Mechanism of action: Inhibitor of the amiloride-sensitive Epithelial Sodium Channel (ENaC)

Preclinical pharmacology

AZD5634 is a potent inhibitor of the epithelial sodium channel in human, sheep and rat in vitro with an IC50 of 3.8 nmol/L for the human ENaC.

Safety and tolerability

In preclinical studies including pivotal 14D 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 DRF studies in dogs with no safety alerts. Two of the dog studies included intravenous administration to increase systemic exposures (NOAEL for this study was 0.480 mg/kg/day with a supplementary daily I.V dose of 6.6 µg/kg/day). 3-month in rat and dog showed good tolerability with a NOAEL of 3.42 mg/kg in rats and 0.422 mg/kg (+10 µg/kg iv top up) in dogs. Preliminary data from the SAD study have demonstrated that AZD5634 at nebulized doses up to 1.69 mg 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 ug) 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.

Additional information

Clinical Trials

Clinical trials: NCT02950805 NCT02679729

Publications for this compound

No publications [Kristensson et al 2019 NACFC Poster 526]

Initial Indication

Cystic Fibrosis

Route of administration

In Part A of the SAD study, seven single inhaled doses of AZD5634 (10, 27, 81, 216, 648, 1296 and 1692 μg) or placebo were given. Eight subjects were randomized in each cohort (six active:2 placebo). In Part B of the SAD study six subjects (who did not participate in Part A) received both IV (65 μg AZD5634) and inhaled (1692 μg AZD5634) dosing (fixed dosing; IV first followed by inhalation), with at least a 14 day washout between the doses.

In the AZD5634 PoM study, nine patients with Cystic Fibrosis received a single inhaled dose of AZD5634 (612 ug) or placebo in a cross-over design with at a 14 days to 21 days washout period between doses.