Exatecan mesilate

TOKYO, Japan & MUNICH, Germany I December 24, 2024 I Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have voluntarily withdrawn the marketing authorization application (MAA) in the EU for datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) based on the TROPION-Lung01 phase 3 trial. The decision to withdraw the MAA was informed by feedback from the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA). Daiichi Sankyo and AstraZeneca will continue to work to bring datopotamab deruxtecan to patients with lung cancer in the EU who can benefit and are committed to unlocking the potential of this medicine in lung cancer through our robust clinical development program which includes seven pivotal trials in various lung cancer settings. Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by Daiichi Sankyo and AstraZeneca. Daiichi Sankyo and AstraZeneca’s application in the EU for datopotamab deruxtecan for the treatment of hormone receptor (HR) positive, HER2 negative metastatic breast cancer based on the TROPION-Breast01 phase 3 trial remains under review. About TROPION-Lung01 TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. The dual primary endpoints of TROPION-Lung01 are progression-free survival (PFS) as assessed by blinded independent central review (BICR) and overall survival (OS). Key secondary endpoints include investigator-assessed PFS, objective response rate, duration of response, time to response, and disease control rate as assessed by both BICR and investigator, and safety. TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov . Primary PFS results and interim OS results from TROPION-Lung01 were presented at the 2023 ESMO (#ESMO23) Congress. Final OS results were presented at IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24) and simultaneously published in the Journal of Clinical Oncology in September 2024. About Advanced Non-Small Cell Lung Cancer Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. 1 In Europe, nearly 500,000 lung cancer cases were diagnosed in 2022. 1 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about 80% of cases. 2 While immunotherapy and targeted therapies have improved outcomes in the first-line setting, most patients eventually experience disease progression and receive chemotherapy. 3,4,5 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects. 3,4,5 TROP2 is a protein broadly expressed in the majority of NSCLC tumors. 6 There is currently no TROP2 directed ADC approved for the treatment of lung cancer. 