医药魔方 / 最新资讯 / 正文

勃林格殷格翰冯耐德:药品开发,应基于医患安心考虑

医药魔方 医药魔方 来源:医药魔方
2019-03-14
药品开发
原文

近日,亚洲抗凝学院专家暨「依达赛珠单抗」上市发布会在上海召开。「依达赛珠单抗」是一种单克隆抗体药物,于2018年6月8日被国家药品监督管理局批准,用于在急诊外科手术/紧急操作或者出现危及生命/无法控制的出血,需要迅速逆转「达比加群酯」的抗凝效应时使用。会议期间,勃林格殷格翰(BI)大中华区人用药品业务负责人Dirk van Niekerk(冯耐德)先生接受了媒体采访。


一、正视药品的优缺点

 

「达比加群酯」是BI近年来主推用于房颤卒中预防的口服新型抗凝药物(NOAC)。在房颤发作时,心房内血液淤滞而易于形成心房内血栓,血栓脱落可引起周围动脉或肺动脉栓塞,是脑卒中的常见原因之一。一旦发生脑卒中,轻者影响患者的生活质量,重者危及生命,后果不堪设想。

 

《2010年全球疾病负担研究》显示:世界范围内房颤患者人数达3300万,中国近11年房颤患病率增加20倍,房颤卒中增加13倍。预防脑卒中已成为房颤患者综合管理策略中的主要内容,抗凝是房颤有效的预防手段之一。

 

传统房颤抗凝药维生素K拮抗剂华法林抗栓塞效果明确,但也有一定缺陷,比如其代谢易受食物、药物等因素影响,药物起效、失效时间长;治疗的窗口窄,需要频繁监测,导致患者服药依从性差等。


对于具有卒中风险的房颤患者,多项指南不再推荐抗血小板药物用于卒中治疗;甚至有研究指出阿司匹林反而增加老年患者缺血性卒中和血栓栓塞事件。十多年来,研究者致力于开发出更安全、有效、使用更方便的新型口服抗凝药物。


这类药物不像传统抗凝药那样作用于多个凝血因子,而是仅抑制某一个凝血因子。根据NOACs的作用靶点,可以将其分为两类:直接凝血因子抑制剂(凝血因子Xa)和直接凝血酶抑制剂(凝血因子IIa)。



1)直接凝血因子抑制剂(凝血因子Xa)

凝血因子Xa是外源性及内源性凝血途径的交汇点。通过在磷脂膜表面形成磷脂复合物(即凝血酶复合物),进而激活凝血酶原。直接凝血因子抑制剂通过与Xa因子的活性位点结合,阻止凝血酶原转变为凝血酶从而发挥抗凝作用,且抗凝作用不依赖内源性抗凝血酶。代表药物包括:阿哌沙班、利伐沙班、依度沙班等。

 

2)直接凝血酶抑制剂(凝血因子IIa)

凝血因子IIa特异性阻滞凝血酶的活性,从而阻止纤维蛋白原裂解为纤维蛋白,阻断了“凝血瀑布”的最终步骤。直接凝血酶抑制剂的抗凝作用不需辅因子,且与维生素K无关;其抗凝效果具浓度依赖性;既能够灭活游离凝血酶,也可以灭活与纤维蛋白结合的凝血酶。代表药物是「达比加群酯」。

 

二、以矛攻盾的开发思路

 

FDA在2010年批准了「达比加群酯」,用于预防心房颤动患者出现中风和全身血栓,以及治疗和预防深静脉血栓形成和肺栓塞。到目前为止,「达比加群酯」已在100多个国家获批上市。BI对外数据称,迄今为止,即凝血酶复合物每年在全球所有获批适应症中的临床经验超过690万患者,与未治疗相比,「达比加群酯」针对非瓣膜性房颤患者的卒中预防预计已达26万余次。

 

不过再好的药,没有逆转方法是非常麻烦的一件事情。在现实生活中服用抗凝药的房颤患者和常人一样可能出现外伤、车祸以及需要进行手术紧急的情况,就需要能够迅速逆转抗凝效果的逆转剂。目前已经上市或正在研发的逆转剂,如依达赛珠单抗(Idarucizumab)、Andexanet alfa和Ciraparantag,给更方便快捷有效的控制出血风险带来新希望。

