Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR

Abstract

Background: The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes.

Methods: We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures.

Results: Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores.

Conclusions: Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function.

Trial registration: ClinicialTrials.gov, NCT01521338.

Funding: CFF Therapeutics (GOAL11K1).

Keywords: Chloride channels; Diagnostic imaging; Pulmonology.

Conflict of interest statement

Conflict of interest: All authors report receiving a grant from the Cystic Fibrosis Foundation during the conduct of the study. SHD reports personal fees from AlgiPharma, Sanofi, Ionis, Novartis, and Pulmatrix, grants and personal fees from Galapagos/AbbVie and Nivalis, and grants from Vertex Pharmaceuticals and Parion Sciences. In addition, SHD has a patent “Regulation of Sodium Channels by PLUNC Proteins” (patent no. US 9,549,967 B2). PJM reports grants fom Vertex Pharmaceuticals and Gilead Sciences outside of the submitted work. SMR reports grants from Nivalis, PTC Therapeutics, RaNa, Eloxx, and Celtaxsys; grants and personal fees from Novartis, Sydedgen and Bayer; grants, personal fees, and other nonfinancial support from Vertex Pharmaceuticals and Galapagos/Abbvie; and nonfinancial support from Proteostasis.

Figures

Figure 1. Study flow diagram.

Figure 2. Mean clearance versus time curves.

Mean clearance versus time curves (± SEM) in (A) whole lung, (B) central lung, and (C) peripheral lung regions of interest.

Figure 3. Waterfall plot of the absolute change.

Waterfall plot of the absolute change in whole lung AveClr60 from baseline at 1 (A) and 3 (B) months, color coded by study site. Distributions demonstrate robust effect of ivacaftor on MCC that is not driven by site differences.