Darovasertib

12月29日，恒瑞医药宣布将其Delta样配体3（DLL3）的抗体偶联药物（ADC）创新药SHR-4849在除大中华区以外的全球范围内开发、生产和商业化的独家权利有偿许可给美国IDEAYA Biosciences。 根据协议条款，IDEAYA将向恒瑞医药支付7500万美元的首付款，研发里程碑款累计不超过2亿美元，销售里程碑款累计不超过7.7亿美元。以上潜在的付款总额可达10.45亿美元（约合76.26亿元）。此外，恒瑞还将收取达到实际年净销售额一到两位数百分比的销售提成。 SHR-4849是恒瑞自主研发且具有知识产权的靶向DLL3的抗体药物偶联物（ADC）。DLL3在多种实体瘤中表达，包括小细胞肺癌和神经内分泌肿瘤，但在正常组织中的表达有限。目前全球范围内暂无DLL3 ADC产品获批上市。 1ADC尚未跑出的肺癌高热靶点DLL3SHR-4849在临床前模型中显示出良好的抗肿瘤活性：SHR-4849对DLL3中、高表达的不同肿瘤细胞系具有较强的增殖抑制活性；并具有明显的旁观者效应，可通过杀伤DLL3高表达细胞释放毒素来杀伤DLL3低表达细胞。 根据恒瑞医药公告，该药物目前正在中国进行针对晚期实体瘤的临床1期试验，目前处于剂量爬坡阶段，并且已经在多个剂量组观察到了临床应答。截至2024年12月10日，有效剂量下可疗效评估的小细胞肺癌（SCLC）患者共11位，其中8位患者达到了部分缓解（PR），总应答率（ORR）约73%；暂无任何药物导致的终止用药不良事件发生，安全性可控。 小细胞肺癌（SCLC）约占肺癌的13%～17%，患者平均生存期仅为1年左右，晚期患者的五年生存率仅为7%。尽管大多数广泛期SCLC患者对初始治疗有反应，但患者很快就会复发并需要后续的治疗，对于二线、三线治疗方案的临床需求迫切。作为发病率较高但又缺乏有效治疗手段的瘤种，SCLC一直是MNC的必争之地。而作为特异性优秀、路径明确的靶点，DLL3研发早已是一片火热： 2016年4月，艾伯维花费58亿美元收购了Stemcentrx，获得其用于治疗SCLC的ADC Rova-T（rovalpituzumab tesirine）。Rova-T临床前的研究结果证明其在高表达DLL3的CDX和PDX模型中具有优异的抗肿瘤效果，进而证明DLL3可能是一个潜在的ADC的有效靶点。不过，Rova-T研发折戟，后期临床数据显示对SCLC总应答率只有18%，中位OS仅为5.8个月，只比SCLC的标准治疗方案多了1个月。因此艾伯维也于2019年放弃了对Rova-T的开发。 不过，ADC药物的安全性和有效性取决于许多因素，包括药物抗体比值、细胞毒性载荷的类型、连接子稳定性等。同时，临床前到临床方案的设计与衔接也可能造成重大影响。虽然ADC首战折戟，但Rova-T的证据已足以将DLL3推上SCLC前三靶点的宝座。 2024年5月，安进DLL3/CD3双抗Tarlatamab（Imdelltra，塔拉妥单抗）获FDA加速批准，用于治疗在铂类化疗后疾病进展的广泛期小细胞肺癌（ES-SCLC），成为全球首款获批上市的DLL3靶点药物。百济神州拥有其中国商业化权益，目前已启动国内3期临床试验。 Tarlatamab是一款靶向DLL3和CD3的双特异性T细胞衔接蛋白（BiTE）。其2期临床数据显示，在可评估抗肿瘤活性和生存率的患者中，100mg组中客观缓解率（ORR）达到32%，10mg组中客观缓解率（ORR）达40%，既往接受标准法治疗复发患者ORR仅有15%；10mg组患者的中位无进展生存期（PFS）为4.9个月，100mg组的中位无进展生存期（PFS）为3.9个月；治疗9个月时，患者的总生存率估计分别为68%（10mg组）、66%（100mg组）。 出色的疗效无疑给全球范围内DLL3靶点药物研发打了一剂强心针，多款DLL3药物交易也已在全球多点开花：2023年4月，再鼎医药合作宜联生物，获得其DLL3 ADC药物YL212的全球开发及商业化权益，目前已在美国启动1期临床。11月，诺华以11.1亿美元的交易总金额拿下传奇生物DLL3 CAR-T LB2102。另外，全球首款靶向DLL3的核药ABD-147也已在2024年获批IND。2为核心管线寻找联合用药，两度拿下中国ADC管线的明星BiotechIDEAYA是一家肿瘤精准医疗公司，致力于为通过分子诊断筛选出的患者群体发现和开发靶向治疗药物。自2015年成立以来，IDEAYA获得了5AM Ventures、罗氏风投基金、谷歌风投、药明康德等多家明星资本的青睐，并在2021年成功IPO，融资总额超3亿美元。 IDEAYA的方法是将发现和验证转化生物标志物的能力与药物研发相结合，以选择最有可能从其靶向疗法中获益的患者群体。IDEAYA正在将其研究和药物发现的能力应用于合成致死（Synthetic lethality，SL）这类新兴的精准医疗靶点。 IDEAYA建立了一个完全集成的SL平台，可实现合成致死靶点和生物标志物发现、药物发现、功能基因组和药理学验证、转化研究和机会扩展一系列研究操作。凭借该平台，IDEAYA目前开发了多个在研管线。 7月31日，IDEAYA与百奥赛图达成协议，买下具有同类首创潜力的B7H3/PTK7拓扑异构酶抑制剂有效载荷双特异性抗体偶联药物（BsADC）的全球独家许可选择权，潜在交易总额达4.065亿美元。 超15亿美元合作的背后，是IDEAYA为其多款在研管线寻找联用药物。 其中，核心管线之一的IDE161是一种选择性PARG抑制剂，用于治疗患有晚期或转移性激素受体阳性（HR+）的（HRD实体瘤）成年患者。凭借良好疗效，IDEAYA已获得FDA授予快速通道资格，并指定其还可用于治疗携带BRCA1/2突变的乳腺癌和卵巢癌患者。 IDEAYA董事长兼CEO Yujiro S. Hata指出：“IDE161作为单一疗法，在子宫内膜癌和结直肠癌等疾病中展示出了良好的治疗效果，但联合用药将解锁更多适应症。”为此，IDEAYA一直在寻找与IDE161配对的分子。 此前公布的数据显示，在临床前肺癌模型中，拓扑异构酶I抑制剂（TOPOi）有效载荷和IDE161联用比单独使用任何一种分子都能产生更强的反应。于是，IDEAYA在中国的两度出手，买下了两款有效载荷为TOPOi的ADC，即百奥赛图B7H3/PTK7双抗ADC BCG034和此次交易的恒瑞DLL3 ADC SHR-4849。 与此同时，IDEAYA还与多家MNC达成了研发与临床合作，探索联用疗法可能： 合作辉瑞，评估IDE196和Crizotinib联合疗法的疗效及其安全性，用于治疗携带GNAQ/GNA11突变葡萄膜黑色素瘤；合作安进，IDE397（MAT2A抑制剂）与AMG 193（PRMT5小分子抑制剂）作为联合疗法，评估在治疗MTAP缺失实体瘤患者中的组合疗效和安全性。 与GSK达成战略伙伴关系，聚焦IDEAYA的三个合成致死研发项目，分别靶向MAT2A、Polθ和Werner解旋酶，并探索双方研发项目组合的可能性。在此交易中，IDEAYA获得1亿美元的前期现金付款，以及2000万美元的股权投资。3恒瑞第二款出海ADCADC是恒瑞创新药管线布局的重点方向之一。 