Preclinical data shows that Arrowhead Pharmaceuticals‘ investigational inhaled treatment for cystic fibrosis (CF), called ARO-ENaC, accelerates mucus clearance and preserves lung function while being safe for the kidneys in animal models.
The data was shared recently at the 2019 North American Cystic Fibrosis Conference (NACFC) in Nashville, Tennessee.
Results were presented in the poster “Therapeutic Inhibition of ENaC With a Lung-Targeted RNAi Molecule Delivery Platform Preserves Normal Mucus Clearance in a Mucostatic Sheep Model of Cystic Fibrosis.”
ARO-ENaC is an investigational RNA therapy designed to reduce the production of the epithelial sodium channel alpha subunit (αENaC) in the airways of the lung. ENaC is a sodium transport channel that is hyperactivated in the lungs of people with CF. This increased activity contributes to dehydration and mucus buildup in the lungs, a hallmark of CF.
ARO-ENaC is a small molecule that works by preventing the production of ENaC channels, and by triggering a pathway called RNA interference (RNAi). It targets for destruction, or silences, αENaC mRNA molecules, which are genetic messengers that carry the information necessary for making αENaC proteins.
Arrowhead uses a proprietary Targeted RNAi Molecule, or TRiM platform, that is designed to enable tissue-specific delivery of RNAi therapies.
“We view the epithelial sodium channel, ENaC, as an exciting target in the treatment of CF, and one that is well suited to an RNAi-based intervention. Based on its mechanism of action, ARO-ENaC has the potential to provide clinical benefit to all patients with CF, regardless of genotype, and may prove useful in combination with existing or new CFTR-targeted therapies,” Bruce Given, MD, chief operating officer and head of Research and Development at Arrowhead, said in a press release.
Several studies have supported ENaC as a potential target for CF, but the development of inhaled small molecule inhibitors has been limited by toxicity to the kidneys and short duration of action.
The preclinical data shared by Arrowhead at NACFC 2019 shows that inhaled ARO-ENaC doubled mucociliary clearance (MCC) in healthy sheep, paralleling the magnitude of effect of Kalydeco (ivacaftor, an approved CF therapy) in humans. Moreover, the agent proved effective for preserving lung clearance in a sheep model of mucus obstruction.
Data also showed that the TRiM platform increases the potency of RNAi-triggered silencing of mRNA, and durably reduces the production of ENaC in the lungs of rodent models.
Importantly, data on animal models indicated that ARO-ENaC can target ENaC in the lung while avoiding negative effects on the kidney.
Overall, the data showed “that ARO-ENaC can accelerate mucociliary clearance in normal sheep and also preserve airway physiology in a sheep disease model of impaired mucociliary clearance. In addition, animal models indicate that ARO-ENaC can reduce ENaC activity in the lung but avoid impact in the kidney, which has historically been a key safety liability for prior investigational small molecule ENaC inhibitors,” Given said.
Based on the results, the team concluded that “ARO-ENaC offers a new renal-sparing, genotype-agnostic mucokinetic therapy for all CF patients, with an extended duration of action that should minimize treatment burden,” researchers wrote in the poster.
Arrowhead reported that studies to support an investigational new drug (IND) application are underway, and expected to earn regulatory approval for the first human studies with ARO-ENaC in 2020.