7,8 About Datopotamab Deruxtecan (Dato-DXd) Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Additional regulatory submissions in breast cancer are under review in China, Japan, the U.S. and other regions. Datopotamab deruxtecan has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFR-mutated) NSCLC with disease progression on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. Daiichi Sankyo and AstraZeneca have submitted a Biologics License Application for datopotamab deruxtecan for this potential indication. About the Datopotamab Deruxtecan Clinical Development Program A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple negative breast cancer and HR positive, HER2 low or negative breast cancer. The program includes seven phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings. About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan 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. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com . References 1 World Health Organization. Global Cancer Observatory: Lung. Accessed December 2024. 2 American Cancer Society. Key Statistics for Lung Cancer . Accessed December 2024. 3 Chen R, et al. J Hematol Oncol . 2020:13(1):58. 4 Majeed U, et al. J Hematol Oncol . 2021;14(1):108. 5 Pircher A, et al. Anticancer Research . 2020;70(5):287-294. 6 Mito R, et al. Pathol Int . 2020;70(5):287-294. 7 American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer . Accessed December 2024. 8 Rodríguez-Abreau D, et al. Ann Onc . 2021 Jul;32(7): 881-895. SOURCE: Daiichi Sankyo

2023 年至 2024 年期间有多个创新药的上市申请被受理，参考既往创新药上市审评进度，大多产品将有望于 2025 年获批上市。其中包含来自恒瑞、乐普等多家企业的ADC药物。 MRG003 维贝柯妥塔单抗（MRG003）是一款靶向EGFR的抗体偶联药物（ADC），也是国内首个申报上市的EGFR ADC。 结构：由EGFR靶向单抗，通过缬氨酸-瓜氨酸连接子，与微管抑制有效载荷一甲基澳瑞他汀E分子偶联而成。 作用机制：药物高亲和力特异性地结合肿瘤细胞表面的EGFR，通过内吞及溶酶体蛋白酶裂解后释放强效的有效载荷，导致肿瘤细胞死亡。 2024年09月25日 ，根据中国国家药监局药品审评中心（CDE）官网公示，乐普生物的注射用维贝柯妥塔单抗的上市申请获得受理，用于既往经至少二线系统化疗和 PD-1/PD-L1 抑制剂治疗失败的复发/转移性鼻咽癌（NPC）患者。 2023年底，MRG003完成注册临床的入组，预计最快将于2025年获批上市，有望成为国内首个获批的EGFR ADC。 在IIa期临床试验中（针对复发/转移性鼻咽癌），MRG003具有显著的疗效。61例患者入组，既往经至少二线系统化疗和PD-1/PD-L1抑制剂治疗失败的复发/转移性鼻咽癌。疗效评估结果显示，ORR为47.4%，DCR为79.0%。 2.0mg/kg剂量组的ORR为39.3%，DCR为71.4%；而2.3mg/kg剂量组的ORR高达55.2%，DCR高达86.2%。 关于EGFR ADC EGFR是一种跨膜蛋白，在细胞生长、发育和分化过程中发挥重要作用。 EGFR的过度表达，及其特异性配体EGF、TGFα等结合，可使得EGFR异常激活，活化后的EGFR进一步激活、调控多条信号转导通路，进而抑制肿瘤细胞凋亡，促进肿瘤细胞增殖、迁移，并通过介导VEGF表达促进肿瘤血管新生。 通过阻断EGFR介导的信号转导通路，达到治疗肿瘤的效果。 SHR-A1811  SHR-A1811为第三代HER2 ADC. 抗体：曲妥珠单抗， Liker:可裂解连接子 Payload:为恒瑞自主研发的拓扑异构酶 I 抑制剂(SHR169265)，SHR169265的活性比DXd类似物SHR167971强3倍左右。 DAR值为6。 该药物在连接子与毒素之间，引入了手性环丙基设计，提升了药物的稳定性，可有效控制毒素的精准释放，降低药物提早释放可能引发的副作用。 作用机制： 注射用SHR-A1811特异性结合肿瘤细胞表面上HER2，随后药物被内吞至细胞内，并转运至溶酶体中，携带的载药在肿瘤细胞内产生药物作用，诱导细胞凋亡。 2023年2月10日，SHR-A1811被CDE拟纳入突破性治疗品种公示名单。 用于HER2 阳性的复发或转移性乳腺癌患者，用于HER2 低表达的复发或转移性乳腺癌患者。 