By Debbie Strickland

In the early 1990s, a group of University of North Carolina researchers discovered that adenosine triphosphate (ATP) — a workhorse of a compound whose functions were long thought to be exclusively intracellular — appears to play a role in cell-to-cell signaling.

For example, in the lungs, the invasion of bacteria appears to provoke the release of a small amount of ATP, in a reaction akin to the release of epinephrine when a person is frightened.

The subsequent identification of a P2Y₂ class cell-surface receptor with which ATP interracted bolstered the scientists' case.

Of immediate therapeutic interest was ATP's potential role in fostering hydration of airway secretions. Drugs that boost hydration could potentially treat many pulmonary diseases: cystic fibrosis, chronic bronchitis, primary ciliary dyskinesia and ventilator-associated pneumonia.

The adenosine in ATP is an extreme irritant, but the Chapel Hill group soon found that a similar compound, uridine triphosphate, works just as well without the side effect.

"Since the [P2Y₂] receptor really didn't care, we picked UTP," said Richard Boucher, director of the Pulmonary Division and of the Cystic Fibrosis Research and Pulmonary Treatment Center, both at UNC. "The idea is to supply these compounds, particularly UTP, by an aerosol route to keep secretions normal — thin and watery and hydrated."

The research caught the eye of entrepreneur and former Glaxo Inc. executive Jeffrey Leighton, and a company was born in March 1995: Inspire Pharmaceuticals Inc., of Durham, N.C., which started with the UNC scientists' concept and compounds, but quickly moved forward to develop second- and third-generation versions, in addition to creating the Mucosa assay system, which measures P2Y₂ response.

"It looks like this class of receptors that recognize naturally occuring high-energy phosphate compounds are part of the body's innate defenses against the outside world," said Boucher, an Inspire founder and chairman of the company's scientific advisory board. "The research has evolved rapidly. This receptor may be interesting in other parts of the body."

Lead Product In Phase II

In two and a half years, the 20-employee company has guided its lead UTP-based drug candidate, INS316, to the Phase II level, and has just raised $13 million to fund its respiratory-centered drug development program.

Inspire's private placement of preferred stock "substantially exceeded" expectations and attracted the company's original investors, Burr Egan Deleage, of Boston; Domain Associates, of Princeton, N.J.; Intersouth Partners, of Durham, N.C.; and Medical Science Partners, of Boston. They were joined by Benefit Capital Management Corp., of Danbury, Conn., a registered investment advisor wholly owned by Union Carbide; Japan Associated Finance Company, of Tokyo, the largest venture capital fund in Japan; and Children's Health Investment Corp., of Kansas City, Kan., an investment alliance comprising more than 30 children's hospitals nationwide.

To date, Inspire has raised $22.2 million and has at least a year's worth of cash on hand.

Delivered via inhaler, INS316 has completed a Phase II trial in an indication undisclosed due to a pending patent application. The company expects to complete final statistical analysis by the end of the year.

INS316 is also in Phase I/IIa trials for chronic bronchitis, cystic fibrosis and primary ciliary dyskinesia. Ventilator-associated pneumonia is another potential indication.

"We are leveraging among [several] diseases — there's a unifying principle we're testing," said David Drutz, president and CEO. "All of these patients have something wrong with their mucociliary clearance [function]. What we have done is to examine these diseases side by side in very carefully designed trials."

Early Trial Data Encouraging

To date, 275 patients, ranging in age from 4 to 70, have received the drug.

Early efficacy data indicate INS316 increased the rate of mucociliary clearance in normal subjects. Mucociliary clearance is the natural process that keeps surfaces of the lungs free of inhaled particles, harmful microorganisms and excessive secretions.

In adult patients with primary ciliary dyskinesia, the drug increased cough clearance for two hours and increased the rate of sputum production. Results were all statistically significant and placebo controlled.

A Phase III trial in the lead indication could begin in the second half of 1998, pending FDA approval, and the company plans to submit an investigational new drug application for its second-generation compound, INS365, in the first quarter of 1998.

Both INS316 and INS365 are unpartnered, but Inspire's business plan calls for seeking collaborations once its drugs clear Phase II trials.

Boucher said that as a physician specializing in pulmonary diseases, he especially hopes that one of the company's achievements will be a convenient drug that could stall progression of pulmonary complications in children with cystic fibrosis.

"All of us who take care of patients feel that we don't need blockbusters. Cystic fibrosis is a chronic disease, so we don't have to have something mindboggling," said Boucher. "Something that will consistently help a little bit every day will go a long way toward helping these patients live longer and feel better." *