Chest
Volume 143, Issue 1, January 2013, Pages 14-18
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Commentary
Change in Sweat Chloride as a Clinical End Point in Cystic Fibrosis Clinical Trials: The Ivacaftor Experience

https://doi.org/10.1378/chest.12-1430Get rights and content

Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV1 and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV1 and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV1 (10%–12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV1, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 was apparent. The lack of correlation of sweat chloride with improvement in FEV1 speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

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Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The views expressed in this commentary are those of the authors and do not necessarily reflect the views or policies of the US Food and Drug Administration.

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    The relationship between modulator-induced SC response and clinical outcomes has proven elusive. There have been clear genotype-level [26] but limited patient-level, associations observed between SC concentration and lung function changes, in particular within the setting of recent clinical studies of ivacaftor ([27,28]) and lumacaftor/ivacaftor [29]. More recently, a modest correlation between SC response and short term lung function change was observed among a cohort initiating ETI, suggesting that large effect sizes combined with heterogeneity as defined by factors including CFTR genotype use may prove useful in elucidating such an association [13].

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