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重磅炸弹药物的开发,是时候换个思路了

医药魔方 医药魔方 来源:医药魔方
2019-02-04
创新药
原文

一直以来,制药行业通常会以“是不是重磅炸弹”来评价一个药物的开发是否成功。年销售额10亿美元是一个药物获得重磅炸弹身份的硬性标准,如果年销售超过100亿美元,则会被称为“超级重磅炸弹”。


重磅炸弹模式的好处是显而易见的,比如这个药物会变得众所周知,公司品牌能够得到极大的提升,能够产生充足而稳定的现金流等。但是随着精准医疗的兴起,开发和评价药物惯用的“重磅炸弹模式”可能要改变了。


精准医疗背后体现的是个性化的用药需求。只针对很小一部分患者群体的用药需求进行新药开发,这与重磅炸弹模式下的新药开发思路有很大不同。精准医疗指导下的新药开发可以为细分领域的患者创造更大的临床获益,同时可以缩减研发成本,创造更大的利润,或许可以称之为新药开发的“利基模式”。


利基(niche)是一个商业术语,代表基于企业自身优势细分出来的目标市场。由于这个市场的群体通常不大,而且没有得到令人满意的服务,当产品推进这个市场时 ,就有盈利的基础。企业在确定利基市场后,往往是用更加专业化的经营来获取最大限度的收益,提供的则是针对性、专业性很强的产品。


单个利基导向的新药很可能达不到10亿美元的重磅炸弹药物门槛,但是多个利基导向的药物(也包括罕见病)组合就会创造出新的重磅炸弹效应。从另一个角度讲,新模式下的重磅药物的商业化开发更少依赖面向消费者的广告营销,更多依赖前沿的分子药物学技术。


精准型新药开发模式逐渐兴起


DalCor公司的核心候选药物是CETP抑制剂dalcetrapib,这个靶点也是新药开发的重灾区之一(见:安进放弃开发TA-8995:最后一个巨头离场,明星靶点CETP黯然落幕)。


dalcetrapib此前由罗氏开展的III期研究宣告失败,但是DalCor发现dalcetrapib可以对一群带有特殊基因的急性冠状动脉综合征患者产生治疗效果。这些患者的ADCY9基因在rs1967309位点有AA多态性,并在所有的受试者中占到了近20%。当这些患者服用他汀类药物,并使用dalcetrapib后,他们的心血管疾病发作率降低了39%。


因此,DalCor募资1.5亿美元,重新将dalcetrapib推上III期临床,目前在32个国家的680个中心招募了6000例携带ADCY99 AA基因型的患者。


另外一个例子,ArQule公司专注于实体瘤或血液肿瘤小分子药物开发,核心项目是一款可逆型BTK抑制剂ARQ 531,可以抑制野生型和C481S突变型BTK。一些携带C481S突变的慢性CLL患者对伊布替尼响应不佳,ARQ 531可以不考虑这个突变状态,即将进入II期阶段。伊布替尼是一个多样性的重磅炸弹药物,但是在细分人群上跟ARQ 531没有直接竞争关系。伊布替尼大获成功给大家推广了BTK抑制剂的概念,ARQ 531也会因此受益。


重新定义重磅炸弹药物


“重磅炸弹药物的定义正在改变,年销售额不再是确立重磅炸弹身份的唯一标准。因为药物的研发和审评效率越来越高,更少的销售收入就能实现与之前达到重磅炸弹级别药物相同的投资回报”,DalCor 制药公司CEO Fouzia Laghrissi-Thode接受GEN采访时表示。


Fouzia Laghrissi-Thode,DalCor公司CEO


ArQule公司高级副总裁&战略、财务负责人Marc Schegerin则认为:“大家无需再用重磅炸弹药物来证明自己的成功。科学成功的定义在之前是开发出一款重磅炸弹药物,现在的标准就是发现一药物有成药潜力并且用数据证明自己的眼力。商业成功的衡量标准也在变化,现在是看给予合适的目标治疗能否让患者的获益最大化。”


