Safety and tolerability demonstrated with inhaled αenac antisense oligonucleotide (ION-827359) in patients with cystic fibrosis

Background: Epithelial sodium channels (ENaC) have been demonstrated to be hyperactive in patients with Cystic Fibrosis (CF) and to contribute to reduced airway surface liquid, mucus dehydration and airway mucus accumulation. An antisense oligonucleotide (ASO) which inhibits murine αENaC expression was demonstrated to be efficacious in two different mouse models of CF. ION-827359 is a chemically modified ASO, 16 nucleotides in length with a phosphorothioate backbone and constrained ethyl (cEt) modifications. In healthy volunteers the ASO was found to decrease ENaC mRNA expression in bronchial brushings by a mean of 56%.Methods: This ascending dose trial was conducted in three parts, the first two of which were in healthy volunteers. The third part of this trial was a randomized, double-blind, placebo-controlled multiple ascending dose (MAD) study in patients with CF. Patients were allowed to stay on their usual CF medications throughout the trial. The primary objective was the evaluation of safety and pharmacokinetics of ION-827359 delivered via a Pari eFlow © mesh nebulizer. A total of 33 subjects in 4 cohorts received doses of 10, 37.5, 75, or 100 mg once weekly for 4 doses, with an additional dose administered during the first week. Subjects were followed for 13 weeks after dosing. Results: ION-827359 was well-tolerated with an acceptable safety profile after multiple inhalations. The rate of adverse events was similar between ION-827359 and placebo treated groups. There were no clinically relevant changes in chemistry, hematology, urinalysis, ECG, or vital signs. There were no drug related serious adverse events or discontinuations due to adverse events although three subjects discontinued early due to concerns about COVID-19. Pharmacokinetics demonstrated low systemic exposure with a plasma half-life of approximately 2 weeks. Spirometry showed a numerical dose dependent increase in FEV1 at the end of the 4-week treatment period (4.5% difference for 100mg group from placebo). Conclusions: These results demonstrate strong evidence of tolerability and safety at the doses and regimens tested and supports further investigation of ENaC ASO ION-827359 in patients with cystic fibrosis.