Abbvie Contract Manufacturing

作者｜零星 自身免疫疾病（AID）是指机体免疫系统对自身组织或细胞的攻击所引发的一类疾病，包括类风湿性关节炎、系统性红斑狼疮、炎性肠病等。 随着科学研究的深入发展和治疗方法的创新，自免并购活动在过去几十年中不断增加，推动了行业的快速发展。本文简要梳理！   01   自免并购的早期阶段: 20世纪末期 20世纪末期，各大生物技术和制药公司开始认识到自身免疫疾病治疗市场的潜力，虽然这一时期行业内相关的并购活动相对较少，但仍为后续蓬勃发展的市场以及并购活动的发展奠定了一定基础。 这一时期重要的并购案包括： 53亿美元：罗氏收购Syntex（1994） 罗氏（Roche）以53亿美元收购美国生物技术公司Syntex，帮助罗氏加强了在风湿性关节炎和其他自免疾病治疗领域的产品组合； 图2：《芝加哥论坛报》报道罗氏收购Syntex的新闻 820亿美元：辉瑞收购Warner-Lambert（1999） 辉瑞（Pfizer）以约820亿美元的价格收购了Warner-Lambert。这次并购虽然主要是为了取得著名的降胆固醇药物立普妥（Lipitor），但也极大增强了辉瑞在自身免疫疾病药物开发方面的实力。 图3：《华盛顿邮报》辉瑞收购Warner-Lambert的新闻 赛诺菲-安万特（Sanofi-Aventis）成立（1999） 1999年，赛诺菲（Sanofi）和霍诺（Hoechst Marion Roussel）合并成立了赛诺菲-安万特（Sanofi-Aventis），这次合并使赛诺菲在自身免疫疾病治疗领域拥有更强的研发能力和市场份额。 图4：赛诺菲（Sanofi）和霍诺（Hoechst Marion Roussel）的相关报道 160亿美元：Amgen收购Immunex（2001） 在这一时期，还有一个典型的收购案例，2001年，Amgen以160亿美元收购Immunex，获取了其重磅药物Enbrel（依那西普）。Enbrel是一种抗肿瘤坏死因子（TNF）药物，主要用于治疗类风湿性关节炎和其他自身免疫疾病。这次收购不仅使得Amgen在免疫疾病治疗领域的地位显著提升，也为其带来了可观的财务回报 。 图5：Nature Technology网站对Amgen收购Immunex的报道 图6：Amgen官网新闻 自身免疫领域（自免领域）的并购案反映了生物技术和制药行业的整合趋势这些并购案不仅加速了自身免疫疾病治疗药物的开发和上市，也推动了生物技术和制药行业的整合和创新。通过并购，这些公司能够获取更多的资源、技术和市场，进而提升其竞争力和市场地位。   02   自免并购的汹涌浪潮：2015~2020 进入21世纪第二个十年，自身免疫疾病治疗市场迅速扩展，生物技术的进步和新疗法的开发推动了大量并购交易。 这十年间，若干生物技术和制药公司纷纷加入并购浪潮，自免领域并购案例如雨后春笋般涌现，时常占据医药行业新闻头条，引起国内外众多关注。 210亿美元：AbbVie收购Pharmacyclics（2015） 2015年AbbVie以210亿美元的价格收购了Pharmacyclics，通过本次收购，Abbvie获得了Pharmacyclics的于治疗多种血液系统疾病的药物Imbruvica（依鲁替尼）。虽然Imbruvica主要用于癌症治疗，但其研究成果为自身免疫疾病治疗提供了新的思路，并增强了AbbVie在免疫学领域的研发能力 。 图7：AbbVie官网并购内容 72亿美元：Celgene收购Receptos（2015） Celgene以72亿美元收购Receptos，主要是为了其在研药物Ozanimod，这是一种用于治疗多发性硬化症和溃疡性结肠炎的S1P受体调节剂。Ozanimod的开发成功使Celgene在自身免疫疾病治疗领域的布局更加完善 。 图8：Market Screen对此次并购的相关报道 25亿美元：Sanofi收购Synthorx（2019） 2019年，Sanofi收购Synthorx。Sanofi以25亿美元收购了Synthorx，获取其以工程化IL-2为基础的免疫治疗技术。Synthorx的技术平台旨在增强免疫系统的选择性，开发新型治疗方法来治疗癌症和自身免疫疾病，进一步拓展了Sanofi在免疫治疗领域的产品线 。 图9：Sanofi官网对此次并购的说明   03   自免并购继续升温：近五年情况 再把视野转向2020年至今，我们可以直观地看到，在过去的几年中，自身免疫领域的并购活动继续升温，主要驱动力包括对创新疗法的需求、企业间的战略整合以及资本市场的支持。 3.1亿美元：Novartis收购IFM Therapeutics的自身免疫部门（2020） 2020年，Novartis收购IFM Therapeutics的自身免疫部门。Novartis以3.1亿美元的价格收购了IFM Therapeutics的自身免疫资产。这些资产包括多个用于治疗自身免疫疾病的小分子药物，旨在通过靶向炎症信号通路来调节免疫反应，极大地增强了Novartis在自身免疫治疗领域的研发能力。 图10：Fierce Biotech网站对此次收购的报道 390亿美元：AstraZeneca收购Alexion Pharmaceuticals（2021） 2021年，AstraZeneca收购Alexion Pharmaceuticals。 