杰克说药丨修美乐何以成为“药王”？
The following article is from 同写意 Author 李杰教授
翻译：同写意团队
杰克说药是著名药史专家Jie Jack Li（李杰）教授专为同写意打造的药林外史精品专栏，将讲述一个个药物发现背后的故事。李杰教授现为上海睿智的副总裁，先后出版了30本有机和药物化学方面的书籍以及药物发现史，其中10本与诺奖得主E. J. Corey合作完成。其《Blockbuster Drugs》一书获 2015 Alpha Sigma Nu Science Book 奖，并被翻译成中文出版，深受欢迎。
开设写意专栏，请联系同写意秘书处（微信号tongxieyimishuchu）
其中最引人注目的案例便是修美乐——药中的利润之王。
2020年，Abbvie的TNF-α抑制剂阿达木单抗（Humira，修美乐）是美国有史以来最赚钱的药物，销售额达214亿美元。到目前为止，Humira已创造了超过1,300亿美元的收入，这么多钱足以购买一个小国家！
与此同时，同样种类的TNF-α抑制剂去年都表现很好。安进公司的Enbrel销售额为81亿美元，强生公司的Remicade销售额为47亿美元。Humira、Enbrel和Remicade是2019年第一、第三、和第十大畅销药物，请见下图。
人们不禁要问，什么是THF-α抑制剂？它们是如何生产的？为什么它们如此有利可图？
TNF-α抑制剂
Humira是生物药”阿达木单抗”的商品名,是一种单克隆抗体药。阿达木单抗有结合并抑制肿瘤坏死因子-α（TNF-α）的功能。TNF是一种与许多炎症性疾病如类风湿关节炎、银屑病、克罗恩病、溃疡性结肠炎等相关的蛋白。
1973年，纽约纪念斯隆-凯特琳癌症中心（Memorial Sloan-Kettering Cancer Center）的Lloyd Old分离出了人体在细菌感染过程中产生的一种可溶性蛋白。因为它能杀死老鼠的肿瘤而被命名为肿瘤坏死因子（TNF）。[1]当时的他做梦也没想到，TNF-α将成为我们这个时代最值钱的靶点。
巨噬细胞和活化的T细胞在肠道损伤时产生的TNF是一种具有促炎和免疫调节双重功能的多效性细胞因子。TNF-α有膜结合形式和可溶性形式2种，这2种形式都是作为同三聚体活性。可溶性TNF-α与慢性炎症相关，而跨膜TNF-α与对病原体的免疫相关。
细胞因子又是由巨噬细胞、肥大细胞、自然杀伤细胞、淋巴细胞、中性粒细胞、基质细胞、B和T细胞等细胞分泌的激素样调节蛋白。它们对调节我们身体的免疫和炎症反应非常重要。自20世纪50年代以来，许多细胞因子被确定，包括白细胞介素-1、神经生长因子、干扰素、当然还有肿瘤坏死因子（TNF）。[2]
如果我们能阻断TNF的主要亚型——肿瘤坏死因子-α蛋白，就可以治疗炎症和自身免疫性疾病。
阻断TNF-α蛋白说起来容易做起来难。TNF-α结合两个独立的细胞表面TNF受体。因为它们的分子量分别为55和75 KDa,这两个受体被称为p55的I型受体和称为p75的II型受体。当三个TNF-α分子（同三聚体）交联三个受体时，激发TNF-α信号。所以使用小分子阻断TNF受体是很难实现的。
因此，大多数成功阻止TNF受体的方法都是用结合TNF-α的大的生物制剂，从而防止其结合到TNF受体进而减少炎症。在阻断TNF蛋白质的生物制剂中，单克隆抗体作为抗肿瘤坏死因子-α的药物尤其成功。
高特异性的单克隆抗体是由César Milstein和Georges Kohler发现的，他们因这项发现于1984年获得诺贝尔奖。当哺乳动物暴露于外来抗原物质如细菌、病毒或化学物质时，产生的抗体是多克隆抗体。但是，单克隆抗体是由单细胞的克隆后代产生的。从动物中分离并保持在培养中，单克隆抗体可以作为一个相同的，高度均一的媒介，并一代又一代地无限繁殖、生产以满足治病的巨量需求。
单克隆抗体通常是从专有的细胞系中产生的。开发这些新的生物药物是非常具有技术性和挑战性的。由于其复杂的结构和制造这些药物的复杂性，即使在同一生物药物批次之间的生产过程中轻微的变化，也可能带来微变异。自1975年建立利用杂交瘤技术生产单克隆抗体以来，单克隆抗体已被公认为治疗性药物。
简而言之，单克隆抗体的生产始于用抗原免疫动物。从脾脏中分离出产生抗体B细胞后，用聚乙二醇（PEG）将B细胞与肿瘤细胞融合，形成杂交瘤细胞。杂交瘤技术是生物技术成功的关键。是杂交瘤使单克隆抗体通过一个相当复杂的技术过程而获得。
并不是所有的抗肿瘤坏死因子-α生物制剂都是一样的。Enbrel是二聚体融合蛋白， Remicade是嵌合型单克隆抗体，而Humira则是用噬菌体展示技术生产的具有完全人源氨基酸序列的完全人源单抗。
