Tuvusertib

关注并星标CPHI制药在线 近日，德国默克集团宣布，其备受瞩目的IAP抑制剂Xevinapant与放化疗联合治疗局部晚期头颈癌的三期临床试验惨遭终止。该决定是基于独立数据监测委员会进行的期中分析而做出的，此分析认为该研究不太可能达到主要终点，即延长患者无事件生存期。这一突如其来的消息犹如一颗重磅炸弹，让市场对默克公司的前景产生了严重质疑，股价应声暴跌8%！ 除此以外，考虑到数据的完整性，默克还决定停止xevinapant联合放疗对比安慰剂联合放疗用于接受过手术切除的局部晚期头颈癌患者的III期X-Ray Vision研究。 Xevinapant是一款first-in-class高效口服小分子细胞凋亡蛋白抑制因子（IAP）的抑制剂。2021年3月，德国默克宣布与Debiopharm公司达成一项全球性许可协议，以约9亿欧元获得该药在全球范围内的开发和推广权益。 彼时，Xevinapant被寄予厚望。在II期临床研究中，xevinapant加放化疗的患者五年生存率几乎是安慰剂的两倍（53% vs 28%）。2020年2月，它成为了首个获得FDA突破性疗法认定（Breakthrough Therapy Designation）的IAP抑制剂。结合目前的护理标准，用于先前未治疗的局部晚期头颈部鳞状细胞癌（LA SCCHN）。 Xevinapant及其II期临床研究结果简介 图片来源：参考来源1 IAP蛋白高度表达且与多种癌症相联，包括肺癌、头颈癌、乳腺癌、胃肠癌，以及黑色素瘤和多发性骨髓瘤等，并且和预后密切相关。因此，IAPs是抗肿瘤药物研发的重要方向。不过，目前并没有IAP类药物获批上市，Xevinapant是目前全球研发进展最快的IAP抑制剂产品之一，其通过抑制IAP，不但促进癌细胞的死亡，还可以增强抗肿瘤的免疫反应。 作为行业的领头羊，本次研究的终止对于默克来说，是一个很大的打击，直到2024年5月，默克的高管还在向分析师们保证，Xevinapant的三期试验“不太可能（unlikely）”失败。 除了本次终止的两项III期研究外，目前默克产品管线中已经没有列出针对Xevinapant开展的其他试验。 默克肿瘤产品管线 图片来源：默克公司官网 频繁出手扫货肿瘤创新药 去年以来，默克相继与国内和誉医药和恒瑞医药达成独家许可协议，分别引进一款CSF-1R抑制剂（Pimicotinib）和一款高选择性PARP1抑制剂（HRS-1167/M9466）。 Pimicotinib 由和誉医药自主研发，是一款全新的口服、高选择性、高活性CSF-1R小分子抑制剂，当前已在中国、美国、加拿大和欧洲同步开展全球多中心三期临床试验，该研究是腱鞘巨细胞瘤疾病领域首个在中国、美国、加拿大和欧洲同步开展的全球III期研究。  在去年11月的CTOS年会上，和誉医药还更新了Pimicotinib治疗TGCT患者的临床Ib期试验一年长期随访数据，ORR达到87.5%，展现出了药物的抗肿瘤活性和良好的安全性。 此外，NMPA已批准Pimicotinib用于慢性移植物抗宿主病、晚期胰腺癌的临床试验，和誉医药也仍在探索该药物在多种实体瘤中的临床潜力。 HRS-1167（M9466）是恒瑞医药研发的一款选择性、高活性、可口服的 PARP1 小分子抑制剂，属于第二代 PARP 抑制剂。与第一代PARP抑制剂相比，HRS-1167对PARP1的选择性更高、亲和力更强，且可诱导DNA捕获。 M9466用于晚期实体肿瘤的Ⅰ期研究入选了ASCO 2024年会的壁报展示环节，研究显示：M9466在伴HRR突变的晚期实体肿瘤患者中显示出了突出的抗肿瘤疗效，对晚期卵巢癌患者的缓解效果更佳。 再往前追溯，默克还曾于2022年9月斥资6500万美元首付款囊获Nerviano旗下PARP1抑制剂NMS-293的开发和商业化权益。两笔交易传达出的信号已十分明显，默克对于PARP1抑制剂是坚定看好而且势在必得。 此外，今年年初默克还引进了Inspirna开发的一款first in class的结直肠癌药物ompenaclid的专利权。ompenaclid是肌酸转运通道SLC6A8的一流口服抑制剂，目前正在开发用于RAS突变（RASm）二线（2L）晚期或转移性结直肠癌（mCRC）和SLC6a8靶向后续化合物。去年10月在欧洲肿瘤内科学会（ESMO）大会上报告的Ib/II期数据表明，Ompenaclid与标准二线疗法（FOLFIRI化疗和贝伐珠单抗）结合有可能改善疗效，同时不会增加其毒性负担。该药物总缓解率可达37%（41名接受治疗的患者中有11名病情得到了缓解），中位无进展生存期（PFS）为10.2个月，中位总生存期（OS)为19.1个月。 深耕“合成致死”领域 ATR，即共济失调毛细血管扩张突变（ATM）基因和Rad3相关激酶，激活后可通过多种信号调控细胞生物过程, 包括细胞周期阻滞、抑制复制起点、促进脱氧核苷酸合成、启动复制叉以及修复DNA双链断裂。 研究发现，ATM和ATR 激酶在癌细胞中被激活或上调，同时ATR是ATM突变的合成致死靶点，ATM缺失的肿瘤细胞对于ATR抑制剂更加敏感。二者间的选择性抑制为肿瘤治疗提供了新的思路，也为肿瘤研究提供了新的工具。 除了PARP1抑制剂，默克在“合成致死”领域还分别布局了一款ATR抑制剂(M1774)和ATM抑制剂(M4076)，其中M1774进展较快已经进入II期临床，M4076尚处于I期临床。 Tuvusertib(M1774)是默克开发的一款潜在的best-in-class ATR抑制剂。2024年美国临床肿瘤学会(ASCO)年会上发布的DDRiver 301 Part B数据表明，预测有效剂量的tuvusertib与PARP抑制剂尼拉帕利联合治疗具有能力，并且在PARP预处理过的卵巢癌中具有令人鼓舞的活性。这些发现补充了4月份在美国癌症研究协会(AACR)年会上首次提出的tuvusertib和lartesertib联合疗法的数据。默克正在三个II期研究中探索tuvusertib： 1.正在进行的Ib/II期DDRiver NSCLC 322研究(NCT05882734)联合cemiplimab治疗具有生物标志物分层的耐药晚期非小细胞肺癌(NSCLC)； 2.最近开展的2期DDRiver EOC 302研究(NCT06433219)将tuvusertib联合lartesertib或尼拉帕利用于生物标志物选择的parp耐药卵巢癌; 3.近期开展的JAVELIN DDRiver膀胱II期研究(NCT06424717)联合BAVENCIO®(avelumab)治疗ci耐药晚期尿路上皮癌。 ADC：新兴靶点打头阵 默克的ADC管线以靶向CEACAM5 M9140为首，CEACAM5作为一种细胞表面蛋白，在健康的成年人组织中表达较少，但在多种腺癌中却高度表达，特别是在结直肠癌中，高达90%的病例都有CEACAM5的表达。该药物的治疗窗宽，并且在血液循环中也稳定，该药与DDR抑制剂合用可产生协同作用。M9140中的细胞毒性有效负载是拓扑异构酶1 (TOP1) 抑制剂，可防止DNA修复。目前，M9140处于结直肠癌的Ⅰ期临床研究阶段。 在今年的ASCO大会上，M9140的Ⅰ期临床试验结果备受瞩目。该试验纳入了来自美国、欧盟和日本的40名晚期结直肠癌患者，他们在接受标准治疗后病情仍有所进展。在接受7个不同剂量的M9140治疗后，10%的患者出现了明确的治疗反应，而42.5%的患者病情保持稳定，其中6名患者的病情稳定期超过了100天。此外，15%的患者病情出现进展。初步数据显示，中位无进展生存期为6.7个月。截至数据统计时，仍有15名患者（占比37.5%）正在接受M9140的治疗。 参考来源:        1.Bourhis, J., Burtness, B., Licitra, L. F., Nutting, C., Schoenfeld, J. D., Omar, M., … Cohen, E. E. (2022). Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design. Future Oncology, 18(14), 1669– 2.James Waldron. Merck KGaA drops xevinapant with phase 3 head and neck cancer trial on course for failure. FierceBiotech. Jun 25, 2024. 3.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. 4.默克公司官网 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~

