#ATS2018 — Arrowhead’s Investigational CF Treatment ARO-ENaC Shows Potential in Preclinical Studies

Alice Melão, MSc avatar

by Alice Melão, MSc |

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Arrowhead Pharmaceuticals’ investigational cystic fibrosis treatment candidate ARO-ENaC can effectively target the epithelial sodium channel alpha subunit (αENaC) in the lungs of rats, preclinical studies show.

Given that ENaC is a well-known mediator of common cystic fibrosis symptoms, such as airway dehydration and mucus accumulation, these results suggest that ARO-ENaC may be a potential therapeutic option to treat this disease.

Arrowhead recently presented the new data at the American Thoracic Society (ATS) 2018 International Conference, taking place through May 23 in San Diego. The poster, “Targeting αENaC with an epithelial RNAi trigger delivery platform for the treatment of cystic fibrosis,” will be presented by Erik Bush, PhD, director of extra-hepatic targeting at Arrowhead.

ENaC is a sodium transport channel that is hyperactivated in the lungs of people who have mutations in the CFTR gene — the hallmark cause of cystic fibrosis. Its increased activity contributes to airway dehydration and mucus accumulation, as well as reducing the lungs’ ability to clear toxins and other potential harmful agents.

CF patients with inherited faulty ENaC genes have milder lung disease, which suggests this sodium transport channel could be an attractive CF target.

To date, different therapeutic strategies tested to target ENaC have had limited effectiveness. They either lacked stability, their effects were short-lived, or they caused severe adverse effects because they inhibited ENaC in the kidneys.

To overcome these limitations, Arrowhead developed ARO-ENaC, formerly known as ARO-Lung1. The product is based on the company’s Targeted RNAi Molecule (TRiM) platform that combines a specific RNA sequence that targets ENaC with a small protein sequence (ligand), enhancing its uptake by lung epithelial cells.

“The Targeted RNAi Molecule, or TRiM™, platform has several important advantages over the prior generation and competing technologies, including the ability to target tissues and diseases outside of the liver,” Christopher Anzalone, PhD, president and CEO at Arrowhead, said in a press release. “ENaC is a genetically and biologically validated target for cystic fibrosis with a profile that we believe is well-suited for an RNAi-based intervention.”

Data presented at the meeting showed that treatment with ARO-ENaC reduced the amount of αENaC in the lungs of rats by approximately 50%. Results also suggested that ARO-ENaC’s effects on αENaC inhibition is long-lasting, requiring only an every-other-week maintenance dose regimen.

The team also tested an inhaled ARO-ENaC formulation in rats, and found that a single administration continued to show great capacity to reduce the levels of αENaC in the lungs, even at doses tenfold lower than those tested previously.

Further analysis confirmed that the therapy was specific, decreasing αENaC in the lungs but not affecting kidney αENaC levels or CFTR lung levels.

Researchers are currently assessing the effects of αENaC inhibition on airway hydration, mucus clearance, and disease progression in animal models of CF.

“We view ARO-ENaC as an important proof of concept for future TRiM™ enabled candidates targeting additional pulmonary diseases,” Anzalone said.