Tullis, E., Doucette, S., Fergusson, D., Freitag, A., Paterson, N., Jackson, M., Lougheed, M. D., Kumar, V., et al. (2011) · Thorax · doi:10.1136/thx.2011.161117 · Cited by 271 · see citing works
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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Self-citationHeijerman, H. G. M., McKone, E. F., Downey, D. G., Van Braeckel, E., Rowe, S. M., Tullis, E., Mall, M. A., Welter, J. J., Ramsey, B. W., McKee, C. M., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32597-8 · Cited by 1,414 · see citing works
Self-citationShteinberg, M., Haq, I. J., Polineni, D., & Davies, J. C. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32542-3 · Cited by 682 · see citing works
Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis
Berkers, G., van Mourik, P., Vonk, A. M., Kruisselbrink, E., Dekkers, J. F., de Winter-de Groot, K. M., Arets, H. G. M., Marck-van der Wilt, R. E. P., Dijkema, J. S., Vanderschuren, M. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.068 · Cited by 310 · see citing works
Ramos, K. J., Smith, P. J., McKone, E. F., Pilewski, J. M., Lucy, A., Hempstead, S. E., Tallarico, E., Faro, A., Rosenbluth, D. B., Gray, A. L., et al. (2019) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2019.03.002 · Cited by 227 · see citing works
Self-citationCFTR modulator therapy: Transforming the landscape of clinical care in cystic fibrosis
Taylor-Cousar, J. L., Robinson, P. D., Shteinberg, M., & Downey, D. G. (2023) · The Lancet · doi:10.1016/s0140-6736(23)01609-4 · Cited by 173 · see citing works
Self-citationDaines, C. L., Tullis, E., Costa, S., Linnemann, R. W., Mall, M. A., McKone, E. F., Polineni, D., Quon, B. S., Ringshausen, F. C., Rowe, S. M., et al. (2023) · European Respiratory Journal · doi:10.1183/13993003.02029-2022 · Cited by 100 · see citing works
Self-citationAwatade, N. T., Wong, S. L., Hewson, C. K., Fawcett, L. K., Kicic, A., Jaffe, A., & Waters, S. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01429 · Cited by 92 · see citing works
Salazar, M. D., Zelt, N. B., Saldivar, R., Kuntz, C. P., Chen, S., Penn, W. D., Bonneau, R., Koehler Leman, J., & Schlebach, J. P. (2020) · Biochemistry · doi:10.1021/acs.biochem.9b00956 · Cited by 25 · see citing works
- Authors
- Taylor-Cousar, J. L., Munck, A., McKone, E. F., van der Ent, C. K., Moeller, A., Simard, C., Wang, L. T., Ingenito, E. P., McKee, C., Lu, Y., Lekstrom-Himes, J., & Elborn, J. S.
- Affiliations
- University College Dublin (IE)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-11-23
- Volume
- 377
- Issue
- 21
- Pages
- 2013-2023
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4206217612
- Cited by
- 794
- References
- 2
- Citations by year
- 2026: 38 · 2025: 64 · 2024: 72 · 2023: 78 · 2022: 112 · 2021: 126 · 2020: 123 · 2019: 104 · 2018: 72 · 2017: 5
- FWCI
- 66.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Research Portal (Queen's University Belfast) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Gilead Sciences
- Teva Pharmaceutical Industries
- Vertex Pharmaceuticals
- PTC Therapeutics
- ProQR Therapeutics
- Genentech
- 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, tezacaftor, ivacaftor, CFTR modulators, combination therapy, FEV1, pulmonary exacerbations, lung function, adverse events, adolescents and adults, drug safety and efficacy, treatment discontinuation, serious adverse events, gastrointestinal adverse effects
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