MAGL

“宇宙第一大药厂”辉瑞，2023年遭遇了一系列挫折，对其业绩的增长构成了重大挑战。好在，辉瑞迅速调整状态，以管线及专利为基石，坚固其堡垒，以“自我革命”穿越新周期。本文重点分析了辉瑞自2018年以来申请并公开的重点专利，并结合最新公开管线信息，探讨了其变革方向与重点。注：各表格中出现在最新管线中的靶点标识为*。01小分子所述专利类型是根据所列专利公开文本的权利要求1判断，不同国家/地区的公开文本甚至同一国家/地区的不同文本（申请公开vs.授权公告，分案vs.原案，美国的延续或部分延续申请）的权利要求1的技术类型都可能存在差异。1.1化合物专利*代表相关靶点被辉瑞最新的管线所覆盖，提示辉瑞对相关的在研靶点进行了迭代更新的探索。其他靶点（包括Hemoglobin、HPK1、ITK、JAK1/TYK2、KRAS、M4R、MAGL、STING、TLR7/8、TTR）则代表了辉瑞最新的研发方向。1.2晶型专利晶型专利是小分子药物专利保护的第二道重要防线，近年国内关于晶型专利的无效案件屡屡引起业界关注，提示该专利的重要性。辉瑞近年申请并公开的小分子化合物晶型专利如下表所示。*与化合物专利类似的，代表相关靶点出现在辉瑞最新公开的管线中，提示辉瑞对该先导化合物进行了晶型专利布局，以期延长其市场独占权。其他靶点（包括EIF4E、HPK1、JAK1/TYK2、JAK3、KHK、PDE9、PRMT5、TAM/C-MET、TGFβ、TLR7/8、TYK2、γ-分泌酶）则代表了辉瑞最新的重点研发方向。1.3用途专利用途专利的医药专利保护的第三道防线，曾经的格列卫治疗胃癌的用途专利无效案，将该类专利的重要性展示得淋漓尽致。辉瑞近年申请的小分子药物用途专利如下所示。需要指出的是，中国专利法不保护疾病的诊断与治疗方法，因为诊断与治疗方法用途权利要求需要以制药用途的形式获得中国专利保护。1.3.1联合用药*定义如前所述，未出现在最新的管线、最新化合物专利、最新晶型专利的靶点包括：ATM、BET、CDC25A、c-MET、PKC、TGFβ、TGFβR1。1.3.2单药治疗*的定义同前文，未出现在最新的管线或前文表格中的靶点包括IRAK4与PRMT5。1.4组合物专利辉瑞自2018年以来，申请并获公开的小分子组合物专利还涉及CDKs、CGPR与JAKs，相关主题化合物在1.2节与1.3节均已有展示，故此处省略。PI3K/MTOR未出现在最新管线或前文的表格中。1.5化合物制备方法专利辉瑞自2018年以来，申请并获公开的小分子化合物制备方法专利还涉及CDKs、EZH2、JAKs，相关主题化合物在1.2节与1.3节均已有展示，故此处省略。02生物大分子2.1核苷酸（包括基因治疗）2.2 ADC2.3CAR（嵌合抗原受体）2.4抗体2.5抗原2.6其他蛋白（蛋白变体、融合蛋白等）03总结在小分子领域，除了管线中所反映的靶点，辉瑞2018年以来还对以下靶点进行了化合物专利布局：Hemoglobin、HPK1、ITK、JAK1/TYK2、KRAS、M4R、MAGL、STING、TLR7/8、TTR；对以下靶点进行了外周专利布局：ALK、ATM、BET、CDC25A、c-MET、HPK1、IRKA4、JAK1/TYK2、JAK3、KHK、PDE9、PI3K/MTOR、PKC、PRMT5、TAM/C-MET、TGFβ、TGFβR1、TLR7/8、TYK2、γ-分泌酶。在生物大分子领域，除了管线中所反映的靶点，辉瑞2018年以来还对以下靶点进行了专利布局：FimH抗原性多肽（基因治疗）、β-葡糖脑苷酶（基因治疗）、谷草转氨酶（基因治疗）、流感病毒抗原性多肽（基因治疗）、迷你抗肌萎缩蛋白（基因治疗）、水痘-带状病毒糖蛋白E多肽（基因治疗）、HER（ADC）、CD45（CAR）、CD70（CAR）、DLL3（CAR）、4-1BB（抗体）、AVB8（抗体）、CD1a（抗体）、CD21（抗体）、CD47（抗体）、CD70（抗体）、CDCP1（抗体）、Erhythroferrone（抗体）、E-Selectin（抗体）、FGFR3（抗体）、Lymphotoxin Beta受体（抗体）、NGF（抗体）、Tnfr2（抗体）、VEGF（抗体）、BCMA（抗原）、肺炎克雷伯菌（抗原）、肺炎链球菌（抗原）、CD80（其他蛋白）、IgG（其他蛋白）、IL-15（其他蛋白）、LFA3（其他蛋白）、OSPA（其他蛋白）、Sirp Alpha、巨细胞病毒GB（其他蛋白）、脑膜炎奈瑟菌（其他蛋白）。本文发现，辉瑞2018年以来申请并公开的专利涉及了该最新管线中未涵盖的大量靶点，提示该公司持续不断的靶点创新，为将来业绩的提升注入新鲜血液。附表：最新的管线信息（截至2023年10月）声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 依依转载开白 | 马老师 18996384680（同微信）商务合作 |  张武龙 13368443108（同微信） 阅读原文，是昨天最受欢迎的文章哦

The prevalence of Epilepsy has been rising over the past few years, which prompts the growing demand for treatment options. The increasing prevalence of Epilepsy and the growing research and development activities to develop novel therapies to treat Epilepsy to drive the market. The companies developing the potential therapies in the last stage of development include Xenon Pharmaceuticals, Engage Therapeutics, Janssen