AZD5634 / AstraZeneca - LARVOL DELTA

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo. (PubMed, J Cyst Fibros) - "These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024."

Journal • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Preclinical evaluation of the ENaC inhibitor AZD5634 and implications on human translation. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "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. 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."

Journal • Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis. (PubMed, J Cyst Fibros) - P1, P1b | "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."

Clinical • Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

New generation ENaC inhibitors detach cystic fibrosis airway mucus bundles via Sodium/Hydrogen Exchanger inhibition. (PubMed, Eur J Pharmacol) - "Airway mucus bundles were immobile in untreated newborn CF piglets but were detached by the therapeutic drug candidate AZD5634 (patent WO 2015140527). These results suggest that the ENaC inhibitor AZD5634 causes detachment of CF mucus in the ileum and airway via NHE inhibition and that drug design should focus on NHE instead of ENaC inhibition."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR