Elexacaftor/tezacaftor/ivacaftor Treatment Reduces Airway Inflammation in Cystic Fibrosis

Vuyst, Richard C. De; Bennard, Erin; Kam, Charissa; McKinzie, Cameron J.; Esther, Charles R.

doi:10.22541/au.167170864.42960149/v1

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…CFTR is not only present in the apical epithelial membrane, but it is also intracellularly detectable in professional phagocytes where it regulates pH and chloride homeostasis of the post-Golgi network. ELX/TEZ/IVA therapy improved chloride efflux and the phagocytic and bactericidal activities of CF monocytes (Zhang et al, 2022b;Cavinato et al, 2022;Gabillard-Lefort et al, 2022), reduced neutrophilic inflammation in the lung (De Vuyst et al, 2023), reduced systemic pro-inflammatory cytokines and normalized circulating immune cell composition (Sheikh et al, 2023) even in pwCF with advanced lung disease (Dhote et al, 2023).…”

Section: Immunology and Airway Microbiologymentioning

confidence: 99%

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

Tümmler

2023

Front. Pharmacol.

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Triple combination therapy with the CFTR modulators elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA) has been qualified as a game changer in cystic fibrosis (CF). We provide an overview of the body of literature on ELX/TEZ/IVA published between November 2019 and February 2023 after approval by the regulators. Recombinant ELX/TEZ/IVA-bound Phe508del CFTR exhibits a wild type conformation in vitro, but in patient’s tissue a CFTR glyoisoform is synthesized that is distinct from the wild type and Phe508del isoforms. ELX/TEZ/IVA therapy improved the quality of life of people with CF in the real-life setting irrespective of their anthropometry and lung function at baseline. ELX/TEZ/IVA improved sinonasal and abdominal disease, lung function and morphology, airway microbiology and the basic defect of impaired epithelial chloride and bicarbonate transport. Pregnancy rates were increasing in women with CF. Side effects of mental status changes deserve particular attention in the future.

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Section: Immunology and Airway Microbiologymentioning

confidence: 99%

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

Tümmler

2023

Front. Pharmacol.

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The influence of highly effective modulator therapies on the sputum proteome in cystic fibrosis

Maher

Barry

Emmott

et al. 2023

Preprint

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Background: There have been dramatic clinical improvements in cystic fibrosis (CF) patients commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in people with CF. Methods: Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry. Results: Post-ETI, mean FEV1% increased by 13.7% (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged. Conclusions: Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.

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Elexacaftor/tezacaftor/ivacaftor Treatment Reduces Airway Inflammation in Cystic Fibrosis

Cited by 2 publications

References 6 publications

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

The influence of highly effective modulator therapies on the sputum proteome in cystic fibrosis

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