TACTIVE-U: AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL UMBRELLA STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH OTHER ANTICANCER TREATMENTS IN PARTICIPANTS AGED 18 AND OLDER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER, SUB-STUDY C (ARV-471 IN COMBINATION WITH SAMURACICLIB)

The purpose of this study is to learn about the safety and effects of the study medicine called vepdegestrant. The safety and effects of vepdegestrant will be see when given with other medicines. Vepdegestrant is studied to see if it can be a possible treatment for advanced metastatic breast cancer. This type of cancer would have spread from where it started (breast) to other parts of the body and would be tough to treat.
The study is seeking for participants who have breast cancer that:
* is hard to treat (advanced) and may have spread to other organs (metastatic). is sensitive to hormonal therapy (it is called estrogen receptor positive).
* is no longer responding to treatments taken before starting this study.
This study is divided into separate sub-studies.
For Sub-Study C:
All the participants will receive vepdegestrant and a medicine called samuraciclib.
Vepdegestrant and samuraciclib will be taken once in a day by mouth. The medicines will be taken at home. The experience of people receiving the study medicines will be studied. This will help see if the study medicine is safe and effective.
Participant will continue to take vepdegestrant and samuraciclib until:
* their cancer is no longer responding, or
* side effects become too severe.
They will have visits at the study clinic about every 4 weeks.

开始日期2024-01-10

申办/合作机构

Pfizer Inc.

[+2]

NCT05963984

/ Active, not recruiting临床2期

An Open-label, Interventional, Multicenter, Randomized, Phase 2 Study of Fulvestrant With or Without Samuraciclib in Participants With Metastatic or Locally Advanced Hormone Receptor (HR) Positive and Human Epidermal Growth Factor Receptor (HER)2-Negative Breast Cancer (BC)

The purpose of this study is to evaluate the safety and efficacy of samuraciclib in combination with fulvestrant versus fulvestrant alone in adult participants with metastatic or locally advanced Hormone Receptor (HR) positive and Human Epidermal Growth Factor Receptor (HER)2-negative breast cancer.

开始日期2023-12-14

申办/合作机构

Carrick Therapeutics Ltd.初创企业

[+1]

NCT05963997

/ Active, not recruiting临床1/2期

A Phase 1b/2 Open-label Study of Samuraciclib in Combination With Elacestrant in Participants With Metastatic or Locally Advanced Hormone Receptor-positive and Human Epidermal Growth Factor Receptor 2-negative Breast Cancer

This is an international, multisite, open-label, Phase 1b/2 study, to confirm safety and efficacy of samuraciclib in combination with elacestrant in adult participants with metastatic or locally advanced Hormone Receptor (HR) positive and Human Epidermal Growth Factor Receptor (HER)2-negative breast cancer.

开始日期2023-10-09

申办/合作机构

Carrick Therapeutics Ltd.初创企业

[+1]

100 项与 Samuraciclib hydrochloride 相关的临床结果

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100 项与 Samuraciclib hydrochloride 相关的转化医学

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100 项与 Samuraciclib hydrochloride 相关的专利（医药）

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项与 Samuraciclib hydrochloride 相关的文献（医药）

2024-05-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer

Article

作者: Naumenko, Sergey ; Cohen Feit, Gabriella ; Schiff, Rachel ; Guarducci, Cristina ; De Angelis, Carmine ; Bergholz, Johann S. ; Shapiro, Geoffrey I. ; Malorni, Luca ; Zhao, Jean J. ; Jeselsohn, Rinath ; Fraenkel, Ernest ; O'Donnell, Madison ; Grinshpun, Albert ; Feiglin, Ariel ; Hermida-Prado, Francisco ; Russo, Douglas ; Zhang, Qi ; Feit, Avery ; Morlando, Antonio ; Nardone, Agostina ; Leventhal, Mathew Joseph ; Liu, Weihan ; Lim, Elgene ; Nagy, Zsuzsanna ; Nguyen, Quang-Dé ; Freelander, Allegra ; Ma, Wen ; Heraud, Capucine ; Huang, Ying ; Kesten, Nikolas ; Huang, Shixia

Abstract:

Purpose::

Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.