基于模块化ADC创新平台（HRMAP），恒瑞目前已有包括SHR-4849在内的12个新型、具有差异化的ADC分子成功获批临床，其中HER2 ADC SHR-A1811（瑞康曲妥珠单抗）进入上市申报阶段，3款产品处于临床Ⅲ期，6款产品实现国际同步开发，还有多个创新药产品布局各个实体肿瘤治疗领域。 从靶点布局来看，除了HER2、TROP2、CLDN18.2、c-MET等常见靶点外，恒瑞也布局了一些相对蓝海的靶点管线，例如此次交易的DLL3 ADC，以及PSMA ADC、LIV-1 ADC等。 不过，在恒瑞过往的License Out中，多以化药和抗体药为主，ADC仅有2例（包括此次合作IDEAYA），但都为重磅的大额交易。2023年10月，默克以1.6亿欧元首付款、14.15亿欧元潜在总额，拿下PARP抑制剂HRS-1167、Claudin18.2 ADC新药SHR-A1904的中国外全球权益，并获得中国共同商业化的选择权。 珠玉在前，SHR-A1904不仅是恒瑞与MNC的首次License Out，还打响了恒瑞ADC出海第一炮。目前已在国内开展胃癌Ⅲ期临床，Ⅰ期数据显示客观缓解率（ORR）和疾病控制率（DCR）分别达到55.6%和88.9%。 综合来看，恒瑞的创新靶点ADC布局有其共性：全球竞争格局良好、管线多在IND或早期临床阶段；靶点已有数据及相关有效性证据；聚焦有临床缺口的适应症，如小细胞肺癌、转移性三阴性乳腺癌等；MNC或全球ADC领军企业已有布局或相关规划；发挥ADC潜在的广泛联用可能。 押注“黑马”靶点，恒瑞ADC出海已经走通了MNC和明星Biotech的双路径。 此外，恒瑞已有4款ADC产品获得FDA授予快速通道，已布局全球多国的临床试验，分别为SHR-A2009（HER3 ADC）、SHR-A2102（Nectin-4 ADC）、SHR-A1912（CD79b ADC）、SHR-A1921（TROP-2 ADC）。 参考资料：动脉网－融资总额超3亿美元，与安进、GSK等MNC合作，IDEAYA开发合成致死癌症新疗法动脉新医药－29.3亿！又一国产双抗ADC出海Insight数据库－恒瑞这三款突破性 ADC，也有出海潜力！

Independent Data Monitoring Committee (IDMC) recommends move-forward dose in Part 2a of potential registration-enabling trial in 1L HLA-A2-Negative MUM, based on clinical efficacy and safety observed Over 185 patients enrolled in potential registration-enabling trial in 1L HLA-A2-Negative MUM, and the darovasertib and crizotinib combination has received U.S. Food and Drug Administration (FDA) Fast Track designation in MUM SAN FRANCISCO, Dec. 17, 2024 /PRNewswire/ -- IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, today announced the Independent Data Monitoring Committee (IDMC) recommendation of a move-forward dose and the completion of the Part 2a dose optimization consistent with the U.S. Food and Drug Administration's (FDA) Project Optimus guidelines for the potential registration-enabling Phase 2/3 trial evaluating the combination of darovasertib and crizotinib in the first-line (1L) setting in patients with HLA-A2-negative (HLA-A2(-)) metastatic uveal melanoma (MUM). "We are pleased with the recommendation of the IDMC and the selection of the move-forward dose for our potential registration-enabling trial evaluating the darovasertib and crizotinib combination in first-line HLA-A2(-) MUM patients. This allows us to complete the Part 2a portion of the study and seamlessly continue to enroll in Part 2b towards a potential accelerated approval based on the primary endpoint of median progression free survival," said Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences. "The combination of darovasertib and crizotinib as first-line treatment has shown compelling preliminary clinical results in patients with HLA-A2(-) MUM. The IDMC recommendation of the move-forward dose supports the advancement of this potentially registration-enabling Phase 2/3 trial and is an important step in bringing a new treatment option to patients with MUM. Additionally, the continued rapid enrollment further validates the strong interest from physicians and patients, and highlights the significant unmet need in these patients, who historically have faced a poor prognosis," added Meredith McKean, M.D., MPH, Director, Melanoma and Skin Cancer Research at Sarah Cannon Research Institute, and clinical investigator