2019年十大生物制药事件

红茶.

全文机翻，英文看二楼。

今年标志着生物制药行业又出现了一系列有趣，令人兴奋且有时令人困惑的故事。Alex Keown和Mark Terry评选了年度最佳十大故事。


百健的Aducanumab过山车之旅


在过去的几年中，随着阿尔茨海默氏病的治疗继阿尔茨海默氏病失败之后，尽管许多批评家对此持怀疑态度，但Biogen的aducanumab似乎是最后的最大希望。然后，在2019年3月，Biogen及其合作伙伴东京总部的Eisai 宣布，他们将停止针对阿兹海默氏症轻度认知障碍患者的aducanumab的全球III期临床试验ENGAGE和EMERGE，以及EVOLVE II期试验以及PRIME Ib期长期试验。一个独立的数据监控委员会表示，这些试验不太可能在无效性分析中达到其主要终点。


但是在10月下旬，两家公司宣布，在与美国食品和药物管理局（FDA）讨论并进一步分析数据之后，他们将寻求对该药物的监管批准。EMERGE III期临床试验达到了其主要终点，显示临床下降显着减少。该公司认为，来自一部分患者的足够高剂量药物的数据对认知和功能（包括记忆力，方向和语言）以及对日常生活活动的益处具有重要意义。


12月5日，该公司在圣地亚哥举行的第12 届阿尔茨海默氏病临床试验（CTAD）会议上介绍了阿杜那单抗的全部数据。结果是……更多的是坐过山车。尽管有一些非常令人感兴趣的积极数据，但在两项试验之间存在一些有关安全性信号和混合结果的争论，这很可能使FDA激烈辩论是否应真正批准该药物。在这方面，过山车行驶不可能结束。


埃博拉疫苗在欧洲获得批准


欧盟委员会批准了世界上第一个埃博拉疫苗。该疫苗由默克公司生产，商品名为Ervebo。


默克公司董事长兼首席执行官肯尼斯·弗雷泽（Kenneth C. Frazier）表示：“欧洲委员会对Ervebo的营销授权是前所未有的合作的结果，全世界都应该为此感到自豪。” “这是一个历史性的里程碑，也是科学，创新和公私伙伴关系力量的证明。”




刚果民主共和国东部的“同情使用”计划正在使用Ervebo，该地区有史以来第二大埃博拉疫情爆发。自2018年8月以来，该国有3,000多人对埃博拉病毒呈阳性反应，有2,000多人因此而死亡。去年，刚果民主共和国已向超过25万人接种了默克疫苗。


强生公司正在开发的另一种埃博拉疫苗，正在戈马市给50,000人服用，该市位于刚果东部卢旺达边界，有200万人。强生疫苗需要间隔八周注射两次，而默克疫苗只需要注射一次即可。


遗传基因组编辑暂停


2018年，中国研究人员利用CRISPR-Cas9基因编辑技术改变了7对夫妇的胚胎DNA，引发了丑闻，主要科学家呼吁暂停遗传性基因组编辑。


2018年11月，中国深圳的研究员何建奎宣布，他已使用CRISPR在7对夫妇的胚胎中禁用了一个名为CCR5的基因。七对夫妇中的所有男人都控制了艾滋病毒，但女人没有。他声称，基因编辑的目的并不是要预防艾滋病毒的传播，而是要给儿童提供保护。一组双胞胎出生，并且至少有另一名妇女怀孕。


来自七个国家的18位领先的研究人员和生物伦理学家写了要求暂停执行死刑的呼吁，其中包括张峰和Emmanuelle Charpentier，他们在不同的实验室中被称为CRISPR的竞争发明者。


暂停并不要求永久禁止，而是说：“相反，我们呼吁建立一个国际框架，在该框架中，各国在保留自行决定权的同时，自愿承诺不批准任何使用临床种系编辑的做法除非满足某些条件。”


