2014
DOI: 10.1164/rccm.201404-0703oc
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Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis

Abstract: Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation.Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers.Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months… Show more

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Cited by 447 publications
(486 citation statements)
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“…Current drugs targeting the mutated CFTR (potentiators/correctors) improve expression and function of CFTR on epithelial surfaces, and patients showed improved lung function and reduced frequency of pulmonary exacerbations, hospitalization, and use of i.v. antibiotics, but augmented CFTR function failed to reduce inflammatory markers in sputum (e.g., IL-1, -6, -8) (26), and heterogeneous responses to the treatment have been reported (27), suggesting that CFTR correction/potentiation may not directly improve the underlying compromised immune response. The negative NF-κB regulator A20 (TNFAIP3) is reduced in CF airway epithelial cells, basally and after LPS stimulation (23), and is associated with markers of inflammation and decreased lung function (12).…”
Section: Discussionmentioning
confidence: 99%
“…Current drugs targeting the mutated CFTR (potentiators/correctors) improve expression and function of CFTR on epithelial surfaces, and patients showed improved lung function and reduced frequency of pulmonary exacerbations, hospitalization, and use of i.v. antibiotics, but augmented CFTR function failed to reduce inflammatory markers in sputum (e.g., IL-1, -6, -8) (26), and heterogeneous responses to the treatment have been reported (27), suggesting that CFTR correction/potentiation may not directly improve the underlying compromised immune response. The negative NF-κB regulator A20 (TNFAIP3) is reduced in CF airway epithelial cells, basally and after LPS stimulation (23), and is associated with markers of inflammation and decreased lung function (12).…”
Section: Discussionmentioning
confidence: 99%
“…In clinical studies, ivacaftor has improved pulmonary function and nutritional status and reduced the number of pulmonary exacerbations, antibiotic use and number of hospital stays. Additionally, improvement in quality of life, mucociliary clearance, gastrointestinal pH, higher levels of exhaled nitric oxide, lower doses of insulin (in diabetics), and fewer infection with Pseudomonas aeruginosa have been observed during ivacaftor treatment [13][14][15][16][17] . Lower sweat chloride concentration has also been clearly documented and the sweat test can be utilized as a marker of compliance with ivacaftor therapy 18 .…”
Section: Discussionmentioning
confidence: 99%
“…However, although successfully improving expression and function of CFTR, airway inflammation was not reduced. In CF patients aged 6 years and above with Gly551Asp-CFTR, 6 months of treatment with Ivacaftor did not reduce inflammatory markers in sputum such as IL-1, IL-6 and IL-8 [7] and heterogeneous responses to the corrector/potentiator treatment have been reported in patients homozygous for Phe508del-CFTR [8]. This suggests that CFTR correction/potentiation may not directly improve the underlying compromised immune response, thus there is still an unmet need to normalise the inflammatory response in CF airways.…”
Section: Introductionmentioning
confidence: 83%