Biotech, and several others LAS VEGAS, April 11, 2023 /PRNewswire/ -- DelveInsight's ' Epilepsy Pipeline Insight – 2023 ' report provides comprehensive global coverage of available, marketed, and pipeline epilepsy therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the epilepsy pipeline domain. Key Takeaways from the Epilepsy Pipeline Report DelveInsight's epilepsy pipeline report depicts a robust space with 70+ active players working to develop 75+ pipeline therapies for epilepsy treatment. Key epilepsy companies such as Alexza Pharmaceuticals, Xenon Pharmaceuticals, GW Pharmaceuticals, Equilibre Biopharmaceuticals, Takeda Pharmaceuticals, Abide therapeutics, Otsuka pharmaceutical, H. Lundbeck A/S, Spark Therapeutics, Equilibre Biopharmaceuticals, ES Therapeutics, Supernus Pharmaceuticals, Inc., MGC Pharmaceuticals, Engrail Therapeutics INC, SK biopharmaceuticals, Longboard Pharmaceuticals, Janssen Research & Development, LLC, Equilibre Biopharmaceuticals, Cerevel Therapeutics, LLC, Neurona Therapeutics, Praxis Precision Medicines, UCB Pharma, Receptor Life Sciences, NeuroPro Therapeutics, Inc., Avicanna, Amring Pharmaceuticals Inc., Ovid Therapeutics, Addex Therapeutics, IAMA Therapeutics, CODA Biotherapeutics, Cerebral Therapeutics, Engrail Therapeutics, and others are evaluating new epilepsy drugs to improve the treatment landscape. Promising epilepsy pipeline therapies in various stages of development include Alprazolam, XEN1101, XEN-496, XEN 901, GWP42006, EQU-001, TAK-935, Lu AG06466, OPC-214870, CG 01, EQU-001, ES-481, SPN-817, MGCND00EP1, NBI 827104, ENX-101, Cenobamate, SKL-24741, LP-352, JNJ-40411813, EQU-001, CVL-865, NRTX 1001, PRAX 628, Padsevonil, RLS103, NPT 2042, AVCN-319302, PRAX-020, AMZ002, OV 350, IAMA-6, CT-010, ENX-101, and others. In March 2023, IAMA Therapeutics, a preclinical-stage pharmaceutical company focused on the discovery, development, and commercialization of novel medicines to make a difference in the lives of individuals suffering from brain disorders, announced that preclinical data supporting its IAMA-6 program in focal refractory epilepsy will be presented at the 75th American Academy of Neurology (AAN) Annual Meeting, taking place on April 22-27 in Boston, Massachusetts. In February 2023, Addex Therapeutics announced that enrollment into Part 1 of Phase 2 clinical study of ADX71149 (JNJ-40411813) for the treatment of epilepsy had been completed. ADX71149 is a selective metabotropic glutamate type 2 (mGlu2) receptor-positive allosteric