Arrowhead 'changing horses' for ENaC pulmonary program as phase 1/2 asset shelved

Arrowhead Pharmaceuticals is ditching a pulmonary drug after it failed to hit the mark in a phase 1/2 trial last year. But the biotech is filling up its quiver with at least two more prospects in the program as a replacemen

Executives reported the pipeline changes in the company’s fourth-quarter earnings (PDF) Wednesday afternoon. President and CEO Chris Anzalone, Ph.D, said Arrowhead is making progress on the ENaC target, or epithelial sodium channels, which is a potential pathway in cystic fibrosis to rehydrate airway surfaces and improve the work of mucus in the body.

But that progress has not been seen with ARO-ENaC. The company paused a phase 1/2 cystic fibrosis study last year after rats in a preclinical study showed unexpected lung inflammation. Anzalone said Arrowhead “will likely not continue” with the candidate.

Instead, Arrowhead has two or three next-gen compounds in the works to fill the gap. These candidates “appear to have favorable pharmacologic properties compared to ARO-ENaC,” according to the CEO.

RELATED: Arrowhead slams brakes on early-stage cystic fibrosis study after rat study triggers lung inflammation concerns

“So, we are likely changing horses in the ENaC program, but we have not yet settled on which new horse,” Anzalone said.

The decision to abandon ARO-ENaC was not a surprise to RBC Capital Markets analysts, who pointed out the discontinuation in a note to clients.

Arrowhead’s James Hamilton, M.D., senior VP, discovery and translational medicine, said the preclinical inflammation seen in rats has since been confirmed in nonhuman primates as well.

Hamilton said the problems could have stemmed from an overdose in the preclinical animal studies, which could have been tweaked to find a cleaner toxicity profile for future trials.

“That could provide a faster path back to the clinic, but we decided that the better long-term path is to focus on next-generation ENaC candidates,” he said.

RELATED: Arrowhead can see the Horizon with $700M biobucks pact for an early RNA gout med

Arrowhead plans to file two new clinical trial applications with the FDA for ARO-RAGE and ARO-MUC5AC in various muco-obstructive and inflammatory pulmonary conditions over the next quarter, according to the CEO. Preclinical data is expected at the American Thoracic Society meeting in May.

Hamilton said that these drugs have been tested at a lower exposure level than the first-generation ENaC program and appear to be more potent. The expectation is that less of the drug can be used with less frequent dosing.

A third application is also expected by the end of the year in an unnamed target and disease area.