Potential best-in-class ATR inhibitor tuvusertib being explored in Phase II combination clinical studies; recently licensed PARP1 inhibitor M9466 to be evaluated in Phase Ib combination dose-finding studies Potential first-in-class anti-CEACAM5 ADC with an exatecan payload, M9140, which entered Phase Ib in colorectal cancer this year, to be explored in other CEACAM5-expressing tumors beginning in 2025 First-in-class anti-GD2 ADC M3554, leveraging company’s novel exatecan-based technology, set to enter first-in-human study in adults in 2024 and in pediatric patients in 2025 Not intended for UK-based media DARMSTADT, Germany--(BUSINESS WIRE)-- Merck KGaA, Darmstadt, Germany a leading science and technology company that operates its Healthcare business as EMD Serono in the US and Canada, today shared updates on the company’s oncology pipeline and focused approach to the research and development of potential new medicines designed to improve the futures of people with cancer. This year, the company plans to open multiple new Phase Ib and II clinical studies for tuvusertib and M9466, key assets from its broad portfolio of DNA damage response (DDR) inhibitors; has advanced its lead antibody-drug conjugate (ADC), M9140, to Phase Ib based on positive signs of clinical benefit, and plans to expand to additional tumors; and progress M3554, its next ADC based on the company’s proprietary exatecan-payload platform, into clinical development. These and other updates were shared at the company’s Oncology R&D Update Call. “The advancements in our strong early-stage clinical pipeline of ADCs created with our in-house platform and DDR inhibitors are grounded in encouraging data, particularly for M9140 and tuvusertib. The addition of M9466 to our pipeline further supports our focus on synergistic approaches in oncology, with the potential for combination with tuvusertib as well as with multiple other modalities,” said Danny Bar-Zohar, Global Head of Research & Development and Chief Medical Officer for the Healthcare business sector of Merck KGaA, Darmstadt, Germany. "With our preclinical research programs in ADCs, DDR inhibitors, next-generation immuno-oncology compounds and oncogenic signaling assets, we are well-positioned to continue to fuel our clinical development efforts as we work to improve the futures of people touched by cancer.” Realizing the Full Potential of DNA Damage Response Inhibition The company’s leading pipeline of DDR inhibitors is being investigated across core hypotheses including synthetic lethality, activation of immune response, and synergy with cytotoxic drugs, to identify relevant combinations and understand which cancers are most likely to respond to different treatment regimens. Four investigational DDR inhibitor medicines in clinical