AstraZeneca以390亿美元的价格收购了Alexion Pharmaceuticals，这是近年来规模最大的并购案之一。Alexion是开发罕见病和自身免疫疾病治疗药物的领导者，其主要产品Soliris和Ultomiris用于治疗一系列罕见的自身免疫疾病。这次收购使AstraZeneca在免疫学和罕见病领域的地位显著提升。 图11：Pharmaceutical Technology网站对此次并购的报道 自2019年受到COVID-19新冠疫情的影响，资金短缺与市场不确定性、监管审批延误、临床试验停滞、供应链中断、战略优先级变化等多方面的影响和挑战，制药和生物技术行业相关自身免疫疾病领域的并购活动相对减少，但是趋势仍不容忽略。   04   自免并购案屡见不鲜的2024年 让我们目光再转回到2024年，截至五月底，自免相关的并购、收购案例屡见不鲜，并购活动呈现活跃态势。这里聚焦几个比较典型的案例： 2.5亿美元：Novartis收购Calypso Biotech（2024.01） 1月，Novartis以2.5亿美元的价格收购了Calypso Biotech，这家公司开发的CALY-002针对IL-15，用于治疗乳糜泻和嗜酸性食管炎。Novartis计划利用该产品针对多种高未满足需求的自身免疫病适应症进行开发。 图12：European Biotechnology网站关于此次并购的报道 Regeneron收购2seventy Bio的肿瘤和自身免疫资产（2024.04） 4月，Regeneron收购了2seventy Bio的肿瘤和自身免疫资产，并成立了新的研发部门Regeneron Cell Medicine。此次收购包括雇佣了2seventy Bio的160名员工，初步将重点放在CAR-T和CAR-NK疗法的开发上。 图13：Regeneron官网对此次收购的相关内容 Eliem Therapeutics收购Tenet Medicines（2024.04） 同月，Eliem Therapeutics收购了Tenet Medicines，其主要资产是抗CD19抗体TNT119，潜在适应症包括系统性红斑狼疮（SLE）和免疫性血小板减少症等。此次收购使Eliem能够扩展其在自身免疫疾病治疗领域的产品线。 图14：Eliem官网对此次收购的相关内容 强生收购Numab、Ashahi Kasei Corporation收购Calliditas（2024.05） 本文开篇就已经提到，今年5月强生并购Numab，同时五月还有几起自免领域相关的并购案，就在强生并购案的当天，日本化工企业旭化成（Ashahi Kasei Corporation）也宣布准备以10.6亿美元收购瑞典生物技术公司Calliditas Therapeutics，本次收购后，旭化成将获得Calliditas的Nefecon（用以治疗IgA肾病）等。 图15：Ashahi Kasei Corporation公司对本次收购的相关内容   写在最后   随着2024年下半年的到来，预计自身免疫领域的并购活动将继续活跃。 各大生物科技和医药公司将继续通过战略性收购和合作，寻求在自身免疫疾病治疗领域的突破和创新。这些并购活动不仅有助于提升公司在市场上的竞争力，还将加速新疗法的开发和商业化进程，为患者带来更多的治疗选择和希望。 参考资料： [1]强生官网；Numab官网；Amgen官网；AbbVie官网；Sanofi官网；Novartis年报；Regeneron官网；Eliem官网 [2] Switzerland’s Roche Holding Ltd. agreed to buy Syntex Corp. for $5.3 billion [3] Pfizer Bids $82 Billion for Warner-Lambert [4] Amgen's big-ticket play for Immunex [5] Novartis ponies up $310M for IFM Therapeutics’ inflammation-focused unit [6] Novartis AG to buy immunology specialist Calypso Biotech BV [7] J&J to Acquire Rights to Investigational Bispecific Antibody 10.12日，深圳；BiG第二届自免研讨会 8:50-8:55 联合主办方致辞 张  战：卫光控股董事长、卫光生物董事长 8:55-9:00 联合主办方致辞 涂   欢：深圳医学科学院副院长、深圳湾实验室副主任 9:00-9:30 Keynote—炎症免疫检查点与AI驱动药物研发 陈有海：美国医学与生物工程院士、欧洲科学院院士、深圳理工大学药学院院长 9:30-10:00 Keynote—临床视角，创新药开发自免，如何选择适应症？ 徐沪济：海军军医大学长征医院大内科主任兼风湿科主任/清华大学医学院教授 10:00-10:25 MNC视角，AZ在肿瘤+自免的布局和开发策略 章   宇： 阿斯利康产品管线和项目管理副总裁 10:25-10:50 茶歇 10:50-11:40 Panel：自免创新药如何立项？MNC&biotech的布局策略，BD合作背后的故事？ 