伦敦帝国学院的Marc Feldmann和Ravinder Maini发现抗TNF治疗是类风湿关节炎和其他自身免疫性疾病的有效治疗方法。1984年，当细胞因子领域还比较新的时候，Feldmann和Maini合作研究细胞因子是类风湿关节炎发病机制中重要因素的假说。
他们发现了TNF刺激其他炎性细胞因子产生的细胞因子级联反应。Feldmann和 Maini随后在实验动物身上验证了他们的理论，并表明抑制TNF的确阻断了胶原诱导的关节炎。[3]
尽管是最畅销的药物，Humira却不是市场上第一个、也不是第二个TNF-α靶向生物制剂。第一个上市的抗肿瘤坏死因子药物是Remicade。
1998年，FDA批准的Centocor公司的infliximab（Remicade）：第一个治疗类风湿关节炎的抗TNF单克隆抗体。
在20世纪90年代初，Feldmann和Maini获得了成功的临床前数据来支持他们的想法，并说服了费城附近的一家生物技术公司Centocor生产Remicade。Centocor与强生（Johnson&Johnson）共同开发了Remicade，强生于1999年以49亿美元收购Centocor，以获得Remicade的全部控制权。
Remicade是一种嵌合免疫球蛋白-1（IgG1）单克隆抗体，75%人源，25%鼠源。IgG，IgA和IgE是更专门的抗体，而IgM则是最常见的抗体。小鼠蛋白倾向于使人体免疫系统产生自身抗体以消灭外来抗体（免疫原性），与器官移植的排斥反应没有什么不同。
小鼠抗体的人源化可以通过一种称为定点突变的技术来实现，该技术是将一个人类基因剪接到在生物反应器中被大批量培养的中国仓鼠卵巢（CHO）细胞中。人源化单克隆抗体后来被命名为英夫利昔单抗（Remicade），通过静脉输药。[4],[5]
继Remicade之后，FDA于1999年批准了另一种治疗类风湿关节炎的抗肿瘤坏死因子药etanercept（Enbrel，恩布雷）。Enbrel是皮下注射，比静脉输液更方便。Enbrel是一种完全人抗TNF-α抑制剂，是一种生物工程化的p75 TNF受体-II二聚体，其氨基酸序列完全与人IgG1的Fc部分相连。Fc代表可结晶的片段，这是抗体的恒定结构域。Enbrel是利用重组DNA技术在中国仓鼠卵巢（CHO）细胞系中制备的。安进最终于2004年以160亿美元收购了Immunex，这是当时生物技术史上规模最大的一笔交易。
FDA于2002年批准的阿达木单抗（Humira）是第三个抗TNF-α药物。2008年，第四个抗TNF-α生物制剂、比利时UCB的certolizumab pegol（Cimzia）也获得了FDA的批准。尽管Cimia是一种单克隆抗体，它只包含有Fab段和Fc段的调节性抗体的Fab部分。
人源化的Fab部分被聚乙二醇化的以提高其半衰期，使其在体内停留时间更长。它不含IgG1 Fc区，因此不能引起抗体依赖性细胞介导的毒性。此外，杨森的 golimumab（Simponi）是另一种抗TNF-α药物，于2013年获得FDA批准。和阿达木单抗一样，golimumab也是完全的人单克隆抗体。
Humira（修美乐）是如何制造的？
Humira是一种针对人TNF-α的完全人IgG1单克隆抗体。阿达木单抗的主要作用是与肿瘤坏死因子-α（TNF-α）结合并阻断其与p55和p75细胞表面的相互作用。TNF受体因此中和炎症条件下TNF的作用。
阿达木单抗（Humira）是第一个上市的人单克隆抗体。它是由英国剑桥MRC分子生物学验室的Gregory Winter于1989年联合创立的剑桥抗体技术公司（Cambridge Antibody Technology）发现的。
Winter后来因为肽和抗体的噬菌体展示技术而获得2018年诺贝尔化学奖。阿达木单抗是利用Winter的噬菌体展示技术创造的，并在哺乳动物表达系统中成功生产。
阿达木单抗是由两条kappa轻链和两条IgG1链组成的重组人抗体。阿达木单抗 Fab通过一个很大而高度互补、强而稳定的界面（包括氢键和盐桥的形成）特异性地与TNF-α结合。通过结合，阿达木单抗通过阻断TNF-α与p55和p75细胞表面的相互作用来中和其生物学功能。
TNF受体阿达木单抗可以被认为是“完全的人源抗体”，因为编码基因序列不包含任何其他物种克隆的元素。由于其结构中没有任何非人类蛋白，因此似乎比英夫利昔单抗（infliximab）的免疫原性更低。
20世纪90年代末，剑桥抗体技术公司（Cambridge Antibody Technology）与巴斯夫•诺尔制药公司（BASF Knoll Pharma）合作进行阿达木单抗第一阶段的临床试验。2000年，雅培以69亿美元收购了Knoll。