特拉维夫大学研究人员3D打印人心


在所谓的生物打印方面已经有了重大进展，即使用一种3D打印技术来制造生物组织。但是直到现在，还没有完成一个真正的器官。


特拉维夫大学的研究人员成功地打印了第一个3D人类心脏。研究小组使用了患者自身的细胞以及各种生物材料，例如胶原蛋白和糖蛋白。


首席研究员塔尔·德维尔（Tal Dvir）说：“心脏是由人类细胞和患者特定的生物材料制成的。” “在我们的过程中，这些材料用作生物墨水，是由糖和蛋白质制成的物质，可用于复杂组织模型的3D打印。过去，人们可以3D打印心脏的结构，但不能通过细胞或血管来3D打印。我们的结果证明了我们的方法在将来工程化个性化组织和器官置换的潜力。”


这只是今年的一个大故事，显示了我们在3D打印器官方面的发展以及我们为研究目的和潜在的器官替换方向。


Roivant与Sumitomo Dainippon Pharma达成的30亿美元交易


尽管并没有像百时美施贵宝（Bristol-Myers Squibb）以740亿美元收购Celgene那样大的交易，但在Vivek Ramaswamy的总公司Roivant Sciences旗下出售了五家'Vant公司之后，这标志着Ramaswamy的业务模式和对生物技术公司的态度得到了验证。该交易最初是在9月宣布的，但更多细节在11月公布。


Roivant以30亿美元的价格将五家“ Vant”公司的所有权出售给了日本住友大日本制药公司（Sumitomo Dainippon Pharma）。Sumitomo Dainippon也购买了Roivant超过10％的股份。


住友将创建一家尚未命名的公司，以将这五家公司转变为一家公司。它们将由前Genentech高管默特尔·波特（Myrtle Potter）负责，他自2018年7月起担任Roivant的运营主席。


有30亿美元的预付款。此外，住友商事将向Myovant提供3.5亿美元的贷款安排，以资助推出relugolix，如果批准，将其用于子宫肌瘤的三期候选药物。这家日本公司还将向Urovant贷款2亿美元，用于膀胱过度活动的vibegron。


如果住友选择其他六家公司，它将在2020年至2022年期间获得超过25种临床项目的管道，并可能有多个项目启动。除了购买这五家初始公司外，这笔交易还使住友可以使用Roivant的专有技术平台DrugOme和数字创新。它还将与Datavant和Alyvant进入单独的战略客户关系。


五个Vant公司分别是Myovant Sciences，Urovant Sciences，Enzyvant Therapeutics，Altavant Sciences和Spirovant Sciences。Spirovant是一种新型Vant，专注于开发用于囊性纤维化的基因疗法。


普渡的沦陷


2019年标志着OxyContin的制造商Purdue Pharma倒下了。九月份，普渡申请破产，并同意在其针对OxyContin的积极营销策略对公司提起数千起诉讼后，支付10至120亿美元的法律和解金。州和地方政府实体指责该公司的举动助长了美国的阿片类药物危机，这场危机已导致数以千计的与阿片类药物相关的药物过量死亡。


在公司申请破产的同时，它将继续采用新的管理架构。新公司将由索赔人选定并由破产法院批准的董事会管理。新公司成立后，它将以很少或没有成本的方式提供“数千万剂”的阿片类药物过量逆转药物和治疗，这些药物和疗法旨在使阿片类药物成瘾，如纳美芬和纳洛酮。


除了普渡100％的资产被包括在破产中之外，作为私人控股公司大股东的萨克勒家族同意出资至少30亿美元，并有可能从该公司获得进一步的货币捐款。他们在美国之前的制药业务（例如Mundipharma）的销售额在整个和解讨论中的价值约为15亿美元。


致癌物召回年


尽管由于众多问题而召回毒品的情况并不少见，但2019年似乎有许多召回事件都涉及制造过程中发现的致癌物质问题。这一年始于对召回存在致癌物的血压药物的多次召回。FDA召回了来自不同制造商的许多不同类型的血管紧张素II受体阻滞剂，原因是存在一种称为N-亚硝基-N-甲基-4-氨基丁酸（NDMA）的杂质，这是一种已知的致癌物。像Teva和Camber Pharmaceuticals这样的公司召回了许多氨氯地平和氯沙坦钾片，发现它们被已知的环境污染物NMBA污染。几个月以来，有许多批次被召回，因此不可避免的是将对受污染的血压药物提起诉讼。


