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A2317 - The ENaC Inhibitor AZD5634 Provides Efficacious and Resilient Mucociliary Clearance of Sheep Airways
Author Block: A. Astrand1, M. Hemmerling1, W. Lindberg1, J. R. Sabater2, W. M. Abraham2, A. Malmgren1; 1Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden, 2Department of Research, Mount Sinai Medical Center, Miami Beach, FL, United States.
Rationale: The epithelial sodium channel (ENaC) is one of the main regulators of airway hydration and is under the control of the cystic fibrosis transmembrane conductance regulator (CFTR). Cystic fibrosis and COPD are characterized by mucus obstruction and increased respiratory infections due to dysregulation of both of these channels. The aim of the study was to investigate the nebulized ENaC inhibitor AZD5634 with respect to effect on mucociliary clearance (MCC) and its duration of effect in the airways of conscious sheep. Methods: Studies were approved by the Mount Sinai Medical Center Animal Research Committee. Animals were conscious and intubated throughout the study. MCC was measured with an aerosolized technetium-labeled sulfur colloid (99mTC-SC). Animals (2-3/group) were administered a total of 3 mL of AZD5634 at various concentations, or vehicle, by a nebulizer-dosimeter system. Depending on whether the aim was to evaluate the immediate efficacy of the drug or the duration of effect, the 99mTC-SC aerosol was given either immediately after compound administration or at later time points (from 4 to 24 hours). A gamma camera integrated with a computer was used to record and analyze the clearance of 99mTC-SC every 5 minutes for 1 hour. Results are expressed as a per cent increase of MCC from baseline counts. Results: AZD5634 demonstrated a clear dose-response relationship from 1 to 330 μg/kg and a duration of effect over at least 24 hours by a submaximal dose of 12 μg/kg. A maximal improvement of MCC was obtained at approximately 40%, in line with previously published results for ENaC inhibition in this model. Repeated dosing twice daily of 3 μg/kg for 4 days demonstrated similar efficacy after the last dose as a single dose of 12 μg/kg (an approximate 20% improvement of MCC 8-9h after dosing), indicating the potential to reduce the daily drug load by 50% while still retaining the same efficacy. A loading dose, 40-fold the maintenance dose, followed by twice daily dosing at 3 μg/kg, did not result in better efficacy at steady state. Conclusions: AZD5634 produced a potent and prolonged improvement of MCC in sheep. From these data we predicted the human therapeutic dose and recommended dosing regimen for clinical benefit in human disease. A clinical study with AZD5634 in patients with cystic fibrosis is currently ongoing in order to evaluate the potential of AZD5634 to improve MCC in disease.