modulator (PAM). Janssen Pharmaceuticals, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, is conducting the trial. In January 2023, Equilibre Biopharmaceuticals Corp., reported positive topline results from the Phase 2 clinical trial evaluating the clinical safety, tolerability, and preliminary efficacy of EQU-001 – a novel anti-inflammatory anti-seizure medication - administered as once-daily oral adjunctive therapy for focal seizures in adults with epilepsy. The results of the EQU-001 study are encouraging because they demonstrate impressive tolerability and encouraging efficacy for adult patients with focal epilepsy, especially for those with seizures that are difficult to treat. In January 2023, Signant Health, introduced a novel electronic diary (eDiary) data capture solution designed to simplify the experience for patients and research sites participating in epilepsy trials while ensuring robust outcome assessment data to support trial endpoints. Developed in collaboration with The Epilepsy Study Consortium (TESC), the new patient-reported outcome measure offers clinical research sponsors and organizations a standardized solution to capture common seizure data elements with high-quality data. In June 2022, CODA Biotherapeutics, Inc. announced that preclinical data from the Company's focal epilepsy program demonstrated that treatment with the Company's lead-engineered receptor and small molecule activator drug significantly reduced focal seizure frequency in vivo. Results showed that the rapid reduction in seizures is consistent with the pharmacokinetics of the activator drug in mouse models. Data also demonstrated that the expression of CODA's lead receptor is highly correlated with a reduction in seizure frequency. In September 2022, Avicanna Inc. was pleased to announce that it has expanded its research collaboration in the field of Epilepsy with a new collaboration with the University of Toronto and Dr. Mac Burnham's research team to explore the efficacy of Avicanna's proprietary formulations in pre-clinical models for Epilepsy. The research collaboration led by Dr. Mac Burnham's team will explore the efficacy of Avicanna's drug candidates, including AVCN319302, in animal models for Epilepsy. In December 2022, Praxis Precision Medicines, Inc. and UCB announced a strategic collaboration, based upon Praxis' PRAX-020 program, for the discovery of small molecule therapeutics as potential treatments of KCNT1-related epilepsies. Under the terms of the collaboration, UCB retains an