被发现被污染的不仅是血压药物。由于存在NDMA，还被召回了雷尼替丁片，雷尼替丁片用于减少由胃产生的酸量。11月，Aurobindo加入了赛诺菲，葛兰素史克，诺华，雷迪博士实验室，Perrigo，Novitium Pharma和Lannett Company等公司，召回雷尼替丁片。


Keytruda成为癌症治疗的基石


在六月份的投资者日会议上，默克公司首席商务官弗兰克·克莱伯恩（Frank Clyburn）在很短的时间内说，Keytruda已成为一种基础的癌症治疗方法。“我们在25种不同的癌症类型中开展活动……而Keytruda正在改变当今治疗患者的方式，” Clyburn当时说。随着默克公司夸张的检查站抑制剂的批准数量不断增加，克莱伯恩的话被证明对提振股价并不是吹牛的。实际上，分析家认为Keytruda会取代AbbVie的Humira（在2023年失去专利保护），到2025年成为世界上销量最大的药物。Keytruda 自2015年以来已经获得了22多次批准，并且有望在未来获得更多收入。


默克公司最近宣布，Keytruda作为一种单一疗法，在其肿瘤表达PD-L1的转移性非鳞状非小细胞肺癌（NSCLC）患者中，显示了其总生存，无进展生存和总缓解率的显着改善。 KRAS突变。在对数据进行分析时，与化学疗法相比，Keytruda将具有任何KRAS突变的患者的死亡风险降低了58％，将具有KRAS G12C突变的患者的死亡风险降低了72％。随着新的一年的到来，Keytruda也可能会获得更多的批准。

艾滋病毒的持续改善


去年11月，雅培实验室的研究人员发现了一种新的HIV毒株，这是近二十年来第一个HIV-1亚型。研究人员发现了一种新的亚型“ M组” HIV病毒，其起源可以追溯到非洲的刚果民主共和国。新菌株的发现意味着研究人员可以开始针对它开发潜在的新疗法。自全球艾滋病流行开始以来，已有超过7500万人感染了艾滋病毒。曾经是一次虚拟的死刑，但是，随着新药和新疗法的发展，超过3790万人能够控制自己的病毒并继续过上有生产力的生活。


今年有许多新的HIV批准，包括默克的Pifeltro和Gilead Science的HIV暴露前预防的Descovy。公司的管道中也有许多潜在的治疗方法，包括使用CRISPR技术进行骨髓移植并调节BRD4蛋白，这已被视为治疗该病的潜在方法。在长的非编码RNA的遗传修饰中也有治愈的潜力。随着2019年完成的有希望的工作，2020年将为HIV患者带来更多的治疗选择。

大型并购年


并购是制药和生物技术行业日新月异的组成部分。但是今年，随着一些最大的公司成为一体，格局发生了几项大规模变化。一切始于1月，百时美施贵宝宣布将以740亿美元收购 Celgene。两家制药业巨头的合并在肿瘤学，血液学，免疫学和心血管疾病领域创造了强大的力量。自合并以来，合并后的公司取得了数项新的监管胜利，包括FDA 批准Celgene的Reblozyl（luspatercept-aamt）用于治疗某些成人β地中海贫血的贫血。


六个月后的6月，AbbVie宣布以630亿美元收购肉毒杆菌毒素生产商Allergan 的“ 转型举措 ”。当交易宣布时，AbbVie表示，增加Allergan的产品线和产品将为该公司的增长平台立即扩大规模，并实现其减少对Humira的依赖的战略目标，Humira是该公司的主要摇钱树。合并后的公司将在免疫学，血液肿瘤学，医学美学，神经科学，妇女健康，眼保健和病毒学领域拥有多个强大的专营权。


虽然这是2019年的两个最大的合并，但还有其他一些肯定会改变格局，包括Mylan与辉瑞的非专利药品公司Upjohn的合并。预计这家新公司的2020年收入将达到200亿美元。新公司将拥有众多知名品牌，包括Epi-Pen，Viagra，Lipitor，Celebrex等。

红茶.