华尔街对这笔交易非常挑剔，并指出Knoll公司并没有重磅的药物供应。这一回银行家们的判断大错特错了。Humira于2002年被FDA批准治疗类风湿关节炎。因为Humira对病人来说使用方便，尽管是第三种进入市场的抗肿瘤坏死因子-α药物，但其优越的给药方案和比已有疗法耐受性提高，使其成为最好的抗肿瘤坏死因子-α药物。
Humira何以这么赚钱？
首先，蛋白质和抗体药物的制造成本要比小分子药物高得多。Enbrel和Humira的治疗费用在首次推出时为每年12000至15000美元。其次，由于美国没有价格管制，药企可以随时提高药价。对于Humira来说，使用该药物的患者的年费用从 2012年的19000美元上升到了50000美元以上。
如今，Humira每年费用超过60000美元。如下图所示，Humira已经变成Abbvie 的摇钱树。
Humira何以成为药中翘楚？
如前所述，良好的疗效、较少的副作用、方便的给药途径是至关重要的。Abbvie甚至发明了Humira笔，让患者使用起来更加方便。市场营销的助力毫无疑问。此外，雅培和后来的Abbvie都采取了双管齐下的策略，以保护他们的Humira专营权。一是扩大Humira的适应症。二是建立专利丛林，防止和延缓生物仿制药的出现。
从阿达木单抗（Humira）在2002年被FDA批准用于治疗类风湿关节炎始，艾伯维（AbbVie）就继续寻求其他炎症和自身免疫性疾病的新适应症。2005年FDA批准其用于银屑病关节炎，2006年批准其用于强直性脊柱炎。
随后批准的阿达木单抗使用范围扩大到用于治疗成人克罗恩病（2007年）、牛皮癣（2008年），幼年特发性关节炎（2008）、溃疡性结肠炎（2012年）等。总之，Humira已获得最广泛的适应症，并已被批准治疗约15炎症和自身免疫性疾病。难怪有人称这些抗TNF-α药物为“药物中的万金油”。
艾伯维拥有约136项Humira专利，这就是被广泛用来避免竞争的“专利丛林”策略。Abbvie的阿达木单抗在欧洲的专利地位较弱，那里现在已经有阿达米单抗的生物仿制药在销售。然而，Abbvie在美国的专利地位更强，虽然生物仿制药已经获得FDA的批准，但要到2023年才能开始销售。[8]
然而，竞争即将来临。研究发现，一种称为Janus激酶（JAK）的激酶抑制剂是治疗类风湿关节炎的有效方法。Incyte/Lilly的巴立替尼（Olumiant）于2017年获得FDA批准用于治疗类风湿关节炎，辉瑞的托法替尼（Xeljanz）于2018年获批。
Abbvie推出了自己的JAK1/2抑制剂upadacitinib（Rinvoq），该药在2019年被批准用于治疗类风湿关节炎。在美国一年的Rinvoq要花59000美元，还是满贵的。
2023年,一旦第一个阿达木单抗生物仿制药在美国出现，Abbvie的市场份额将受到严重威胁。据报道，艾伯维三分之二的收入来自于Humira。在短短两年的时间里，一场变革的海啸正在逼近Abbvie。
（滑动查看英文原文）
How has Humira become the king of all drugs ?
Profit is grease for the capitalism engine. The US has been the powerhouse of medicines largely because there is no price control in America and other favorable policies that reward innovative drugs. On the other hand, companies with blockbuster drugs take advantage of all available legal loops to delay generic drugs and biosimilars, keeping drug prices high. Unbridled capitalism invariably fosters greed.
No case is more conspicuous than the case of Humira, the King of all drugs in terms of profit.