trials include: Tuvusertib (M1774), a potentially best-in-class small-molecule oral inhibitor of the ataxia telangiectasia and Rad3-related (ATR) kinase; M9466, a next-generation potent and selective PARP1 (poly (ADP-ribose) polymerase 1) inhibitor, recently licensed from Jiangsu Hengrui Pharmaceuticals Co. Ltd. (Hengrui); Lartesertib (M4076), an ataxia telangiectasia mutated (ATM) kinase inhibitor; and Peposertib, a DNA-PK inhibitor. Recently presented data lay the foundation for combination Phase II studies with tuvusertib. Data from DDRiver 301 Part B presented today at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting show the ability to combine tuvusertib at a predicted efficacious dose with the PARP inhibitor niraparib, as well as encouraging activity in PARP-pretreated ovarian cancer. These findings complement data for the first-in-class tuvusertib and lartesertib combination first presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 in April. The company is exploring tuvusertib across three Phase II studies: Ongoing Phase Ib/II DDRiver NSCLC 322 study (NCT05882734) in combination with cemiplimab in ICI-resistant advanced non-small cell lung cancer (NSCLC) with biomarker stratification; Recently opened Phase II DDRiver EOC 302 study (NCT06433219) of tuvusertib plus lartesertib or niraparib in biomarker-selected PARP-resistant ovarian cancer; and Recently opened Phase II JAVELIN DDRiver Bladder study (NCT06424717), in combination with BAVENCIO® (avelumab) in ICI-resistant advanced urothelial cancer. For M9466 (also known as HRS-1167), data presented during the 2024 ASCO Annual Meeting from Hengrui’s first-in-human clinical trial show a favorable safety pro promising efficacy in PARP-naïve, PARP-sensitive tumors, supporting Merck KGaA, Darmstadt, Germany’s plans to further develop this investigational medicine in various combinations. The recently opened DDRiver 501 study (NCT06421935) will evaluate M9466 in combination with tuvusertib in solid tumors with relevant mutations and/or prior PARP inhibitor exposure, with a focus on castration-resistant prostate and ovarian cancers. The clinical development program will build on the company’s expertise in genitourinary and gastrointestinal cancers and aims to expand the list of indications beyond the tumors shown to be sensitive to first-generation PARP inhibitors. Driving Innovation in Antibody-Drug Conjugates The company has developed a proprietary technology platform for the creation of exatecan-based ADCs, with M9140 the first of these to enter clinical development. M9140 utilizes an antibody specific for CEACAM5, which is highly expressed in several tumor types, and an exatecan payload joined by a β-glucuronide linker that is specifically cleaved in tumors, releasing the cytotoxic agent into the cells. In preclinical research, M9140 has shown high bystander activity, as exatecan released in the target tumor cells can kill these cells and also permeate the cell membrane to induce cell death in neighboring cells. First-in-human data from the PROCEADE-CRC-01 clinical trial presented at the 2024 ASCO Annual Meeting show encouraging clinical activity and a manageable and predictable safety pro M9140 in this population. Following the completion