FDA授予Portola解毒剂PRT4445突破性疗法认定

Portola制药11月26日宣布，FDA已授予其实验性抗凝血剂解毒剂PRT4445（andexanet alfa）突破性疗法认定。FDA授予的突破性疗法认定，旨在加快严重危机生命的疾病的药物开发和审查。

PRT4445是一种通用型Xa因子抑制剂的解毒剂（antidote），处于临床开发阶段，旨在逆转任何Xa因子抑制剂的抗凝血活性。

PRT4445是唯一一种已被证明能够实现Xa因子抑制剂抗凝血活性临床逆转的解毒剂。目前，还没有任何药物获批用于逆转Xa因子抑制剂的活性。

目前，Portola已与所有生产直接Xa因子抑制剂的制药商达成了临床合作协议，包括百时美施贵宝（BMS）和辉瑞（Pfizer）[Eliquis（apixaban，阿哌沙班）]、拜耳（Bayer）和强生（JNJ）[Xarelto（rivaroxaban，利伐沙班）]、第一三共（Daiichi Sankyo）[Lixiana（edoxaban）]，Portola保留PRT4445全部的全球开发及商业化权利。

口服Xa因子抑制剂能够解决需抗凝治疗的患者中严重未获满足的医疗需求。重大出血事件在服用Xa因子抑制剂的患者中很少发生（临床研究中年发生率为1%~4%），同时也有一些标准的措施来管理这些事件。但开发可逆转Xa因子抑制剂活性的解毒剂，有望在极少数情况下，为那些遭遇不受控制的重大出血事件或需要紧急手术的患者提供帮助。

英文原文：“Breakthrough Therapy” status for Portola’s andexanet alfa

Portola Pharmaceuticals Receives Breakthrough Therapy Designation From FDA for Andexanet Alfa (PRT4445*), Investigational Factor Xa Inhibitor Antidote

Only Agent That Has Demonstrated Clinical Reversal of Anti-Xa Activity of Factor Xa Inhibitors

SOUTH SAN FRANCISCO, Calif., Nov. 25, 2013 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals, Inc. (Nasdaq:PTLA) today announced that it has been granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for andexanet alfa, its investigational Factor Xa inhibitor antidote. The FDA's breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.i Portola is pursuing an Accelerated Approval pathway for andexanet alfa, a first-in-class agent, and plans to initiate registration-enabling studies in 2014. By the year 2020, Portola estimates that the number of patients presenting to the hospital who could benefit from an antidote could approach 500,000 in the United States, Japan and the five largest European Union countries alone.

"The FDA's decision to designate andexanet alfa as a breakthrough therapy reaffirms the urgent need for an antidote to Factor Xa inhibitors, and we believe it demonstrates that andexanet alfa's properties and data distinguish it from currently used agents or others in development," said William Lis, Portola's chief executive officer. "Pro-coagulant agents being used in the absence of an antidote are unproven, have limited biological rationale for their effectiveness to reverse Factor Xa inhibitors, and have been shown to cause serious blood clots. Therefore, andexanet alfa marks an important advance in the field, and our goal is to bring it to market as quickly as possible."

The Company has previously reported data from its ongoing Phase 2 proof-of-concept studies  of andexanet alfa and the Factor Xa inhibitors Eliquis? and XARELTO?. Additional studies are ongoing with Lovenox? (enoxaparin), Lixiana? and Portola's investigational oral Factor Xa inhibitor, betrixaban, which is being studied in a Phase 3 clinical trial and has the potential to be the first oral Factor Xa inhibitor approved for venous thromboembolism (VTE) prevention in acute medically ill patients.

Phase 2 results to date have demonstrated andexanet alfa's ability to immediately reverse the anticoagulant activity of Factor Xa inhibitors by the administration of a short intravenous bolus. Additional data have shown that this reversal can be prolonged when necessary by the addition of an extended infusion of andexanet alfa. Unlike pro-coagulant agents or other compounds in development, once administration is stopped, andexanet alfa is rapidly cleared and anticoagulant therapy can be re-initiated, which is critical for patients who have pre-existing (underlying) prothrombotic conditions. Andexanet alfa's specific mechanism of action may also reduce the potential for serious adverse events and interactions with other commonly used drugs. No serious adverse events or antibodies to Factor Xa or Factor X have been observed in the ongoing Phase 2 studies.

About Andexanet Alfa (PRT4445*)

Andexanet alfa is a first-in-class recombinant, modified Factor Xa molecule that directly reverses the effects of Factor Xa inhibitors in patients who suffer an uncontrolled bleeding episode or who require emergency surgery. Andexanet alfa acts as a Factor Xa decoy that targets and sequesters with high specificity both direct and indirect Factor Xa inhibitors in the blood. Once bound, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa, thus allowing for the restoration of normal hemostatic processes. Through its mechanism of action, andexanet alfa has the potential to act as a universal antidote and address the direct cause of the patient's inhibited clotting activity without being prothrombotic.

Portola has entered into clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors, including Bristol-Myers Squibb and Pfizer (Eliquis?  [apixaban]), Bayer HealthCare and Janssen Pharmaceuticals (XARELTO? [rivaroxaban]), and Daiichi Sankyo (Lixiana? [edoxaban]), while retaining all rights to the program.