Experimental Design::

We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.

Results::

We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.

Conclusions::

Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.

2024-04-15·Cancer

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

Article

作者: Wu, Jiayi ; Gao, Lu ; Wang, Wei ; Shao, Xiying ; Wang, Xiaojia

ABSTRACT:

Background:

Clinical studies on programmed death‐ligand 1 (PD‐L1) immune checkpoint inhibitors for treating triple‐negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor‐infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin‐dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies.

Methods:

The authors tested three CDK inhibitors on the TNBC cell lines MDA‐MB‐231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune‐related mechanisms of different combination therapy experiments in a 4T1 cell‐transplanted BALB/c mouse model.

Results:

Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell‐cycle arrest and induced apoptosis in human breast cancer MDA‐MB‐231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD‐L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels.

Conclusions:

Combination therapy with CDK and PD‐L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

2023-11-01·Molecular cell

Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Article

作者: Lauring, Josh ; Maizels, Rory J ; de Bruin, Robertus A M ; Huard, Caroline ; Ali, Simak ; Bertomeu, Thierry ; Vuina, Karla ; Wilson, Gemma A ; Tyers, Mike ; Sava, Georgina ; Kriston-Vizi, Janos ; Meneguello, Leticia ; Bertoli, Cosetta ; Coulombe-Huntington, Jasmin

Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells.