 

2015年10月和11月,FDA和EMA先后批准了依达赛珠单抗作为达比加群的特异性逆转剂,适用于接受达比加群酯治疗的患者因急诊外科手术、紧急操作或出现危及生命或无法控制的出血,需要快速逆转达比加群抗凝效果时使用。

依达赛珠单抗是针对达比加群设计的单克隆抗体,也是针对后者首个获批的特异性逆转剂。数据显示:在健康受试者试验中可以捕捉血浆中的「达比加群」,静脉输注结束后5分钟血药浓度达峰,绝大多数血浆中的「达比加群」都被捕获。「依达赛珠单抗」与「达比加群」的亲和力是其与凝血酶的350倍,也就是说,达比加群会因与依达赛珠单抗拥有更高的亲和力而和结合的IIa因子即凝血酶解离,而和依达赛珠单抗相结合。这种逆转效果,如“反导”拦截般又快又准,能够较好地满足临床需求。

 

三、让医患安心的研发初衷


2017年「达比加群酯」全球销售收入为14.38亿欧元,自2011年上市来呈现稳步上升趋势。「依达赛珠单抗」的销售数据并未公开。


 

大家都知道,开发一款单抗药物并不容易,成本非常高。如果从药物经济学角度来说,对药企而言似乎不太合算,当记者提出这个疑问时,冯耐德先生表示,开发这款抗体药物并不是从盈利的角度考虑,而是一方面看好「达比加群酯」的未来市场,为了让医生在使用时更安心,给患者上双保险;二来是想通过这款药物的上市,降低老百姓对抗凝药物的使用疑虑,增强老百姓对房颤卒中预防的认知。


附:记者采访实录


问:冯耐德先生您好!请问目前达比加群酯在市场的占有率是多少?


冯耐德:从市场市值来讲,我们在房颤预防卒中的市场是占据领导性地位的,约有 45%的市场份额,也就是说,在新型口服抗凝药预防卒中的市场,达比加群酯占到了市场份额的45%。但从量来看,达比加群酯是小于华法林的,毕竟华法林在市场上已经使用了20到30多年。

 

问:BI打算如何进一步提高药物可及性? 

 

冯耐德:达比加群酯在2017年进入了医保的,我想一方面是因为它作为新型口服抗凝药具有很好的优势,另一方面是政府也意识到对一些服用华法林的老年患者确实有很大的隐患,比如较难控制凝血,这或是政府把达比加群酯纳入到医保的一个重要原因。


依达赛珠单抗暂时还没有纳入医保,它是一类生物制剂,我们会基于生产制造成本的考量以一个合理的价格推出市场。


现在达比加群酯纳入医保后的价格是很有竞争优势的,我相信很多病人是可以负担得起达比加群酯的。据我所知现在很多药物为了进医保,在各个省份有一些竞标行为。随着招标集采带来的竞标压力以及仿制药的出现,我相信达比加群酯的价格还可能会有进一步的下降,从而让更多患者可以负担得起。


问:依达赛珠单抗在中国是作为罕见性疾病用药上市的,从药企经济学层面来看,投入的研发和最后回报可能会不成正比,BI研发依达赛珠单抗最初是基于什么考虑的?

 

冯耐德:我们在开发依达赛珠单抗之初,经济回报并不是我们考虑的一个重点。那为什么我们还是要开发这个药物?主要是因为达比加群酯的抗凝效果还是不错的,而且全球使用的量也在增加,越来越多的患者开始长期使用达比加群酯。中国已在逐渐步入老龄化社会,未来将有越来越多的老年房颤患者对达比加群酯有长期使用的需求,在这样的市场前提下,我们有必要让医生和患者在使用达比加群酯后“更放心”。

 

当患者发生紧急外科手术情况,他需要及时快速地逆转抗凝效果。如果我们有依达赛珠单抗这样的药物可以迅速逆转,这样就可以极大降低患者和医生的顾虑和担心,让他们更加放心、更大胆使用达比加群酯,从而让泰毕全能够得到更长期的使用。所以,我们并不是出于商业目的才设计开发依达赛珠单抗,而是为了在紧急状况下让医生和患者更放心地使用,这确实是我们感到非常自豪的地方。

 

问:在您看来,中国跟国外房颤患者在治疗卒中方面还有哪些差距?