exclusive option to in-license global development and commercialization rights to any resulting KCNT1 small molecule development candidate. In January 2022, Ovid Therapeutics Inc. announced the company has entered into an exclusive license agreement with AstraZeneca for a library of early-stage small molecules targeting the KCC2 transporter, including lead candidate OV350. The company seeks to optimize and accelerate the development of these KCC2 transporter activators in epilepsies and potentially other neuropathic conditions. In August 2021, Marinus Pharmaceuticals, Inc. announced that it has entered into an agreement with Orion Corporation whereby Orion received exclusive rights to commercialize the oral and intravenous (IV) dose formulations of ganaxolone in the European Economic Area, United Kingdom, and Switzerland for CDKL5 deficiency disorder (CDD), tuberous sclerosis complex (TSC) and refractory status epilepticus (RSE). Request a sample and discover the recent advances in epilepsy drug treatment @ Epilepsy Pipeline Report The epilepsy pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage epilepsy drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the epilepsy clinical trial landscape. Epilepsy Overview Epilepsy is a chronic condition characterized by unprovoked, recurrent seizures. A seizure is an uncontrollable surge of electrical activity in the brain. Seizures are classified into two types. Seizures that affect the entire brain are known as generalized seizures. Focal seizures, also known as partial seizures, affect only one part of the brain. A mild seizure can be difficult to detect. It can last a few seconds, and you are unaware of it. Stronger seizures, lasting from a few seconds to several minutes, can cause spasms and uncontrollable muscle twitches. Epilepsy symptoms vary according to the area of the brain where seizure activity occurs and the type of seizure. Epilepsy symptoms may include: stiff muscles, Become stiff and falling backward, muscles relaxing and going floppy, confusion, breathing becomes difficult, unconscious, visual disturbances/hallucinations, uncontrollable jerking and shaking, called a "fit," losing awareness and staring blankly into space, strange sensations, such as a "rising" feeling in the tummy, unusual smells or tastes, and a tingling feeling in your arms or legs and collapsing. Epilepsy treatment can help most people with epilepsy have fewer seizures or completely stop having seizures. Find out more about drugs for epilepsy @ New Epilepsy