title: Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience.
abstract: 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 FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) 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 FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent. The lack of correlation of sweat chloride with improvement in FEV(1) 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.
authors.affiliation: Division of Pulmonary, Allergy, and Rheumatology Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD. Electronic address: anthony.durmowicz@fda.hhs.gov.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Durmowicz
authors.affiliation: Division of Pulmonary, Allergy, and Rheumatology Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Witzmann
authors.affiliation: Office of Drug Evaluation II, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Rosebraugh
authors.affiliation: Division of Pulmonary, Allergy, and Rheumatology Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Badrul A
authors.initials: BA
authors.lastname: Chowdhury
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use*; D002712:Chlorides / Q000032:analysis*; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D017063:Outcome Assessment, Health Care / Q000379:methods*; D015363:Quinolones / Q000627:therapeutic use*; D013542:Sweat / Q000737:chemistry* / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000627:Aminophenols; C505032:CFTR protein, human; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor