AZD5634
Preclinical pharmacology
AZD5634 is a potent inhibitor of the epithelial sodium channel in human, sheep and rat in vitro with an IC50 of 3.8nmol/L for the human ENaC.
Safety and tolerability
In preclinical studies, including pivotal 14-day GLP repeat dose (aqueous) inhaled-toxicity studies in rats and dogs, AZD5634 was well tolerated. In addition, 4-day and 35-day non-GLP dose-finding studies in rat have been performed and three dose-range finding studies in dogs with no safety alerts. Two of the dog studies included IV administration to increase systemic exposures (NOAEL for this study was 0.480 mg/kg/day with a supplementary daily IV dose of 6.6µg/kg/day). 3-month in rat and dog showed good tolerability with a NOAEL of 3.42mg/kg in rats and 0.422mg/kg (+10µg/kg iv top up) in dogs. Preliminary data from the SAD study have demonstrated that AZD5634 at nebulized doses up to 1.69mg have been well tolerated with no relevant treatment-related adverse events (AEs), laboratory tests, ECG findings, or spirometry changes.
Clinical pharmacology
The Ph1b study was a randomized, blinded, placebo-controlled, cross-over study to assess the effect of AZD5634 on mucociliary clearance (MCC) as well as safety, tolerability, and pharmacokinetic parameters following a single inhaled dose (612 µg) administration to patients with CF. PK profile demonstrated lung absorption in CF patients after single AZD5634 nebulization. Nasal membrane transepithelial potential difference (NPD) measurement in CF patients demonstrate target engagement (TE) in situ. PoM was thus not achieved based on MCC but TE was shown in the nose.
Suitable for and exclusions
Approaches that modulate hydration of tissues such as lung, skin, or eye may be interesting areas for investigation given the AZD5634 MoA. Subjects with a history of hypersensitivity to ENaC inhibitors should not be included in studies with AZD5634. Inclusion of WOCBP will be considered for each proposal.
Mechanism of Action
Inhibitor of the amiloride-sensitive Epithelial Sodium Channel (ENaC)
Original Therapeutic Area
Respiratory and Immunology
CNS Penetrant
Unknown
Route of administration
Inhaled
Modality
Small Molecule
Additional Information
1. Giorgetti M., et al. (2021).
New generation ENaC inhibitors detach cystic fibrosis airway mucus bundles via sodium/hydrogen exchanger inhibition. Eur J Pharmacol. May 8;904:174123. doi: 10.1016/j.ejphar.2021.174123. Epub ahead of print. PMID: 33974881.