This year marked yet another series of interesting, exciting and occasionally puzzling stories coming out of the biopharma industry. Our breaking news writers, Alex Keown and Mark Terry, picked their top 10 stories of the year.

Biogen’s Aducanumab Rollercoaster Ride

For the last few years, as Alzheimer’s drug after Alzheimer’s drug met with failure, Biogen’s aducanumab appeared to be the last best hope, even though many critics were skeptical. Then, in March 2019, Biogen and its collaboration partner, Tokyo-based Eisai, announced they were discontinuing the global Phase III trials, ENGAGE and EMERGE, of aducanumab in patients with mild cognitive impairment from Alzheimer’s, as well as the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial. An independent data monitoring committee indicated the trials were unlikely to hit their primary endpoints in a futility analysis.

But in late October, the companies announced that after discussions with the U.S. Food and Drug Administration (FDA), and further analysis of the data, they were going to pursue regulatory approval for the drug. The Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. The company believes that data from a subset of patients that were given a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation, and language, as well as benefits on activities of daily living.

On Dec. 5, the company presented full data on aducanumab at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) conference to held in San Diego. And the results were … more of a rollercoaster ride. Although there were positive data that’s very intriguing, there were some concerning safety signals and a mixed result between the two trials that are likely to have the FDA debating intensely over whether the drug should actually be approved. In that respect, the rollercoaster ride is unlikely to be over.

Ebola Vaccine Approved in Europe

The European Commission approved the world’s first Ebola vaccine. The vaccine is manufactured by Merck & Co. and has a trade name of Ervebo.

“The European Commission’s marketing authorization of Ervebo is the result of an unprecedented collaboration for which the entire world should be proud,” said Kenneth C. Frazier, Merck’s chairman and chief executive officer. “It is a historic milestone and a testament to the power of science, innovation and public-private partnership.”


Ervebo was being used under a “compassionate use” program in the eastern Democratic Republic of Congo (DRC), where there has been the second-largest Ebola outbreak on record. Since August 2018, more than 3,000 people in the country have tested positive for Ebola and more than 2,000 people have died of it. In the last year, more than 250,000 people have been dosed with the Merck vaccine in DRC.

Another Ebola vaccine being developed by Johnson & Johnson, is being administered to 50,000 people in Goma, a city with two million people on the Rwandan border of eastern Congo. The J&J vaccine requires two injections eight weeks apart, while the Merck vaccine only requires a single shot.

Moratoriums on Heritable Genome Editing

In the wake of the 2018 scandal caused by a Chinese researcher’s use of CRISPR-Cas9 gene editing to alter the DNA of embryos for seven couples, leading scientists called for a moratorium on heritable genome editing.

In November 2018, He Jiankui, a researcher in Shenzhen, China, announced that he had used CRISPR to disable a gene called CCR5 in the embryos of seven couples. All the men in the seven couples had controlled HIV, but the women did not. The gene editing’s goal wasn’t to prevent transmission of HIV, but, He claimed, to give the children protection. A set of twins were born and at least one other woman is pregnant.

The call for a moratorium was written by 18 leading researchers and bioethicists from seven countries, including Feng Zhang and Emmanuelle Charpentier, who in separate labs, are noted as the competing inventors of CRISPR.

The moratorium does not call for a permanent ban, but states, “Rather, we call for the establishment of an international framework in which nations, while retaining the right to make their own decisions, voluntarily commit to not approve any use of clinical germline editing unless certain conditions are met.”

Tel Aviv University Researchers 3D-Print a Human Heart

There has been significant progress in so-called bioprinting—using a type of 3D printing to manufacture biological tissues. But an actual organ hadn’t been accomplished—until now.

Researchers at Tel Aviv University successfully printed the first 3D human heart. The research team used the patient’s own cells and various biological materials such as collagen and glycoprotein.

