Newcomer drug company takes aim against TB

Three promising new drugs in development

PathoGenesis Corp., a pharmaceutical newcomer based in Seattle, has set its sites on a big target: respiratory illnesses, including tuberculosis, where a critical need exists for new and better drugs. So far, the company boasts an impressive track record with two promising TB candidate drugs in Phase II trials and a third candidate in development.

There’s rifalazil, with a half-life of 48 hours, longer than that of any other rifamycin, and a strikingly high intracellular concentration. Such traits suggest that anti-TB regimens incorporating the drug might lend themselves to fewer doses, abbreviated treatment time, or both, TB experts say.

With rifalazil’s long half-life, "It might be given once a week or even once every two weeks," says Rick O’Brien, MD, chief of the research and evaluation branch at the division of tuberculosis elimination at the Centers for Disease Control and Prevention. There is a potential problem, O’Brien adds: In Phase I trials, patients didn’t tolerate dose equivalents extrapolated from animal studies as well as had been hoped, so doses have been scaled back for Phase II trials.

Enrollment was completed in July for those trials, which are being conducted in Brazil in collaboration with the tuberculosis research unit of the National Institute of Allergy and Infectious Diseases. The contractor is Gerald Ellner of Case Western Reserve University in Cleveland, says Maryellen Thielen, a spokes woman for PathoGenesis.

Also in Phase II trials is a second anti-TB drug candidate, tobramycin. Given in aerosolized form using a nebulizer, tobramycin offers the advantage of being delivered directly to the lungs instead of systemically, says Thielen. If the drug works as hoped — by quickly reducing bacterial loads in patients’ sputum — it could prove useful as an adjunct to conventional therapy by reducing the time patients are infectious, she says.

Tobramycin already has been approved for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis patients, and it is being evaluated in Phase II trials for use against bronchiectasis, a severe form of chronic bronchitis. As an anti-TB agent, the drug has shown efficacy in all strains of TB against which it’s been tested, including multidrug-resistant strains, says Thielen. It works as a ribosomal subunit inhibitor.

That leaves a third anti-TB drug, PA824, now in preclinical development. In test tube and animal studies, this third agent, a nitroimidazopyran compound, has proven as effective as isoniazid against both drug-sensitive and multidrug-resistant strains of TB, she says.

Even better, PA824 has shown efficacy against nonreplicating latent organisms, suggesting it may prove useful in treating latent TB as well as active disease. PA824 appears to work by a novel mode of action, by inhibiting protein synthesis and the formation of cell wall ketomycolic acid, Thielen says.

PathoGenesis was founded in 1991 by Wilbur Gantz, former president of the pharmaceutical firm Baxter International, and it began research and development in 1993, she notes.

Remarkably, PathoGenesis moved its first drug, tobramycin, from research and development to market in just five years, she says. "For a small company like this one, it’s essential to bring drugs to the market as quickly as possible. TB research takes longer than usual in part because the organism is especially slow-growing, but we’ve developed some assays to help us work more quickly."

The need for more anti-TB drugs makes research in this arena an attractive niche, she says, but it also raises the stakes.

"That there is a relative lack of competition makes it a nice place to be, but if we can’t provide a significant benefit with a new therapy, there is no point to our work," Thielen explains. "As you know, current TB drugs are generic and low-cost, so that the cost to the system lies in hospitalization, directly observed therapy, and the like. If we can find a way to trim those costs, we can support the development of new drugs."