In 2020, Abbvie’s TNF-α inhibitor adalimumab (Humira) was the best-selling drug in the United States ever with $21.4 billion sales. Humira alone thus far has generated over $130 billion revenue, a large enough fortune to buy a small country! Meanwhile, the same class of TNF-阿尔法 inhibitors all did very well last year. Amgen’s Enbrel had $8.1 billion sales and Johnson & Johnson’s Remicade, $4.7 billion. As shown on the chart below Humira, Enbrel, and Remicade were the first, the third, and the tenth best-selling drugs in 2019.
One wonders, what are THF-α inhibitors? How are they made? Why are they so profitable?
TNF-α Inhibitors
Humira is the brand name of the biologic drug adalimumab. The suffix “mAb” signifies that the drug is a monoclonal Antibody. Adalimumab binds and inhibits the function of tumor necrosis factor-alpha (THF-α), a protein that has been associated many inflammatory diseases such as rheumatoid arthritis (RA), psoriasis, Crohn’s disease, ulcerative colitis, etc.
In 1973, Lloyd Old at the Memorial Sloan-Kettering Cancer Center in New York isolated a soluble protein produced by the body in the course of bacterial infection. He named it tumor necrosis factor (TNF) because it killed tumor in mice.}【1】Little did he know, TNF-α would go on to become the most valuable therapeutic target of our times.
Produced by macrophages and activated T cells in response to intestinal injury, TNF is a pleiotropic cytokine with both proinflammatory and immunoregulatory functions. TNF-α has a membrane-bound form and a soluble form, both of which are active as homotrimers. Soluble TNF-α is associated with chronic inflammation, whereas transmembrane TNF-α is associated with immunity to pathogens. Cytokines, in turn, are hormone-like regulatory proteins secreted by cells including macrophages, mast cells, natural killer cells, lymphocytes, neutrophils, stromal cells, B and T cells. They are important in modulating our bodies’ immune and inflammatory responses. Since the 1950s, many cytokines have been identified including interleukin 1 (IL-1), nerve growth factor (NGF), interferon (IFN), and of course, TNF.【2】
If we could block the TNF-α protein, the major subtype of TNF, we could treat inflammatory and autoimmune diseases.