 

冯耐德:我不太了解从哪个维度去衡量“差距”,但我所知道的不同点在于,中国国土面积和国外对比太大了,所以在治疗中风的紧急时会受到一些限制。在欧洲有很多小国家,患者卒中发病时到医院接受治疗的距离并不是很远,可以很及时接受治疗,并且医院都配备非常专业的医生和抢救设施。


但在中国,由于国土面积确实太大,如果卒中的患者住在乡村或偏远地区,一旦发病,他们要花很长的时间才能到达可以治疗卒中的大医院,这显然对卒中治疗要求的“黄金3小时”是远远不利的。


问:作为房颤卒中的参与方之一,BI是否有一些计划来帮助中国缩短差距?


冯耐德:事实上,现在中国政府、卫生部门官员以及医护人员也认识到这个问题。我们牵手中国卒中学会(CSA)和美国心脏协会/美国卒中学会(AHA/ASA),资助一项培训课程。

 

这个培训课程有三个模块,通过这个课程,我们努力给更多偏远地区以及基层医院的卒中领域医生提供与国际接轨的培训机会,进一步推进中国卒中诊疗标准化、规范化。整个项目称之为“卒中综合培训中心”,由BI支持赞助,在北京和上海两地开展临床培训基地。

 

据我所知,两地每周都各有50个医生参加培训,周五飞过来,周末再返回。经过这三个模块的培训,医生们会收到一个证书,回去后给更多卒中患者提供更安全有效的治疗。同时,这些基层医生经过培训后,他们所在的基层医院也可以得到认证,意味着医院具备卒中治疗的标准。


可以预见的是,随着培训课程不断深化,中国可以得到专业治疗的卒中患者人数将迅速赶上美国和欧洲。因此,像这样的培训项目,我们还会继续加大投入,让它能够持续地进行下去,从而让更多的中国卒中患者得到更加安全有效的、标准化的治疗。

机器翻译

Recently, the launch of Idarucizumab, an expert from the Asian College of Anticoagulation, was held in Shanghai.Idarucizumab, a monoclonal antibody drug, was approved by China Food and Drug Administration on June 8, 2018, for use in emergency surgery/emergency operation or in case of life-threatening/uncontrollable hemorrhage requiring rapid reversal of anticoagulant effect of dabigatran etexilate.During the meeting, Mr. Dirk van Niekerk, head of Boehringer Ingelheim's (BI) human pharmaceuticals business in Greater China, spoke to the media.

I.Face up to the advantages and disadvantages of medicines

Dabigatran etexilate" is a new oral anticoagulant (NOAC) promoted by BI for stroke prevention in atrial fibrillation in recent years.In the onset of atrial fibrillation, blood stasis in the atrium and easy to form intra-atrial thrombus, thrombus shedding can cause peripheral artery or pulmonary artery embolism, is one of the common causes of stroke.In the event of a stroke, the patient's quality of life is affected in mild cases and life-threatening in severe cases, with unimaginable consequences.

The Global Burden of Disease Study 2010 shows that the number of patients with atrial fibrillation worldwide is 33 million, the prevalence of atrial fibrillation in China has increased 20-fold and stroke in atrial fibrillation has increased 13-fold in the past 11 years.Prevention of stroke has become the main content of the comprehensive management strategy for patients with atrial fibrillation, and anticoagulation is one of the effective prevention measures for atrial fibrillation.

The traditional anticoagulant for atrial fibrillation, the vitamin K antagonist warfarin, has a clear antiembolic effect, but it also has certain defects, such as its metabolic susceptibility to food.Drugs and other factors affect the effectiveness of drugs.Long expiry time.The therapeutic window is narrow and requires frequent monitoring, resulting in poor medication compliance.

For patients with atrial fibrillation at risk for stroke, several guidelines no longer recommend antiplatelet therapy for stroke.There are even studies suggesting that aspirin actually increases ischemic stroke and thromboembolic events in elderly patients.For more than a decade, researchers have been working to develop safer.Valid.More convenient use of new oral anticoagulants.

