ETD001: A long-acting inhaled ENaC blocker, is well tolerated in humans

Abstract

Background: To assess the safety, tolerability and pharmacokinetic (PK) profile in humans of the novel, inhaled epithelial sodium channel (ENaC) blocker, ETD001.

Methods: Inhaled ETD001 or placebo have been administered via a nebuliser in a 3:1 ratio to 96 healthy subjects in a blinded, first in human clinical trial. Part A of the study evaluated single ascending doses (SAD) up to 10.8 milligrams (mg), and Part B evaluated multiple ascending doses (MAD) up to 4.65mg twice daily (BID) for 14 days. Safety was assessed by monitoring of adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG) and spirometry. Systemic exposure was assessed by serial PK blood draws.

Results: There were no serious AEs. Thirty-eight AEs, all of mild to moderate intensity and all resolved, were reported by 24 subjects. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B, all considered unrelated to study drug. PK parameters were approximately dose proportional in Part A, with peak concentrations at 1-2 hours post dose and exposure out to 12-24 hours at all doses, indicating good lung retention. Part B displayed dose independent kinetics and showed minimal accumulation, with 1.0-1.2 fold observed at steady state.

Conclusions: ETD001 was well tolerated at SAD up to 10.8mg and MAD up to 4.65mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.