C4891024 - 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) - C4891024

开始日期2024-05-08

申办/合作机构

Pfizer Inc.

NCT06347861 / Active, not recruiting临床1期

A PHASE 1, RANDOMIZED, OPEN-LABEL, 3-PERIOD, 3-TREATMENT, 6-SEQUENCE, CROSSOVER, SINGLE-DOSE STUDY IN HEALTHY ADULT PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF THE REGISTRATION TABLETS OF VEPDEGESTRANT (ARV-471, PF-07850327) RELATIVE TO THE PHASE 3 TABLETS

The purpose of the study is to look at how various tablets of a study medicine called vepdegestrant are processed in the body. This will be studied in healthy adult participants after food.
This study looks at how the medicine is changed and removed from the body after a participant takes it.
This study is seeking for participant who:
* are healthy males, and healthy females who do not have the possibility to have children.
* are 18 years of age or older.
* weigh more than 45 Kilograms (99 pounds).
The study consists of 3 treatments. Each participant will be assigned by chance to receive the 3 treatments in a certain sequence. This will be done over 3 study periods. Each treatment consists of a single amount of vepdegestrant taken by mouth in each study period. There will be a washout period between each study periods. The washout period is the time allowed for the medicine to get washed out from the body. How the medicine was processed will be calculated following each dose in each period. The total study duration is about 13 weeks.

开始日期2024-04-02

申办/合作机构

Pfizer Inc.

[+1]

NCT06275841 / Completed临床1期

A PHASE 1, OPEN-LABEL, 2-PERIOD STUDY TO EVALUATE THE EFFECT OF MULTIPLE DOSES OF ESOMEPRAZOLE ON THE PHARMACOKINETICS OF SINGLE DOSE VEPDEGESTRANT (ARV-471, PF-07850327) UNDER THE FED CONDITION IN HEALTHY ADULT MALES AND HEALTHY ADULT FEMALES OF NONCHILDBEARING POTENTIAL

The purpose of the study is to investigate the effect of multiple doses of a proton-pump inhibitor (PPI) esomeprazole on the PK of vepdegestrant under fed conditions in healthy adult participants.
All participants in this study will receive one dose of vepdegestrant alone by mouth in Period 1. In Period 2, everyone will receive esomeprazole by mouth once a day for multiple days. Participants will also receive one dose of vepdegestrant by mouth. The levels of vepdegestrant in Period 1 will be compared to the levels of vepdegestrant in Period 2 to determine if the PPI affects how vepdegestrant is processed differently in healthy adults.

开始日期2024-02-23

申办/合作机构

Pfizer Inc.

[+1]

100 项与 Vepdegestrant 相关的临床结果

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100 项与 Vepdegestrant 相关的转化医学

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100 项与 Vepdegestrant 相关的专利（医药）

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项与 Vepdegestrant 相关的文献（医药）

2024-10-01·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

Development and validation of LC-MS/MS methods for the pharmacokinetic assessment of the PROTACs bavdeglutamide (ARV-110) and vepdegestrant (ARV-471)

Article

作者: Indulkar, Anura ; Koziolek, Mirko ; Dahlgren, David ; Borchardt, Thomas ; Hedeland, Mikael ; Nilsson, Jenny M ; Peters, Karsten ; Niessen, Janis ; Lennernäs, Hans

Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing. In this study, two highly sensitive LC-MS/MS methods (LLOQ = 0.5 ng/mL) were developed and validated for the quantification of bavdeglutamide (ARV-110) and vepdegestrant (ARV-471) in rat plasma. Plasma samples were processed by protein precipitation and separated on a C18 column over a gradient of acetonitrile and water with 0.1 % formic acid. Selected reaction monitoring in positive ESI mode was applied to quantify ARV-110 and ARV-471. Both methods showed linearity, accuracy, and precision as well as matrix effects and carry-over within the predefined acceptance criteria. High stability of the compounds in plasma was demonstrated at long-term storage for seven weeks at -20 °C, three freeze-thaw cycles, up to 20 min at room temperature, and as extracts in the autosampler. The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs.

2024-08-15·CLINICAL CANCER RESEARCH

Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models

Article

作者: Digianantonio, Katherine ; Quinn, Connor ; Gordon, Debbie ; Békés, Miklós ; Cadelina, Gregory ; Drulyte, Ieva ; Rousseau, Emma ; Willard, Ryan ; Bookbinder, Mark ; Corradi, John ; Soto, Leofal ; Gedrich, Richard ; Morgan, Alicia ; Taylor, Ian C ; Pannone, Melissa ; Wang, Jing ; Pizzano, Jennifer ; Teh, Jessica ; Houston, John ; Bortolon, Elizabeth ; Flanagan, John J ; Andreoli, Monica ; Wang, Gan ; Ferraro, Caterina ; Langley, David R ; Dong, Hanqing ; Davenport, Kim ; Chen, Xin ; Gough, Sheryl M ; Macaluso, Jennifer

Abstract:

Purpose::

Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.

Experimental Design::

A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).