As is often the case, blocking the TNF-α protein is easier said than done. TNF-α binds to two separate cell surface TNF receptors. They are TNF receptor type I called p55 and TNF receptor type II called p75 because their molecular weights are 55 and 75 kDa, respectively. TNF-α signaling occurs when three TNF-α molecules (a homotrimer) crosslink three receptors. Therefore, blocking TNF receptors is difficult to achieve using small molecules. As a consequence, most successful approaches in blocking the TNF receptor have been accomplished using large biologics that bind to TNF-α thus preventing it from binding to the TNF receptors thus minimizing inflammation. Among biologics to block the TNF protein, monoclonal antibodies have been very successful as anti-TNF-α drugs.
Highly specific monoclonal antibodies were discovered by César Milstein and George Köhler, who won Nobel Prize in 1984 for the discovery. When a mammalian is exposed to a foreign antigenic substance such as a bacterium, a virus, or a chemical, antibodies generated are polyclonal antibodies. On the other hand, monoclonal antibodies are produced by clonal descendants of a single cell. Isolated from an animal and maintained in culture, monoclonal antibodies can be obtained as a homogeneous, highly uniform agent, propagated indefinitely, and produced time and time again in the huge quantities needed for treatment of a disease.
Monoclonal antibodies are often developed from proprietary cell lines. Development of these novel biologic drugs is extremely technical and challenging. Due to their complex structures and the complexity of manufacturing these drugs, there can be micro-variability even with slight changes in the production process between batches of the same biologic drug. After the establishment of monoclonal antibody production using hybridoma technology in 1975, monoclonal antibodies have been recognized as therapeutic agents.
In a nutshell, production of monoclonal antibodies begins with immunization of an animal with an antigen. After isolation of the antibody-producing B-cells from the spleen, the B-cells are fused with a tumor cell using polyethylene glycol (PEG) to form a hybrid cell known as hybridoma. Hybridoma technology has been pivotal to the success of biotechnology. It is from the hybridoma that monoclonal antibodies are obtained via a quite technically sophisticated process.
Not all anti-TNF-α biologics are created equal. Enbrel is a dimer fusion protein, Remicade is a chimeric monoclonal antibody, and Humira is a fully human monoclonal antibody with fully human amino acid sequences produced by phage display.
Marc Feldmann and Ravinder Maini at Imperial College in London discovered that anti-TNF therapy was an effective treatment for rheumatoid arthritis and other autoimmune diseases. In 1984, when the cytokine field was still relatively new, Feldmann and Maini collaborated to investigate the hypothesis that cytokines were important in the pathogenesis of rheumatoid arthritis. They uncovered the cytokine cascade in which TNF stimulates the production of other inflammatory cytokines. Feldmann and Maini then tested their theory in experimental animals and showed that inhibition of TNF indeed blocked collagen-induced arthritis.【3】
Despite being the best-selling drug, Humira was not even the first, or even the second TNF-α targeted biologic on the market. The first anti-TNF-α drug was Remicade.
Centocor’s infliximab (Remicade) was the first anti-TNF-α monoclonal antibody approved by the FDA in 1998 for the treatment of rheumatoid arthritis. In the early 1990s, Feldmann and Maini obtained successful pre-clinical data to support their idea, persuaded Centocor, a biotechnology company near Philadelphia, to make Remicade. Centocor codeveloped Remicade with Johnson & Johnson, which in turn bought Centocor in 1999 for $4.9 billion to gain full control of Remicade.
