Ezobresib

近日，BMS与Avidity达成全球许可和研究合作协议，利用Avidity的平台技术，专注多达5个心血管抗体-寡核苷酸偶联(AOC)药物靶点的发现、开发和商业化。根据协议，Avidity将获得1亿美元预付款，其中含6000万美元现金支付，及按每股7.88美元购买约4000万美元的Avidity普通股，此外，还有高达13.5亿美元的研发里程碑，和高达8.25亿美元的商业里程碑付款等等，BMS潜在累计付款23亿美元（约合人民币160亿元）。与“魔法子弹”ADC一个字母之差的AOC，眨眼间身价暴涨。01AOC的价值，远不止160亿元一切皆可联，越联越值钱。ADC的成功,让越来越多的“对象”进入到偶联“配对”范围，AOC就是其中之一。通过将单抗和寡核苷酸偶联，达到有效的靶向治疗能力，相比寡核苷酸，具有精准靶向和更好药代动力学特性，其结构与ADC相似，主要由发挥组织靶向作用载体（抗体）、连接子（linker）和治疗载荷（小核酸）等三部分构成。图1 AOC结构图片来源：美迪西官微全球首款进入临床的AOC药物AOC 1001就来自Avidity，除AOC 1001之外，Avidity还有2款AOC候选药已进入临床阶段，分别为AOC 1044和AOC 1020。Avidity在开发AOC项目时，结合3种不同罕见病进行研发，即AOC 1001用于治疗1型肌强直性营养不良症(DM1)，AOC 1044用于治疗杜氏肌营养不良症(DMD)，AOC 1020用于治疗面肩肱肌营养不良症(FSHD)。图2 Avidity研发管线图片来源：Avidity官网目前，全球并无AOC药物获批，据不完全统计，全球进入临床阶段（含IND申请）超过5款，最早“出线”的AOC 1001目前最高也只推进至2期临床，就算临床进展一切顺利，离获批上市也还较遥远，但BMS不仅愿意花160亿元，且还愿意承担所有未来临床开发、监管和商业化活动的资金，这就已让双方合作的AOC项目价值远超160亿元。AOC到底有何魅力，让BMS不惜花重金拿下？可以从其临床数据窥探一二。作为首个临床的AOC项目，AOC 1001的研究数据也是最先出炉。2023年4月，Avidity在第75届美国神经病学学会(AAN)年会上，公布了1/2期MARINA试验顶线数据，显示DM1患者各种功能评估有方向性改善，包括6个月期间的肌强直和肌肉力量，且具有良好安全性和耐受性。美国FDA在5月就放宽了部分临床限制，允许12名参与者将剂量升至4mg/kg，并允许新参与者以2mg/kg入组。图3 AOC 1001 1/2期MARINA试验不良事件图片来源：Avidity官网2023年10月，Avidity在第28届世界肌肉协会(WMS)年度大会上，公布了AOC 1001新的数据，增强了先前报道的肌强直、肌肉力量和活动能力改善的积极数据，且超过200次输注，总计46.2患者年的暴露数据，继续显示出良好安全性和耐受性，大多数不良事件为轻度至中度。图4 AOC 1001 4mg/kg临床疗效图片来源：Avidity官网越来越好的临床试验数据，让AOC在偶联药圈中，继ADC之后脱颖而出。02重押AOC，只为应对GLP-1？心血管领域是BMS支撑业绩的最重要“阵地”，仅抗凝血药物Eliquis在2022年的销售额就达117.89亿美元，比BMS的O药还高出42.91%，占全年总营收（461.59亿美元）的25.54%。图5 BMS产品2022年销售额图片来源：BMS 2022年报“阵地”还在，但有所松动。据BMS的2023年Q3财报显示，Eliquis前三个季度合计销售额为93.32亿美元，同比增长2.54%，而2022年同期销售额为91.01亿美元，同比增长达12.48%，增长有所放缓。图6 BMS产品2021年和2022年前三季销售情况图片来源：BMS 2021/2022年Q3财报其实BMS一直非常重视心血管“阵地”的防守，一方面，延长重磅药物专利保护期，2017年，美国专利商标局授予Eliquis一项关键组合物专利，保护期从2023年2月延至2026年11月；另一方面，寻找接力药物，2020年，BMS斥资131亿美元收购MyoKardia，增强心血管研发管线，获得了mavacamten。2022年4月，mavacamten获美国FDA批准上市，是FDA批准的首款用于HCM治疗的心肌肌凝蛋白变构调节剂，尽管BMS对mavacamten寄予厚望，预测其2029年销售将达40亿美元，但Eliquis成绩太好了，专利到期的市场缺口，不是Mavacamten就能弥补的。“魔法子弹”ADC近年来的大火，让BMS注意到其“胞弟”AOC，2021年，BMS子公司MyoKardia就与Avidity开展了合作，研究AOC在心脏组织中的潜在效用。上个月，诺和诺德在美国心脏协会（AHA）年度会议上公布了其有史以来开展的最大规模临床试验--司美格鲁肽心血管获益3期临床SELECT研究最新数据，患有心血管疾病与超重/肥胖症的17604名受试者入组，主要不良心血管事件风险降低20%，值得注意的是，受试者未患糖尿病。GLP-1的临床数据再次引爆了全球药企的追逐，面对未来Eliquis仿制药的围猎，以及GLP-1进军心血管领域的可能，BMS将重注押在了AOC上，从子公司合作升级到亲自“操刀”，且以购股方式与Avidity共进退。按合作协议计算，BMS将购入Avidity普通股超500万股，在众多持股者中，也算是“土豪级”了，这也为BMS以后在AOC上向心血管领域外拓展埋下了伏笔。图7 Avidity持股机构情况图片来源：东方财富网03不止AOC，BMS还有后手除了重押AOC巩固心血管“阵地”，BMS还留有后手，在2023年9月的研发日活动上，BMS透露了未来管线发展计划，在18个月内将注册资产数量翻一番，从6个增至12个，新注册资产关键管线更新包括：细胞疗法BMS-986353扩展到免疫疾病临床试验，包括严重难治性系统性红斑狼疮；潜在的first-in-class蛋白质降解剂golcadomide正在进入一线大B细胞淋巴瘤的3期临床试验；潜在的best-in-class BET抑制剂BMS-986158，用于骨髓纤维化，期待概念验证数据……另外，从BMS研发管线布局来看，在肿瘤学领域的布局最多，其次是血液学和免疫学领域，均比心血管领域丰富。图8 BMS研发布局管线图片来源：BMS官网就在研发日活动后不久，BMS就以最高58亿美元（含10亿美元潜在价值）收购Mirati，而Mirati的上市产品Krazati是全球第2款获批的KRAS药物，2022年12月获美国FDA加速批准，用于治疗KRAS G12C突变的局部晚期或转移性非小细胞肺癌（NSCLC）患者，而管线中，除了Krazati的适应症拓展外，MRTX1719、MRTX1133和MRTX0902，均用于肿瘤领域。图9 Mirati产品及管线图片来源：BMS官网在肿瘤学布局本来就最丰富的BMS，又收购Mirati，明显是加强和多样化肿瘤学投资组合，除了继续巩固心血管“阵地”，BMS欲将肿瘤领域推至“阵地”最前沿。04结语创新药赛道上从不缺乏爱冒险的勇士，在踏上赛道的那一刻起，无论将来成功与否，就注定了创新药“盲盒”打开时的刺激。BMS的押注，无论是巩固心血管领域地位，还是壮大肿瘤领域影响，都是大“赌局”，期待更精彩的表现。参考来源：1.Avidity官网2.BMS官网、财报3.凯莱英药闻官微《BMS：将心血管领域的未来，押注在AOC！》4.美迪西官微《小核酸抗体偶联药物(AOC)》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 | shara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