肖昌春：赛诺菲中国研究负责人、赛诺菲研究院负责人 徐亚南：武田制药全球外部创新合作部中国区负责人 邓天敬：炎明生物联合创始人/CEO 靳照宇：明济生物董事长兼CEO 朱向阳：华奥泰生物总经理 周潇薇：松禾资本董事总经理（主持） 11:40-12:30 Panel：从肿瘤转战自免，创新疗法（CAR-T/CAR- NK/双抗/ADC/PROTAC等）如何选择适应症，不同modality各自开发优势及挑战，在哪里？未来有哪些新靶标值得关注？ 范晓虎：湾岛细胞创始人/CEO 花海清：映恩生物研发副总裁 冯   焱：领泰生物创始人/CEO 张   雷：深圳湾实验室特聘研究员 卢宏韬：科望医药联合创始人/CSO、BiG总干事（主持） 12:30 闭幕致辞&研讨会主持 李  圆：BiG秘书长 12:30-14:00 午餐&参观&自由交流 ● 深圳医学科学院（SMART）、卫光生命科学园、湾有引力（光明生物医药创新中心） 报名入口  PS：免费席位有限，均为审核制 观众门票：0元 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AbbVie officially announced on September 26 that its new drug has successfully met its primary efficacy goal in late-stage clinical trials for patients with early-stage Parkinson's disease. Specifically, when two fixed doses of tavapadon were compared with placebo as monotherapy, patients showed statistically significant improvement on the rating scale developed by the Movement Disorders Association to comprehensively assess the symptoms of Parkinson's disease. The study included 529 adults between the ages of 40 and 80 who had been diagnosed with Parkinson's disease for less than three years. Over the course of the 26-week treatment period, tavapadon at 5mg and 15mg doses not only effectively relieved the patients' dyspraxia symptoms, but also significantly improved the motor skills needed to perform daily activities, meeting the second efficacy goal of the trial. Notably, AbbVie managed to gain ownership of this innovative treatment through its $8.7 billion acquisition of Cerevel Therapeutics. Tavapadon is currently in advanced research with the aim of being developed as a once-daily treatment for people with Parkinson's disease. Parkinson's disease is a degenerative neurological disorder that causes progressive brain damage, which can lead to a variety of symptoms including movement disorders, tremors, stiffness, and impaired balance. In addition, in another late-stage clinical trial, tavapadon, as an adjunct to levodopa, also showed the potential to improve symptom control in patients. Levodopa is one of the standard treatments for Parkinson's disease, and its efficacy has been widely recognized. Abbvie also revealed that results from another late-stage clinical trial of tavapadon as a flexible dose monotherapy are expected before the end of the year, which undoubtedly brings new hope and anticipation to the Parkinson's disease community.

