Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor

Abstract

Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals.

CFTR‐dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy

“…Notably, the same positive and significant correlation between reduction in sweat chloride and change from the baseline in FEV 1 % predicted has been very recently shown by analyzing multiple cohorts of patients with different CFcausing mutations who were treated with ivacaftor. 44 Not only these results confirm the robustness of our statistical analysis, although performed on a limited cohort of five patients, but also indicate sweat chloride as a putative predictive pharmacodynamic biomarker of lung function changes. On the other hand, HVCN1 mRNA levels appeared to be an independent variable because of its loose interactions with the other parameters, being only and not significantly correlated with neutrophils' unstimulated oxidative burst.…”

“…Above all, the sweat chloride significantly anticorrelated with both FEV 1 and FVC, while chloride MNC positively correlated with the same parameters. Notably, the same positive and significant correlation between reduction in sweat chloride and change from the baseline in FEV 1 % predicted has been very recently shown by analyzing multiple cohorts of patients with different CF‐causing mutations who were treated with ivacaftor …”

Rapid therapeutic advances in CFTR modulator science

“…As lumacaftor/ivacaftor has been studied in younger CF subjects (Ages 6‐11 years), more robust reductions in SC and improvements in lung function (measured by the nitrogen multiple breath washout test and the lung clearance index or LCI) have been observed compared with studies in older populations . It is clear that individual changes in SC are not directly associated with improvements in clinical outcome measures during CFTR modulator therapy, but group changes in SC do directly correlate with changes in FEV 1 percent predicted . Thus, it is exciting to speculate that CFTR modulators may have higher efficacy in younger CF subjects with early disease, therefore, serving a disease preventive role in CF management.…”

Toward inclusive therapy with CFTR modulators: Progress and challenges

“…Although biomarkers or CFTR activity are now well established for predicting efficacy on a group‐wise basis, they have limited utility in predicting efficacy of CFTR modulators on an individual basis . The sweat gland, in particular, is the source of several attractive biomarkers for precision medicine.…”

“…67 predicting efficacy on a group-wise basis, they have limited utility in predicting efficacy of CFTR modulators on an individual basis. [71][72][73][74][75][76] The sweat gland, in particular, is the source of several attractive biomarkers for precision medicine. The sweat gland has a distinct CF defect: impaired absorption of salt in the sweat duct, and impaired β adrenergic secretion in the sweat coil.…”