Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor for 24 Weeks or Longer in People with Cystic Fibrosis and One or More <i>F508del</i> Alleles: Interim Results of an Open-Label Phase 3 Clinical Trial

Griese, Matthias; Costa, Stéfano; Linnemann, Rachel W.; Mall, Marcus; McKone, Edward F.; Polineni, Deepika; Quon, Bradley S.; Ringshausen, Felix C.; Taylor‐Cousar, Jennifer L.; Withers, Nicholas; Moskowitz, Samuel M.; Daines, Cori

doi:10.1164/rccm.202008-3176le

Cited by 130 publications

(96 citation statements)

References 8 publications

(15 reference statements)

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“…Patients with F508del/minimal function (F/MF) or F508del/F508del (F/F) mutations were included, allowing those who were on placebo in primary studies 9,10 to be provided open label ETI. Efficacy was similar to the primary phase 3 studies, with increases in FEV1pp by 14.9% and 12.8%, in F/MF and F/F participants, respectively, when transitioning from placebo to ETI 8 . The reduction in annual PEx rate from 0.98 to 0.37 per year seen in the original F/F 24-week phase 3 study was maintained in this extension trial.…”

Section: Open Label Extension Eti Trialsupporting

confidence: 62%

“…] 12 years old, and an open label extension study is still ongoing. An early interim analysis of the phase 3, open label extension trial results for ETI through week 24, in 506 participants was published 8 . Patients with F508del/minimal function (F/MF) or F508del/F508del (F/F) mutations were included, allowing those who were on placebo in primary studies 9,10 to be provided open label ETI.…”

Section: Open Label Extension Eti Trialmentioning

confidence: 99%

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Review of CFTR Modulators 2020

Goetz

Savant

2021

Preprint

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CFTR (cystic fibrosis transmembrane conductance regulator) modulators are small molecules that directly change the CFTR protein, improving function of the CFTR chloride channel. Beginning in 2012 with the FDA approval of the first CFTR modulator, ivacaftor, this class of medication has had largely positive effects on many outcomes in people with cystic fibrosis (pwCF), including lung function, quality of life, and growth. There have been continued exciting developments in the current research on CFTR modulators, expanding beyond original studies. This first part of a three-part Cystic Fibrosis (CF) Year in Review 2020 will focus on research on CFTR modulators. Subsequent parts of the CF year in review will cover pulmonary and infectious inflammatory aspects, and the multisystem effects of CF in the 2020 literature. The review focuses on articles from Pediatric Pulmonology, but it includes articles from other journals that are of particular interest to clinicians. New developments in CF research continue to be brought forth to the CF community, deepening the understanding of this disease and improving clinical care.

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Section: Open Label Extension Eti Trialsupporting

confidence: 62%

Section: Open Label Extension Eti Trialmentioning

confidence: 99%

Review of CFTR Modulators 2020

Goetz

Savant

2021

Preprint

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“…The development of VX-445 has radically changed the therapeutic perspective for many patients with CF. Indeed, the inclusion of VX-445 (elexacaftor) with the corrector VX-661 (tezacaftor) and the potentiator VX-770 (ivacaftor) in a combinatorial drug therapy has demonstrated considerable clinical benefit even for patients with a single F508del allele [ 13 , 15 , 25 , 26 , 27 ]. This marked therapeutic effect is expected from the synergy of the two correctors that act with complementary mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the combination of VX-445 with either VX-809 or VX-661 was particularly effective in the primary bronchial epithelial cells of CF patients. The net rescue effect was equivalent to 50–70% of CFTR-dependent Cl - secretion in non-CF cells, a notable result that explains the clinical benefit of Trikafta ® compared to Orkambi ® [ 15 , 25 , 27 ]. However, despite this large effect, our experiments revealed that the combination of the two correctors does not fully prevent the folding and stability defects caused by F508del mutation.…”

Section: Discussionmentioning

confidence: 99%

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Capurro

Tomati

Sondo

et al. 2021

IJMS

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Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

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“…Mucus hypersecretion appears as a therapeutic target for multiple chronic airway diseases, including severe asthma, COPD, cystic fibrosis (CF), and bronchiectasis ( 15 ). In CF, highly effective CF transmembrane conductance regulator modulators have been developed for restoring ion transport, and these drugs have beneficial effects on lung function and clinical outcomes ( 16 ), presumably by improving mucociliary clearance and reducing mucus plugging in airways ( 17 ). Currently available drugs have limited effects on mucus in COPD ( 18 ), and CF transmembrane conductance regulator modulators have been proposed for targeting mucus hypersecretion in patients with COPD ( 19 ).…”

mentioning

confidence: 99%