Registrational assets expected to double from six to 12 over next 18 months Cell Therapy and Targeted Protein Degradation platforms offer potential to expand treatment options across multiple therapeutic areas Enhanced approach to R&D expected to drive top-tier productivity PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) is today holding a Research and Development (R&D) Day in New York to discuss the company’s R&D strategy and capabilities and to provide insight into its robust pipeline supporting long-term sustainable growth. Members of the company’s leadership team will also highlight its differentiated research platforms and enhanced R&D framework, which are expected to drive top-tier productivity that delivers high quality early-stage candidates and meaningfully accelerates R&D timelines. “We are seeing the impact of our focused efforts to strengthen our R&D engine and pipeline as we’ve executed against our priorities over the past four years,” said Giovanni Caforio, M.D., board chair and CEO, Bristol Myers Squibb. “By combining the best assets, capabilities and platforms within our company, we are well-positioned to deliver more medicines to patients even faster in the future.” “Science and innovation derived from research and development are critical to the continued success of our company and represent the core of Bristol Myers Squibb’s vision to transform patients’ lives,” said Chris Boerner, Ph.D., executive vice president and chief operating officer, Bristol Myers Squibb. “We are further enhancing our R&D engine to strengthen scientific leadership, accelerate our promising pipeline and drive increased productivity. This work is a key enabler of our goal of delivering long-term sustainable growth and ensuring we help more patients prevail over serious diseases.” Strengthening Scientific Leadership and Advancing Promising Pipeline The company expects to double the number of registrational assets over the next 18 months from six to 12. Key pipeline updates for the newly anticipated registrational assets include: CD19-directed NEX T cell therapy BMS-986353, expanding into clinical trials for immunologic diseases, including severe, refractory systemic lupus erythematosus. Potential first cell therapy targeting GPRC5D, our CAR T BMS-986393, starting a registrational trial in relapsed/refractory multiple myeloma (RRMM). BCMA x CD3 T-cell engager, alnuctumab, advancing into a Phase 3 trial for RRMM. Potential first-in-class protein degrader, golcadomide, progressing into a Phase 3 trial in first-line large B-cell lymphoma. The first asset from BMS’ novel ligand-directed protein degradation platform, androgen receptor degrader, moving into pivotal studies in metastatic castration-resistant prostate cancer. Potential best-in-class BET inhibitor, BMS-986158, for myelofibrosis expecting proof-of-concept data. This complements six assets already in registrational trials: Repotrectinib, a potential best-in-class ROS1 inhibitor with a U.S. FDA PDUFA goal date of November 27, 2023. Iberdomide and mezigdomide, protein degraders in registrational trials with first data expected in 2026. Cendakimab, an anti-IL-13 asset in eosinophilic esophagitis. BMS-986278, our first-in-class LPA1 antagonist, with potential to become the new standard of care in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Today, the company outlined Phase 3 trials in each disease that will evaluate both 60mg and 120mg doses of this potentially important medicine for patients. Milvexian in secondary stroke prevention, acute coronary syndrome and atrial fibrillation, in collaboration with Janssen Pharmaceuticals Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson. In addition to its growing registrational portfolio, the company has more than 25 indication expansion opportunities on the horizon and nine, high-potential early assets expected to advance in the pipeline. Taken together, this leads to increased depth across the company’s therapeutic areas, including oncology, hematology, immunology, cardiovascular and a growing presence in neuroscience. “The work we’re undertaking to accelerate our clinical pipeline and extend scientific leadership across therapeutic areas make it an incredibly exciting time to be a part of this company and our R&D organization,” said Samit Hirawat, M.D., executive vice president and chief medical officer, Drug Development, Bristol Myers Squibb. “Our integrated approach to R&D will allow us to maximize innovation and get more medicines to more patients faster.” Differentiated Research Platforms Support Long-Term Growth The company is uniquely positioned with differentiated research platforms including Cell Therapy and Targeted Protein Degradation supporting its innovative work across therapeutic areas. Building on our leadership in Cell Therapy BMS is the only company with two cell therapies approved against two distinct targets, exhibiting growing leadership in the space with strong positioning at the center of the innovation ecosystem. The company is expanding manufacturing capacity, exploring innovative technologies such as dual-targeting CARs and allogenic approaches, advancing multiple next-generation assets including new targets. BMS is also rapidly expanding into immunology, including lupus and multiple sclerosis. Expanding to new targets with Targeted Protein Degradation The company has a strong legacy in the protein degradation field and has been advancing its pipeline with an expansive library of assets spanning molecular glues, ligand-directed degraders and antibody drug conjugates. With three assets in registrational trials, four others in the clinic and more than 15 being studied pre-clinically, this growing platform has potential across several diseases, and is positioned to deliver approximately four investigational new drugs (INDs) each year. Enhancing R&D Productivity and Bringing Treatments to Patients Faster The company is undertaking efforts to further increase and sustain the productivity of its R&D engine, enabling an approach to research and development that will allow it to identify higher-quality candidates with increased probability of making it to market. Moving forward, BMS is focused on three objectives for establishing and sustaining top-tier R&D productivity: Driving toward approximately 10 INDs per year. Increasing success rates from first-in-human to approval to approximately 20%. Reducing research and drug development timelines to achieve a median of 6.5 years from first-in-human to approval. “Bristol Myers Squibb is committed to harnessing our integrated R&D approach to deliver high-quality assets with an increased chance of success based on a deep understanding of causal human biology,” said Robert Plenge, M.D., Ph.D., executive vice president and chief research officer. “Our research