Arrowhead Pharmaceuticals is pausing a phase 1/2 study for an RNAi therapeutic after rats in a preclinical study showed unexpected lung inflammation.
The Pasadena, California-based biopharmaceutical company is developing ARO-ENaC to treat patients with cystic fibrosis. The therapy aims to reduce production in the lungs' airways of a protein associated with airway dehydration and reducing the transport of mucus in patients with the disease.
A clinical trial, dubbed AROENaC1001, is now on hold after the preclinical data in rats flagged the inflammation concerns. Arrowhead said they were voluntarily and immediately halting new patient screening, enrollment and further dosing of the medicine while they await more data from the rat study and another primate toxicology study.
“This is difficult news for cystic fibrosis patients, who are in need of new therapeutic options, but we place above all else our obligation to ensure the safety of those enrolled in our clinical trials,” Arrowhead President and CEO Christopher Anzalone, Ph.D., said in the statement.
The trial included 92 healthy volunteers and patients with cystic fibrosis to assess safety and tolerability. The main goal was to assess the number of participants who experience adverse events that could be linked to treatment.
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Arrowhead Chief Medical Officer Javier San Martin, M.D., said in a statement that the company has not seen any concerning safety or tolerability signals in the subjects who have already been enrolled in the study.
“After we receive the full data from these studies, we will assess whether there is an acceptable path forward for further clinical investigation,” San Martin said.
What occurred in the rat study may not necessarily mean the same will happen in humans, but the company wants to better understand the findings and how they may translate to humans in the clinic, according to Anzalone.
The discontinuation is disappointing but not surprising, according to RBC Capital Markets analysts. A number of big names have tried to tackle the ENaC pathway, or epithelial sodium channels, with little success. Current research suggests that blocking the ENaC, which transports sodium in the body, could rehydrate airway surfaces and improve the work of mucus in the body.
Ionis Pharmaceuticals scrapped its candidate, called IONIS-ENAC-2.5, also because of safety concerns that arose in a preclinical study earlier this year. Gilead, Vertex, AstraZeneca, Novartis, Amgen, Boehringer Ingelheim and Parion all have ENaC-targeting therapies on the scrap heap.
RBC wants to know more details from Arrowhead before making a determination on whether AROENaC1001 has a future, but the firm has "always been cautious" on this target.
Shares of Arrowhead plummeted 28% to around $61 around noon Friday. this pullback surprised RBC, which considers the setback a normal part of drug development. The firm also sees a strong pipeline in liver and hepatic indications.
Meanwhile, Arrowhead will turn its attention to the eight other drugs in the clinic and other preclinical assets, San Martin said.
Anzalone seemed to have the same view as RBC. While the development may delay Arrowhead’s pulmonary program, “it’s just part of drug development,” the CEO said.
The company remains committed to two other candidates from the program that have been flagged for advancement into human testing.
Editor's note: This story was updated to include analyst commentary.