Sweat chloride as a biomarker of CFTR activity: proof of concept and ivacaftor clinical trial data

Abstract

Background: We examined data from a Phase 2 trial {NCT00457821} of ivacaftor, a CFTR potentiator, in cystic fibrosis (CF) patients with aG551D mutation to evaluate standardized approaches to sweat chloride measurement and to explore the use of sweat chloride and nasal potential difference (NPD) to estimate CFTR activity.

Methods: Sweat chloride and NPD were secondary endpoints in this placebo-controlled, multicenter trial. Standardization of sweat collection, processing,and analysis was employed for the first time. Sweat chloride and chloride ion transport (NPD) were integrated into a model of CFTR activity.

Results: Within-patient sweat chloride determinations showed sufficient precision to detect differences between dose-groups and assess ivacaftor treatment effects. Analysis of changes in sweat chloride and NPD demonstrated that patients treated with ivacaftor achieved CFTR activity equivalent to approximately 35%–40% of normal.

Conclusions: Sweat chloride is useful in multicenter trials as a biomarker of CFTR activity and to test the effect of CFTR potentiators.

Conflict of interest statement

Conflict of interest statement: MWK is supported by P30 DK27651 from NIDDK/NIH to Case Western Reserve University School of Medicine. JPC is supported by grants AMIN09YO and R457-CR11 from the CFF. SMR is supported by grants UUL1025777 and P30 DK072482 from the NIH and CLANCY05Y2 from the CFF. BWR is supported by grants RAMSEY03Y0 from the CFF, 2UL1TR000423-06 from NCATS and P30– DK089507 from NIDDK. FVG, AS, and QD are current employees of Vertex Pharmaceuticals Incorpororated who may own stock or options in that company. JZ and CO are former employees of Vertex Pharmaceuticals Incorporated who may own or may have owned stock or options in that company at the time this work was performed.

Figures

Figure 1

Within- and between-patient variance in sweat chloride over repeated measures by dose of ivacaftor and placebo. Data are shown for Parts 1 and 2 of the clinical trial. Within-patient variances were similar across treatment groups, indicating a consistent treatment effect in given individuals. Between-patient variances were high in the treatment groups, indicating variable effects of ivacaftor in different individuals.

Figure 2

Sweat chloride levels vs. CFTR activity in patients with varying CF genotypes and patients treated with ivacaftor at varying dose levels.* % CFTR activity with ivacaftor was estimated using NPD measurements taken at the same time as the sweat chloride. Data are shown for 22 cohorts reported in 10 published studies (15-24), described and tabulated in Table 3. *Baseline median (vs mean) sweat chloride is plotted for ivacaftor Phase 2 study population. CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; PI = pancreatic insufficient; PS = pancreatic sufficient.