Results::

Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%–123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%–80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.

Conclusions::

Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2− breast cancer.

2024-07-01·DRUG METABOLISM AND DISPOSITION

Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry

Article

作者: He, Yifei ; Zhu, Mingshe ; Long, Zhimin ; Hou, Pengyi ; Tang, Chongzhuang ; Zheng, Yuandong ; Diao, Xingxing ; Jones, Elliott

Drug metabolite identification is an integrated part of drug metabolism and pharmacokinetics studies in drug discovery and development. Definitive identification of metabolic modification sides of test compounds such as screening metabolic soft spots and supporting metabolite synthesis are often required. Currently, liquid chromatography-high resolution mass spectrometry is the dominant analytical platform for metabolite identification. However, the interpretation of product ion spectra generated by commonly used collision-induced disassociation (CID) and higher-energy collisional dissociation (HCD) often fails to identify locations of metabolic modifications, especially glucuronidation. Recently, a ZenoTOF 7600 mass spectrometer equipped with electron-activated dissociation (EAD-HRMS) was introduced. The primary objective of this study was to apply EAD-HRMS to identify metabolism sites of vepdegestrant (ARV-471), a model compound that consists of multiple functional groups. ARV-471 was incubated in dog liver microsomes and 12 phase I metabolites and glucuronides were detected. EAD generated unique product ions via orthogonal fragmentation, which allowed for accurately determining the metabolism sites of ARV-471, including phenol glucuronidation, piperazine N-dealkylation, glutarimide hydrolysis, piperidine oxidation, and piperidine lactam formation. In contrast, CID and HCD spectral interpretation failed to identify modification sites of three O-glucuronides and three phase I metabolites. The results demonstrated that EAD has significant advantages over CID and HCD in definitive structural elucidation of glucuronides and phase I metabolites although the utility of EAD-HRMS in identifying various types of drug metabolites remains to be further evaluated. SIGNIFICANCE STATEMENT: Definitive identification of metabolic modification sites by liquid chromatography-high resolution mass spectrometry is highly needed in drug metabolism research, such as screening metabolic soft spots and supporting metabolite synthesis. However, commonly used collision-induced dissociation (CID) and higher-energy collisional dissociation (HCD) fragmentation techniques often fail to provide critical information for definitive structural elucidation. In this study, the electron-activated dissociation (EAD) was applied to identifying glucuronidation and oxidative metabolism sites of vepdegestrant, which generated significantly better results than CID and HCD.

