Assistant

A few weeks after dropping work on allergic rhinitis drug bilastine, Inspire Pharmaceuticals Inc. turned its attention to denufosol, launching the second of two pivotal studies of the inhaled solution in cystic fibrosis patients.

Considered by analysts to be the star of Inspire's pipeline, denufosol, a selective P2Y2 receptor agonist, has shown great promise in earlier studies, particularly in cystic fibrosis patients with mild lung impairment. The drug is designed to activate an ion channel that enhances the lung's mucosal hydration and mucociliary clearance, said Don Kellerman, senior vice president of development at the Durham, N.C.-based company.

"It's really about epithelial rehydration," he told BioWorld Today. "CF patients have dry mucus in their airways, and [denufosol] rehydrates those airways and reduces the potential for infections and exacerbations."

Kellerman added that Inspire's Phase III program is the first to test a P2Y2 agonist in CF. The program emerged from the firm's founding technology, licensed from the University of North Carolina. That technology previously generated Prolacria (diquafosol tetrasodium), Inspire's approvable candidate for dry-eye syndrome, but the CF indication is what the firm has aimed at from the get-go.

"From the first day we opened," Kellerman said, work at Inspire focused on research stemming from UNC investigators at the Cystic Fibrosis Research Center, who discovered that the activation of P2Y2 increases airway surface hydration and improves mucociliary clearance. "So this is really our heritage technology," he added.

Phase II testing of denufosol demonstrated the drug's efficacy in improving mucociliary clearance, especially in patients with milder lung impairment, and that subset is believed to comprise anywhere from 50 percent to 70 percent of the overall CF population. According to Inspire, there are an estimated 30,000 CF patients in the U.S.

Based on those Phase II data, Inspire began enrolling patients with FEV1 (forced expiratory volume in one second) greater than or equal to 75 percent of predicted normal in the first Phase III trial, initiated in July 2006, with results anticipated in the middle of this year. The second study, designated TIGER-2 (Transport of Ions to Generate Epithelial Rehydration), will be similar in design to the first, involving about 350 CF patients who will be randomized to receive either 60 mg of denufosol tetrasodium inhalation solution or placebo three times daily.

The primary endpoint will be the change from baseline in FEV1 at 24 weeks, and secondary endpoints will include other lung function parameters, pulmonary exacerbations, requirements for concomitant CF medications and quality of life.

The only difference between the studies is that the first trial will conclude with a 24-week open-label extension aimed at providing additional safety data, Kellerman said.

Inspire anticipates completing the pivotal studies and finishing up carcinogenicity work in the second half of 2009, after which, pending positive data, the company will submit a new drug application to the FDA. Though it still awaits trials results, the firm is "very hopeful and optimistic," Kellerman said. "We've worked with the CF community for a long time, and we feel very connected" to CF patients.

Denufosol has orphan drug and fast-track status in the U.S. and orphan drug status in the European Union.

Depending on its success in the two ongoing Phase III studies, Inspire might move into additional studies with denufosol, testing the drug in CF patients with more severe lung function impairment, as well as possibly exploring other indications that could be treated by mucociliary clearance.

Elsewhere in its pipeline, Inspire continues to work on Prolacria, which got a second approvable letter in 2005 due to inconsistent efficacy findings. The firm has been working with the FDA and said it plans to update investors on that program in the third quarter.

It also has epinastine, a nasal spray in late-stage development for allergic rhinitis, though the firm abandoned work last month on a second allergic rhinitis drug, oral bilastine, which Inspire licensed from Madrid, Spain-based FAES Farma SA in 2006. Bilastine, a nonsedating selective H1-antihistamine, had completed Phase III testing in Europe, but Inspire reported later that the FDA requested additional work and said an expanded QT/QTc comparative trial likely would be needed for regulatory review. (See BioWorld Today, Jan. 15, 2008.)

The company's marketed products include ophthalmic products AzaSite (azithromycin) for bacterial conjunctivitis, Elestat (epinastine) for allergic conjunctivitis and Restasis (cyclosporine) for dry eye. Rights to AzaSite were licensed from InSite Vision Inc., and Inspire picked up rights to the Elestat and Restasis from Allergan Inc.

Shares of Inspire (NASDAQ:ISPH) closed at $3.97 Wednesday, up 3 cents.