Remicade is a chimeric immunoglobin-1 (IgG1) monoclonal antibody, which is 75% human and 25% murine. IgG, IgA, and IgE are more specialized classes of antibodies while IgM is the most general class. Mouse protein tends to cause the human immune system to respond with its own antibodies to destroy the foreign one (immunogenicity), not unlike the rejection response to organ transplant. Humanization of a mouse antibody can be achieved using a technique called site-directed mutagenesis by splicing a human gene into Chinese hamster ovary (CHO) cells, which are brewed in giant batches in bioreactors. The humanized monoclonal antibody was later named infliximab (Remicade), which is given by intravenous (IV) infusion.【4、5】
On the heels of Remicade’s approval, another anti-TNF-α biologic, Immunex’s etanercept (Enbrel), was approved by the FDA in 1999 also for the treatment of rheumatoid arthritis. Enbrel is administered subcutaneously so it is more convenient than IV infusion. A fully human anti-TNF-α inhibitor, Enbrel is an engineered p75 TNF receptor-II dimer with a fully human amino acid sequence linked to the Fc portion of human IgG1. Fc stands for crystallizable fragment, which is the constant domain of an antibody. Enbrel is manufactured using recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell line. Immunex was eventually acquired by Amgen for $16 billion in 2004, the largest deal in biotech’s history at the time.
In 2002, adalimumab (Humira) was the third anti-TNF-α drug approved by the FDA. And in 2008, the fourth anti-TNF-α biologic, certolizumab pegol (Cimzia) by UCB in Belgium also gained regulatory approval. Even though Cimia is a monoclonal antibody, it only contains the fab portion of a regulatory antibody that has the Fab section and the Fc section. The humanized Fab section is pegylated to boost its half-life so it stays in the body longer. It does not contain the IgG1 Fc region, and thus cannot fix complement or cause antibody-dependent cell mediated toxicity. In addition, Janssen’s golimumab (Simponi) is another anti-TNF-α drug approved by the FDA in 2013. Like adalimumab, golimumab is also a fully human monoclonal antibody.
How is Humira made?
Humira is a fully human IgG1 monoclonal antibody specific for human THF-a. primary action of adalimumab is to bind to tumor necrosis factor-alpha (THF-α) and block its interaction with the p55 and p75 cell surface TNF receptors. Therefore, neutralizing the effect of TNF found in inflammatory conditions.
Adalimumab (Humira) was the first human monoclonal antibody on the market. It was discovered by Cambridge Antibody Technology, co-founded in 1989 by Gregory Winter at the MRC Laboratory of Molecular Biology in Cambridge, England. Winter later on won the Nobel Prize of Chemistry in 2018 for the phage display of peptides and antibodies. Adalimumab was created utilizing Winter’s phage display technology and successfully produced in a mammalian expression system.
Adalimumab is recombinant human antibody composed of two kappa light chains and two IgG1 chains. The adalimumab Fab binds specifically to TNF-α through a large and highly complementary, strong and stable interface including the formation of hydrogen bonds and salt bridges. Through the binding, adalimumab neutralizes the biological function of TNF-α by blocking its interactions with the p55 and p75 cell surface TNF receptors. Adalimumab can be considered “fully human” in the sense that the coding gene sequences contain no elements cloned from any other species. Because of the absence of any non-human protein in its structure, it seems to be less immunogenic than infliximab.
It is given as a 40-mg dose every other week by subcutaneous injection. Its bioavailability is 64% after one injection, and its half-life is 2 weeks. Its therapeutic effects become evident within 24 h to 1 week after administration. It reaches maximum effect after 1–2 weeks. Adalimumab is supplied dissolved in a buffered sterile saline solution and is refrigerated prior to use.【7】
In the late 1990s, Cambridge Antibody Technology collaborated with BASF Knoll Pharma, on phase I clinical trials of adalimumab. Abbott acquired Knoll for $6.9 billion in 2000. The Wall Street was highly critical for the transaction, pointing out that Knoll had no blockbuster drugs in their pipeline. The bankers could not have been more wrong with their judgement. Humira was approved by the FDA treating rheumatoid arthritis in 2002. Since Humira can be given to patients via a convenient regimen. Despite being the third anti-TNF-α drug to enter the market, its superior dosing schedule and improved toleration over existing therapies enabled it to become the best-in-class (BIC) anti-TNF-α drug.
Why Humira is so profitable?
