ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo

•ETD001 is a novel inhaled ENaC blocker for the treatment of cystic fibrosis (CF).•A single low dose of ETD001 that enhances mucus clearance in sheep airways for ≥16 h has been well tolerated in healthy volunteer studies.•The ENaC blockers VX-371, BI 1265162, AZD5634 and QBW276 enhanced mucus clearance in sheep but only at doses significantly larger than those tested in their respective (negative) clinical trials.•ETD001 provides an opportunity to validate the concept of inhibiting ENaC as an effective therapeutic approach for CF. Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed? Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose. Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies. 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.