206

项与 Vepdegestrant 相关的新闻（医药）

2024-09-12

·药明康德

造福数百万患者！这类疗法正在改变癌症治疗

▎药明康德内容团队编辑乳腺癌是全球范围内第二常见的癌症。根据国际癌症研究机构（IARC）统计，超过80%的乳腺癌为雌激素受体阳性（ER+）。近年来，针对ER的蛋白降解疗法已一跃成为重要的乳腺癌治疗模式，得到了业内的广泛看好，也引来罗氏、阿斯利康、辉瑞等大型药企纷纷布局，药明康德亦有幸能为其中的多款疗法进行赋能。今天的这篇文章里，药明康德内容团队将结合公开资料，对这些已经获批，或近期内有望获批的疗法进行盘点。相关阅读：潜在“best-in-class”雌激素受体降解剂是怎样“炼”成的？相关阅读：PROTAC技术的过去与未来：从辉瑞的20亿美元合作说起…… 口服选择性雌激素受体降解剂（SERD）疗法降解ER的小分子药物可以分为两大类，其中一种称为SERD。SERD与ER结合后通过引发ER的结构变化，使得细胞里的E3泛素连接酶能更好地识别ER，并在其表面打上“垃圾”标签，最终使ER被送到细胞的蛋白酶体中降解。早在2002年，首款SERD药物就获得美国FDA的批准上市，治疗对tamoxifen产生耐药性的ER受体阳性乳腺癌患者。然而它只能通过肌肉注射给药，限制了它与靶点的结合和效力。开发能够口服、疗效更好的SERD药物，便成了业内关注的重要方向。疗法：Elacestrant 研发公司：Stemline Therapeutics 研发阶段：已获批在诸多口服SERD药物中，Orserdu（elacestrant）率先撞线，于2023年获得美国FDA的批准。一项3期EMERALD试验显示，与标准治疗相比，elacestrant可以显著延长患者的无进展生存期（PFS）。此外，在肿瘤具有ESR1突变（会导致耐药）的患者组中，elacestrant也能将患者疾病进展或死亡的风险降低45%（HR=0.55，95% CI：0.39-0.77）。疗法：Giredestrant（GDC-9545）研发公司：罗氏研发阶段：3期临床 Giredestrant具有独特的作用机制，在降解ER之前就可以抑制它的功能，从而更好地抑制其介导的基因表达。在2期临床试验coopERA中，giredestrant与CDK4/6抑制剂palbociclib联用作为新辅助疗法，在治疗早期ER阳性、HER2阴性乳腺癌患者时，与活性对照组相比，可更有效地降低生物标志物Ki67的水平（Ki67的水平昭示了癌细胞的分裂速度）。 ▲Giredestrant简介（图片来源：罗氏官网）疗法：Camizestrant（AZD9833）研发公司：阿斯利康研发阶段：3期临床 Camizestrant在2022年2期临床试验的结果显示，与活性对照组相比，在晚期ER阳性，HER2阴性乳腺癌患者中，camizestrant可显著减少患者疾病进展或死亡风险。阿斯利康认为camizestrant有望成为未来乳腺癌内分泌疗法的新支柱，目前它在多项3期临床试验中接受检验，治疗早期乳腺癌患者。 ▲Camizestrant的临床开发规划（图片来源：阿斯利康官网）疗法：Palazestrant 研发公司：Olema Oncology 研发阶段：3期临床 Palazestrant是一款ER的完全拮抗剂和SERD，能够完全阻断野生型和突变型转移性ER阳性乳腺癌中，由ER驱动的转录活性，展示了良好的抗肿瘤效果。此前公布的1b/2期临床试验结果显示，无论是在ESR1突变型肿瘤还是ESR1野生型肿瘤患者中，都观察到了肿瘤的缓解和持久的疾病稳定（SD）。 ▲Palazestrant作为单药，或与CDK4/6抑制剂联用，均展现抗癌活性（图片来源：Olema Oncology公司官网）疗法：Imlunestrant（LY3484356）研发公司：礼来研发阶段：3期临床 Imlunestrant是一款可穿越血脑屏障的SERD药物。它的设计目标是无论ESR1突变状态如何，均能够在整个给药期间持续抑制ER靶点的活性。去年12月公布的临床试验结果显示，imlunestrant作为单药疗法与CDK4/6抑制剂Verzenio（abemaciclib）和芳香酶抑制剂联用，在治疗ER阳性HER2阴性晚期乳腺癌时达到62%的客观缓解率（ORR）和79%的临床获益率（CBR）。 ▲Imlunestrant简介（图片来源：礼来公司官网） PROTAC疗法近年来火热的蛋白降解嵌合体（PROTAC）技术也能用于降解ER。这种双功能分子的一端可与ER结合，另一端与E3泛素连接酶结合，将E3泛素连接酶募集到ER附近，驱动蛋白酶体介导的ER降解。此类疗法有望解决部分ER阳性乳腺癌的耐药性，包括ESR1突变产生的耐药性。疗法：Vepdegestrant（ARV471）研发公司：辉瑞/Arvinas 研发阶段：3期临床 2021年，辉瑞与Arvinas达成超20亿美元的研发合作，共同开发这款广受关注的PROTAC疗法。今年5月公布的1b期临床试验结果显示，vepdegestrant联合CDK4/6抑制剂palbociclib，在接受过多种前期治疗的局部晚期或转移性ER阳性、HER2阴性乳腺癌患者中，达到42%的ORR。两家公司期望这款疗法能成为治疗ER阳性乳腺癌患者的支柱性疗法。 ▲Vepdegestrant的研发布局（图片来源：辉瑞公司官网）改变乳腺癌的治疗方式得益于乳腺癌早期诊断技术的进步，越来越多的乳腺癌患者在癌症的早期就能得到确诊，尽早接受治疗，从而大幅延长了她们的生命。展望未来，此类能够降解ER的药物不仅有望治疗晚期乳腺癌，还可以预防早期乳腺癌患者在术后的复发，能改变未来乳腺癌的治疗方式，造福更多患者。在本文介绍的几款潜在重磅疗法之外，还有多家其它生物医药公司开发的疗法也已经进入后期临床开发阶段（详情请见下表）。我们很高兴能为此类具有重大意义的药物赋能，也期待这些疗法的临床开发顺利，为ER阳性乳腺癌患者提供更多更好的治疗选择。 ▲部分处于后期临床开发阶段靶向ER的蛋白降解疗法（数据来源：公开资料，药明康德内容团队制图，截至2024年8月28日） ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Neupane et al., (2024). Oral SERD, a Novel Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer. Cancer, https://doi-org.libproxy1.nus.edu.sg/10.3390/cancers16030619 [2] Patel et al., (2023). An emerging generation of endocrine therapies in breast cancer: a clinical perspective. npj Breast Cancer,https://doi-org.libproxy1.nus.edu.sg/10.1038/s41523-023-00523-4 [3] Global cancer burden growing, amidst mounting need for services. Retrieved August 27, 2024, from https://www-who-int.libproxy1.nus.edu.sg/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services [4] Roche Pharma Day 2023. Retrieved August 27, 2024, from https://assets.roche.com/f/176343/x/72a34572bc/pharma-day-2023.pdf [5] IN VITRO EVALUATION OF PROTAC® DEGRADER ARV-110 (BAVDEGALUTAMIDE) FOR CYTOCHROME P450- AND TRANSPORTER-MEDIATED DRUG-DRUG INTERACTION. Retrieved August 27, 2024, from https://www.arvinas.com/wp-content/uploads/2022/09/ISSX-Poster_Zhang_2022.pdf 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床3期蛋白降解靶向嵌合体上市批准临床2期临床结果