Protein and antibody drugs are much more expensive to make than small molecule drugs. Treatment with Remicade, Enbrel, and Humira costed $12,000 to $15,000 per year when they were first launched. Again, since there is no price control in America, drug companies can raise the price of drugs whenever they want. For Humira, annual costs for patients using the drug rose from $19,000 in 2012 to more than $50,000. Today, Humira, at an annual cost of over $60,000. As shown in the chart below, Humira has become a goose that lays golden eggs for Abbvie.
Why is Humira is so successful to become the king of all drugs?
As alluded earlier, good efficacy, fewer side effects, and convenient dosing regimen were critical. Abbvie even invented the Humira-pen to make it even more convenient for patients. Marketing definitely helps. Furthermore, Abbott and later Abbvie have taken a two-pronged strategy to protect their Humira franchise. One is to expand indications for Humira. The other is to build a patent thicket, preventing and delaying the appearance of biosimilars.
Once adalimumab (Humira) was approved by the FDA in 2002 for treating rheumatoid arthritis, AbbVie has continued to seek approval for new indications for other inflammatory and autoimmune diseases. Its indication for psoriatic arthritis was approved in 2005 and ankylosing spondylitis in 2006. Subsequent approvals extended the use of adalimumab to treat Crohn’s disease in adults (2007), plague psoriasis (2008), juvenile idiopathic arthritis (2008), ulcerative colitis (2012), etc. In all, Humira has received the widest range of indications and has been approved to treat about 15 inflammatory and autoimmune diseases. No wonder some called those anti-TNF-α drugs “the Swiss army knife of pharmaceutical drugs”.
AbbVie holds about 136 patents for Humira. This is the “patent thicket” strategy widely used to stave off competitions. Abbvie’s adalimumab patent position in Europe is weaker and there are biosimilars of adalimumab on sale there already. However, Abbvie’s patent position in the US is stronger and biosimilars, although having been approved by the FDA already, will not be able to start marketing them until 2013.【8】
However, competitions are on the horizon. It was discovered that inhibitors of a kinase known as Janus kinase (JAK) are effective treatment of rheumatoid arthritis. Incyte/Lilly’s baricitinib (Olumiant) was approved by the FDA for treating rheumatoid arthritis in 2017 and Pfizer’s tofacitinib (Xeljanz) in 2018. Abbvie came up with their own JAK1/2 inhibitor, upadacitinib (Rinvoq), which was approved in 2019 for treating rheumatoid arthritis. Rinvoq is sold for $59,000 a year in the US.
Once the first adalimumab biosimilar appears in the US in 2023, Abbvie’s market shares will be serious threatened. Reportedly, AbbVie is generating about two thirds of its revenues with Humira. A tsunami of change is looming over Abbvie in a matter of just two years.
References
参考文献
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1. Old, Lloyd J. Tumor Necrosis Factor In Scientific Americans 1988, 258, 69–75, 59–60.2. Vilčel, Jan; Feldmann, Marc Historical review: Cytokines as therapeutics and targets of therapeutics In Trends in Pharmacological Sciences 2004, 25(4), 201–209.3. Toussirot, Éric; Wending, Daniel The use of THF-a blocking agents in rheumatoid arthritis: an overview In Expert Opinion in Pharmacotherapy 2004, 5(3), 581–594.4. Mikuls, Ted R.; Moreland, Larry W. TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept Expert Opinion in Pharmacotherapy 2001, 2(1), 75–84.5. Zashin, Scott J.; Hesser, M. Laurette Arthritis without Pain: The Miracle of the TNF Blockers Sarah Allison Publishing Company: Dallas, TX. 2004. 6. Lovinger, Sarah P. Use of biologics for rheumatoid arthritis tempered by concerns over safety, cost. In JAMA 2003, 289(24), 3229–3230.7. Reichert, Janice M. Adalimumab (Humira) In Handbook of Therapeutic Antibodies (2nd Edition), eds., Duebel, Stefan; Reichert, Janice M. 2014, 3, 1309–1321.8. Norman, Peter Humira: the impending patent battles over adalimumab biosimilars In Pharmaceutical Patent Analyst 2016, 5(3), 141–145.
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