项与 Samuraciclib hydrochloride 相关的新闻（医药）

2025-01-24

·智药邦

Nat Cancer｜人工智能对于癌症药物研发的作用

2024年12月17日，Nature Cancer上发表文章Beyond the hype of AI in cancer R&D。以下是全文。人工智能有望更快、更廉价、更精准地助力药物制造。尽管由人工智能驱动的生物技术公司吸引了大笔资金，还登上了耀眼的头条新闻，但它们尚未将产品成功推向市场终点。到目前为止，人工智能的最大影响体现在何处呢？由人工智能驱动的生物技术公司宣称要“重新思考药物发现”以及“实现研发产业化”，这成功吸引了数十亿美元的资金投入。2024年4月，ARCH孵化的Xaira公司筹集了破纪录的10亿美元，用于部署其人工智能辅助药物设计工具套件。总体而言，以人工智能为核心的生物技术公司在2024年所筹集的风险资金，有望超过2021年以来的任何一年。随着所有运用复杂计算的公司都在寻求搭乘人工智能的发展顺风车，各公司的宣传内容也在不断更新。这种兴奋是有充分理由的。从靶点发现、假设生成和药物设计，到生物标记物识别、试验设计以及患者招募，人工智能有潜力加速并改善生物医学的几乎每一个环节。鉴于有大量“组学”技术、成像及其他患者数据可用于机器训练，癌症研发领域自然非常适合大规模应用人工智能。然而，人工智能并非仅仅是几十年来以各种形式应用于生物技术领域的高能数据处理。如今的算法能够大规模地分析和处理数据，挖掘出以前未知的联系，产生并测试新想法，还能助力确定生物途径和机制。拥有足够的训练数据后，最强大的人工智能引擎能够生成新的分子结构，这些结构可单独或组合使用，以有效治疗疾病。2024年5月发布的谷歌DeepMind蛋白质结构数据库AlphaFold3，涵盖了预测蛋白质如何与核酸等其他分子结合的内容。图2 AF3能够准确预测生物分子复合物的结构细胞生物学初创公司Cellanome的联合创始人、液体活检平台GRAIL（今年被Illumina剥离）的前任联合创始人Mostafa Ronaghi总结：“随着定量生物学的兴起，人工智能是这场游戏中的关键调味品。” 然而，尽管有几种人工智能候选药物正在进行临床试验，但还没有一种人工智能候选药物通过监管机构的审批。第一代人工智能驱动的药物发现公司，如BenevolentAI和Exscientia（2024年8月被竞争对手Recursion兼并），均曾遭遇挫折。 Lantern Pharma公司CEO Panna Sharma表示：“人工智能公司有很多‘学习很酷东西’的活动，但很少能看到公司充分利用人工智能并将药物推进到有意义的临床试验阶段。” Insilico Medicine和Recursion的非肿瘤生成式人工智能项目，最近公布的II期数据很有希望，但因缺乏足够的统计细节，所以难以表明人工智能明显领先于传统方法。REC-994是一种治疗症状性脑海绵状畸形的药物，其II期试验数据显示该药物安全且可耐受，但12个月后的疗效有限，Recursion的股价也随之下跌。即便如此，Recursion首席研发官兼首席商务官、强生前任首席数据科学官Najat Khan表示：“我们并不期望任何技术的首次迭代就是完美的。我们正在寻找具有潜力的早期迹象。” 迄今为止，人工智能对医疗保健最显著的影响体现在诊断成像方面。机器的模式识别能力有助于提高乳腺癌的早期发现率，能够突出显示异常情况，或标记检查结果以便后续跟进。FDA批准的大多数人工智能工具都与成像相关，尽管在广泛应用和临床转化方面存在挑战，但人工智能驱动的诊断工作仍在持续拓展。例如，数字病理学公司Owkin最近与默克（Merck MSD）合作开展了一项试点计划，试图借助分析肿瘤组织的机器学习（ML）算法，提高结直肠癌诊断的准确性。聚焦于药物发现阶段在幕后，人工智能工具正在变革研发工作。但是，自第一家人工智能公司诞生以来的十多年间，大部分工作集中在早期发现阶段，而这一阶段较难吸引大众关注、获取头条新闻。 Sharma说到：“这项技术能够缩短从早期发现到确定明确候选药物的时间。与传统方法相比，Lantern的癌症项目从最初的人工智能洞察到首次人体临床试验的时间缩短了约一半，成本降低了80%。成本约为100万到250万美元，耗时仅两到三年，而不是通常的四到七年。”Recursion和Insilico Medicine的情况也与之类似。 Insilico Medicine创始人兼首席执行官Alex Zhavoronkov表示：“对于一个中等新颖的靶点，从构思到临床前候选研究平均需要13个月，而开展人体临床试验则需要20-24个月。” 这种速度得益于人工智能能够生成数十种可行的候选药物，并大规模地进行多次实验和模拟。