Drugs A snapshot of the Epilepsy Pipeline Drugs mentioned in the report: Learn more about the emerging epilepsy pipeline therapies @ Epilepsy Clinical Trials Epilepsy Therapeutics Assessment The epilepsy pipeline report proffers an integral view of epilepsy emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Epilepsy Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Intra-articular, Intraocular, Intrathecal, Intravenous, Ophthalmic, Oral, Parenteral, Subcutaneous, Topical, Transdermal Therapeutics Assessment By Molecule Type: Oligonucleotide, Peptide, Small molecule Therapeutics Assessment By Mechanism of Action: KCNQ potassium channel agonists, Monoacylglycerol lipase inhibitors, Cholesterol 24-hydroxylase inhibitors, NMDA receptor modulators, AMPA receptor antagonists, GABA A receptor agonists, Cannabinoid receptor modulators Key Epilepsy Companies: Alexza Pharmaceuticals, Xenon Pharmaceuticals, GW Pharmaceuticals, Equilibre Biopharmaceuticals, Takeda Pharmaceuticals, Abide therapeutics, Otsuka pharmaceutical, H. Lundbeck A/S, Spark Therapeutics, Equilibre Biopharmaceuticals, ES Therapeutics, Supernus Pharmaceuticals, Inc., MGC Pharmaceuticals, Engrail Therapeutics INC, SK biopharmaceuticals, Longboard Pharmaceuticals, Janssen Research & Development, LLC, Equilibre Biopharmaceuticals, Cerevel Therapeutics, LLC, Neurona Therapeutics, Praxis Precision Medicines, UCB Pharma, Receptor Life Sciences, NeuroPro Therapeutics, Inc., Avicanna, Amring Pharmaceuticals Inc., Ovid Therapeutics, Addex Therapeutics, IAMA Therapeutics, CODA Biotherapeutics, Cerebral Therapeutics, Engrail Therapeutics, and others. Key Epilepsy Pipeline Therapies: Alprazolam, XEN1101, XEN-496, XEN 901, GWP42006, EQU-001, TAK-935, Lu AG06466, OPC-214870, CG 01, EQU-001, ES-481, SPN-817, MGCND00EP1, NBI 827104, ENX-101, Cenobamate, SKL-24741, LP-352, JNJ-40411813, EQU-001, CVL-865, NRTX 1001, PRAX 628, Padsevonil, RLS103, NPT 2042, AVCN-319302, PRAX-020, AMZ002, OV 350, IAMA-6,CT-010, ENX-101, and others. Dive deep into rich insights for new drugs for epilepsy treatment; visit @ Epilepsy Medications Table of Contents For further information on the epilepsy pipeline therapeutics, reach out @ Epilepsy Drug Treatment Related Reports Epilepsy Market Epilepsy Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key epilepsy companies including Takeda Pharmaceuticals, Abide therapeutics, Otsuka pharmaceutical, among others. Epilepsy Epidemiology Forecast Epilepsy Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epilepsy epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Refractory Epilepsy Pipeline Refractory Epilepsy Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key refractory epilepsy companies, including Eisai Co.LTD., Alexza Pharmaceuticals, Xenon Pharmaceuticals, among others. Partial Epilepsy Pipeline Partial Epilepsy Pipeline Insight – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key partial epilepsy companies, including GW Pharmaceuticals, Equilibre Biopharmaceuticals, among others. Refractory Epilepsy Market Refractory Epilepsy Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key refractory epilepsy companies including Eisai Co.LTD., Alexza Pharmaceuticals, Xenon Pharmaceuticals, among others. Partial Epilepsy Market Partial Epilepsy Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key partial epilepsy companies, including GW Pharmaceuticals, Equilibre Biopharmaceuticals, among others. 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It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Connect with us on LinkedIn |Facebook|Twitter Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

全球顶尖 Big Pharm 的整体水平，也难逃新药研发 10% 成功的铁律。从大药企失败的临床项目以及管线策略出发，看国内创新药的研发。大药企创新药研发成功率辉瑞 21 年初对公司 5 年临床试验成功率做了更新（只统计新分子实体 NME 项目，2 期和 3 期临床的 5 年滚动平均值，1 期研究的 3 年滚动平均值），以及行业平均水平的比较（Industry 包括艾伯维、礼来、吉列德、强生、BMS、默克、诺华、辉瑞、罗氏、赛诺菲、艾尔建、拜耳 12 家企业）。我们可以看到，即便是全球顶尖 Big Pharm 的整体水平，也难逃新药研发 10% 成功的铁律。新药临床成功率不单与药企研发能力挂钩，也受到临床开发策略（保守 or 激进），管线与临床的数量，涉足的技术方向、用药领域等多因素影响。这也导致各大企业间临床成功率有较大的差异（本文主要从临床失败项目反面角度进行讨论）。我们根据能够统计的信息对礼来、罗氏、艾伯维、默沙东、阿斯利康、BMS、赛诺菲 7 家大药企近 5 年失败项目进行整理，下面根据市值排序逐一分析。礼来礼来的管线聚焦于糖尿病、肿瘤、免疫、神经系统 4 大用药领域，也仅一页 PPT 便概括了在研的临床项目，属于走简而精的高品质路线。同时礼来也是大药企中少数管线不以肿瘤为先的公司之一，且在各领域相对平均的布局，这样的战略让礼来一直低调而稳健前进。当下礼来储备的产品管线储备具有强劲的周期前景，短期内虽有专利到期的培美曲塞与胰岛素市场严重下滑，但阿贝西利、依奇珠单抗、恩格列净、度拉糖肽的强劲增长也让营收保持稳定，更重要的是 Tirzepatide 与 Donanemab 两款重磅炸弹前景广阔，商业化成型后将带来可观的收入，帮助公司带来新的增长。图 1 礼来临床管线储备（来源：礼来）2017 年至 2022Q3 礼来终止或失败项目共 53 项，其中 1 期阶段终止的项目占比超 50%，而 3 期及以上失败的项目有低于 20%，这一定程度上与礼来肿瘤管线占比较小有关。其中重要的后期项目失败包括：阿贝西利在 KRAS 突变 NSCLC 在 III 期临床中错失 OS 终点；雷莫芦单抗挑战 1L 线胃癌失败；JAKi 巴瑞替尼 SLE 的 3 期临床失败；恩格列净 1 型糖尿病拓展的失败；以及迫于市场激烈的竞争压力放弃的阿贝西利 HER2+BC III 期临床、IL23 单抗 mirikizumab 银屑病 sBLA。此外 18 亿美元收购 ARMO Bioscience 获得的 IL-10 项目 pegilodecakin，首个 III 期临床失败后也不再继续推进。图 2 2017 年至 2022Q3 礼来失败的后期临床项目（来源：礼来，丰硕创投整理）罗氏罗氏当下处于产品管线「新旧交替」的关键时期，制药业务中肿瘤「老三驾马车」遭到生物类似药的冲击，近两年合计收入下滑 30% 以上，2020、2021 年分别留下了高达 $70 亿、$40 亿的销售大坑。近些年罗氏也不断扩充管线储备，其中 NME 在 1/2/3 期临床研究达到 51/21/10 项；上市产品适应症拓展临床也高达 65 项，其中 3 期临床高达 46 项。图 3 罗氏临床管线储备（来源：官网）罗氏的临床项目中肿瘤药占了半壁江山，而 2、3 期失败的项目也多发生在肿瘤领域。