Pimicotinib

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 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 profile and 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 profile for 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 https://www.emdseronooncology.com/home.html . 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. All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group website. In case you are a resident of the USA or Canada, please go to www.emdgroup.com/subscribe to register for your online, change your selection or discontinue this service.

关注并星标CPHI制药在线慢性移植物抗宿主病（cGVHD）是指异基因造血干细胞移植（allo-HSCT）后，受者在重建供者免疫的过程中，来源于供者的淋巴细胞攻击受者脏器产生的临床病理综合征（包括经典型 cGVHD 和重叠综合征）。cGVHD发生机制复杂，临床表现多样，个体差异大，病程迁延持久，其主要病理生理过程是免疫炎症反应，常见和特征性的病理改变是纤维化。       cGVHD是造血干细胞移植(HSCT)的主要并发症之一，发生率约为30%-70%。而且，cGVHD是导致非复发死亡率(NRM)最常见的原因（37.8%）。       cGVHD治疗现状       目前，cGVHD的一线治疗是糖皮质激素联合或不联合钙调神经磷酸酶抑制剂（CNI，如环孢素、他克莫司、西罗莫司），但其-线治疗有效率仅为50%，超一半患者需要在2年内接受二线治疗。而且长期大剂量使用容易导致不良反应。       cGVHD二线治疗目前还无标准的优选治疗方案，但临床上有多个药物可供选择，如甲氨蝶呤、芦可替尼、伊布替尼、利妥昔单抗、伊马替尼、间充质干细胞、小剂量白介素-2（IL-2）、吗替麦考酚酯等，不过具体选择哪个药物药根据患者的病情进行个体化选择。       其中芦可替尼是一款口服JAK1/2抑制剂，2021年9月被FDA批准用于治疗曾接受过一种或两种全身性治疗的成人和12岁cGVHD患者。新英格兰医学杂志（NEJM）上发表的芦可替尼治疗cGVHD的3期临床试验REACH3结果显示：与当前最 佳疗法相比，芦可替尼可显著提高青少年和成人cGVHD患者的客观缓解率（ORR）、无失败生存率（FFS）和症状缓解率（SR）。此外，芦可替尼还于2023年4月在国内被批准用于治疗对糖皮质激素或其他系统治疗应答不充分的12岁及以上急性移植物抗宿主病（aGVHD）患者。       伊布替尼是FDA批准的首个cGVHD治疗药物，它一款口服BTK抑制剂抑制剂，2017年8月被FDA批准用于治疗经过一次或多次治疗失败的cGvHD成年患者，2022年8月又被FDA批准用于治疗1岁及以上、曾接受过一次或多次治疗失败的cGVHD患儿。已公布的伊布替尼治疗cGVHD的单臂临床试验数据显示：67% cGVHD患者症状得到改善，48％患者实现5个月或更久的持续症状改善。       不过芦可替尼和伊布替尼这两款药物主要作用于cGVHD的炎症阶段，没有直接的抗纤维化作用机制。而且，这两款药物也存在明显副作用，其中芦可替尼治疗后发生≥3级不良事件的比例高达57%，而且有5.5%患者发生任意级别的CMV感染或再激活。伊布替尼治疗后发生≥3级感染发生率高达47.4%，其中最常见的有肺炎（21.1%）和蜂窝织炎（15.8%），且还有10.5%的患者发生≥3级血小板减少。       cGVHD三线治疗有限，据不完全统计仅有芦可替尼、伊布替尼和贝舒地尔。而且，尤其对于糖皮质激素耐药（SR）cGVHD的三线治疗，临床上存在明显未满足的医疗需求。