Capivasertib

关注并星标CPHI制药在线 近期，国家药品监督管理局药品审评中心（CDE）官网显示，齐鲁制药提交的阿贝西利片的4类仿制上市申请已获得受理。 阿贝西利是一款CDK4/6抑制剂，由礼来原研。而在CDK4/6抑制剂仿制药领域，齐鲁制药还获批上市了哌柏西利胶囊，成为国内市场上的首仿。 随着仿制药的陆续上市，CDK4/6抑制剂赛道必将迎来一场混战。 CDK4/6抑制剂的作用机制 CDK（Cyclin-dependent Kinase）全称为“细胞周期蛋白依赖性激酶”，是丝氨酸/苏氨酸蛋白激酶家族成员，在细胞周期调节中起着至关重要的作用。CDK4/6即细胞周期蛋白依赖性激酶4和6，二者生化特性、结构和功能相似。CDK4和CDK6被D型细胞周期蛋白（Cyclins D）激活后，将磷酸化视网膜母细胞瘤蛋白（pRb），导致其灭活，进而诱导细胞从G1期到S期，导致癌细胞无序增殖扩散。CDK4/6抑制剂通过抑制CDK4/6的活性，阻断细胞从G1期到S期的进程，从而抑制肿瘤细胞增殖。 卷成红海的CDK4/6抑制剂，还值得入局吗？ CDK自发现以来，一直被视为破坏癌细胞分裂和增殖的关键靶点，尤其在乳腺癌领域。多年来，药企对CDK4/6抑制剂的研发热情高涨，该赛道竞争十分激烈。 2015年，由辉瑞研发的哌柏西利（Palbociclib）获FDA批准上市，用于激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）的局部晚期或转移性乳腺癌的治疗，这是全球首款获批上市的CDK4/6抑制剂，分为片剂和胶囊两种剂型。 目前，哌柏西利已成为HR+/HER2-乳腺癌患者的一线疗法，并获全球超90个国家批准，用于HR+/HER2-乳腺癌的一线、二线治疗。2018年-2022年，哌柏西利业绩营收均在40-50亿美元左右。 随着2023年1月，哌柏西利的化合物专利到期，迎来更为激烈的市场竞争。2020年12月，齐鲁制药的哌柏西利胶囊获批上市，是国内首仿。2022年，豪森、山香药业的哌柏西利胶囊也先后获批上市。 2024年6月，石药集团子公司欧意药业的哌柏西利片获批上市，是国内该款药物的首仿产品。正大天晴的哌柏西利片剂仿制药申请正在接受药监局审查。齐鲁也曾于2022年4月提交过哌柏西利片的3类注册申请。哌柏西利的竞争，一目了然。 第二款获批上市的是诺华/大冢的瑞波西利（ribociclib），该药于2017年3月获FDA批准上市，与芳香酶抑制剂联合使用作为内分泌的初始疗、绝经后女性激素局部晚期或转移性乳腺癌的一线治疗。后续瑞波西利又被FDA批准用于治疗HR +/HER2-晚期或转移性女性乳腺癌患者，成为首款联合AI治疗绝经前、围绝经、绝经后女性患者的CDK4/6抑制剂。 2017年9月，礼来的阿贝西利（Abemaciclib）获FDA批准上市，用于治疗某些类型的HR+/HER2-晚期或转移性乳腺癌，并在后续获批用于治疗淋巴结阳性，高复发风险且Ki-67≥20%的HR+/HER2-早期乳腺癌患者的辅助治疗，成为全球首 款获批此适应症的CDK4/6抑制剂。 自从阿贝西利拿下早期乳腺癌适应症后，市场格局彻底改变。据礼来2023年财报显示，阿贝西利的全球销售额为38.63亿美元，同比上涨56%。 不过阿贝西利的核心专利将于2029年到期，已有众多药企对其仿制药虎视眈眈。 后续上市的CDK4/6抑制剂还有G1 Therapeutics的曲拉西利（Trilaciclib）和恒瑞医药的达尔西利。其中，曲拉西利获批适应症为骨髓抑制的治疗，是全球首个全系骨髓保护创新药物。 恒瑞的达尔西利于2021年获NMPA批准上市，适应症为联合氟维司群用于HR+/HER2-的经内分泌治疗后进展的复发或转移性乳腺癌的治疗。后续适应症扩大至联合芳香化酶抑制剂治疗HR+/HER2-局部晚期或转移性乳腺癌患者。 除已上市药物外，据公开资料，目前国内至少有8款CDK4/6抑制剂的临床阶段推至III期，而且适应症主要集中在HR+乳腺癌，涉及的药企包括正大天晴、贝达药业、复星医药、轩竹生物、先声药业等。另外还有至少9款CDK4/6抑制剂处于临床Ⅱ期阶段，涉及的药企包括豪森药业等。 而且除了创新药以外，国内CDK4/6抑制剂仿制药竞争也相当激烈。那么，国内药企此时入局CDK4/6抑制剂赛道还是好时机吗？ 答案是肯定的。主要基于两方面原因，一方面，目前CDK4/6抑制剂市场仍以辉瑞、诺华、礼来三家产品为主流，仅2023年，三家销售总额就接近100亿美元，国内药企还有弯道超车的机会。 另一方面，乳腺癌已成为全球第一大癌症，从市场空间看，CDK4/6抑制剂的主要适应症——HR+/HER2-，是乳腺癌的主要亚型，占所有病例的近70%，市场空间巨大。据Nature Reviews Drug Discovery预计，到2029年，CDK4/6抑制剂预计将贡献200亿美元，占乳腺癌药物销售市场份额的42%。这一数字足以让任何药企为之动容。 不过光鲜背后也有隐忧，CDK4/6抑制剂也会存在患者耐药或副作用等问题，同时吸引了全球药企投身其中寻求新的突破口。 如何突破内卷？ 在耐药性问题方面，PIK3CA/AKT1/PTEN的改变在乳腺癌中经常发生，影响到多达50%的HR+晚期乳腺癌患者。在这一背景下，AKT抑制剂Truqap（capivasertib）应运而生。 AKT（磷酸激酶B），是PAM信号通路中的关键分子，PAM是细胞内重要的传导通路之一，发挥着抑制细胞凋亡，促进细胞增殖的作用，与人类肿瘤的发生、发展密切相关。 Truqap是一款AKT1/2/3高效选择性抑制剂。2023年11月，Truqap获FDA批准上市，用于治疗HR+/HER2-局部晚期或转移性乳腺癌患者，这些患者在接受内分泌基础方案治疗过程中或之后疾病复发或进展。 国内目前有8款AKT抑制剂进入临床阶段，涉及药企包括南京正大天晴、海昶生物、来凯医药、恒瑞医药等。 在副作用方面，目前困扰CDK4/6抑制剂的一个问题就在于毒性问题。最常见的不良反应是中性粒细胞减少和骨髓抑制，尤其是哌柏西利和瑞波西利出现比例最高，3-4级中性粒细胞减少的比例为60%-66%。 为了降低副作用，CDK家族成员CDK2成为目前研究热点之一。同时，CDK2抑制剂还可能克服CDK4/6抑制剂耐药难题。研究表明，在CDK4被抑制后，CDK2会接管其作用并促进癌细胞增殖。这些癌细胞不仅会继续生长，还可能对之前的CDK抑制剂治疗产生耐药。这表明CDK2可能是CDK4/6耐药机制之一。 根据公开资料，目前围绕CDK2靶点，全球已有几十款在研新药，大部分处于临床前阶段。其中，辉瑞的PF-07104091片、阿斯利康的AZD8421等CDK2抑制剂处于I/II期临床研究阶段。国内百济神州与昂胜医药达成合作，引进后者一款在研CDK2抑制剂ETX-197，已于2024年8月在国内获批临床。 事实上，CDK这个靶点已有很长的研究历史，一直未能取得重大临床突破。随着对更多CDK家族成员作用机制研发的深入，未来乳腺癌的治疗必将更加波澜壮阔。 主要参考资料： 1、https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d. 2、https://doi.org/10.1016/j.cell.2023.05.013. 3、https://ensemtx.com/science/pipeline/. 扫码领取CPHI & PMEC China 2025展会门票 【智药研习社近期直播】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

Based on DESTINY-Breast06 Phase III trial results which showed ENHERTU demonstrated superiority vs. chemotherapy with a median progression-free survival of more than one year Approval brings AstraZeneca and Daiichi Sankyo’s ENHERTU to an earlier HR-positive treatment setting and broadens the patient population eligible for treatment with a HER2-directed therapy to those with HER2-ultralow disease WILMINGTON, DE, USA I January 27, 2025 I AstraZeneca and Daiichi Sankyo’sENHERTU ® (fam-trastuzumab deruxtecan-nxki) has been approved in the US for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a Food and Drug Administration (FDA)-approved test, that has progressed on one or more endocrine therapies in the metastatic setting. The approval was granted by the FDA after securing Priority Review and Breakthrough Therapy Designation and was based on results from the DESTINY-Breast06 Phase III trial, which were presented at the 2024 American Society of Clinical Oncology (ASCO) Meeting and published in The New England Journal of Medicine . Aditya Bardia, MD, MPH, Program Director of Breast Oncology and Director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center, US, and investigator in the DESTINY-Breast06 trial, said: “Endocrine therapy is typically used in the initial treatment of HR-positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes. With a median progression-free survival exceeding one year and a response rate of more than 60 percent, trastuzumab deruxtecanoffers a potential new standard of care for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.” Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca, said: “Building on the practice-changing previous approvals for ENHERTU, this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2-expressing metastatic breast cancer. The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining with astandard IHC test to identify those who may be eligible for treatment with ENHERTU following endocrine therapy.” Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, said: “ENHERTUcontinues to redefine the classification and treatment of HR-positive metastatic breast cancer with important new data across the spectrum of HER2 expression. Today’s approval underscores our ongoing commitment to realizing the full potential of this innovative antibody drug conjugate and represents another paradigm shift in how certain breast cancers can be treated.” Krissa Smith, Vice President, Education, Susan G. Komen, said: “We are excited to see more treatment options for these patients which enable more personalized care. It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumors that are HER2-low or HER2-ultralow now have more options to consider with their healthcare team.” In the trial, ENHERTU showed a 36% reduction in the risk of disease progression or death versus chemotherapy (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76; p<0.0001) in the overall trial population of patients with chemotherapy-naïve HER2-low or HER2-ultralow metastatic breast cancer. A median progression-free survival (PFS) of 13.2 months was seen in patients randomized to ENHERTUcompared to 8.1 months in those randomized to chemotherapy. The confirmed objective response rate (ORR) in the overall trial population was 62.6% for ENHERTUversus 34.4% for chemotherapy. In an exploratory analysis of patients with HER2-ultralow expression, results were seen to be consistent between patients with HER2-low expression and HER2-ultralow expression. HER2 status in the trial was confirmed by a central laboratory and was performed on a tumor sample obtained at the time of initial metastatic diagnosis or later. Approximately 85-90% of patients with HR-positive, HER2-negative metastatic breast cancer were determined to have actionable levels of HER2-expression. 1 Further, nearly two-thirds of patients previously assessed as IHC 0 at a local laboratory were classified as HER2-low or HER2-ultralow upon central analysis of the tumor sample. 1 The safety profile of ENHERTU in DESTINY-Breast06 was consistent with previous clinical trials of ENHERTUin breast cancer with no new safety concerns identified. ENHERTU is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo. ENHERTUis already approved in more than 75 countries, including the US, for patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. Regulatory applications are under review in the EU, Japan and several other countries based on the DESTINY-Breast06 results. Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . Notes Financial considerations Following this approval for ENHERTUin the US, an amount of $175m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the HER2-low and HER2-ultralow chemotherapy-naïve breast cancer indication. The milestone will be capitalized as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalized milestones and will be amortized through the profit and loss statement. Sales of ENHERTU in the US are recognized by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from ENHERTU sales in the US as Alliance Revenue in the Company’s financial statements. Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration. Breast cancer and HER2 expression Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 2 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally. 2 In the US, more than 300,000 cases of breast cancer are diagnosed annually. 3 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis. 4 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer. 5 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-directed therapies, representing approximately 15-20% of all breast cancers. 6 Historically, tumors that were not classified as HER2-positive were classified as HER2-negative. 7 HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers. 4 Endocrine therapies are widely given consecutively in the early lines of treatment for HR-positive metastatic breast cancer. However, after initial treatment, further efficacy from endocrine therapy is often limited. 8 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes. 8-11 Despite being classified as HER2-negative, many of these tumors may still carry some level of HER2 expression. 7 Prior to the approvals of ENHERTU in HER2-low or HER2-ultralow metastatic breast cancer based on the DESTINY-Breast04 and DESTINY-Breast06 trials, there were no targeted therapies specifically approved for these patient populations. 12,13 DESTINY-Breast06 DESTINY-Breast06 is a global, randomized, open-label, Phase III trial evaluating the efficacy and safety ofENHERTU (5.4mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients were also eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting 1st-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months. The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by blinded independent central review (BICR). Key secondary endpoints include PFS by BICR in the overall trial population (HER2-low and HER2-ultralow), overall survival (OS) in the HER2-low patient population and OS in the overall trial population. Other secondary endpoints include ORR, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) in Asia, Europe, Australia, North America and South America. For more information about the trial, visit ClinicalTrials.gov . ENHERTU ENHERTU is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTUis the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. ENHERTU (5.4mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridization [ISH]+) breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU(5.4mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. ENHERTU (5.4 mg/kg) is approved in the US for adult patients with unresectable or metastatic hormone receptor HR-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic settingbased on the results from the DESTINY-Breast06 trial. ENHERTU (5.4mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 ( ERBB2 ) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 , DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population. ENHERTU (5.4mg/kg) is approved in the US, Russia, Israel and Brazil for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on the results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU development program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers. Trials in combination with other anti-cancer treatments, such as immunotherapy, also are underway. Daiichi Sankyo collaboration AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan-dlnk in July 2020 , except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan-dlnk. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment. With ENHERTU, a HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive and HER2-low metastatic breast cancer and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicinesfulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, and next-generation SERD and potential new medicine camizestrant. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan-dlnk, in this setting. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the potential of datopotamab deruxtecan-dlnk alone and in combination with immunotherapydurvalumab, capivasertib in combination with chemotherapy, and durvalumab in combination with other oncology medicines, including olaparib and ENHERTU. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca . References SOURCE: AstraZeneca