National Editor

As expected, Chiron Corp. started its Phase III trial testing tifacogin, a recombinant tissue factor pathway inhibitor, against severe community-acquired pneumonia (CAP).

Tifacogin, which was developed by Chiron and in November 2001 became one of many drugs defeated by sepsis, goes up against CAP in a randomized, placebo-controlled study - one that, if successful, likely will lead Chiron to ask for a sepsis label, said Craig West, analyst with A.G. Edwards in St. Louis.

"Everybody would do that," West said. "It's a no-brainer. You always ask for the broadest thing."

The company's stock (NASDAQ:CHIR) dipped 50 cents Tuesday to close at $43.12.

Named CAPTIVATE, the trial comprises three arms: placebo, low-dose tifacogin and higher-dose tifacogin. It's expected to accrue about 2,100 patients at 200 centers in 16 countries. The primary endpoint is reduction in mortality at 28 days.

"The subset analysis that they did [in the sepsis trial] showed statistically significant efficacy in the confirmed pneumonia without heparin subset," West told BioWorld Today. "If that's predictive, and I don't see a reason why it wouldn't be at the moment, and if they can control enrollment well, then it should work."

Getting a sepsis label from a successful CAP trial could be tricky, he noted, given the varied nature of the former condition, compared to the latter.

"The majority of patients don't get sepsis secondary to CAP," he said. At the same time, "mechanistically, the same things are what kill the patients" in both diseases - inflammation and clotting, both of which tifacogin aims to remedy, West said.

"Even if you can just get it out there for severe CAP, you can do investigator-sponsored studies [for sepsis]" and then seek a broadened label, he said. Reimbursement would be hard to get for a drug used off-label for sepsis, he added.

Severe CAP afflicts some 300,000 patients in the U.S. each year, about one-third of whom die, despite physicians' efforts to hold back the disease with antibiotics and supportive care. There is no approved adjunct therapy, and hope has been buoyed by such findings as those from a study published in the March 22, 2004, issue of the Archives of Internal Medicine. Researchers examining outcomes of 18,209 Medicare patients found a 15 percent reduction of mortality when antibiotics were given within four hours of arrival at the hospital.

South San Francisco-based Genesoft Therapeutics Inc. won FDA approval last April for Factive (gemifloxacin mesylate), a fluoroquinolone antibiotic for CAP, but even antibiotics don't always fare well against the disease.

Cidecin, the injectable daptomycin from Cubist Pharmaceuticals Inc., of Lexington, Mass., failed in a Phase III trial against CAP more than two years ago. Cubist's drug, renamed Cubicin, was approved for skin infections in September, and the company in October signed with a partner for marketing outside the U.S. - and that partner, coincidentally, is Chiron. (See BioWorld Today, Sept. 16, 2003, and Oct. 6, 2003.)

In late 2001, tifacogin, which Chiron was developing with Pharmacia Corp., of Peapack, N.J., missed its primary endpoint of reducing 28-day all-cause mortality. The double-blind, placebo-controlled trial involved about 2,000 patients with severe sepsis from 16 countries.

Pharmacia's co-development rights transferred to Pfizer Inc. when the New York-based pharmaceutical firm took over Pharmacia. Chiron has since retained full rights from Pfizer.

Getting the best-suited patients for sepsis trials has been "a nightmare," West said, thanks partly to the disease and partly to criteria such as those in the Acute Physiology and Chronic Health Evaluation, or APACHE test.

"These people are going to die soon, so there's a large sense of urgency," he said. "You've got a need to make a decision quickly and a poor instrument in terms of trying to type the patients."

Sepsis, he noted, "can be Gram-positive, it can be Gram-negative. It can be more of an inflammatory problem or more of a clotting problem. I'm not all that surprised to see any one targeted therapy just not work well."

Yet it might have been just that heterogeneity that let Chiron find the 225-patient subset with pneumonia who hadn't received heparin and who benefited from tifacogin.

"You get heparin when you're fairly far gone, when you're in serious trouble," West said. "They could have been looking at patients in terms of severity of disease, and saw a signal."

Tissue factor pathway inhibitor (TFPI), of which Chiron's tifacogin is a recombinant version, is a naturally occurring protein, and other companies are exploring it in areas other than CAP. Rockville, Md.-based EntreMed Inc. reported at the start of this year that the company has identified a peptide fragment of TFPI that inhibits metastatic tumor and blood vessel growth, but apparently does not affect normal blood clotting. Scientists also identified the TFPI peptide's mechanism of action, and EntreMed said they are using it as a template to design small molecules with similar but improved properties.

Working with the immune system, whether against sepsis, CAP or other disorders, is anything but cut and dried.

"We know about 25 percent of what we should know," West said.