2024-09-04

·药智网

下一个大BD密码

当大家还在看ADC时这类大分子的主流偶联方式时，有一小分子偶联方式即将改写小分子药物的底层逻辑。在国外，该疗法的最快管线已经被推进至III期临床，做的也是癌症中最大的市场之一——乳腺癌市场。而在国内，创新药一哥也表现出了对该疗法的青睐，其相关管线BGB-16673已经在近日获得了FDA快速通道认证。 PROTAC疗法正在对传统的小分子药物呈现降维打击之势，未来拥有巨大的颠覆传统小分子药物市场逻辑的潜力。 PROTAC，降维打击的小分子疗法 PROTAC疗法的生物学底层逻辑是用细胞内的泛素-蛋白酶体蛋白降解机制来实现对目标蛋白的降解。泛素（简称Ub）是体内的一种用于标记蛋白质的小号蛋白（仅76个氨基酸），经由它标记的蛋白质将经过E1，E2，E3三种泛素酶，完成泛素的激活，转运，最后连接到E3酶上（该酶是特异性识别靶蛋白的酶），通过E3酶，泛素完成和靶蛋白的结合，形成泛素-蛋白复合物。在蛋白完成泛素化后，26S蛋白酶体可以特异性地识别这个带有泛素标签的底物蛋白，进而将其降解。该过程可以完成细胞内大部分短寿命蛋白质的降解。于是，能够降解特异性蛋白质的PROTAC疗法应运而生。 PROTAC全称为蛋白水解‒靶向嵌合体，其结构由三部分组成：蛋白结合配体、E3泛素连接酶结合配体和linker，其底层逻辑是把目标蛋白通过PROTAC分子和E3泛素酶连接，使得该目标蛋白被打上泛素的标记，然后便会按上问的泛素降解过程形成泛素-蛋白复合物，继而进入26S蛋白酶体完成降解。在该过程中，PROTAC分子可以被循环使用，在完成一个靶蛋白的催化降解后迅速进入另一个靶蛋白的降解过程，因此，PROTAC分子仅仅是作为催化剂的作用而存在。对于传统小分子药物来说，小分子药物首先必须要找准靶蛋白上的活性位点，亲和力要高，且为了维持活性浓度，必须频率较高去给药。而作为催化剂的PROTAC分子没有这个顾虑，它偶联的靶蛋白靶点不需要考虑活性的问题，只要能够连接便可。而从这样的逻辑来说，PROTAC分子将对于传统的小分子药物来说，可以看作是一次非常成功的迭代，其相对传统小分子药物的优势如下： 1.小分子药物需要不断用较高的浓度去刺激靶蛋白的活性靶点，但时间一长便会产生耐药性的问题。而作为催化剂的PROTAC而言，不需要传统小分子那样的大剂量不停刺激活性靶点，这样使其耐药性更加难以产生。 2.PROTAC由于不是必须去偶联靶蛋白中的活性位点，因此理论上它将大大拓宽未来对于蛋白质靶点的选择，众多不可成药的靶点未来都有可能被用于PROTAC分子上。此外，值得一提的是，运用泛素-蛋白酶体蛋白降解机制来开发的疗法并不只有PROTAC，另一项进展较快的疗法是分子胶。虽然都是通过E3酶进行作用，但二者有相当大的差异性。从优势上说，分子胶的分子量相较于PROTAC而言要更小一些，改结构和优化理化性质更加方便。而PROTAC由于分子量相对较大，可能从传统的成药角度来看，药代动力学特性相对而言可能没有分子胶好。此外，分子胶可以很好地避免PROTAC的一个重要问题：钩状效应(hook effect)。对于PROTAC而言，当作为中介的PROTAC浓度过高时，它更倾向于和E3或者靶蛋白中的一种形成二元复合物，而不是预期的三元复合物，而三元复合物不形成，预期内的降解就无法发生。该效应对PROTAC的治疗浓度产生了一定的限制。分子胶很好，它避免了PROTAC的诸多问题，但它目前而言由于太过前沿，对于它的很多机制研究还不是很明确，而导致对分子胶相应分子的筛选机制还不是特别明确，目前筛出来并商业化的分子胶基本都是通过偶然的方式发现的。从这个角度而言，目前在泛素-蛋白酶体降解途径疗法中，离可以大规模商业化最近的，仍然是PROTAC。即将打开商业化大门的PROTAC先驱在深耕PROTAC疗法的biotech中，目前距离商业化最近的则是深耕该疗法十余年的Arvinas。其实从Arvinas的管线布局中也可以看出，开拓者们在肿瘤领域多会选择在乳腺癌和前列腺癌两个瘤种上去进行突破，因为这两种癌症都与性激素密切相关，因此可以通过PROTAC疗法去降解性激素的受体，来达到治疗癌症的目的。 Arvinas在癌症领域进展最快的管线是针对乳腺癌适应症的ARV-471，在乳腺癌中，它主要针对的是ER＋/HER2-的分型。