Portola Pharmaceuticals Inc. announced that it has initiated a Phase 2 study evaluating the safety and effectiveness of PRT4445, its universal antidote for Factor Xa inhibitor anticoagulants, in healthy volunteers who have been administered approved and investigational Factor Xa inhibitors, including the oral investigational drug apixaban and Portola’s oral investigational drug betrixaban. PRT4445 is the first agent with a mechanism of action to reverse the anticoagulant activity of any Factor Xa inhibitor. Reversal of the anticoagulant activity has the potential to stop or attenuate bleeding in patients experiencing an uncontrolled bleeding episode or requiring emergency surgery.

Multiple cohorts are planned for the Phase 2 study, which is expected to be completed in 2013. The first cohort will test PRT4445 with apixaban to evaluate further the safety of PRT4445 and the dose required to reverse the anticoagulant effect of apixaban. Portola announced in November that it had entered into a clinical collaboration agreement with Bristol-Myers Squibb and Pfizer for the apixaban cohort of the Phase 2 study.

Portola has completed its Phase 1 single ascending dose safety and tolerability study of PRT4445, which was conducted in 32 healthy volunteers in the United States. Final results showed that PRT4445 was generally safe and well tolerated. Analysis of anticoagulation markers in blood samples taken from the subjects and mixed with a novel Factor Xa inhibitor in a test tube to simulate the effects of PRT4445 on reversing anticoagulation indicated that PRT4445 had a rapid (five minute) and sustained (three hour) effect on reversing the activity of that Factor Xa inhibitor.

“Oral Factor Xa inhibitors are transforming the care of patients requiring anticoagulant therapy, and it is well recognized that an antidote is needed to reverse the activity of these agents when a patient has an uncontrolled bleeding event or requires emergency surgery. Our goal is to advance PRT4445 through the approval process as quickly as possible,” said Michael Kitt, M.D., senior vice president and chief medical officer of Portola. “We have discussed the positive Phase 1 trial results with the FDA, and assuming the Phase 2 trial is successful, we intend to initiate a Phase 3 registration study with the agreement of the FDA. If successful, we will seek approval of PRT4445 as a universal reversal agent for Factor Xa inhibitors.”

Major bleeding events occur infrequently in patients taking Factor Xa inhibitors (1% to 4% per year in several clinical studies involving patients taking a Factor Xa inhibitor on a chronic basis), and standard measures are currently employed to manage these events. However, there is presently no approved antidote or reversal agent that is specifically intended for use against Factor Xa inhibitors. Development of an agent specifically designed to reverse the activity of Factor Xa inhibitors may provide an antidote for patients who, in rare instances, experience an uncontrolled major bleeding event or require emergency surgery.

Date: December 10, 2012
Source: Portola Pharmaceuticals Inc.