Randomised, phase 1/2a trial of ION-827359, an antisense oligonucleotide inhibitor of ENaC

Hyperactivity of epithelial sodium channel (ENaC) with increased sodium absorption is a feature of cystic fibrosis (CF). ION-827359 is a 2.5-generation antisense oligonucleotide targeted to reduce ENaC protein. This study evaluated ION-827359 safety, pharmacokinetics and pharmacodynamics. In this three-part phase 1/2a, double-blind, randomised study, healthy volunteers received single doses of placebo or ION-827359 (3, 10, 37.5 or 100 mg; Part 1) or multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg or 10×37.5 mg; Part 2). People with CF (pwCF) received multiple doses of placebo or ION-827359 (5×10 mg, 5×37.5 mg, 5×75 mg and 5×100 mg; Part 3). Treatments were administered Pari eFlow mesh nebuliser. The primary outcome was safety; pharmacokinetic and pharmacodynamic parameters were also assessed. 64 healthy volunteers and 34 pwCF were enrolled. ION-827359 was well tolerated with an acceptable safety profile. There were no clinically relevant changes in laboratory values, ECG or vital signs. Systemic drug exposure was low (plasma half-life ∼2 weeks). Multiple doses of ION-827359 were associated with dose-dependent reductions in ENaC mRNA in bronchial epithelium. After multiple dosing, forced expiratory volume in 1 s was slightly higher in pwCF receiving ION-827359 (+2.9% with ION-827359 100 mg placebo; p=0.27). The tolerability and safety of ION-827359 appear favourable at this stage of investigation. Reduction in ENaC mRNA supports mechanistic efficacy at the doses and regimens tested, and supports further investigation of ION-827359 in pwCF.