“This heart is made from human cells and patient-specific biological materials,” stated Tal Dvir, lead researcher. “In our process these materials serve as the bioinks, substances made of sugars and proteins that can be used for 3D printing of complex tissue models. People have managed to 3D-print the structure of a heart in the past, but not with cells or with blood vessels. Our results demonstrate the potential of our approach for engineering personalized tissue and organ replacement in the future.”

This is only one big story this year showing how far we’ve come and the direction we’re headed in 3D-printing organs for research purposes and potentially for organ replacement.

Roivant’s $3 Billion Deal with Sumitomo Dainippon Pharma

Although not as big a deal as, say, Bristol-Myers Squibb’s $74 billion acquisition of Celgene, the sale of five ‘Vant companies under Vivek Ramaswamy’s umbrella company, Roivant Sciences, marked a validation of Ramaswamy’s business model and approach to biotech companies. The deal was originally announced in September, but more details came out in November.

Roivant sold ownership of five ‘Vant companies to Japan’s Sumitomo Dainippon Pharma for $3 billion. Sumitomo Dainippon also was buying an equity stake of more than 10% of Roivant shares.

Sumitomo will create an as-yet unnamed company to shift the five companies into. They will be run by Myrtle Potter, a former Genentech executive who has been the operating chair of Roivant since July 2018.

There is a $3 billion upfront fee. In addition, Sumitomo will offer a $350 million loan facility to Myovant to fund the launch of relugolix, its Phase III candidate for uterine fibroids if it is approved. The Japanese firm will also loan Urovant $200 million for its vibegron for overactive bladder.

If Sumitomo options the other six companies, it will have acquired a pipeline of more than 25 clinical programs with multiple possible launches from 2020 to 2022. In addition to buying the five initial companies, the deal gives Sumitomo access to Roivant’s proprietary technology platforms, DrugOme and Digital Innovation. It will also enter separate strategic client relationships with Datavant and Alyvant.

The five Vant companies are Myovant Sciences, Urovant Sciences, Enzyvant Therapeutics, Altavant Sciences, and Spirovant Sciences. Spirovant is a new Vant that focuses on developing gene therapies for cystic fibrosis.

The Fall of Purdue

The year 2019 marked the fall of Purdue Pharma, the makers of OxyContin. In September, Purdue filed for bankruptcy and agreed to pay $10 to $12 billion in legal settlements after thousands of lawsuits were filed against the company over its aggressive marketing tactics for OxyContin. State and local government entities accused the company’s maneuvers of contributing to the opioid crisis in the United States, a crisis that has resulted in thousands of opioid-related overdose deaths.

While the company is filing for bankruptcy, it will continue under a new management structure. The new company will be governed by a board selected by the claimants and approved by the bankruptcy court. When the new company is formed, it will contribute “tens of millions of doses” of opioid overdose reversal medications and treatments aimed at opioid addiction at little or no cost, such as nalmefene and naloxone.

In addition to 100% of Purdue’ assets being included in the bankruptcy, the Sackler family, which is the majority owner of the privately-held company, agreed to contribute a minimum of $3 billion, with the potential for substantial further monetary contributions from the sales of their ex-U.S. pharmaceutical businesses, such as Mundipharma, which has been pegged at a value of about $1.5 billion throughout the settlement discussions.

Year of the Carcinogen-Related Recalls

While drug recalls are not uncommon due to a myriad of issues, 2019 seemed to have a number of them all involving issues with carcinogens discovered in the manufacturing process. The year began with a number of recalls of blood pressure medications that were found to have carcinogens present. The FDA recalled lots of different types of angiotensin II receptor blockers from different manufacturers due to the presence of an impurity called N-Nitroso-N-methyl-4-aminobutyric acid (NDMA), a known carcinogen. Companies like Teva and Camber Pharmaceuticals recalled lots of Amlodipine and losartan potassium tablets that were found to be contaminated with NMBA, a known environmental contaminant. With the multiple lots recalled over the course of months, it was inevitable that lawsuits would be filed regarding the tainted blood pressure medications.