以癌症为重点的Turbine首席执行官Szabolcs Nagy说：“你可以测试更多的想法。先导优化--使化合物更接近药物的状态，是研发中的一大难题，而人工智能可以帮助解决这一问题。”Turbine的细胞模拟平台利用机器学习建立人体细胞组织的计算机模型，使开发人员能够在进行湿实验室实验之前，观察特定治疗方法的效果。机器虽然还无法取代实验室测试，但它们能让研究人员更快地开展正确的实验，从理论上讲，这有助于提高日后的成功率。再利用和组合人工智能对癌症治疗的一些早期影响，可能体现在对失败或废弃药物的重新利用上。Lantern有三个临床项目，分别涉及非小细胞肺癌（NSCLC）、晚期实体瘤和非霍奇金淋巴瘤。先导药物是一种II期二硫化物，可在某些从不吸烟的肺癌患者中增强酪氨酸激酶抑制剂的作用，它是一种重新利用的药物，是通过Lantern的人工智能平台确定的。该平台整合了来自研究、试验和数据库的数百亿肿瘤数据点，并运用机器学习策略预测患者对候选药物的反应。 Sharma说：“人工智能可用于快速发现被忽视的新适应症，或识别尚未完全明确的新癌症亚型（含生物标志物）。” 同样，Recursion的精准肿瘤学管线，由武田一项已停产的NSCLC资产打头阵：一种MEK1和MEK2的异位小分子抑制剂，目前正快速应用于晚期AXIN1或APC突变癌症。为了更好地了解该分子的作用机制，Recursion利用机器学习算法将其与各种疾病和细胞模型进行交叉对比，从而确定了该药物的最佳作用位点。针对AXIN1或APC基因突变的晚期或转移性癌症患者的II期试验正在进行中，预计将于2025年获得初步数据。 Recursion产品管线确定抗癌药物的有效组合，是另一个容易取得成果的领域。Sharma说：“人工智能使我们能够“浏览所有试验数据，找出应该联合使用的药物”。当前的联合用药试验既艰巨又耗时，有时sponsor之间的利益分歧也会阻碍试验的进行。人工智能能够更快地提供更可靠的证据基础。Turbine利用其细胞模拟平台，为Debiopharm的I期WEE1抑制剂Debio 0123寻找新的组合疗法，帮助确定并验证了治疗搭档cabozantinib（Exelixis的酪氨酸激酶抑制剂）。” 快速开发新化合物人工智能能够为特定治疗效果量身定制新结构，这一点令一些支持者最为兴奋。在Zhavoronkov看来，这种“生成”能力将“真正的”人工智能与机器学习区分开来，机器学习中计算机只是学会遵循特定指令，无法超越指令的范畴。“真正的人工智能是深度学习--这意味着能够进行推理和处理多模态数据，创造出原本不存在的东西，而且比人类做得更好。在生物科学领域之外，一个备受瞩目的例子是谷歌的AlphaGo，它在没有经过专门针对围棋的明确训练的情况下，就学会了下围棋，并且足以打败人类专家。” 如今，人工智能生成的生物分子与现有的生物分子较为相似，都是经过调整，以提高选择性或降低脱靶毒性。考虑到算法训练数据的特性，这种情况并不意外。Insilico Medicine用于治疗BRCA突变型癌症的USP1抑制剂，源自该公司的小分子生成人工智能平台Chemistry42。USP1是一种调节DNA损伤反应途径的去泛素化酶，并非新靶点。但这种抑制剂具有新颖的结构，而且其临床前研究内容，包括抗肿瘤活性、耐受性和药代动力学，足以吸引许可合作伙伴Exelixis在2023年预付8000万美元，目前该药物正在进行I期测试。Tango Therapeutics的一个类似候选药物，因肝毒性于2024年5月被放弃。罗氏也在寻找一种有效的USP1抑制剂，以补充另一种合成致死靶点PARP的抑制剂。 Insilico Medicine三项处于临床阶段的癌症资产中的另一项，是利用该生物技术公司的靶点识别平台PandaOmics设计的QPCTL抑制剂。QPCTL与CD47-SIRPα轴相关，有助于癌症躲避免疫监视。该化合物与上海复星医药合作，于2024年5月在中国进入1期剂量递增试验，用于治疗CD47-SIRPα高度参与的淋巴瘤和晚期实体瘤。 Recursion唯一处于临床阶段的新癌症候选药物，是Exscientia精确设计的CDK7抑制剂，目前正处于1/2期试验阶段，用于治疗对标准疗法无反应的实体瘤患者。CDK7是调控癌基因转录和细胞周期进展的关键因素，是另一个研究较为深入的靶点。目前正在进行的1b/2期试验，包括Carrick Therapeutics的samuraciclib，这是一种CD47抑制剂，目前正与一种口服PROTAC雌激素受体降解剂联合治疗ER阳性、HER2阴性转移性乳腺癌患者，这些患者之前曾接受过CDK4/6抑制剂治疗。其中一些竞争药物在争取足够广泛的治疗窗口期方面一直面临困难。Recursion/Exscientia设计的小分子药物具有严格控制的结合范围和持续时间，这有望使其在同类产品中脱颖而出。对于一流的癌症资产，Khan指出Recursion的RBM39强效选择性降解剂，RBM39是肿瘤相关基因表达的调控因子，在许多癌症中均有富集。该公司计划在2024年申请研究性新药批准，并于次年开始在生物标志物筛选出的实体瘤或淋巴瘤患者中进行试验。试验设计和执行先导候选药物必须在人体中证明其有效性。临床试验耗费了大部分研发成本和时间，因此即使是微小的疗效提升，也会产生巨大的影响。“临床开发中最大的挑战之一，就是我们没有针对合适的患者。”Khan说。利用来自Tempus等专业数据采集器的临床和多组学数据，Recursion部署了因果人工智能模型，以识别最佳受试者。改进患者选择意味着可以缩小试验规模，理论上也能提高成功率。人工智能--这里指的是标准的数据运算迭代，而非更具创新性的生成版本，还可用于定位符合条件的患者，并确定最佳试验地点，以最大程度加快招募进程。Khan表示，大型制药公司多年来一直在试验运营中部署人工智能（诺华于2018年推出了试验监测中心），这提高了招募率和多样性。进化，而非革命人工智能的支持者承认，人工智能的强大威力尚未得到充分展现。它加快了研发的某些环节，但还未能比药物化学家和生物学家更快地提供更优质的药物。迄今为止，人工智能对药物研发的影响是渐进式的，而非革命性的。这在一定程度上是因为人工智能的价值，来源于与其他技术的融合，以及人类的专业知识和精心策划。将人工智能工具融入传统研发流程并非易事。大型制药公司面临着内部阻力，员工担心会因此失去工作。规模较小的人工智能公司则缺乏资金来升级和重建整个流程，它们必须努力证明自己的解决方案切实可行。随着人工智能的广泛应用，不同的商业模式也在不断涌现（见box 1）。人工智能揭示疾病复杂性的能力，仍然受到输入数据质量的限制，这些数据比人工智能所带来的兴奋感所暗示的更杂乱、更不完整、更不全面。Cumulus Oncology的首席数据科学家Phil Chapman说：“大量的健康数据确实存在，但其中大部分数据仅来自少数人，而且往往复杂、混乱，也不是纵向的。”监管机构也必须跟上步伐：FDA最近成立了一个人工智能监督委员会，以指导如何在监管申报中考虑人工智能因素，但详细的政策似乎仍需时日才能出台。尽管面临诸多挑战，但Zhavoronkov相信，在本十年内，人工智能对药物研发的影响将出现令人信服的证据。他表示，这将涉及展示“从靶点发现到药物设计的一条清晰、有据可查的途径”，以及提供能够造福患者的重磅疗法。“如果没有战争或经济崩溃等重大变故，我预计这将在2026年至2029年之间实现。” 同时，随着人工智能持续渗透到各个领域和活动中，“当然会存在炒作现象。”他补充道。 Box 1 端到端人工智能与聚焦人工智能随着人工智能在研发领域的广泛应用，各种商业模式不断涌现。Xaira、Insilico Medicine和Recursion等公司，试图将从药物研发构思到获批的整个流程进行高端化改造，研究多种疾病和治疗假设，并建立自己的研发管线来验证自身方法。Insilico Medicine还通过向制药公司授权其人工智能平台来获取收入。其他一些公司则专注于研发的特定环节，如小分子发现（Atomwise或Iktos）、蛋白质设计（Cradle）或试验招募。法国初创公司Cure51正在建立一个癌症幸存者数据库，并利用人工智能寻找这些人的共性，从而揭示生存机制，为治疗提供灵感。人工智能还被用于创建细胞、蛋白质组和分子相互作用的基础图谱和模型，以揭示生物的复杂性，并提供加速研发的工具。Turbine的团队利用机器学习网络来反映、理解和预测蛋白质的相互作用，从而建立了一个适用于任何细胞的人类蛋白质逻辑模型。相关人员表示，这一模型可应用于药物发现以外的领域，一直到临床概念验证阶段，在任何需要决定“选择哪种分子、哪种剂量或哪种适应症”的情况下都能发挥作用。Cellanome的目标是建立细胞和细胞相互作用的基础模型，将基因组学、蛋白质组学、代谢组学等多模态测量数据纳入其中，并进行长期采集。Owkin正在收集病人的多模态数据，以生成分子空间环境图集，绘制肿瘤微环境图以及肿瘤与免疫细胞相互作用的图谱。参考资料： Senior, M. Beyond the hype of AI in cancer R&D. Nat Cancer 5, 1759–1761 (2024). https://doi.org/10.1038/s43018-024-00857-3 --------- End --------- 感兴趣的读者，可以添加小邦微信加入读者实名讨论微信群。添加时请主动注明姓名-企业-职位/岗位或姓名-学校-职务/研究方向。

