Portola Pharmaceuticals, Inc. Initiates Phase 2 Study of PRT4445, Universal Antidote for Factor Xa Inhibitor Anticoagulants
Published: Dec 10, 2012
SOUTH SAN FRANCISCO, CA--(Marketwire - December 10, 2012) - Portola Pharmaceuticals, Inc. today 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 (1-4 percent 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.
PRT4445 is a novel recombinant protein designed to reverse the anticoagulant activity in Factor Xa inhibitor-treated patients suffering from an uncontrolled bleeding episode or undergoing emergency surgery. It is similar to native Factor Xa but has structural modifications intended to restrict its biological activity to reversing the effects of Factor Xa inhibitors. PRT4445 works by acting as a decoy for Factor Xa inhibitors in the blood, thereby preventing them from inhibiting the activity of native Factor Xa. As a result, the native Factor Xa is available to participate in the coagulation process and restore hemostasis (normal clotting).
Portola has evaluated PRT4445 in numerous preclinical studies and developed substantial evidence supporting its safety, efficacy and rapid activity. In vitro studies have shown that PRT4445 reverses the anticoagulant effects of all Factor Xa inhibitors with which it has been studied, including rivaroxaban, betrixaban, apixaban, enoxaparin and fondaparinux. PRT4445 has also been shown in preclinical bleeding models to significantly reduce the amount of blood loss compared to placebo in animals treated with enoxaparin or rivaroxaban (with or without aspirin).
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics in the areas of thrombosis, other hematologic disorders and inflammation for patients that currently have limited or no approved treatments. In thrombosis, Portola is developing betrixaban, a novel, oral, once-daily inhibitor of Factor Xa in development for extended duration venous thromboembolism (VTE) prophylaxis in acute medically ill patients (for up to 35 days). Portola also is developing PRT4445, a universal antidote for Factor Xa inhibitor anticoagulants. Portola has a short-term clinical collaboration agreement with Bristol-Myers Squibb and Pfizer for the initial Phase 2 clinical development of PRT4445, in which Portola retains 100 percent ownership.
Portola scientists have discovered novel dual inhibitors of Spleen Tyrosine Kinase (Syk) and Janus Kinase (JAK) for hematologic cancers and inflammation. Portola's lead compound in that program, PRT2070, has completed preclinical testing and, subject to regulatory approval, will enter the clinic in 2013. In inflammation, Portola has a collaboration agreement with Biogen Idec to develop specific inhibitors of Syk, including PRT2607 for which Biogen Idec is leading development for the treatment of allergic asthma. The collaboration is also focusing on additional selective backup compounds in chronic autoimmune and inflammatory diseases. For more information, visit www.portola.com.