2023年3月，恒瑞医药ADC创新药SHR-A1811治疗既往含铂化疗失败的HER2突变的晚期非小细胞肺癌被国家药品监督管理局药品审评中心拟纳入突破性治疗品种公示名单。 2024年9月13日，恒瑞医药公告，其子公司苏州盛迪亚生物医药有限公司收到国家药监局下发的《受理通知书》，注射用瑞康曲妥珠单抗（SHR-A1811）的药品上市许可申请获受理并被纳入优先审评程序。 ADC新药SHR-A1811 ，曾获六项突破疗法认证，分别为： HER2阳性的复发或转移性乳腺癌； HER2低表达的复发或转移性乳腺癌； 既往含铂化疗失败的HER2突变的晚期非小细胞肺癌； 既往经奥沙利铂、氟尿嘧啶和伊立替康治疗失败、HER2阳性结直肠癌； 既往至少一线抗HER2治疗失败的HER2阳性晚期胃癌或胃食管结合部腺癌； 既往接受过一种或一种以上治疗方案的HER2阳性不可切除或转移性胆道癌患者。 A166 A166 (商品名：舒泰来, 代号：A166)作为第三代靶向HER2的ADC药物，通过循环系统中更稳定的 Val-Cit 连接子(蛋白酶可裂解Linker), 将新型毒素分子(Duo-5，微管蛋白抑制剂)定点偶联至曲妥珠单抗(HER2抗体) ,DAR 值为 2，适应症：HER2阳性晚期乳腺癌。 作用机制：药物靶向HER2表达的肿瘤细胞，通过内吞作用进入细胞后，在胞内溶酶体中被切割并释放毒素分子。A166的毒素分子针对肿瘤细胞的作用机理为微管抑制，通过抑制微管影响细胞分裂周期，致使G2/M期细胞周期阻滞，从而高效杀伤肿瘤细胞。 SYD985 SYD985 (Trastuzumab duocarmazine)是Byondis研发的一款HER2 靶向 ADC药物, 抗体为trastuzumab(赫赛汀)，可裂解的连接体-杜康霉素有效载荷（活性毒素烷基化DNA），DAR值为2.4至2.8。 作用机制：SYD985抗体部分通过与癌细胞表面的HER2靶向结合，药物被细胞内化，连接子被水解切割后，细胞毒素药物vc-seco-DUBA被激活，从而诱导DNA损伤，导致肿瘤细胞死亡。药物具有旁观者效应。 U3-1402 ( Patritumab Deruxtecan，HER3-DXd)  Patritumab Deruxtecan (代号：U3-1402，HER3-DXd)是Daiichi Sankyo（第一三共公司）开发的一款靶向HER3的抗体偶联药物，由人源化抗HER3 IgG1单克隆抗体，通过可裂解四肽连接肽，与拓扑异构酶I抑制剂有效载荷（依喜替康衍生物DXd）组合而成。 Patritumab deruxtecan采用第一三共公司专有的DXd ADC技术设计，由人源化抗HER3抗体与拓扑异构酶I抑制剂有效载荷，通过一个四肽连接子连接而成。 Dato-DXd （德达博妥单抗，简称：Dato-DXd，代号：DS-1062a） Dato-DXd（通用名：Datopotamab deruxtecan，代号：DS-1062a）是一款靶向Trop-2的DXd抗体偶联药物（ADC)，其细胞毒性部分为拓扑异构酶1抑制剂。 Dato-DXd采用第一三共专有的DXdADC技术设计，由人源化抗TROP2 IgG1单克隆抗体，通过稳定的四肽可裂解Linker与拓扑异构酶 I抑制剂有效载荷exatecan衍生物（DX-8951衍生物，DXd）偶联而成。 2020年7月，阿斯利康与第一三共达成第二次合作共同开发和商业化DS-1062a。双方的第一次合作产品为DS-8201. 2024年4月2日，阿斯利康和第一三共datopotamab deruxtecan（Dato-DXd）的生物制品许可申请（BLA）已在美国受理，用于治疗不可切除或转移性激素受体（HR）阳性、HER2阴性的乳腺癌成人患者，这些患者既往接受过不可切除或转移性疾病的全身治疗。 2024年11月12日,阿斯利康和第一三共于宣布已提交Datopotamab deruxtecan生物制品许可申请（BLA），适应症为治疗既往接受过全身治疗（包括EGFR靶向治疗）的局部晚期或转移性表皮因子受体突变（EGFR）非小细胞肺癌（NSCLC）成人患者。 2024年12月9日，阿斯利康和第一三共宣布，美国FDA授予Datopotamab deruxtecan（Dato-DXd）突破性疗法认定（BTD），用于治疗在接受EGFR-酪氨酸激酶抑制剂（TKI）和铂类化疗后仍出现疾病进展的局部晚期或转移性表皮生长因子受体突变（EGFRm）的非小细胞肺癌（NSCLC）成人患者。 2025年Datopotamab deruxtecan将有望获批。 Teliso-V Telisotuzumab vedotin(商品名:Teliso-V,研发代号:ABBV-399)是一种新型c-MET靶点抗体药物偶联物 (ADC),由抗 c-Met 人源化单克隆抗体（ABT-700）通过 mc-val-cit-PABC （缬氨酸-瓜氨酸连接子）与细胞毒性单甲基 auristatin E (MMAE) 偶联组成。 Teliso-V由AbbVie公司开发，专门针对非小细胞肺癌（NSCLC）的治疗。 作用机制：Teliso-V 以特异性、高亲和力结合靶向表达 c-Met 的肿瘤细胞，并介导 MMAE 递送至肿瘤细胞，连接子蛋白水解后 MMAE 细胞内释放，MMAE与微管蛋白结合，抑制有丝分裂，最终导致肿瘤细胞死亡。 2022 年 1 月 Telisotuzumab Vedotin(ABBV-399)被 FDA 授予突破性疗法资格,用于治疗晚期或转移性铂类治疗后进展的 EGFR 野生型、具有 c-Met 过度表达的非鳞状 NSCLC 患者。 2024年9月27日，艾伯维宣布向美国FDA提交Telisotuzumab Vedotin（Teliso-V）生物制品许可申请 (BLA)，用于治疗先前接受过治疗的局部晚期或转移性表皮生长因子受体(EGFR) 野生型、非鳞状非小细胞肺癌 (NSCLC)且 c-Met蛋白过表达的成年患者。 越来越多的ADC 药物上市被受理，据有关数据显示，有三十多个ADC药物处于临床3 期，预计 2025 年中国 ADC 市场将迅猛增长。 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。