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Cited by 105Cystic Fibrosis Research AdvancesInhalation and Respiratory Drug DeliveryGenetic and Kidney Cyst Diseases

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles

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Taylor-Cousar, Jennifer L., Mall, Marcus A., Ramsey, Bonnie W., McKone, Edward F., Tullis, Elizabeth, Marigowda, Gautham, McKee, Charlotte M., Waltz, David +4 more·2019·ERJ Open Research
DOI 10.1183/23120541.00082-2019PMC PMC6571452
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Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel.F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e.lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation,i.e.a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

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Authors
Taylor-Cousar, J. L., Mall, M. A., Ramsey, B. W., McKone, E. F., Tullis, E., Marigowda, G., McKee, C. M., Waltz, D., Moskowitz, S. M., Savage, J., Xuan, F., & Rowe, S. M.
Affiliations
  • German Center for Lung Research (DE)
  • Seattle Children's Hospital (US)
  • University College Dublin (IE)
  • St. Michael's Hospital (CA)
  • Vertex Pharmaceuticals (United States) (US)
  • University of Alabama at Birmingham (US)
ORCID
Venue
ERJ Open Research
Publisher
European Respiratory Society (ERS)
Published
2019-04
Volume
5
Issue
2
Pages
00082-2019
ISSN
2312-0541 (ISSN-L)
DOI
10.1183/23120541.00082-2019
PMC
PMC6571452
OpenAlex
W2952212183
Cited by
105
References
2
Citations by year
2026: 6 · 2025: 10 · 2024: 12 · 2023: 22 · 2022: 13 · 2021: 14 · 2020: 17 · 2019: 11
FWCI
9.93
Type
journal article
Language
en
Open access
Licence
Locations
  • ERJ Open Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Heart, Lung, and Blood Institute (R35HL135816)
  • Vertex Pharmaceuticals Incorporated
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072482)
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, F508del-CFTR, triple combination therapy, tezacaftor/ivacaftor, CFTR correctors, CFTR potentiators, ECLIPSE trial

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