These drugs do not act on multiple clotting factors as traditional anticoagulants do, but rather inhibit only one clotting factor.According to the target of NOACs, they can be divided into two categories: direct coagulation factor inhibitors (factor Xa) and direct thrombin inhibitors (factor IIa).

1) Direct Factor Inhibitors (Factor Xa)

Factor Xa is the intersection of the extrinsic and intrinsic coagulation pathways.Prothrombin is activated by the formation of a phospholipid complex, the thrombin complex, on the surface of the phospholipid membrane.Direct coagulation factor inhibitors exert their anticoagulant effect by binding to the active site of factor Xa and preventing the conversion of prothrombin to thrombin, and the anticoagulant effect is independent of endogenous antithrombin.Representative drugs include: Apixaban.Rivaroxaban.Edoxaban et al.

2) direct thrombin inhibitor (factor IIa)

Factor IIa specifically blocks the activity of thrombin, thereby preventing the cleavage of fibrinogen to fibrin and blocking the final steps of the "coagulation cascade."The anticoagulant effect of direct thrombin inhibitors does not require cofactors and is independent of vitamin K.The anticoagulant effect is concentration dependent.It inactivates both free thrombin and fibrin-bound thrombin.Represents "dabigatran etexilate".

Two.Thinking of developing spear shield

The FDA approved "dabigatran etexilate" in 2010 for the prevention of stroke and systemic thrombosis in patients with atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.So far, "dabigatran etexilate" has been approved in more than 100 countries.According to BI's external data, to date, the clinical experience of thrombin complex in all approved indications worldwide is more than 6.9 million patients per year, and the stroke prevention of "dabigatran etexilate" in patients with non-valvular atrial fibrillation is expected to reach more than 260,000 times compared to no treatment.

No good medicine, no reversal is a very troublesome thing.Patients with atrial fibrillation who are taking anticoagulants in real life are as likely to develop trauma as the general population.Car accidents and urgent cases requiring surgery require reversal agents that can quickly reverse the effects of anticoagulation.Reversal agents currently marketed or under development, such as idarucizumab.Andexanet alfa and Ciraparantag offer new hope for more convenient, efficient and effective control of bleeding risk.

In October and November 2015, the FDA and EMA approved idarucizumab as a specific reversal agent for dabigatran etexilate in patients undergoing emergency surgery.Use when emergency procedures or life-threatening or uncontrolled bleeding require rapid reversal of the anticoagulant effect of dabigatran.

Idarucizumab is a monoclonal antibody designed for dabigatran and the first approved specific reversal agent for the latter.The data showed that "dabigatran" in plasma could be captured in trials in healthy subjects, with peak plasma concentrations occurring 5 minutes after the end of the intravenous infusion, and the majority of "dabigatran" in plasma were captured."Idarucizumab" has a 350-fold higher affinity for "dabigatran" than it has for thrombin, that is, dabigatran dissociates from the bound factor IIa, thrombin, due to its higher affinity for idarucizumab, and binds to idarucizumab.This reversal effect, such as "anti-missile" interception as fast and accurate, can better meet the clinical needs.

three.The original intention of R & D to reassure doctors and patients

Sales of "dabigatran etexilate" in 2017 were 1.438 billion euros worldwide, a steady increase since its launch in 2011.Sales data for idarucizumab are not publicly available.

As we all know, developing a monoclonal antibody is not easy, and the cost is very high.If, from a pharmacoeconomic point of view, it does not seem to be very cost-effective for drug companies, Mr. von Ned said when the reporter raised this question, the development of this antibody drug is not from a profitable point of view, but on the one hand, it is optimistic about the future market of "dabigatran etexilate", in order to give doctors more peace of mind when using it, give patients double insurance.Second, through the marketing of this drug, people reduce the use of anticoagulants doubts, to enhance the awareness of people with atrial fibrillation stroke prevention.

Attached: Interviews with reporters

Q: Hello Mr. Von Ned!What is the current market share of dabigatran etexilate?

Von Ned: In terms of market value, we are leading the market for stroke prevention in atrial fibrillation, with a market share of about 45%, that is, dabigatran etexilate accounts for 45% of the market share in the new oral anticoagulant stroke prevention market.But dabigatran etexilate is smaller than warfarin, which has been on the market for 20 to 30 years.