It wasn’t just blood pressure medications that were found to have been contaminated. Ranitidine tablets, which are used to decrease the amount of acid created by the stomach, have also been recalled due to the presence of NDMA. In November, Aurobindo joined the likes of Sanofi, GlaxoSmithKline, Novartis, Dr. Reddy’s Laboratories, Perrigo, Novitium Pharma and Lannett Company in the recall of ranitidine tablets.

Keytruda Becomes a Cornerstone of Cancer Treatment

During an Investor’s Day conference in June, Merck's Chief Commercial Officer Frank Clyburn said in a short time, Keytruda has become a foundational cancer treatment. “We have activity across 25 different cancer types… and Keytruda is changing the way in which patients are being treated today,” Clyburn said at the time. And with the number of approvals Merck’s vaunted checkpoint inhibitor keeps racking up, Clyburn’s words are proving not to be a boast to boost share prices. In fact, analysts have pegged Keytruda to become the number one selling drug in the world by 2025, supplanting AbbVie’s Humira, which loses patent protection in 2023. Keytruda has been approved more than 22 times since 2015 and is well on its way to earning more.

Most recently, Merck announced that Keytruda, used as a monotherapy, demonstrated significant improvement in overall survival, progression-free survival and overall response rate in patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 regardless of KRAS mutation. In its analysis of the data, Keytruda reduced the risk of death by 58% in patients with any KRAS mutation and by 72% in patients with the KRAS G12C mutation compared to chemotherapy. With a new year on the horizon, it’s likely more approvals for Keytruda are as well.

Continued Improvements in HIV

In November, researchers at Abbott Laboratories discovered a new strain of HIV, the first such subtype of HIV-1 in nearly two decades. The researchers uncovered a new subtype of "Group M" HIV virus, whose origins can be traced to the Democratic Republic of the Congo in Africa. The discovery of the new strain means researchers can begin to develop potential new therapies aimed at it. Since the start of the global AIDS epidemic, more than 75 million people have been infected with HIV. At one time, it was a virtual death sentence, however, with the development of new medications and treatments, more than 37.9 million people are able to control their virus and continue living productive lives.

There have been a number of new approvals for HIV this year, including Merck’s Pifeltro and Gilead Science’s Descovy for HIV pre-exposure prophylaxis. There are also numerous potential treatments in the pipelines of companies, including bone marrow transplants using CRISPR technology and regulating the protein BRD4, which has been seen as a potential cure for the disease. There has also been potential for a cure in the genetic modification of long noncoding RNA. With the promising work done in 2019, 2020 could bring even more treatment options for HIV patients.

Year of the Mega Mergers

Mergers and acquisitions are part of the ever-changing landscape of the pharma and biotech industry. But this year, there have been several large-scale changes to the landscape as some of the biggest companies have become one. It all started in January when Bristol-Myers Squibb announced it was acquiring Celgene for $74 billion. The merger of the two pharma giants created a powerhouse in oncology, hematology, immunology and cardiovascular disease. Since the merger, the combined companies have seen several new regulatory wins, including the FDA approval of Celgene’s Reblozyl (luspatercept-aamt) for the treatment of anemia in certain adult patients with beta thalassemia.

Six months later, in June, AbbVie announced a “transformational move” with the $63 billion acquisition of Botox-maker Allergan. When the deal was announced, AbbVie said the addition of Allergan’s pipeline and products would deliver immediate scale to the company’s growth platform, as well as meet its strategic goal to reduce reliance on Humira, which has been the primary cash cow of the company. The combined companies will have several strong franchises across immunology, hematologic oncology, medical aesthetics, neuroscience, women's health, eye care and virology.

While those were the two biggest mergers of 2019, there have been others that will certainly change the landscape, including Mylan’s merger with Pfizer’s off-patent medicines company, Upjohn. The new company is already projected to post 2020 revenues of $20 billion. The new company will have numerous well-known brands in its portfolio, including the Epi-Pen, Viagra, Lipitor, Celebrex and others.

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