of the ongoing dose-optimization part, the company plans to assess combinations in colorectal cancer with standard-of-care agents with alternative scheduling options. A basket trial planned to launch in early 2025 will further explore M9140 monotherapy in tumors with high CEACAM5 expression, with the potential for further exploration in various combinations. M3554 is the next ADC based on the company’s platform, linking an exatecan payload with an anti-GD2 antibody. This potentially first-in-class ADC will enter its first-in-human study later in 2024. M3554 will be evaluated in patients with solid tumors with high GD2 prevalence such as neuroblastoma, where GD2 has been validated as a target as a naked antibody, as well as soft tissue sarcoma, glioblastoma and osteosarcoma. ADCs are one of several modalities being explored in preclinical research. By maximizing the exatecan platform, delivering next-generation cytotoxins and targeted payloads, expanding into novel antigens, and discovering immune agonist ADCs, the company anticipates expansion in the organic clinical ADC portfolio over the next several years. Guided Approach to External Innovation Recent agreements continue to support the company’s oncology strategy, guided by focus areas across research, development and commercialization. These collaborations align with the company’s goal of driving over 50% of launches in the coming years with external innovation. In addition to the agreement with Hengrui for M9466, the company has executed agreements with Caris Life Sciences to support target discovery that may accelerate discovery and development of first-in-class ADCs; with Inspirna for ompenaclid, a first-in-class compound being investigated in colorectal cancer, complementing the company’s expertise in this tumor type; and with Abbisko Therapeutics Co. Ltd., for pimicotinib, for which the Phase III study in tenosynovial giant cell tumor recently completed enrollment. Advancing the Future of Cancer Care At Merck KGaA, Darmstadt, Germany, we strive every day to improve the futures of people living with cancer. Our research explores the full potential of promising mechanisms in cancer research, focused on synergistic approaches designed to hit cancer at its core. We are determined to maximize the impact of our standard-of-care treatments and to continue pioneering novel medicines. Our vision is to create a world where more cancer patients will become cancer survivors. Learn more at . About Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates across life science, healthcare and electronics. Around 63,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From providing products and services that accelerate drug development and manufacturing as well as discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2023, Merck KGaA, Darmstadt, Germany, generated sales of € 21 billion in 65 countries. The company holds the global rights to the name and trademark “Merck” internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life science, EMD Serono in healthcare and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company’s technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company. 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