在这个33人的三期临床实验中，andexanet alfa快速逆转施贵宝-辉瑞抗凝药Eliquis（阿哌沙班）的抗凝血作用，使Xa因子水平恢复到正常值。这个结果使Portola股票今天上扬16%。Portola还在做andexanet alfa对其它Xa因子抑制剂出血的逆转实验，估计明年可以申请在美国上市。

传统的抗凝药是华法林和低分子肝素，华法林代谢个体差异很大，使用非常不方便，尤其是医院外使用。低分子肝素只能注射，局限于医院内使用。自2008年起，新一代抗凝药开始陆续上市，目前主要有勃林格殷格翰的达比加群酯(凝血酶抑制剂)，和Xa因子抑制剂如拜耳的利伐沙班及施贵宝-辉瑞的阿哌沙班。

其中以阿哌沙班临床数据最为过硬，以前一直被认为是best-in-class，将占有抗凝药市场的主要份额，峰值预测年销售50亿美元。但其上市就一波三折，因为中国地区的临床实验数据有造假嫌疑被延迟9个月上市。2012年上市后也一直表现低迷，最近施贵宝和辉瑞加大市场推广力度，Eliquis上季度销售有较大改善。

今天这个实验结果不仅对Portola，对施贵宝和辉瑞也是一个好消息。当然病人可以更放心地使用这些新抗凝药，对病人更是好消息。

抗凝药最大的问题是出血事件，严重可以致命。仅德国去年一年就有72例利伐沙班造成的出现死亡事件。老药华法林虽然也出血，但有维生素K或血浆作为解药。但新型抗凝药一直没有解药，一旦出现出血失控后果十分严重。这是这类药物市场吸收缓慢的一个关键因素。

这些抗凝药是现在药物不良反应的主要罪魁祸首，其中达比加群酯为2012年不良反应数目最多的药物。这当然和它的广泛使用有一定关系，不能说明它比其它抗凝药更不安全。现在勃林格殷格翰也在研制针对达比加群酯的解药。一旦这些解药上市，这些新型抗凝药的不良反应有望得到有效控制，其使用估计会有较大的增长。

由于安全性是限制新型抗凝药使用的主要原因，andexanet alfa获得FDA突破性药物地位，而Portola自去年IPO后股票已经翻翻。抗凝药一直被认为是个超大市场，但几个新型抗凝药包括抗血小板聚集药物Brilinta的市场吸收一直不尽人意。在研解药的逐渐上市或许能给这些药物一个有力的推动。
 

Andexanet alfa achieved primary, secondary efficacy endpoints in phase 3 trial
Portola Pharmaceuticals announced that a phase 3 trial assessing the factor Xa inhibitor antidote andexanet alfa has achieved its primary and secondary endpoints with a high degree of statistical significance and favorable safety results.

According to a press release, results from the first of two planned ANNEXA-A studies indicated that IV treatment with andexanet alfa led to the immediate and significant reversal of anticoagulation activity following administration of apixaban (Eliquis; Bristol-Myers Squibb and Pfizer).

The randomized, double blind, placebo-controlled trial included 33 older, healthy volunteers treated with apixaban 5 mg twice daily for 4 days. Participants were randomly assigned in a 3:1 ratio to receive either placebo or a 400 mg IV bolus of andexanet alfa. The primary endpoint was anti-factor Xa levels, with secondary endpoints including levels of plasma unbound apixaban and thrombin generation. Andexanet alfa was well-tolerated, and no participants experienced serious adverse events, according to the release.

"Andexanet alfa represents a potential important advance to the field of anticoagulation for factor Xa inhibitor patients who suffer a major bleeding event or those requiring emergency surgery," William Lis, chief executive officer of Portola, said in the release. “…These highly statistically significant phase 3 ANNEXA-A data demonstrate that andexanet alfa has the potential to be the first agent approved as a universal factor Xa inhibitor antidote.”

The full results from the trial will be presented during the Clinical Science: Special Reports session at the American Heart Association Scientific Sessions in November.

The second ANNEXA-A trial will include 32 healthy volunteers who will receive apixaban followed by IV andexanet alfa similarly to the first trial, and will be randomly assigned at a 3:1 ratio to receive either placebo or a continuous 4 mg/min infusion of andexanet alfa for 120 minutes. Results from this trial are anticipated for early next year, the company stated in the release.

The company intends to file a Biologics License Application with the FDA for Accelerated Approval by the end of 2015. Additional study of andexanet alfa will also assess its efficacy for other factor Xa inhibitors, including betrixaban, edoxaban, enoxaparin and rivaroxaban, John T. Curnutte, MD, PhD, executive vice president of research and development for Portola, said in the release.