On September 12, 2024, the domestic public began to pay attention to the litigation case brought by AbbVie against Beigene. Abbvie accused Beigene of violating its trade secrets in relation to BTK's chimeric biodegradation-activated compound (CDAC) BGB-16673. Abbvie had filed an infringement lawsuit against Beigene in June last year, claiming that it infringed ibrutinib's patent rights. The lawsuit is more direct than the previous one, with AbbVie claiming that Beigene "induced and encouraged" its scientist to move, resulting in the scientist carrying the relevant patent information for the BTK deactivator. It is said that the BTK depressant has better efficacy than the mainstream BTK inhibitors currently on the market, and can completely degrade the relevant proteins. Abbvie is developing ABBV-101 in Phase I clinical trials in B-cell malignancies; Beigene's BGB-16673, for the treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, has received FDA fast-track status. Beigene has denied AbbVie's allegations, insisting that BGB-16673 was independently developed and patented years before AbbVie filed its patent application for BTK. Beigene also pointed out that BGB-16673 is currently the most advanced BTK inhibitor in clinical trials, and AbbVie filed the lawsuit in order to impede its development. The dispute stems from an incident involving the flow of talent. Abbvie alleges that Beigene "lured and encouraged" a scientist named Liu to a new job, carrying with him information on AbbVie's development of a BTK-degrading drug. Dr. Liu worked at AbbVie and its predecessor Abbott Laboratories for more than a decade, from 1997 to 2013, and subsequently continued to work at AbbVie until his retirement in 2019. It is worth noting that Dr. Liu served as a Senior Research Scientist at AbbVie's BTK Degraders Program from September 2018 to September 2019. Abbvie noted that during this time, Dr. Liu had access to the company's trade secrets and confidential research, design, development synthesis, testing, analysis and data related to the BTK deactivator program. In addition, Dr. Liu understands the future direction of AbbVie's BTK deactivator program. Abbvie alleges in its lawsuit that Beigene identified, targeted and recruited Dr. Liu to leave AbbVie and join Beigene's BTK depressant program while he was still employed at AbbVie. Abbvie further noted that Dr. Liu began working for Beigene immediately after his retirement and filed the first of a series of BGB-16673 patent applications six months later. Abbvie believes that the patents filed for BGB-16673 use key information from the trade secret and confidential designs developed by Dr. Liu prior to his departure and are identical in several respects to AbbVie's work. As a result, AbbVie named Dr. Liu as a defendant along with Beigene, accusing Dr. Liu of "stealing trade secrets and confidential information about AbbVie's BTK deactivator and disclosing that information to Beigene and ultimately using that information at Beigene." However, filing a lawsuit does not mean Beigene necessarily violated AbbVie's trade secrets. Lawyer GUI Xin, a partner in the life sciences legal team of Dehe Heng Tianma, told the Health Bureau: "The case is still in the early stages of litigation, and it is impossible to judge whether Beigene has violated AbbVie's trade secrets before the formal judgment." Since the U.S. launched the China Action Plan in November 2018, a significant percentage of U.S. cases involving trade secrets have involved Chinese companies." Beigene also denied AbbVie's allegations, insisting that the drug candidate was developed independently and that AbbVie's allegations were intended to impede the development of BGB-16673. This is not the first time AbbVie has taken legal action. On June 15, 2023, AbbVie sued Beigene's Zebutinib, claiming that it infringed Ibutinib's patent. In response, Beigene launched a patent invalidation counterattack. Over the past few years, Zebutinib's strong market performance has steadily eroded AbbVie's market share of ibutinib. In 2023, Zebutinib's global sales will be close to $1.3 billion; In the first half of 2024, Zebutinib's global sales reached $1.126 billion, an increase of 117% year-on-year. By contrast, sales of ibrutinib, which once made up the bulk of AbbVie's revenues, have declined. In the first half of 2024, ibrutinib's global sales were $3.225 billion, down 6% from the same period last year. Litigation is a common means in business competition. On the one hand, it can be used to protect its own legitimate rights and interests, on the other hand, it may also be used to hinder the business plan of competitors. At its core, this is still a battle for profit. Blood tumor is one of the important areas of drug development of Beigene, the BTK deactivator involved in this time, Beigene and AbbVie are under research and development, AbbVie's product development progress slightly behind Beigene. BTK degraders can induce BTK degradation through ubiquitination and solve the problem of drug resistance of BTK inhibitors, which has great development potential in the future. If the drug development goes smoothly, BGB-16673 will become an important treatment drug for patients with limited options for disease progression after the use of BTK inhibitors, forming complementary advantages with zebutinib, and further consolidating Beigene's position in the field of hematoma. On September 12, 2024, Beigene's A-shares and Hong Kong shares fell by 10% and 5%, respectively.