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十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor

2015-06-24 来源:美中药源 作者: 浏览次数:14  收藏

【新闻事件】:今天美国FDA批准了Medicine’s Company的抗血小板注射剂cangrelor上市(商品名:Kengreal),用于避免成人患者在经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)过程中因凝血造成的冠状动脉堵塞。和其它抗血小板药物一样,Kengreal最严重的风险是大出血,有时甚至危及生命。在一个有1万余人参与的头对头比较Kengreal和Plavix(氯吡格雷)的临床实验中,Kengreal和氯吡格雷相比更能显着降低心肌梗死的发生率,尽管两个组的严重出血事件发生率都比较低,但Kengreal组(1/170)高于氯吡格雷对照组(1/275)。

【药源解析】:经皮冠状动脉介入治疗(PCI)也称血管成形术(angioplasty),是一种经皮穿刺周围动脉,将球囊导管及(或)支架等治疗器械送至冠状动脉,扩张、疏通冠状动脉狭窄病变的一种心脏导管治疗技术。根据美国疾病和控制中心的数据,在美国每年有大约5万人进行PCI疗法。在中国自1977年第一例经皮冠状动脉介入治疗开始,PCI已经成为挽救冠心病患者最有效的疗法之一。

Cangrelor是P2Y12的可逆抑制剂。最早由英国的一个小公司开发,后被阿斯利康收购。也是口服可逆抑制剂Brilinta开发过程中的一个早期tool compound。结构上Cangrelor含有一个三磷酸所以Cangrelor不仅不能口服而且半衰期也很短,只有几分钟。2003年Medicine’s Company从阿斯利康手里收购了Cangrelor的开发权,并且调整了开发方向,利用了Cangrelor半衰期很短的特点开发手术用药。Cangrelor的超短半衰期因此成为一个优势,手术后一停药药效很快消失,理论上降低了出血风险。

尽管如此Cangrelor的开发饱受磨难。在2个大型3期临床实验中Cangrelor作为心脏搭桥手术用药和氯吡格雷相比没有显示任何优势。但是Medicine’s Company百折不挠,又做了第三个3期临床,结果显示对稳定心绞痛患者有更好疗效。但FDA专家组在2014年2月还是以7票反对,2票赞成的投票结果拒绝了Cangrelor用于心脏搭桥手术。而且所有专家反对Cangrelor作为急性心脏病患者手术前的抗凝药。两个月后FDA也正式拒绝了Cangrelor的上市申请。

Medicine’s Company随后又更明确了实验终点、缩小了适用人群并再一次申报上市。今年4月15日FDA专家小组终于以9:2的投票结果支持Cangrelor作为二线药物上市。2015年1月,Cangrelor获得EMA批准在欧盟上市。至此Cangrelor虽然历经磨难但终于熬成正果,但因为氯吡格雷专利过期且临床优势微弱,Cangrelor的销售峰值已经远远低于之前的4亿美元。RBC Capital Market分析师Adnan Butt预计Cangrelor在美国的销售峰值大约8千万至1亿美元。Medicine’s Company股票今天小幅上扬1%至29.64美元。

十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor(Kengreal)上市 - zliming2004 - zliming2004的博客

 

Cangrelor tetrasodium is a fast-acting, reversible, intravenous antiplatelet agent developed by The Medicines Company. In 2015, the product was approved in the E.U. for the reduction of thrombotic cardiovascular events in adult patients with coronary artery disease undergoing percutaneous coronary intervention and who have not received an oral P2Y12 inhibitor prior to the PCI procedure. In the same year, the FDA approved the product for the same indication.


In 2009, phase III clinical trials for the prevention of platelet activation and aggregation during percutaneous transluminal coronary angioplasty (PTCA) were discontinued. This decision was based upon the report of an independent Interim Analysis Review Committee (IARC) which stated that the trial would not meet the goal of demonstrating persuasive evidence of clinical effectiveness that could form the basis for regulatory approval.

Cangrelor tetrasodium acts directly on the P2Y12 platelet receptor which, in turn, prevents coagulation through its inhibitory effect on ADP-stimulated platelet Ca2+ mobilization. It has also been suggested that the compound may have other effects on platelet function through interactions with endogenous platelet inhibitors. 

Originally developed at AstraZeneca Charnwood, the Medicines Company acquired rights to develop, market and sell the non-thienopyridine worldwide excluding Japan, China, Korea, Taiwan and Thailand pursuant to an agreement signed by the companies in December 2003.

十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor(Kengreal)上市 - zliming2004 - zliming2004的博客

 

十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor(Kengreal)上市 - zliming2004 - zliming2004的博客

 


Ingall, A.H.; Dixon, J.; Bailey, A.; et al.   1 Record(s)  Retrieved   WoS Record   WoS CR   WoS RR
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Kindon, N.D.; Bailey, A.; Cage, P.A.; et al.
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Diaz-Ricart, M.; Escolar, G.; Serradell, N.; Rosa, E.; Bolos, J.   十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor(Kengreal)上市 - zliming2004 - zliming2004的博客   WoS Record   WoS CR   WoS RR   Drugs Fut
Cangrelor tetrasodium
Drugs Fut 2008, 33(2): 101

Patent NumberApplicantTitleConditionSubject MatterEP 0683789
JP 1996506335
US 5721219
WO 1994018216
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Angina pectoris, unstable

Percutaneous transluminal coronary angioplasty (PTCA)

Surgery, cardiac

Thrombosis

十年砥砺终成正果:美国FDA批准了Medicine’s Company的注射抗凝药Cangrelor(Kengreal)上市 - zliming2004 - zliming2004的博客   


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