Marc Schegerin,ArQule公司高级副总裁


“制药公司今天可以用更少的钱在较小的患者群体中做得更多,一些小分子药物很可能就会成为重磅炸弹级别。跟很多生物技术公司类似,ArQule不追求产品上市后可以创造庞大的销售数字,而是希望可以给合适的患者提供更符合需求的疗法,创造最大的利润”。Marc Schegerin补充道。


这样一种模式就是精准医疗指导下的新药开发,锚向更窄、更细分的患者人群,让患者和公司都实现最大的获益。


监管机构的态度在变化


FDA在批准一个药物的时候,并不关心它上市后能否成为重磅炸弹,只关心它是否足够的安全、有效。医保付费者也不关心一个新药能否成为重磅炸弹,只关心它是否比现有的疗法更好,以及是否符合报销补偿标准。但是对于企业而言,如果能够摸准FDA的要求,确实可以帮助一个药物更快成为重磅药物。


具来说,当新药研发工作更有效的时候,成为重磅药物的可能性就更大。FDA新的监管指南更强调在药品开发时融入对当前科学进步和临床需求的考虑,也更愿意接受新的前沿技术和现实实践(比如以真实世界数据作为对照组),因此,企业在新药研发过程中可以更多调用相应的资源。


采用数字医疗技术也可以节省研发成本和时间。比如赛诺菲和Kaiser Permanente公司合作在10000例受试者中评估其新疫苗产品和当前标准接种疫苗的差异,通过调用患者的医疗记录确定新疫苗的防护效力。据赛诺菲执行副总裁&全球研发负责人John Reed透露,这项合作仅花费500万美元(500美元/人),并且在几个月内就获得了结果。


数据挖掘提供了理解临床数据的新角度,获取电子健康记录可以提供开展临床研究的新方式,通过人工智能和机器学习的辅助,研究人员可以筛选出更可能从治疗中获益的受试者,可穿戴设备和手机应用可以提供更丰富并且可量化的实时监测数据。


对于监管机构和生物技术公司来讲,都有意愿从不同角度来提高新药研发的效率。今天一个药物在开发时越是锚向特定的人群,就越可能具备成为革命性疗法的潜力。本质上,如果投资回报率改变了,重磅炸弹药物的定义就会改变。


参考资料:GEN. The Blockbuster Is Dead. Long Live the Blockbuster!


机器翻译

The pharmaceutical industry has long used the term "blockbuster" to assess the success of a drug's development.Sales of $1 billion a year is a tough criterion for a drug to gain blockbuster status, and if sales exceed $10 billion a year, it will be called a "super blockbuster".The benefits of the

blockbuster model are obvious, such as the fact that the drug will become well-known, the company's brand can be greatly enhanced, and it can generate sufficient and stable cash flow.But with the rise of precision medicine, the conventional "blockbuster model" of developing and evaluating drugs may have to change.

behind precision medicine is the personalized medication needs.New drugs are being developed only for the needs of a small group of patients, which is very different from the idea of developing new drugs in the blockbuster model.New drug development under the direction of precision medicine can create greater clinical benefit for patients in subdivided areas, while reducing R & D costs and creating greater profits, perhaps called the "niche model" for new drug development.

niche is a business term that represents a target market that is subdivided based on an enterprise's own advantages.Because the market is often small and underserved, there is a basis for profit when products push into the market.After determining the niche market, companies often use more specialized operations to obtain the maximum benefits and provide targeted.Very professional product.

A single niche drug may not reach the $1 billion blockbuster threshold, but multiple combinations of niche drugs (including rare diseases) create new blockbuster effects.On the other hand, the commercial development of blockbuster drugs under the new model relies less on advertisement marketing for consumers and more on cutting-edge molecular pharmacology technologies.

Accurate new drug development model is gradually emerging

DalCor's core drug candidate is the CETP inhibitor dalcetrapib, which is also one of the hardest hit areas for new drug development (see: Amgen abandoned the development of TA-8995: the last giant left, star target CETP overshadowed).

dalcetrapib has failed a previous Phase III study conducted by Roche, but DalCor found that dalcetrapib can produce therapeutic effects in a group of patients with acute coronary syndrome with specific genes.These patients had an AA polymorphism in the ADCY9 gene at rs 1967309, accounting for nearly 20% of all subjects.When these patients were treated with statins and dalcetrapib, they had a 39% reduction in the incidence of cardiovascular disease.

