ATS 2009: Novel Aerosol Epithelial Sodium-Channel Blocker Shows Promise for Cystic Fibrosis

Kristina Rebelo

May 19, 2009

May 19, 2009 (San Diego, California) — A novel aerosol therapy in development for cystic fibrosis (CF) patients that increases airway surface liquid while reducing the buildup of mucous has shown efficacy in a large animal model and is currently in phase 1 clinical trials (Gilead Sciences, Inc), according to research presented here at ATS 2009: American Thoracic Society International Conference.

The drug, known as GS-9411, a licensed molecule belonging to Parion Sciences, is an epithelial sodium-channel (ENaC) blocker that uses a specific ENaC to prevent sodium from being absorbed across the airway, thus allowing the surface to remain hydrated and the user able to more effectively clear the airway of mucous and infectious agents. Currently, there are no therapies available that specifically target this channel in patients with CF.

Dr. Andrew Hirsh

"This was a preclinical study involving in vitro cell culture and whole-animal study going toward a clinical trial for this compound," lead investigator Andrew Hirsh, PhD, senior director of drug discovery and preclinical development at Parion Sciences, Inc, in Durham, North Carolina, told Medscape Pulmonary Medicine. "This research is looking at hydration of the airway, which is the primary lesion of CF, and is connected to the ion-transport defects, which are well recognized in CF. We believe this new agent acts on a specific pathway that is involved in the development of CF and has the potential to improve lung function in patients with CF."

The study compared GS-9411 with amiloride, an established ENaC. Researchers applied GS-9411 to airway surface cells grown in their laboratory and then evaluated the durability in blocking ENaC. The test was repeated in a sheep model that measured the effect on mucociliary clearance, where it was found that the agent enhanced mucous clearance for 4 hours after drug administration.

"We found that when compared to amiloride, GS-9411 rapidly increased clearance from 4 to 5 hours, significantly better than control (water) and the amiloride," said Dr. Hirsh.

Next, drug potency and reversibility were assessed using airway epithelial cells grown at an air/liquid interface.

Dr. Hirsh said his research group had initially set up a screening algorithm to help decide which drug would do the best to improve hydration at the level of the airway and also enhance the mucociliary clearance.

"This in vitro screening algorithm indicated which drug would expand the airway surface liquid and, in this case, increase mucociliary clearance," he explained. "Our delivery via aerosol had limitations. You need a very potent drug; we found that GS-9411 is 100 times more potent than amiloride, so you don't need as much for the same response. Plus, we needed a drug that would stick to the target — the epithelial sodium channel in the airway. We then found that GS-9411 was 7 times less reversible than amiloride and that it has a slower rate of absorption by human airway epithelial cells than amiloride."

The study conclusions were that GS-9411 is a potent and durable ENaC blocker that has the ability to rapidly increase airway surface liquid and maintain surface liquid expansion for 8 hours in vitro when administered to airway epithelial cells. Aerosol administration of GS-9411 was shown to increase and maintain elevated mucociliary clearance in an in vivo sheep model for 4 to 5 hours. Results suggest that GS-9411 could provide a therapeutic benefit for patients with CF.

Next on deck for the study group is to try to outperform the current drug in terms of durability. "We're looking at 12 hours for twice-a-day dosing," Dr. Hirsh said. "We're focused on a library of compounds we've been building on. The good thing is that GS-9441 can be combined with other drugs, such as antibiotics, hypertonic saline, and dornase alpha."

Dr. Hirsh said that in most research situations, the researcher does not see the clinical side of the disease. "I'm passionate about this research because I've seen the clinical side," he said. "If you've ever been present at an autopsy of a 16-year-old boy lying dead on a table from cystic fibrosis, you become passionate."

Paul M. Quinton, PhD, professor of biomedical sciences at the University of California at Riverside and the Nancy MacCracken Chair in Pediatric Pulmonary Medicine, Department of Pediatrics, University of California, San Diego School of Medicine, who comoderated the session, told Medscape Pulmonary Medicine after the presentation that he wished there had been more time to explore Dr. Hirsh's research. "Dr. Hirsh's research answers a lot of questions, but there are other mechanisms in the lung besides the sodium channel that affect CF."

Dr. Hirsh reports that he is employed by Parion Sciences, Inc, and that he owns options. Dr. Quinton has disclosed no relevant financial relationships.

ATS 2009: American Thoracic Society International Conference: Poster 813. Presented May 17, 2009.

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