由于早前错失了 IO 治疗的先机，K 药 O 药已占领了大部分市场，罗氏只得加快阿替利珠单抗的适应症拓展，并重押 TIGIT 靶点力求夺回市场。或许是临床开发过于激进，导致 IM 系列与 Skyscraper 系列临床多个 3 期研究接连受挫。此外，乳腺癌领域口服 SERD giredestrant 也在 2 期临床中错失 PFS 主要终点。神经系统领域也是罗氏仅次于肿瘤的细分领域，产品管线布局的靶点多且适应症广。在这一领域中，罗氏也在不少热门药物如 Aβ 单抗、Tau 蛋白、α-Syn 单抗的后期临床中失败。近一年中，作为原本最有希望带来大体量销售增长的 TIGIT 单抗、SERD、Aβ 单抗接连在 III 期临床中失败，无疑让失去重磅品种的罗氏雪上加霜。图 4 2017 年至 2022Q3 罗氏失败的临床项目（来源：罗氏，丰硕创投整理）艾伯维艾伯维 2019 年收购艾尔建后原有免疫疾病、肿瘤、神经领域上，新增了眼科、医美管线。艾伯维「药王」修美乐专利在 2018 年到期（欧洲市场已开始下滑），最重要的美国市场专利明年也将到期。免疫疾病领域作为艾伯维的核心市场，修美乐之后公司再度推出两颗「超新星」——JAK 抑制剂 Rinvoq 和 IL-23 抑制剂 Skyrizi。图 5 艾伯维临床管线储备（来源：艾伯维）从临床开发上看艾伯维失败的后期临床项目集中在肿瘤、免疫领域。肿瘤领域，主要包括 PARP 抑制剂 Veliparib 在多个实体瘤 III 期临床上失败，以及早期 58 亿美元收购获得的 EGFR ADC 失利。自免领域失败项目多止步与于 2 期研究，3 期临床失败较少出现，证明艾伯维在优势领域发挥相对更为稳定。图 6 艾伯维失败的临床项目（来源：艾伯维，丰硕创投整理）默沙东K 药支撑了默沙东 2021 年 40% 的制药收入，也将在 2028 年迎来专利悬崖。而默沙东现有的管线储备稍显单薄，难以补齐 K 药百亿市场的体量，近两年公司也不断「买买买」寻找 K 药之后的增长动力。肿瘤作为默沙东的核心市场，K 药之后虽有 CTLA-4、TIGIT、LAG-3 一众候补，但 CPI 赛道如今已拥挤过度，默沙东现有的肿瘤管线并不占优。年初重金收购 Seagen 的计划，也是默沙东欲通过 ADC 药物加强在肿瘤的布局。此外，默沙东去年以 115 亿美元收购了 Acceleron 扩充公司心血管产品管线，今年 10 月份主要候选药物 Sotatercept 不负众望在肺动脉高压 3 期临床中获得成功。图 7 默沙东临床管线储备（来源：默沙东）默沙东官网对于临床披露比较简单，因此我们没有对其失败临床进行完整统计，尽可能记录一些重要管线的失败临床项目。K 药获批后已斩获超过 30 多项适应症，开设的临床项目以及涵盖的适应症也非常之多，不免也经历了一些失败的 3 期研究，近期联用仑伐替尼在一线 HCC 中失败令人较为意外。此外，早期备受关注肿瘤免疫治疗 IDOi、AD 药物 BACE1 两款产品「折戟」也颇为遗憾。图 8 默沙东失败的临床项目（来源：默沙东，丰硕创投整理）阿斯利康阿斯利康的管线储备在 Big pharma 中也是数一数二的，截止 2022H1 共有 184 项研发管线，单是短期内预估的产品上市项目数已经让在座的大药企震惊。图 9 阿斯利康管线获批预期图（来源：阿斯利康）阿斯利康管线繁多但公司也擅长于管线「瘦身」，从 2018 开始便有超过 70 项临床试验被移除（包括临床失败与战略清理），不过 2、3 期项目超过半数。尽管阿斯利康今年几款管线产品的表现十分亮眼（DS-8201、口服 SERD），但也无法忽视近些年失败的临床项目。包括 IL-5R 单抗两项 III 期临床折戟，开发近 10 年的合成致死 Wee1 药物被移除，以及早期死磕 CTLA-4 单抗 tremelimumab——与 durvalumab 联用中经历多个失败 III 期临床，心血管领域达格列净在 2 项 III 期临床失败。图 10 阿斯利康失败的临床项目（来源：阿斯利康，丰硕创投整理）阿斯利康优势在于管线多且均衡发展由 5~7 大品种支撑总收入，并且补充的产品未来市场前景十分可观。值得一提的是，阿斯利康在乳腺癌与肺癌两大适应症的布局，乳腺癌上由 ADC 药物 DS-8201、口服 SERD、AKT 抑制剂 capivasertib 形成罗网式布局，肺癌有 EGFR 奥希替尼、PD-L1 单抗、cMET 抑制剂、Trop-2 ADC 多靶点覆盖。百时美施贵宝BMS 在 2019 年收购新基后业务集中在肿瘤、血液、心血管与免疫领域，以免疫检查点抑制剂为主线，细胞疗法、细胞因子作为补充支线的 IO 疗法是 BMS 管线的核心组成，其它重点管线还包括「度胺」类以及抗凝剂系列产品。图 11 百时美施贵宝临床管线布局（来源：百时美施贵宝）近两年，BMS 最令人惋惜的临床项目便是 18 年以 36 亿美元获得 IL-2R 激动剂 Bempeg 作为公司免疫治疗管线强有力的补充，但在接连两项临床错失终点后，只得终止与 Nektar 的合作。以及 O 药与 Y 药在不断拓展适应症的过程中，也经历不少失败的 III 期临床，尤其是在大适应症肺癌上 O 药频频挫败。图 12 百时美施贵宝失败的后期临床项目（来源：BMS，丰硕创投整理）赛诺菲作为大药企的赛诺菲一向为人诟病在研发驱动上高度依赖合作伙伴再生元。2017Q4 至 2022Q3 赛诺菲终止临床项目高达 73 项（其中 2、3 期约占 65%）。2018 年赛诺菲聘请罗氏前高管 John Reed 对其研发业务进行改造直接砍掉了 38 项研究管线，其中包括 13 个临床阶段项目。在 2019 年剥离糖尿病和心脏病业务，专注特药（免疫、罕见病、血液、神经、肿瘤）、疫苗、普药（糖尿病、心血管和成熟药品领域，2020 年至 2021 年赛诺菲并购/引进投资近 150 亿美金，以充实自身管线。