乳腺癌的市场规模有目共睹，根据最新的映恩生物招股书的数据，全球乳腺癌人数在2023年达到了240.8万人，预计将于2032年达到319.6万人，这其中，HER2-/ER+分型占所有乳腺癌的45-50%，根据Arvinas自身的说法，该分型的乳腺癌市场达到了170亿美元。 ER就是雌激素受体，对于雌激素受体阳性的乳腺癌患者而言，雌激素拮抗治疗是小分子药物中最为常见的治疗手段。在这其中，一线疗法可以用AI（芳香酶抑制剂）以及前线的CDK4/6抑制剂，例如哌柏西利这种早期获批的CDK4/6i，而二线治疗则可以使用氟维司群和新型的CDK4/6抑制剂例如瑞博西尼（Ribociclib）联用治疗；但对于小分子药物（例如CDK4/6抑制剂），耐药仍然是目前的大问题，这与前文所述的小分子药物底层逻辑相关。而ARV-471这条管线来说，其早期的临床试验设计则主要也是在针对小分子药物耐药的后线治疗来设计的。今年ESMO乳腺癌年度大会，它的临床Ib期结果较为全面地展现了出来。患者基线上，其患者中87%接受过CDK4/6抑制剂的治疗，45.7%的患者接受过化疗，80%的患者接受过雌激素抑制剂氟维司群的治疗，在31名患者中展现出了非常惊艳的疗效。其联用K药时，评估后的ORR达到了41.9%，这个数字超过了目前众多CDK4/6抑制剂耐药后的后线疗法。目前公布的临床数据中，Ribociclib联合ET化疗方案的ORR是20%（n=35，临床样本量接近），而患者基线二者也较为相似，都是为了处理CDK4/6抑制剂耐药后的情况，该次试验中患者全部接受了CDK4/6抑制剂的治疗，不过接受化疗和氟维司群的患者比例远远比AV-471的早期临床少：接受化疗的比例为6.7%，接受氟维司群的比例为16.8%。在患者基线相差较大的情况下，ARV-471仍然达到了两倍多的ORR，真正实现了对传统小分子疗法的降维打击。在另外的重要指标例如mPFS上，同样达到了两倍多的差距，ARV-471的这mPFS达到了11.2个月，而Ribociclib的此前研究的数字是5.3个月。其它疗法，例如帕博西尼联用ET化疗等，更是没有疗效上的可比性。从目前Arvinas的预期来看，虽然早期该药是专门针对后线治疗去开展临床的，但其也已经在一线治疗上早早开始布局：目前，该药联用帕博西尼的一线治疗ER+/HER2-局部晚期乳腺癌的III期临床试验已经在进行中，而后线治疗则是重头戏，既包括单药治疗，也包括联用小分子靶向药物依维莫司，联用新一代CDK4/6抑制剂PF-07220060(Atirmociclib)等。作为一个和CDK4/6抑制剂机制完全不同的乳腺癌药物，其在CDK4/6抑制剂的同质化内卷中脱颖而出，从远期看，它有着非常高的天花板；从近期看，它在年底到明年初有关键数据读出，是一个股价的关键催化机会。而另一款关于肿瘤的重磅管线则是针对前列腺癌的ARV-766。该药是从PROTAC疗法的元老级药物ARV-110基础上迭代而来，ARV-110可以看作是一个试错品，由于局限性较大，目前已经暂停管线进度推进。 ARV-766在其基础上加以改进。结构上，比较关键的改进是将氟取代的沙利度胺替换为氟取代的苯甲酰胺，这一结构上的改进增强了分子的选择性以及在血浆中的稳定性。而结构上的改进拓宽了该药物的适应症范围：ARV-110不能应对AR L702H突变的情况，而ARV-766成功突破了该困境，增加了可用药人群的数量。根据2023年8月公布的1/2期临床试验数据，3名雄激素受体（AR）H875/T878/L702H突变患者中，前列腺特异性抗原（PSA）水平降幅均大于50%，实现了突变患者疗效上质的突破。当然，ARV-766目前还需要样本量更大的临床去验证。但值得一提的是，MNC诺华对该管线相当看好，今年4月，诺华直接付了预付款1.5亿美元，后续里程碑付款更是达到10.1亿美元，就为拿下ARV-766与另一款处于临床前的前列腺癌药物在全球开发和商业化的权益。除了先驱Arvinas之外，Nurix以及Kymara等早期biotech也值得关注。 Nurix做的PROTAC主要靶向BTK，针对的是各式各样的B细胞血液瘤，并且其管线目前处于非常早期的阶段，进展最快的NX-5948和NX-2127目前处于临床1b期。NX-5948今年得到了较大的进展，6月份发布了其针对CLL（慢性淋巴细胞白血病）较为积极的早期临床数据。在Ia期试验中，患者接受过的中位治疗为4线，包括共价BTK抑制剂（96.8%）、BCL-2抑制剂（90.3%）和非共价BTK抑制剂（25.8%）等。在可评估疗效的CLL患者（n=26）中，接受所有剂量水平NX-5948治疗患者的ORR达到了69.2%，也是非常值得期待的CLL后线治疗的新星。 Kymera目前进展最快的管线KT-474已经进展到了临床II期，其主要针对自免适应症。目前两条个适应症为化脓性汗腺炎(HS)和特应性皮炎(AD)。其针对KT-474与赛诺菲早在2020年就展开了全面的合作，赛诺菲潜在的支付金额高达20亿美元。今年7月8日，Kymera宣布在IDRC审查数据之后，其partner赛诺菲决定扩大KT-474治疗化脓性汗腺炎、特应性皮炎两项二期临床试验，以求更快推进到关键临床。在之后的一个礼拜，股价迎来了非常迅猛的大涨，从7月8号的30美元上涨至7月16号的45美元。 PROTAC的想象力空间，在美股股价上体现的非常充分。国内的突破性进展国内方面，目前药企们也正在紧锣密鼓地追赶。不久前百济神州官宣的BGB-16673无疑是国内PROTAC领域一个巨大的突破。百济本身就是BTK小分子抑制剂深耕十余年的老玩家，以其现有的技术平台为根基去发展靶向BTK的PROTAC，基础上是打得较为牢固的。在2021年的研发日上，百济公布了其PROTAC平台——CDAC平台。根据百济神州的阐述，该平台相较于其它PROTAC平台的差异性优势在于其能够利用更加广泛的E3连接酶，从而达到减轻DLT（剂量依赖性毒性）的效果，其对耐药性的解决方面也有进一步的提升，此外，也进一步拓展了潜在靶点范围。而BGB-16673就是百济利用该平台开发出的第一条PROTAC管线，主要目的是针对BTK小分子抑制剂耐药的后线治疗问题。由于其靶点和适应症与Nurix的NX-5948相类似，因此二者可以进行一定的非头对头比较。从BGB-16673的临床I期剂量递增试验的初步数据来看，其在CLL/SLL适应症中的表现非常不错，患者（n=10）基线BTK抑制剂耐药的情况下，它的ORR达到了70%，该数据与上文的NX-5948疗效相当。后续的大样本临床中，两条管线将进行更为激烈的角逐。另一家Biotech则是深耕PROTAC技术多年的海创药业，其在2016年就建立了自己的PROTAC技术平台，目前主要深耕的适应症为前列腺癌。海创药业PROTAC方面核心的管线是HP518，也是国内首个进入临床阶段的针对AR的PROTAC药物。其于2023年11月获NMPA批准进入临床，目前该管线获得了中国，美国和澳大利亚三地的临床试验批准。除了口服的AR PROTAC药物外，还有药企开发出了外用的AR PROTAC疗法。开拓药业的GT20029用于治疗雄激素性脱发和痤疮，通过降解雄激素受体蛋白来达到治疗雄性激素过盛导致脱发的问题。GT20029也是首款进入临床的外用PROTAC化合物。今年4月，该管线在脱发适应症上达到了II期临床试验终点，从最佳剂量的1.0%浓度且一周两次给药剂量组的效果来看，TAHC（区域内头发计数的指标）较基线增加了11.94根毛发/cm²，比安慰剂多了7.36根毛发/cm²。但非口服的局部给药制剂究竟能不能走通，目前而言是个有待商榷的话题。从临床II期试验设计来看，其临床设计主要终点为12周目标区域内非毳毛数量，这个时间太过短暂，目前需要的是III期临床中更长周期随访的验证，观察期达到平台期的时间。不得不说，这是PROTAC技术在一个意想不到领域上的出色应用，真正做到了在AR降解剂上的差异化竞争。结语：PROTAC疗法的意义主要在于面对目前小分子同质化内卷的困局上打开了一扇新的大门，带来了后线治疗的全新想象力。此外，该疗法目前来看并不只是局限于肿瘤，其想象力空间非常巨大，甚至连外用用于脱发都可以到达III期临床。现在适应症的挖掘上仅仅是冰山一角，未来随着AIDD靶点筛选速度的大大提升，PROTAC疗法的适应症领域也将会得到相当大程度的继续拓展。来源 | 瞪羚社（药智网获取授权转载）撰稿 | Jerry.Z 责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

蛋白降解靶向嵌合体抗体药物偶联物临床3期

2024-09-04

·echemi

Pfizer Spends $43 Billion to Acquire Seagen, But Questions Arise as to Whether Its 8 New Drugs Can Save the Day

Pfizer recently announced that it has completed the acquisition of Seagen, which specializes in antibody drug coupling agents (ADCs), for $43 billion. In talks with investors, the company laid out ambitious plans for its oncology division, aiming to launch eight new cancer drugs by 2020, in addition to its current five best-selling cancer drugs. Dr. Chris Boshoff, Pfizer's new chief oncology officer, emphasized that the company will focus on four main cancer areas: breast cancer, genitourinary cancers (including prostate and urinary cancers), hematological malignations such as lymphoma and multiple myeloma, and chest tumors such as lung cancer and head and neck cancer. Pfizer's portfolio will include small molecule therapeutics, ADCs and bispecific antibodies. Biologics are expected to account for 65 percent of oncology revenues by 2030, compared with about 6 percent of sales today, which are dominated by small molecule drugs. Examples include Ibrance (palbociclib) for breast cancer, Xtandi (enzalutamide) for prostate cancer, and Inlyta (axitinib) for kidney cancer. This business shift helps the company avoid the impact of some of the price cuts in the Inflation Reduction Act (IRA). Under the bill, biologics could be on the market longer before they are selected to participate in Medicare price negotiations. While the future bestsellers have not yet been disclosed, they will come from the approximately 14 product candidates showcased during the company's R&D update. "Our oncology group is expected to be a key driver of potential long-term sustainable sales and profit growth for Pfizer through the first half of 2025 and beyond," said Dr. Boshoff. During the hours-long meeting, Pfizer highlighted seven key Phase 3 trial data and six new Phase 3 trial launches that will underpin its oncology ambitions in the coming years. These data include the VERITAC-2 trial of the protein depressant vepdegestrant in second-line estrogen receptor-positive metastatic breast cancer, the first key data for a drug that Pfizer believes forms the backbone of estrogen-targeted therapy in breast cancer. And BREAKWATER study of BRAF inhibitor Braftovi (encorafenib) as a first-line treatment for BRAF mutated metastatic colorectal cancer. Pfizer also has high hopes for the treatment of non-muscle-aggressive bladder cancer with the PD-1/PD-L1 inhibitor Sasizumab in the CREST study, High hopes are also expressed for CD3xBCMA bisspecific Elrexfio (elranatamab) in MagnetisMM-5 as a treatment for relapsed/refractory multiple myeloma patients previously treated with lenalidomide and proteasome inhibitors. Newly initiated Phase 3 drugs include atirmoiclib, a CDK4 inhibitor for second-line treatment of hormone receptor-positive metastatic breast cancer, IB6-directed ADC sigvotatug vedotin for non-small cell lung cancer (NSCLC), Elrexfio is indicated for patients with multiple myeloma who have progressed after anti-CD38 therapy. "With the energy of our talented colleagues, the tremendous potential of our product line and scientific engine, and the scale of the Pfizer enterprise, we believe we are well positioned to achieve our vision of accelerating breakthroughs that will help cancer patients around the world live better, longer lives," said Dr. Boshoff. Pfizer's accelerated push into cancer, which has underpinned its growth over the past few years, comes amid a sharp contraction in the market for COVID-19 vaccines and was one of the drivers behind the Seagen acquisition. Currently, the company spends 40% of its R&D budget on oncology.

临床3期并购疫苗抗体药物偶联物ASCO会议

100 项与 Vepdegestrant 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性/HER2阴性乳腺癌	临床3期	美国	Pfizer Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	美国	Arvinas Estrogen Receptor, Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	中国	Pfizer Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	中国	Arvinas Estrogen Receptor, Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	日本	Pfizer Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	日本	Arvinas Estrogen Receptor, Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	阿根廷	Pfizer Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	阿根廷	Arvinas Estrogen Receptor, Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	澳大利亚	Pfizer Inc.	2023-03-03
ER阳性/HER2阴性乳腺癌	临床3期	澳大利亚	Arvinas Estrogen Receptor, Inc.	2023-03-03

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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


