CFTR biomarkers: time for promotion to surrogate end-point

Boeck, K. De; Kent, Lisa; Davies, Jane C.; Derichs, Nico; Amaral, Margarida D.; Rowe, Steven M.; Middleton, Peter G.; Jonge, Hugo de; Bronsveld, Inez; Wilschanski, Michael; Melotti, Paola; Danner-Boucher, Isabelle; Boerner, Scott; Fajac, Isabelle; Southern, Kevin W; Nooijer, R.A. de; Bot, A.; Rijke, Yolanda de; Wachter, Elke De; Leal, Teresinha; Vermeulen, François; Hug, MJ; Rault, G.; Nguyen–Khoa, Thao; Barreto, Celeste; Proesmans, Marijke; Sermet‐Gaudelus, Isabelle

doi:10.1183/09031936.00057512

Cited by 96 publications

(79 citation statements)

References 97 publications

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“…Both the sweat test and nasal potential difference have been effectively used as end-points to measure therapeutic efficacy in clinical trials of ivacaftor, VX-809, and ataluren. Nevertheless, test variability and organ-specific treatment responsiveness remain challenging issues [60].…”

Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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102

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Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

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Section: Cftr Correctorsmentioning

confidence: 99%

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Derichs

2013

European Respiratory Review

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102

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“…Normal function of this channel is regulated by a cAMPdependent protein kinase-A process [2][3][4]. Since the discovery of the CFTR gene in 1989, research has been on-going to identify therapeutic strategies to repair the defects in the CFTR gene or CFTR protein [5].…”

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confidence: 99%

Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

Sermet‐Gaudelus

2013

European Respiratory Review

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Cystic fibrosis (CF) is an autosomal recessive lethal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for CFTR, an epithelial cell-surface expressed protein responsible for the transport of chloride (Cl -). Gating mutations associated with defective conductance can be modulated by CFTR potentiators.Ivacaftor is a CFTR potentiator approved for the treatment of CF patients .6 yrs of age with at least one copy of the G551D-CFTR mutation. Herein, the clinical trial development programme for ivacaftor will be reviewed, including two pivotal studies in adolescents/adults and in children. These studies report sustained improvements in lung function and sweat chloride concentrations, and a reduction in pulmonary exacerbations over a 48-week treatment period. In the era of personalised medicine, ivacaftor offers an effective and well-tolerated treatment for the clinical management of CF patients with the G551D mutation. A long-term, open-label study will report the effects of ivacaftor over a further 48 weeks.

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“…The committee is composed of six groups consisting of researchers with expertise in specific outcome measures: CF transmembrane conductance regulator biomarkers [1], respiratory function, inflammatory markers, anthropometrics, microbiology definitions and chest imaging. This article summarises the work of the inflammatory markers group on inflammatory markers obtained via bronchoalveolar lavage (BAL) and is one of a series of documents from the six groups.…”

Section: Introductionmentioning

confidence: 99%

“…Some are currently being considered for ''promotion'' to the status of surrogate end-point. A full description of the classification of outcome measures is provided in the first document in the series of articles from the ECFS-CTN Standardisation Committee [1].…”

Section: Introductionmentioning

confidence: 99%

Clinimetric properties of bronchoalveolar lavage inflammatory markers in cystic fibrosis

Fayon

Kent

Bui

et al. 2013

European Respiratory Journal

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The Standardisation Committee of the European Cystic Fibrosis Society Clinical TrialNetwork has undertaken the evaluation of clinical end-points for therapeutic interventions regarding their use in multicentre clinical trials in cystic fibrosis (CF). This review of biomarkers in bronchoalveolar lavage (BAL) is part of the group's work.The aims of this project were: 1) to review the literature on reliability, validity and responsiveness of BAL in patients with CF; 2) to gain consensus of the group on the feasibility of BAL; and 3) to gain consensus on answers to key questions regarding the promotion of BAL to surrogate end-point status.Assessment of BAL inflammatory markers in the literature indicates that their reliability, validity and responsiveness are adequate for clinical trials. After discussion of the practical characteristics it was concluded that BAL has an attractive validity profile, albeit with limited feasibility. It is particularly applicable to multicentre trials in preschool children with CF and early or mild lung disease. This is the first article to collate the literature in this manner. This provides a rationale to support the use of BAL in early clinical trials in preschool children with CF. @ERSpublications Review of the literature provides rationale to support the use of BAL in well-designed early-phase clinical trials in CF

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CFTR biomarkers: time for promotion to surrogate end-point

Cited by 96 publications

References 97 publications

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Ivacaftor treatment in patients with cystic fibrosis and the G551D-CFTR mutation

Clinimetric properties of bronchoalveolar lavage inflammatory markers in cystic fibrosis

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