strategy will enable us to increase the number and quality of potentially transformational early-stage candidates, leveraging our differentiated research platforms, and accelerate the path from proof-of-concept to regulatory approval.” R&D Day takes place at 9 a.m. ET today and will be available via live webcast here. About Bristol Myers Squibb Company Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop, and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook, and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains statements about Bristol-Myers Squibb Company’s (the “Company”) future financial results, plans and strategy, business development strategy, anticipated clinical trials, results and regulatory approvals that constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These statements may be identified by the fact they use words such as “should,” “could,” “expect,” “anticipate,” “estimate,” “target,” “may,” “project,” “guidance,” “intend,” “plan,” “believe,” “will” and other words and terms of similar meaning and expression in connection with any discussion of future operating or financial performance, although not all forward-looking statements contain such terms. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. No forward-looking statements can be guaranteed and there is no assurance that the company will achieve its future financial results, that the company’s future clinical studies will support the data described in this release, that the company’s product candidates will receive necessary clinical and manufacturing regulatory approvals, that the company’s pipeline products will prove to be commercially successful, that clinical and manufacturing regulatory approvals will be sought or obtained within currently expected timeframes, or that contractual milestones will be achieved. Actual results may differ materially from those expressed in, or implied by, these statements as a result of various factors, including, but not limited to, (i) new laws and regulations, (ii) our ability to obtain, protect, and maintain market exclusivity rights and enforce patents and other intellectual property rights, (iii) our ability to achieve expected clinical, regulatory and contractual milestones on expected timelines or at all, (iv) difficulties or delays in the development and commercialization of new products, (v) difficulties or delays in our clinical trials and the manufacturing, distribution and sale of our products, (vi) adverse outcomes in legal or regulatory proceedings, (vii) risks relating to acquisitions, divestitures, alliances, joint ventures and other portfolio actions and (viii) political and financial instability, including changes in general economic conditions. These and other important factors are discussed in the Company’s most recent annual report on Form 10-K and reports on Forms 10-Q and 8-K. These documents are available on the U.S. Securities and Exchange Commission’s website, on the Company’s website or from Bristol-Myers Squibb Investor Relations. In addition, any forward-looking statements and clinical trial data included in this press release are presented only as of the date hereof. Except as otherwise required by applicable law, the company undertakes no obligation to publicly update any of the provided information, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news