Therefore, DalCor raised funds 1.For $500 million, dalcetrapib has been reintroduced into phase III clinical trials, and 6000 patients with the ADCY99 AA genotype have been enrolled at 680 centers in 32 countries.

In another example, ArQule is focused on small molecule drug development for solid or hematologic cancers, and the core program is ARQ 531, a reversible BTK inhibitor that inhibits wild-type and C481S mutant BTKs.Some chronic CLL patients with the C481S mutation do not respond well to ibrutinib, and ARQ 531 may enter Phase II regardless of the mutation status.Ibrutinib is a diverse blockbuster drug, but does not directly compete with ARQ 531 in subdividing populations.Ibbutini has been successful in promoting the concept of BTK inhibitors, and ARQ 531 will benefit.

Redefining blockbuster drugs

“The definition of blockbuster drugs is changing, and annual sales are no longer the only standard for establishing a blockbuster identity. Because drug discovery and evaluation are becoming more efficient, fewer sales revenues can be achieved with previous heavyweights. The same return on investment for bomb-level drugs”,Fouzia Laghrissi-Thode, CEO of DalCor Pharmaceuticals, said in an interview with GEN.

Fouzia Laghrissi-Thode, Senior Vice President & Strategy, DalCor, Inc.Finance director Marc Schegerin said: "You don't need blockbuster drugs to prove your success.Scientific success, defined as the development of a blockbuster drug, is now based on discovering that a drug has potential as a drug and using data to prove its eyesight.The measure of business success is also changing, and now it is to see if giving the right target treatment can maximize the patient's benefit. ”

Marc Schegerin, Senior Vice President, ArQule

“Pharmaceutical companies can do more today in smaller patient groups with less money, and some small molecule drugs are likely to become blockbuster. Like many biotech companies, ArQule can't create products after they go on the market. With huge sales figures, I hope to provide the right patients with more demanding therapies and create the most profit." Marc Schegerin added.

Such a model is the development of new drugs under the guidance of precision medical treatment, anchoring to a narrower, more segmented patient population, allowing patients and companies to achieve maximum benefits..

The attitude of the regulator is changing

When the FDA approves a drug, it does not care whether it can become a blockbuster after its listing. It only cares whether it is safe enough. The health care payer does not care whether a new drug can become a blockbuster, only concerned about whether it is a bomb. Better than existing therapies and compliance with reimbursement compensation standards. But for companies, if they can meet FDA requirements, they can really help a drug become a heavy drug faster..

In fact, when new drug research and development work is more effective, the possibility of becoming a heavy drug is even greater.. FDA's new regulatory guidance places more emphasis on incorporating considerations of current scientific advances and clinical needs into drug development, and is more willing to accept new cutting-edge technologies and real-world practices (such as using real-world data as a control group). Therefore, companies can use more corresponding resources in the process of new drug development.

Digital technology can also save development costs and time. Sanofi and Kaiser Permanente, for example, collaborated to evaluate the difference between their new vaccine product and the current standard vaccination in 10,000 subjects, and to determine the protective efficacy of the new vaccine by calling the patient's medical records.According to John Reed, Sanofi’s executive vice president and global R&D leader, the partnership cost only $5 million ($500/person) and received results in a few months..

Data mining provides a new perspective on understanding clinical data. Obtaining an electronic health record can provide a new way to conduct clinical research. With the help of artificial intelligence and machine learning, researchers can screen out subjects who are more likely to benefit from treatment. Wearables and mobile apps can provide richer and more quantifiable real-time monitoring data.

For regulators and biotech companies, there is a willingness to improve the efficiency of new drug development from different perspectives. The more a drug is anchored to a specific population today, the more likely it is to become a revolutionary therapy. Essentially If the return on investment changes, the definition of blockbuster drugs will change.

Reference material:GEN.  The Blockbuster Is Dead. Long Live the Blockbuster!

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