on the potential registration-enabling clinical trial. The darovasertib and crizotinib combination in MUM has FDA Fast Track designation and is currently being evaluated in two clinical trials: a potentially registration-enabling Phase 2/3 trial of darovasertib and crizotinib combination in first-line HLA-A2(-) MUM (NCT05987332) and a Phase 2 trial (NCT03947385). Additionally, darovasertib as neoadjuvant monotherapy is currently being evaluated in a Phase 2 trial in primary uveal melanoma (NCT05907954). IDEAYA is also finalizing a clinical trial protocol and is targeting to initiate a potential Phase 3 registration-enabling study for neoadjuvant uveal melanoma patients in the first half of 2025. About IDEAYA Biosciences IDEAYA is a precision medicine oncology company committed to the discovery and development of targeted therapeutics for patient populations selected using molecular diagnostics. IDEAYA's approach integrates capabilities in identifying and validating translational biomarkers with drug discovery to select patient populations most likely to benefit from its targeted therapies. IDEAYA is applying its research and drug discovery capabilities to synthetic lethality – which represents an emerging class of precision medicine targets. Forward-Looking Statements This press release contains forward-looking statements, including, but not limited to, statements related to (i) the progress of the clinical development of the darovasertib and crizotinib combination in first-line HLA-A2 (-) MUM trial, (ii) the potential clinical efficacy, safety and therapeutic benefit of the darovasertib/crizotinib combination (iii) the registrational trial enrollment schedule of darovasertib/crizotinib combination in MUM (iv) the US FDA Fast Track designation and potential accelerated approval of the darovasertib/crizotinib combination in MUM; (v) the unmet need of patients with HLA-A2(-)MUM; (vi) the development progress of Phase 2 trials of darovasertib as neoadjuvant monotherapy in primary uveal melanoma; (vii) the timing of initiating a potential Phase 3 registration enabling study for neoadjuvant uveal melanoma patients in the first half of 2025. Such forward-looking statements involve substantial risks and uncertainties that could cause IDEAYA's preclinical and clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the drug development process, including IDEAYA's programs' early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, IDEAYA's ability to successfully establish, protect and defend its intellectual property, and other matters that could affect the sufficiency of existing cash to fund operations. IDEAYA undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of IDEAYA in general, see IDEAYA's Annual Report on Form 10-K dated February 20, 2024 and any current and periodic reports filed with the U.S. Securities and Exchange Commission. Investor and Media Contact IDEAYA Biosciences Andres Ruiz Briseno SVP, Head of Finance and Investor Relations [email protected] SOURCE IDEAYA Biosciences, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED