RARE Daily

Arrowhead Pauses RNAi Study in Cystic Fibrosis After Tox Study Signals

July 2, 2021

Arrowhead Pharmaceuticals notified regulatory agencies, institutional review boards, and investigators that effective immediately it is voluntarily pausing AROENaC1001, a phase 1/2 clinical study of ARO-ENaC, the company’s investigational RNAi therapeutic being developed as a treatment for patients with cystic fibrosis, after receiving a preliminary update from an ongoing chronic toxicology study in rats that contained unexpected signals of local lung inflammation.

Photo: Christopher Anzalone, president and CEO at Arrowhead

Shares of Arrowhead fell 25 percent after the announcement.

The company said it has instructed investigators to pause new screening, enrollment, and any further dosing of ARO-ENaC pending additional data from the ongoing chronic rat toxicology study and an additional ongoing chronic primate toxicology study.

“While we have not seen any concerning safety or tolerability signals in subjects enrolled in the AROENaC1001 study, out of an abundance of caution we have decided to pause new screening, enrollment, and any further dosing of investigational ARO-ENaC in the study while we await additional information from ongoing nonclinical toxicology studies,” said Javier San Martin, chief medical officer at Arrowhead.

Arrowhead will assess whether there is an acceptable path forward for further clinical investigation after it receives the full data from the tox studies.

Cystic fibrosis (CF) is a rare, progressive, and life-shortening genetic and multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas, and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in several organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death.

ARO-ENaC is designed to reduce production of the epithelial sodium channel alpha subunit (αENaC) in the airways of the lung. In CF patients, increased ENaC activity contributes to airway dehydration and reduced mucociliary transport.

AROENaC1001 is a phase 1/2 dose-escalating study to evaluate the safety, tolerability, and pharmacokinetic effects of investigational the gene silencing candidate ARO-ENaC in normal healthy volunteers and to evaluate the safety, tolerability, and efficacy in patients with cystic fibrosis.

“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, president and CEO at Arrowhead. “This may delay our pulmonary program a bit, but it’s just part of drug development. As the long-term toxicology data come in, we will work as quickly as we can to understand their implications for ARO-ENaC and the patients we hope to serve.”

Author: Rare Daily Staff

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