West Coast Editor

Portola Pharmaceuticals Inc. kicked off a Phase II trial with its oral Factor Xa inhibitor to block deep-vein thrombosis (DVT) and pulmonary embolism (PE) in knee-surgery patients.

The study at 20 sites will evaluate the safety and efficacy of Portola's compound compared to Lovenox (enoxaparin), from Paris-based Sanofi-Aventis Group, which is a standard of care for preventing DVT and PE after knee-replacement operations, "but it's really competing with Coumadin [warfarin]," said Charles Homcy, president and CEO of South San Francisco-based Portola. His firm's drug, like Coumadin, is oral and for chronic use.

"Unlike Coumadin, [our] drug works immediately," Homcy said.

Coumadin, an inhibitor of vitamin K, takes as long as three days to anti-coagulate a patient - and brings more variability, since vitamin K is made by intestinal bacteria. That means regular blood tests, another drawback of Coumadin.

"With an anti-coagulant, if it's not consistent, it's no good," Homcy said. Absence of DVT or PE as determined by venogram will be the primary endpoint in Portola's Phase II study, and results are expected early next year.

"You couldn't start [treating patients at risk for clots] with Coumadin, because it doesn't work fast enough," Homcy explained, so physicians typically use Lovenox first, and then transition to a chronic therapy, overlapping the two for a while.

Many founding members of Portola's team made up the cardiovascular and drug discovery group at South San Francisco-based Millennium Pharmaceuticals Inc., from which Portola was spun out. They previously had been with COR Therapeutics Inc., which merged with Millennium in a $2 billion stock transaction. (See BioWorld Today, Dec. 7, 2001.)

Portola's ambitions, like Millennium's, are large. The Factor Xa inhibitor could be useful for anyone at risk of DVT and others, Homcy said.

"If you are medically ill with cancer, heart disease or otherwise and you're hospitalized, you have a 10 percent chance of DVT, and some percentage of those will have a pulmonary embolism and potentially die," he said.

Another potential use is against atrial fibrillation, which Homcy called an "epidemic." In a patient with irregular heartbeat, because the heart does not contract normally, a blood clot can accumulate in the left atrium and then be expelled into the brain, leg or somewhere else. Portola's compound also might be used for secondary prevention of myocardial infarction in patients who have acute coronary syndrome.

"Coumadin is a tough drug to use, so it hasn't been explored or investigated in this space," Homcy said. The anticoagulant space remains in a "primitive state, like hypertension was 40 or 50 years ago," he said.

After exploring the current indication, Portola plans to conduct separate trials in the others, but "the good news is the dosage will probably be the same, so you don't have to do a lot of groundwork," Homcy said.

Anticoagulants now sell $4.5 billion annually.

"That pie is very small, compared to the potential," he said. "The chance to make it twice that size is very doable."