2024-12-13

·研发客

MNC预付超10亿美元收购的管线进展如何？ | 第一现场

近日，诺华与PTC Therapeutics就口服亨廷顿蛋白 (HTT) mRNA剪接调节剂PTC518达成一项全球许可合作协议。诺华将支付10亿美元预付款，后续还有最多可达19亿美元的里程碑付款。 PTC518的PIVOT-HD II期研究目前正在进行中，预计在明年上半年完成。据诺华的新闻稿，PTC518有潜力成为第一款亨廷顿舞蹈症（HD）的口服药物。此前，因潜在的周围神经病变等副作用，诺华放弃了HD候选产品branaplam的开发。据BioCentury统计，自2009年以来，包括诺华在内，还有BMS、默沙东、罗氏和辉瑞都曾以超10亿美元的预付款来收购单一管线，这些管线的命运喜忧参半。其中，预付款最高的是2018年BMS与Nektar Therapeutics的交易，BMS向Nektar支付了18.5亿美元的预付款，双方计划就CD122偏向型激动剂bempegaldesleukin（NKTR-214）开展全球开发和商业化合作。后来双方开展了NKTR-214联合Opdivo治疗包括膀胱癌、肾癌和黑色素瘤等在内的多项临床研究，然而最终因临床结果不理想这些联合研究项目被终止了。同样以失败告终的还有默沙东与Seattle Genetics（后更名为Seagen）的交易。在该笔2020年达成的交易中，默沙东支付了16亿美元的预付款，交易总额超过了BMS与Nektar的交易，为42亿美元。该交易涉及的产品为针对LIV-1的ADC产品ladiratuzumab vedotin，双方就该产品探索作为单一疗法和联合Keytruda治疗三阴性乳腺癌、激素受体阳性乳腺癌和其它表达LIV-1的实体瘤的潜力。去年8月，默沙东计划终止该项目。据Fierce报道，默沙东曾有意向收购Seagen，但由于双方就收购价格没有达成一致，最终辉瑞以430亿美元收购了该公司。虽然Seagen当时的声明指出，同默沙东的合作协议仍然有效，默沙东后来依然取消了该产品开发的优先级。另外2笔交易为罗氏/Sarepta Therapeutics和辉瑞/Arvinas，首付款分别为11.5亿美元和10亿美元。幸运的是，交易涉及的Elevidys已经上岸，vepdegestrant可能很快将上岸。今年6月，美国FDA批准扩大Sarepta的基因疗法Elevidys的适应症，用于≥4岁杜氏肌营养不良症（DMD）患者。据此前双方达成的协议，罗氏持有该产品美国之外的全球权益。 Arvinas的vepdegestrant是一款PROTAC产品，今年2月，该产品获得了FDA 快速通道认定。据辉瑞官网的信息，目前其针对ER+/HER2-转移性乳腺癌的3期VERITAC-2研究正在评估vepdegestrant作为单药在二线治疗中的疗效，正在进行的3期VERITAC-3研究正在评估vepdegestran与palbociclib联用在一线治疗中的疗效。此外，辉瑞还在探索vepdegestrant与abemaciclib、ribociclib、samuraciclib、everolimus以及辉瑞的新型CDK4抑制剂PF-07220060联用的可行性。总第2277期访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

