The epithelial sodium channel (ENaC) inhibitor AZD5634 may clinically benefit patients with cystic fibrosis (CF), according to a new study published in the Journal of Cystic Fibrosis. The authors reported the outcomes of phase 1 and 1b studies which showed favorable pharmacokinetics and safety, but mucociliary clearance was not improved yet.

AZD5634 was previously demonstrated in preclinical studies to increase airway surface liquid in human lung epithelial cells, improve lung mucociliary clearance rate in sheep, and low risk of hyperkalemia in humans. 

Firstly, the authors conducted a phase 1 human, single-blind, placebo-controlled single ascending dose for assessing the safety, tolerance, and pharmacokinetics of the novel ENaC inhibitor in 53 healthy individuals. It consisted of 2 parts of increasing doses of up to 1700 µg, an inhaled dose of 1700 µg, and intravenous doses of 65 µg.

Subsequently, the phase 1b study was a randomized, double-blind, single-dose, and 2-way crossover assessing the effects of a single 600 µg dose of AZD5634 on mucociliary clearance, pharmacokinetics, and the safety and tolerability in 11 patients with CF. The nasal potential difference was also assessed as an engagement biomarker.

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The authors found minimal systemic distribution as the absolute bioavailability of AZD5634 after inhalation was around 3%, and urinary excretion was only a minor elimination pathway. Although inhaled AZD5634 inhibited ENaC in the nasal epithelium, it showed no improvement in mucociliary clearance in patients with CF.

“There were no AEs [adverse events] leading to discontinuation of study drug, no serious AEs and no deaths. No other clinically relevant changes or abnormalities were reported in vital signs assessments, [electrocardiogram] measurements, physical examinations, clinical laboratory results or spirometry testing,” the authors said. AZD5634 was safe and well-tolerated throughout the studies.

They also explained that just 1 dose of AZD5634 failed to increase mucociliary clearance and that given the safeness and tolerability of the drug, repeated dosing may yield the effectiveness; nevertheless, equivalent study designs for other drugs like amiloride has produced improvement in mucociliary clearance after a single dose, which warrants further studies.

“AZD5634 showed favorable pharmacokinetics and safety in healthy subjects and patients with CF. However, despite achieving target engagement, proof of mechanism was not achieved after a single dose in patients with CF. Further evaluation into multiple dose studies is warranted to explore its therapeutic potential,” the authors concluded. 


Kristensson C, Åstrand A, Donaldson S, et al. AZD5634, an inhaled ENAC inhibitor, in healthy subjects and patients with cystic fibrosisJ Cyst Fibros. Published online February 26, 2022. doi:10.1016/j.jcf.2022.02.010