Arrowhead Pauses ARO-ENaC Study Amid Safety Concerns

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by Forest Ray PhD |

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Arrowhead Pharmaceuticals has voluntarily paused new screening, enrollment, and dosing in its Phase 1/2 trial of ARO-ENaC, an investigational treatment for cystic fibrosis (CF).

The decision came after unexpected signs of local lung inflammation occurred in an ongoing chronic toxicology study taking place in rats.

“The safety of patients that participate in clinical trials of our investigational medicines is paramount to us at Arrowhead,” Javier San Martin, MD, the company’s chief medical officer, said in a press release.

The trial will remain on hold pending additional data from the rat study. Meanwhile, data also will be culled from an ongoing chronic primate toxicology study, Arrowhead said.

“Even though the preliminary information we received from the chronic toxicology study in rats may not necessarily bear directly upon the safety of continuing the current Phase 1 study, we believe that we need to better understand the findings and how they may translate to humans before we treat additional patients,” said Christopher Anzalone, PhD, Arrowhead’s president and CEO.

The AROENaC1001 trial (NCT04375514) was designed to evaluate the medication’s safety, tolerability, and pharmacological properties in up to 92 adults, including both healthy volunteers and CF patients. The first patients received their doses last year, with the trial being conducted in Australia and New Zealand.

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An RNA-based therapy, ARO-ENaC is designed to reduce the body’s production of a sodium channel called ENaC that is overactive in the lungs of people with CF. This overactivity contributes to dehydration and increased mucus in the lungs. This, in turn, raises the risk of persistent infections, lung damage, and the loss of lung function.

Of note, RNA or ribonucleic acid, which is present in all living cells, acts a messenger carrying instructions from DNA for controlling protein production.

Other potential medications have targeted ENaC, but short-lasting therapeutic effects and toxicity to the kidneys have limited their development.

Preclinical data, however, suggest that ARO-ENaC has a durable effect on the lungs, without impacting the kidneys. For example, it associated with mucus clearance from the lungs in a sheep model of lung obstruction.

“This is difficult news for cystic fibrosis patients who are in need of new therapeutic options,” Anzalone said of the trial delay, “but we place above all else our obligation to ensure the safety of those enrolled in our clinical trials.”

As long-term toxicology data is developed, Arrowhead scientists “will work as quickly as we can to understand their implications for ARO-ENaC and the patients we hope to serve,” Anzalone said.

“This may delay our pulmonary program a bit, but it’s just part of drug development,” he said. “We remain committed to the pulmonary platform and are moving ahead aggressively with our other pulmonary programs.”