Arrowhead Asks to Open Phase 1/2 Trial into Inhaled RNAi Therapy

Arrowhead Pharmaceuticals has filed for approval to launch a Phase 1/2a clinical trial in New Zealand testing its candidate inhaled therapy for cystic fibrosis (CF), called ARO-ENaC, the company announced.

ARO-ENaC is an investigational RNA therapy designed to lower the production of the epithelial sodium channel alpha subunit (αENaC) in the lungs of CF patients. ENaC transports sodium and is hyper-activated in their lungs, leading to both airway dehydration and  mucus buildup, a hallmark of CF.

ARO-ENaC is a small RNA interference (RNAi) molecule intending to block the production of ENaC channels. It works by targeting for destruction the αENaC mRNA molecules, which are genetic messengers that carry the information necessary for making αENaC proteins.

Arrowhead’s ARO-ENaC was designed with the company’s proprietary Targeted RNAi Molecule, or TRiM platform, which enables tissue-specific delivery of RNAi therapies. It is the company’s first inhaled RNAi investigational therapy for the lungs.

“ARO-ENaC is Arrowhead’s second investigational RNAi therapeutic utilizing the TRiM platform to target tissues outside of the liver and the first to target a disease of the lungs,” Chris Anzalone, PhD, president and CEO of Arrowhead, said in a press release.

“This CTA [clinical trial authorization] filing is the culmination of years of work by Arrowhead scientists to optimize our TRiM based lung targeting program. We have always believed that for RNAi to reach its full potential, it needs to reach disease targets throughout the body,” Anzalone added. “Arrowhead is leading the RNAi field towards that goal … addressing many diseases that currently do not have adequate treatment options.”

The Phase 1/2 AROENaC1001 trial, if cleared by the New Zealand Medicines and Medical Devices Safety Authority, will test the safety, tolerability, and pharmacokinetics (processing by the body) of escalating doses of ARO-ENaC in healthy volunteers.

Its safety and efficacy will also be evaluated in CF patients, with exploratory goals looking specifically for changes in lung clearance and in forced expiratory volume (FEV1; a measure of how much air can be exhaled in one second after a deep breath).

“We are excited to begin … the AROENaC1001 clinical study, which is designed to … potentially provide an accelerated assessment of efficacy in patients with CF,” said Javier San Martin, chief medical officer at Arrowhead. “The epithelial sodium channel, ENaC, has been a target of great interest due to its potential to help many CF patients.”

Preclinical data using a sheep model of mucus obstruction showed that inhaled ARO-ENaC helped preserve lung clearance. Moreover, ARO-ENaC doubled mucociliary clearance in healthy sheep, paralleling the magnitude of effect of Kalydeco (ivacaftor, an approved CF therapy) in people.

Additional data also showed that the TRiM platform increased the potency of RNAi-triggered silencing of mRNA, leading to stable reductions in the production of ENaC in the lungs of rodent models.

Most importantly, the data showed that ARO-ENaC targeted ENaC specifically in the lungs, while avoiding negatively affecting the kidneys. Previous work on inhaled small molecule inhibitors of ENaC have been hampered by toxicity to the kidneys and short duration of action.

“[O]ur preclinical studies have indicated that ARO-ENaC has an extended duration of action that enables once every 3-4 weeks or even less frequent administration, which may minimize treatment burden for patients with CF,” San Martin added.

ARO-ENaC might also be used in combination with existing or future CF therapies that target the different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the cause of CF. It may prove to be a so-called ‘genotype agnostic’ therapy, meaning it works for everyone with CF regardless of their CFTR mutations.

“ARO-ENaC has the potential to be a genotype-agnostic therapy, which may prove useful in combination with existing or new CFTR-targeted therapies,” San Martin suggested.