图 13 赛诺菲后期临床管线（来源：赛诺菲）但即便是管线瘦身外加「买买买」也难掩赛诺菲药物开发仍旧窘迫，多个被看好的品种临床纷纷折戟：乳腺癌「基石」SERD 药物 amcenestrant 三项临床研究接连失败，25 亿美金收购的偏向性 IL2 抗体宣告停止临床研究，36.8 亿美金收购获得获得的两款 BTKi 药物 rilzabrutinib 在 3 期临床失败、tolebrutinib 被 FDA 暂停两项 III 期研究，以及早期 17 亿美元获得的 SGLT-1/2 抑制剂多个 3 期临床终止。图 14 赛诺菲失败的后期临床项目（来源：赛诺菲）对于大药企管线策略的思考重磅产品专利悬崖，大药企如何应对？大药企均凭借着重磅药物跻身行业前列，一款「重磅炸弹」级产品足以成就一家公司，但也会在专利悬崖之后留下巨大销售空缺，药企管线储备需要有足够强的周期特性，形成新旧产品交替。下面我们看看重磅产品面临专利悬崖的代表公司艾伯维、默沙东、罗氏三家企业不同的表现。艾伯维面临修美乐与伊布替尼两大药王产品专利悬崖来临之际，在自免领域发力推出了 Risankizumab 和 Upadacitinib 两款潜力产品，同时 19 年收购艾尔建入局眼科、医美两大潜力赛道。艾伯维顺利为自己的长久发展打开新的篇章，当下市值也由 2020 年 $130B 翻倍达到 $270B。默沙东近几年来都是 K 药一枝独秀的局面，早期市值也一直在$200B 上下徘徊，默沙东想要有所突破就必须摆脱 K 药独大的局面。然而在肿瘤领域打造出下一个「PD-1」并不容易，免疫检查点赛道拥挤不堪，默沙东接棒的 CPI 单抗差异化优势并未突显（最有看点的 TIGIT 领域罗氏噩耗连连），外加年初欲重金收购 Seagen 进军 ADC 赛道的计划也没了下文。默沙东在去年 115 亿美元收购 Acceleron 后，决心推动管线多元化发展，在今年 4 月投资者会议上表示将大力押注心血管领域——计划在未来 8 年内上市 8 款药物，预计 2030 销售额将达到 100 亿美元以上。距离 K 药专利到期还有 5 年，也给默沙东打造 K 药之后的新增长留有一丝喘息之机，接下去的几年将是决定默沙未来发展走向的重要时间点。罗氏的情况则难言乐观，由于「三架马车」专利到期却未有超重磅产品接棒（新三架马车当下销售表现虽不错，长远来看还稍差点意思），近三年来市值在 $250~$300B 区间里徘徊。2021 年、2022 H1 罗氏诊断业务分别增长 29%、11%，而制药业务仅勉强维持 3%~4% 增长。依靠诊断业务罗氏整体收入虽保持增长，但也难抵今年多款重磅产品在接连宣告失败，市值从 2022Q1 顶峰$320B 一度跌回三年前$250B 水平。大药企「买买买」产品频繁失败，怎么看？在上述失败项目的梳理中，不难发现几乎大药企都有重金并购或 license in 的管线上栽跟头的情况，早期巨额投入一时之间犹如泥牛入海。并购、license in 早已是大药企扩充管线的重要战略手段，部分重金交易项目的失败同样也只是创新药研发「高风险、高投入」特征的投射。同样，创新药「高回报」特征也在交易项目中突显，艾伯维两大药王修美乐和伊布替尼，默沙东的 K 药，赛诺菲 BMS 的 O 药、来那度胺，赛诺菲的度普利尤单抗，阿斯利康的大杀器 DS-8201 均是通过并购引进得到。Drug Discovery Today 杂志上 21 年的一篇研究显示，1999 至 2018 年 20 年间 14 家代表性大药企研发的 NME，60% 来源于并购与药品许可，40% 来自于自研，由此可见外部创新在大药企管线发展中发挥重要作用。大药企局限于稳健却繁杂的内部工业体系，在细分领域的研发上不如 Biotech 高效灵活，但大药企能够利用资源、现金的优势帮助产品将商业化潜力发挥到最大。并购、引进的重点应当回归到产品价值之中，企业结合管线发展战略，对产品风险/回报的综合考量，大药企既不能一通胡买，也不应单靠「自我创新」而断绝外部创新。图 15 14 家代表大药企 1999 至 2018 年间开发 NME 起源（资料 1）在大药企手中折戟项目，怎么看国内快速跟随的产品？我们在大药企失败临床中看到不少熟悉声音：TIGIT 单抗、PD-L1/TGFβ双抗、IL-2 细胞因子、口服 SERD 都是国内药企跟随布局的热门产品。甚至个别品种已是 Biotech 管线的重要价值组成（例如 TIGIT 单抗于百济神州，CD47 单抗于天境生物），大药企在临床失败无疑也让国内 Biotech 研发以及股价都蒙上一层阴影。不过，我们也应当注意到一些大药企折戟项目背后的成功案例：PD-1 治疗一线肝癌 BMS 的 O 药、默沙东 K 药+仑伐替尼王牌组合均在 III 期临床中告败，而信达「双达」组合、恒瑞「双艾」组合、百济替雷丽珠单抗都在 III 期研究中成功。O 药 K 药相继失利后，复宏汉霖斯鲁利单抗成为首个在一线 SCLC III 期临床成功的 PD-1 单抗。乳腺癌「大佬」罗氏口服 SERD、AKTi 两个乳腺癌项目都失败了，阿斯利康在以上两个项目相继成功与前者形成对比，在 SERD 项目中折戟的还有赛诺菲。造成临床失败的因素有很多，不能因一款药物的失利就对同类产品以「失败」一言而蔽之，对于快速跟随的项目而言，后者应汲取前人经验在临床中更加谨慎。国内快速跟随的策略并非不可取，只要跟得够快或是定位「Me Better」产品，需要警惕的是盲目跟风的策略。参考文献资料 1、R&D efficiency of leading pharmaceutical companies – A 20-year analysis免责声明：本文仅作消息分享，并不构成投资建议，也不代表 Insight 数据库的立场，文章观点仅供分享行业见解，请广大投资者谨慎。编辑：加一PR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn点击卡片进入 Insight 小程序国内审评进度、全球新药开发…随时随地查！多样化功能、可溯源数据……Insight 数据库网页版等你体验点击阅读原文，立刻解锁！