其中，Kadmon Holdings/赛诺菲的Rezurock（belumosudil，贝舒地尔）于2021年7月被FDA批准用于治疗先前接受过至少2种系统疗法治疗失败的cGVHD儿科（年龄≥12岁）和成人患者。       贝舒地尔是一款rho相关的含卷曲螺旋蛋白激酶2（ROCK2）抑制剂。而ROCK2介导的信号通路在调节炎症和纤维化反应中具有重要作用。该药通过减轻STAT3的磷酸化，加强STAT5的磷酸化，从而下调过度活化的T辅助细胞（Th17），并增强调节性T细胞（Treg）功能，进而重建免疫平衡。目前，该药已于2023年8月在国内被批准用于治疗cGVHD。       cGVHD在研药物进展       随着对cGVHD研究的深入，以及新药的研发，目前全球还有多款新药被开发用于治疗cGVHD，详见下表。值得一提的是，cGVHD治疗领域出现了新靶点药物，Axatilimab是一种靶向集落刺激因子-1受体（CSF-1R，被认为是控制单核细胞和巨噬细胞存活和功能的细胞表面蛋白）的单抗。在临床前模型中，抑制CSF-1R信号传导已被证明可减少疾病介导的巨噬细胞及其单核细胞前体的数量，并阻止皮肤和肺cGVHD的发展。目前，该药用于治疗至少经过两线系统治疗失败cGVHD的BLA正在美国接受优先审查，PDUFA日期为2024年8月28日。             已公布的Axatilimab治疗复发性或难治性活动性GVHD成人和儿童患者的2期临床AGAVE-201数据显示：治疗前6个月内，每2周接受0.3mg/kg治疗组患者的ORR最高，为74%，而且该治疗组中位反应时间为1.7个月，其中60%的患者在12个月时保持反应。此外，在0.3mg/kg剂量组中，55%患者在改良的Lee症状量表评分（次要终点）中至少获得7分的改善。而且，在基线时观察到所有涉及器官的器官特异性反应，在纤维化主导的器官中有显著反应：食管（78%）、关节和筋膜（76%）、肺（47%）和皮肤（27%）。       安全性方面，试验中最常见出现的治疗相关不良事件是天冬氨酸氨基转移酶、血液肌酸磷酸激酶、脂肪酶、乳酸脱氢酶和丙氨酸氨基转移酶升高。       和誉医药也自主研发了一款CSF-1R靶向药，即ABSK021。与Axatilimab不同，ABSK021是一款全新的口服、高选择性、高活性CSF-1R小分子抑制剂，被开发用于治疗腱鞘巨细胞瘤、cGVHD和晚期胰腺癌等，其中针对腱鞘巨细胞瘤的临床试验已进入3期阶段，针对cGVHD的临床试验已进入2期阶段。2023年12月，和誉医药与默克就该药达成独家许可协议，首付款金额高达5.03亿元。       我国药企也积极布局cGVHD领域，其中泰德制药的TDI01是一款高选择性ROCK2抑制剂，被开发用于治疗特发性肺纤维化、尘肺病、cGVHD等疾病，其中治疗中重度cGVHD的临床试验处于1b/2期阶段。       正大天晴的TQ05105是一个全新具有国家自主知识产权的小分子JAK1/2及ROCK1/2靶向抑制剂，已有临床数据显示：TQ05105对于糖皮质激素相关或依赖性cGVHD治疗有很好的疗效，最 佳缓解率达86%，且对于皮肤黏膜、口腔、肺等器官损伤具有很好的疗效。       与国际上市JAK2抑制剂相比，TQ05105的总体缓解率、疗效、各脏器功能特别是肺纤维化均显示出很好的结果，这或与其为JAK/ROCK双靶点的作用机制相关。       恒瑞医药的SHR0302是其自主研发的一款高选择性JAK1抑制剂，2023年其口服溶液在国内获批开展治疗cGVHD的临床试验。此外，该药还被开发用于治疗类风湿性关节炎、溃疡性结肠炎、特应性皮炎、斑秃、银屑病关节炎等，其中其片剂治疗成人及12岁以上青少年中重度特应性皮炎的3期临床试验已达到共同主要终点及次要终点；其外用软膏用于治疗轻中度特应性皮炎的临床试验也已进入3期阶段。       总结作为造血干细胞移植(HSCT)的主要并发症之一，cGVHD后线治疗还存在很大未满足的市场需求。目前，国内外多家药企积极布局cGVHD后线治疗，其中Axatilimab有望今年出线，成为首款治疗cGVHD的CSF-1R靶向药。和誉医药、恒瑞医药、正大天晴等国内药企也积极布局cGVHD领域，期待我国药企研发的cGVHD新药可以早日迎来重大突破。【智药研习社近期直播预告】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~