*3.12. ENaC Inhibitors*

An imbalance in ion transport across the airway epithelium has been implicated in asthma pathogenesis. Dysfunctions in the cystic fibrosis transmembrane conductance regulator and epithelial sodium channel (ENaC) cause changes in the airway surface liquid permeation, leading to modifications of mucus rheological properties and impairment. Blocking ENaC may reduce airway water reabsorption and increase mucus moist, therefore it is considered a potential target for the treatment of asthma [88].

A Phase I RCT [26] investigated the ENaC inhibitor BI 443651 100 μg, 400 μg, and 1200 μg administered via soft mist inhaler (SMI) to patients with mild asthma following a bolus methacholine (MCh) challenge. In the single-blind, double-dummy Part 1 of the RCT, no difference was detected between BI 443651 and PCB in terms of absolute change from baseline in maximum FEV1 reduction. In the double-blind, double-dummy Part 2 of the RCT, only BI 443651 administered at 1200 μg significantly (*p* < 0.05) improved the maximum FEV1 reduction vs. PCB (MD −157 mL (90%CI −266–−47)). No data are available for symptoms control [26].