并购信使RNA临床3期蛋白降解靶向嵌合体基因疗法

2024-12-11

·PipelineReview

Arvinas and Pfizer Announce Initial Phase 1b Data from the TACTIVE-U Sub-Study of Vepdegestrant in Combination with Abemaciclib at 2024 San Antonio Breast Cancer Symposium

– Vepdegestrant in combination with abemaciclib demonstrated encouraging clinical activity (clinical benefit rate: 62.5%; overall response rate: 26.7%) in patients previously treated with a CDK4/6 inhibitor – – Safety and tolerability of the combination is generally consistent with the profile of abemaciclib and what has been observed in other clinical trials of vepdegestrant; no significant drug-drug interaction was observed between vepdegestrant and abemaciclib – – Recommended Phase 2 dose identified as 200 mg QD vepdegestrant and 150 mg BID abemaciclib – NEW HAVEN, CT and NEW YORK, NY, USA I December 10, 2024 I Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today announced preliminary data from the ongoing Phase 1b portion of the TACTIVE-U sub-study of vepdegestrant in combination with abemaciclib among patients with locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. These data will be presented in a poster at the 2024 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas. Preliminary results from 16 patients in the Phase 1b sub-study demonstrated a tolerable safety profile for the combination of abemaciclib 150 mg twice daily (BID) with the recommended Phase 3 monotherapy dose of vepdegestrant (200mg once daily; QD). An encouraging clinical benefit rate of 62.5% was observed among patients with both mutant ESR1 and wild-type ESR1 disease who had all been previously treated with a CDK4/6 inhibitor. Pharmacokinetic data demonstrated no significant drug-drug interaction between vepdegestrant and abemaciclib and no clinically meaningful effect on abemaciclib exposure was observed. In addition to tolerability, the results demonstrated a safety profile consistent with both the known properties of abemaciclib and observed data in other clinical trials for vepdegestrant. These findings support the ongoing Phase 2 portion of the study, which is evaluating full dose abemaciclib (150mg BID) in combination with vepdegestrant (200 mg QD) in post-CDK4/6 advanced breast cancer. “The preliminary results from this Phase 1b sub-study in patients whose cancer had previously progressed after receiving a CDK4/6 inhibitor are encouraging,” said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas. “These data further reinforce our belief that vepdegestrant can be used in multiple combination regimens across the metastatic breast cancer setting and has the potential to become a best-in-class backbone ER therapy. We are pleased to continue in the Phase 2 portion of the study evaluating the standard starting dose of abemaciclib in combination with vepdegestrant.” “With vepdegestrant, we aim to develop a novel agent that has the potential to become a new backbone endocrine therapy in ER+ metastatic breast cancer,” said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer. “We are pleased to see these initial results, which complement previously reported data demonstrating the potential of combination therapy with vepdegestrant to address unmet needs for patients.” Additional detail on the TACTIVE-U poster presentation at SABCS follows below: Title: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Preliminary Phase 1b Results Date: Thursday, December 12, 2024 Time: 5:30 – 7:00 p.m. CDT Poster: P4-12-03 Key findings included in the poster (data cut-off: August 30, 2024): Arvinas and Pfizer are continuing to evaluate data from the ongoing TACTIVE-U clinical trial, which includes combinations of vepdegestrant plus abemaciclib, ribociclib or samuraciclib (ClinicalTrials.gov Identifiers: NCT05548127, NCT05573555, and NCT06125522). About Vepdegestrant Vepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy and as part of combination therapy across multiple treatment settings for ER+/HER2- metastatic breast cancer. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits. The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- locally advanced or metastatic breast cancer previously treated with endocrine-based therapy. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC (PROteolysis TArgeting Chimera) protein degrader platform, the Company is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; and ARV-102, targeting LRRK2 for neurodegenerative disorders. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X . About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments, and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments, and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com . In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . SOURCE: Pfizer

