Preclinical evaluation of the epithelial sodium channel inhibitor AZD5634 and implications on human translation

Author:

Åstrand Annika1ORCID,Libby Emily Falk2,Shei Ren-Jay23ORCID,Lever Jacelyn E. Peabody23,Kaza Niroop3,Adewale Adegboyega Timothy2ORCID,Boitet Evan2,Edwards Lloyd4ORCID,Hemmerling Martin1,Root James1,Lindberg Botilda1,Wingren Cecilia1,Malmgren Anna1,Sabater Juan5,Rowe Steven M.2367ORCID

Affiliation:

1. Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

2. Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama

3. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

4. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama

5. Mount Sinai Medical Center, Miami, Florida

6. Department of Cellular, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama

7. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama

Abstract

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis (CF), resulting in recurrent respiratory infections and exacerbations. Strategies to rehydrate airway mucus including inhibition of the epithelial sodium channel (ENaC) have the potential to improve mucosal defense by enhancing mucociliary clearance (MCC) and reducing the risk of progressive decline in lung function. In the current work, we evaluated the effects of AZD5634, an ENaC inhibitor that shows extended lung retention and safety profile as compared with previously evaluated candidate drugs, in healthy and CF preclinical model systems. We found that AZD5634 elicited a potent inhibition of amiloride-sensitive current in non-CF airway cells and airway cells derived from F508del-homozygous individuals with CF that effectively increased airway surface liquid volume and improved mucociliary transport (MCT) rate. AZD5634 also demonstrated efficacious inhibition of ENaC in sheep bronchial epithelial cells, translating to dose-dependent improvement of mucus clearance in healthy sheep in vivo. Conversely, nebulization of AZD5634 did not notably improve airway hydration or MCT in CF rats that exhibit an MCC defect, consistent with findings from a first single-dose evaluation of AZD5634 on MCC in people with CF. Overall, these findings suggest that CF animal models demonstrating impaired mucus clearance translatable to the human situation may help to successfully predict and promote the successful translation of ENaC-directed therapies to the clinic.

Funder

AstraZeneca

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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