A Phase 1b Randomized Blinded Placebo-Controlled, Cross-Over Study to Assess the Effect of AZD5634 on Mucociliary Clearance as Well as Safety, Tolerability, and Pharmacokinetic Parameters Following Single Inhaled Dose Administration to Patients With Cystic Fibrosis.
This study will assess the effect of inhaled AZD5634 on Mucociliary clearance (MCC) in patients with Cystic fibrosis (CF) after single-dose administration.
A Phase I, Randomized, Single-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Single-Ascending Inhaled Doses (Part A) and After Single Inhaled and Intravenous Doses (Part B) in Healthy Subjects
This is a Phase 1, first-in-human (FIH) single ascending dose study being conducted to better understand the safety, tolerability and pharmacokinetics of AZD5634 in healthy subjects
2022-09-13·American journal of physiology. Lung cellular and molecular physiology
Preclinical evaluation of the ENaC inhibitor AZD5634 and implications on human translation.
作者: Annika Åstrand ; Emily Falk Libby ; Ren-Jay Shei ; Jacelyn E Peabody Lever ; Niroop Kaza ; A Timothy Adewale ; Evan Boitet ; Lloyd Edwards ; Martin Hemmerling ; James Root ; Botilda Lindberg ; Cecilia Wingren ; Anna Malmgren ; Juan Sabater ; Steven M Rowe
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 lung function decline. In the current work, we evaluated the effects of AZD5634, a selective and potent ENaC inhibitor that shows extended lung retention and safety profile as compared to 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.
2022-02-26·Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society2区 · 医学
AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis.
2区 · 医学
作者: Cecilia Kristensson ; Annika Åstrand ; Scott Donaldson ; Ron Goldwater ; Raolat Abdulai ; Naimish Patel ; Philip Gardiner ; Ulrika Tehler ; Anne-Kristina Mercier ; Marita Olsson ; Eva Ersdal ; Jukka Mäenpää ; Tobias Bramer ; Anna Malmgren ; William Bennett ; Christina Keen
Epithelial sodium channel (ENaC) inhibitors may offer clinical benefit in cystic fibrosis (CF); however, data are limited. We report the outcomes of a Phase I (NCT02679729) and a Phase Ib (NCT02950805) study of AZD5634, a novel inhaled ENaC inhibitor.
A Phase I, first-in-human, single-blind, placebo-controlled, single ascending dose, sequential dose group study assessed the safety, tolerability, and pharmacokinetics of AZD5634 in healthy subjects (n=53) in part A following inhaled doses up to 1700 µg, and, in part B, following administration of single inhaled (1700 µg) and intravenous (65 µg) doses. A Phase Ib, randomized, double-blind, placebo-controlled, single-dose, 2-way cross-over study assessed the effects of a single dose (600 µg) of inhaled AZD5634 on mucociliary clearance (MCC), pharmacokinetics and safety and tolerability in patients with CF (n=11). Nasal potential difference (NPD) was assessed as an in situ target engagement exploratory biomarker.
Absolute bioavailability of AZD5634 after inhalation was approximately 3%, indicating minimal distribution into the systemic circulation. Urinary excretion was a minor elimination pathway. Administration of inhaled AZD5634 did not improve MCC in CF patients, but AZD5634 inhibited ENaC in the nasal epithelium, as measured by NPD. AZD5634 was safe and well tolerated in both studies.
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.
2021-05-08·European journal of pharmacology3区 · 医学
New generation ENaC inhibitors detach cystic fibrosis airway mucus bundles via Sodium/Hydrogen Exchanger inhibition.
3区 · 医学
作者: Melania Giorgetti ; Nikolai Klymiuk ; Andrea Bähr ; Martin Hemmerling ; Lisa Jinton ; Robert Tarran ; Anna Malmgren ; Annika Åstrand ; Gunnar C Hansson ; Anna Ermund
Cystic fibrosis (CF) is a recessive inherited disease caused by mutations affecting anion transport by the epithelial ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The disease is characterized by mucus accumulation in the airways and intestine, but the major cause of mortality in CF is airway mucus accumulation, leading to bacterial colonization, inflammation and respiratory failure. Several drug targets are under evaluation to alleviate airway mucus obstruction in CF and one of these targets is the epithelial sodium channel ENaC. To explore effects of ENaC inhibitors on mucus properties, we used two model systems to investigate mucus characteristics, mucus attachment in mouse ileum and mucus bundle transport in piglet airways. We quantified mucus attachment in explants from CFTR null (CF) mice and tracheobronchial explants from newborn CFTR null (CF) piglets to evaluate effects of ENaC or sodium/hydrogen exchanger (NHE) inhibitors on mucus attachment. ENaC inhibitors detached mucus in the CF mouse ileum, although the ileum lacks ENaC expression. This effect was mimicked by two NHE inhibitors. 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.