Q: How does BI intend to further improve drug accessibility?

Von Ned: Dabigatran etexilate entered Medicare in 2017, I think on the one hand because it has a good advantage as a new oral anticoagulant, on the other hand, the government also realized that some elderly patients taking warfarin do have great dangers, such as more difficult to control coagulation, which is an important reason for the government to include dabigatran etexilate in Medicare.

Idarucizumab is not yet covered by Medicare, a class of biologics that will be marketed at a reasonable price based on manufacturing costs.

Dabigatran etexilate now has a competitive advantage in Medicare prices, and I believe many patients can afford it.As far as I know, many drugs now have some bidding behavior in various provinces in order to get medical insurance.With the pressure of bidding and the availability of generics, I believe that the price of dabigatran etexilate could fall further, making it affordable for more patients.

Q: Idarucizumab is marketed as a rare disease in China. From the perspective of drug company economics, the R & D and final return on investment may not be proportional. What are the initial considerations for the development of Idarucizumab by BI?

P> von Ned: At the beginning of our development of idarucizumab, financial returns were not a priority.So why are we still developing this drug?This is mainly because dabigatran etexilate is still very well anticoagulated, and the number of patients taking dabigatran etexilate worldwide is increasing.China is gradually entering an aging society. In the future, more and more elderly patients with atrial fibrillation will have long-term use demand of dabigatran etexilate. Under the premise of such market, it is necessary to make doctors and patients "more at ease" after using dabigatran etexilate.

When a patient is in an emergency surgical situation, he needs to reverse the effect of anticoagulation quickly and promptly.If we have a drug like idarucizumab that can be quickly reversed, it can greatly reduce the concerns and worries of patients and doctors and make them more at ease.Bold use of dabigatran etexilate allows Pradaxa to be used longer.So, we are not designing idarucizumab for commercial purposes, but to make it easier for doctors and patients to use it in an emergency.

Q: In your opinion, what are the gaps in the treatment of stroke between Chinese and foreign AF patients?

P: I don't really know what dimension to measure the "gap", but what I do know is that China is too big a country to compare with foreign countries, so there are some limitations in treating stroke emergencies.In many small countries in Europe, patients do not come to the hospital for treatment at the onset of a stroke far enough to receive treatment in a timely manner, and hospitals are equipped with very professional doctors and rescue facilities.

However, in China, because the size of the country is really too large, if stroke patients live in rural or remote areas, it will take them a long time to reach the major hospitals that can treat stroke once the disease occurs, which is obviously far less favorable for the "golden 3 hours" required for stroke treatment.

Q: As a participant in AF stroke, does BI have some plans to help China close the gap?

P: In fact, now the Chinese government.Health officials and health care workers are also aware of the problem.We hold hands with the Chinese Stroke Association (CSA) and the American Heart Association/American Stroke Association (AHA/ASA) to fund a training course.

This training course has three modules. Through this course, we strive to provide international training opportunities for stroke doctors in more remote areas and primary hospitals to further promote the standardization of stroke diagnosis and treatment in China.Normalization.The whole project is called "Stroke Comprehensive Training Center", which is sponsored by BI to carry out clinical training bases in Beijing and Shanghai.

As far as I know, each of the two places has 50 doctors training each week, flying over on Friday and returning at the weekend.After training in these three modules, doctors will receive a certificate to provide more stroke patients with safer and more effective treatment.At the same time, these primary care doctors are trained, and their primary hospitals can also be certified, which means that the hospital has the standard of stroke treatment.

Predictably, as training courses continue to deepen, the number of stroke patients in China who can be treated professionally will quickly catch up with the United States and Europe.Therefore, training programs like this one, we will continue to increase investment, so that it can continue to carry on, so that more Chinese stroke patients get more safe and effective.Standardized treatment.

扫码实时看更多精彩文章

版权及免责声明 本文由医药魔方原创,版权归医药魔方所有。未经许可,严禁任何媒体或个人以任何形式摘编、改写、复制、转载本文内容。对于恶意侵权行为,医药魔方保留采用法律手段追究的权利。媒体内容及商务合作请联系医药魔方工作人员(微信号:medicube)

魔方微信公众号