临床1期临床结果快速通道临床2期蛋白降解靶向嵌合体

100 项与 Samuraciclib hydrochloride 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16061

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
HR阳性/HER2阴性乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.初创企业	2023-10-09
HR阳性/HER2阴性乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.初创企业	2023-10-09
局部晚期乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.初创企业	2023-10-09
局部晚期乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.初创企业	2023-10-09
转移性乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.初创企业	2023-10-09
转移性乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.初创企业	2023-10-09
晚期恶性实体瘤	临床2期	美国	Carrick Therapeutics Ltd.初创企业	2017-11-14
晚期恶性实体瘤	临床2期	英国	Carrick Therapeutics Ltd.初创企业	2017-11-14
去势抵抗性前列腺癌	临床2期	美国	Carrick Therapeutics Ltd.初创企业	2017-11-14
去势抵抗性前列腺癌	临床2期	英国	Carrick Therapeutics Ltd.初创企业	2017-11-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03363893 (Pubmed \| Nat Commun)	临床1期	晚期乳腺癌	124	samuraciclib (Module 1A)	衊構繭觸蓋衊積蓋範獵(願顧構鹹選製鏇簾範觸) = dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction 壓窪繭鹹鹹範鏇鬱網齋 (淵獵鏇觸鏇鏇選構膚鹽 ) 更多	-	2023-07-24
NCT03363893 (Pubmed \| Nat Commun)	临床1期	晚期乳腺癌	124	samuraciclib (Module 2A)		-	2023-07-24
P1-18-10 (SABCS2022)	临床1期	晚期三阴性乳腺癌	23	Samuraciclib 360mg OD	壓繭鑰網鬱選獵夢願願(餘廠廠淵窪鹽繭膚構鏇) = following disease progression by RECIST 鏇獵廠積壓獵觸淵鹹衊 (艱蓋憲齋壓蓋願夢醖願 ) 更多	积极	2022-02-15
GS3-10 (SABCS2022)	N/A	HR阳性/HER2阴性乳腺癌 ESR1m \| PI3Km	31	Samuraciclib 240mg QD	鬱夢積製繭憲積繭淵顧(築鬱範糧糧顧齋壓鑰齋) = G1-2 nausea, vomiting and diarrhoea 壓齋積網遞鏇鏇夢鹽夢 (獵願顧獵齋構繭壓製蓋 ) 更多	积极	2022-02-15
GS3-10 (SABCS2022)	N/A	HR阳性/HER2阴性乳腺癌 ESR1m \| PI3Km	31	Samuraciclib 360mg QD		积极	2022-02-15
EUCTR2017-002026-20-GB (ESMO2021)	临床1/2期	晚期恶性实体瘤	33	Samuraciclib	顧餘糧製選餘鹽獵顧顧(蓋蓋壓夢製夢鬱製網淵) = 範範鏇淵鬱遞壓構製鏇鹽獵蓋鏇鹹鑰艱糧夢壓 (衊憲憲蓋夢願艱窪鑰獵 ) 更多	-	2021-09-18
EUCTR2017-002026-20-GB (ESMO2021)	临床1/2期	HR阳性/HER2阴性乳腺癌	31	Samuraciclib + Fulvestrant	夢製蓋簾築鹹醖淵築廠(遞築醖衊鑰窪選觸簾艱) = 廠網蓋繭膚遞廠廠觸襯觸選鹹製窪遞鹽繭憲鏇 (壓膚糧齋壓鬱觸築顧糧 )	-	2021-09-16
ICEC0942 (SABCS2018)	N/A	ER阳性乳腺癌	-	ICEC0942	襯憲醖簾積繭遞製襯醖(範鬱願齋簾觸鬱鏇選衊) = 餘鹽鑰顧憲艱範範製獵鹹淵糧顧壓襯鹹衊網壓 (繭構鹽窪窪餘觸膚憲憲 ) 更多	-	2018-02-15