NCT05463952 (CTgov)	临床1期	乳腺癌	6	ARV-471	遞餘繭廠糧艱顧顧襯範(鹽積鬱糧齋網夢窪獵繭) = 廠簾積餘選夢觸衊獵廠願齋簾淵顧艱蓋餘艱網 (顧製齋淵鹽製艱襯膚廠, 夢窪獵願範積構鹹顧製 ~ 廠蓋願衊築願齋衊獵選) 更多	-	2024-09-23
NCT05538312 (CTgov)	临床1期	-	12	ARV-471 (Period 1: ARV-471 200 mg)	鬱鹹觸積窪窪衊鏇膚簾(壓餘選構淵窪憲廠選淵) = 遞鹹壓鹹夢鏇壓夢積糧艱網構衊醖構窪遞襯衊 (網製鬱遞繭廠觸艱範窪, 繭淵廠鏇蓋願獵廠醖夢 ~ 簾膚膚廠簾壓餘獵襯鑰) 更多	-	2024-09-23
NCT05538312 (CTgov)	临床1期	-	12	Itraconazole+ARV-471 (Period 2: ARV-471 200 mg + Itraconazole 200 mg)	鬱鹹觸積窪窪衊鏇膚簾(壓餘選構淵窪憲廠選淵) = 醖獵艱鹽夢襯膚鬱遞鹽艱網構衊醖構窪遞襯衊 (網製鬱遞繭廠觸艱範窪, 糧糧襯鹽膚衊積鏇製遞 ~ 繭鏇積憲衊齋製鬱壓願) 更多	-	2024-09-23
NCT05673889 (CTgov)	临床1期	-	24	Dabigatran (Period 1: Dabigatran 75 mg)	艱繭鹹顧廠製膚築選獵(齋願膚顧範觸鬱願淵餘) = 鏇範蓋顧獵憲構積觸網觸艱糧獵築選願選壓繭 (醖艱製繭夢襯遞襯淵範, 選顧衊鹽選衊壓糧壓繭 ~ 夢窪憲網糧餘醖餘窪顧) 更多	-	2024-08-16
NCT05673889 (CTgov)	临床1期	-	24	ARV-471+Dabigatran (Period 2: Dabigatran 75 mg + ARV-471 200 mg)	艱繭鹹顧廠製膚築選獵(齋願膚顧範觸鬱願淵餘) = 糧夢夢壓顧艱選鹽糧顧觸艱糧獵築選願選壓繭 (醖艱製繭夢襯遞襯淵範, 顧鬱憲製淵鏇窪簾夢壓 ~ 構觸糧觸鏇製糧積衊齋) 更多	-	2024-08-16
NCT05652660 (CTgov)	临床1期	-	12	Rosuvastatin (Period 1: Rosuvastatin)	醖餘壓艱夢築醖鬱觸選(鹽繭鹹衊鬱鑰齋膚範鏇) = 積淵齋壓範獵鑰餘窪製網鑰網範構獵淵鹽鏇窪 (遞淵壓衊範齋遞淵壓範, 夢襯蓋壓鹽衊繭獵觸蓋 ~ 廠鏇網顧憲遞積積繭蓋) 更多	-	2024-07-26
NCT05652660 (CTgov)	临床1期	-	12	Rosuvastatin+ARV-471 (Period 2: ARV-471 + Rosuvastatin)	醖餘壓艱夢築醖鬱觸選(鹽繭鹹衊鬱鑰齋膚範鏇) = 鏇構齋窪範繭製鹹願繭網鑰網範構獵淵鹽鏇窪 (遞淵壓衊範齋遞淵壓範, 鹹觸簾壓鬱鏇範壓選淵 ~ 鬱顧範壓窪顧顧膚夢醖) 更多	-	2024-07-26
NCT04072952 (ESMO_BC2024) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive \| ESR1 Mutation	46	Vepdegestrant+palbociclib (Total)	鑰蓋顧襯鬱窪夢顧壓範(醖淵齋獵壓鑰夢遞壓鏇) = ≥10% to either vepdegestrant or palbo were neutropenia (91%) and decreased white blood cell count (15%). 廠鹽壓餘醖廠憲餘鑰鏇 (膚艱襯窪餘積獵淵窪築 )	积极	2024-05-16
NCT04072952 (ESMO_BC2024) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive \| ESR1 Mutation	46	Vepdegestrant+palbociclib (Mutant ESR1)		积极	2024-05-16
NCT06206837 (TACTIVE-K, ESMO_BC2024)	临床1/2期	ER阳性/HER2阴性乳腺癌 ER+ \| HER2-	65	Vepdegestrant	願夢衊淵築鑰製繭鑰糧(淵構選窪糧衊鬱壓糧遞) = 鑰鹽壓蓋鏇憲艱齋積鏇鑰廠糧鏇齋淵選膚獵醖 (構淵鏇壓壓遞憲網範鬱 )	-	2024-05-14
NCT04072952 (ARV-471-mBC-101, GlobeNewswire) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 ESR1 Mutation \| HER2 Negative \| ER Positive	46	Vepdegestrant + Palbociclib	廠夢衊構膚淵鬱鹹廠鑰(顧淵鹽餘憲艱鬱範鹹鑰) = 製網願構繭築齋獵選齋醖淵願窪構夢積簾鑰選 (鹽膚鑰蓋廠淵鑰願夢選, 47.5 ~ 76.8) 更多	积极	2023-12-05
NCT05463952 (ESMO_ASIA2023)	临床1期	ER阳性/HER2阴性乳腺癌 estrogen receptor (ER)+ \| human epidermal growth factor receptor 2 (HER2)-	6	Vepdegestrant 200 mg	構窪鹽鹹蓋獵簾壓醖壓(艱憲繭廠蓋選襯製選壓) = 1 event 鑰糧範鬱糧鹽顧簾壓網 (築簾願廠糧窪壓積遞襯 ) 更多	-	2023-12-02
NCT04072952 (ESMO2023)	临床1/2期	ER阳性/HER2阴性乳腺癌	-	Vepdegestrant	淵鑰壓構糧選鏇遞膚齋(鏇窪淵窪願網壓蓋壓醖) = 鑰簾鏇構醖鬱遞壓構餘襯醖構範網蓋衊築蓋構 (醖廠觸膚襯範遞壓顧鏇, 26 ~ 49)	-	2023-10-21
NCT04072952 (VERITAC, ESMO_BC2023)	临床2期	ER阳性/HER2阴性乳腺癌 mutant ESR1	35	ARV-471 200 mg QD	夢醖壓積艱壓夢顧淵艱(襯簾襯鹹獵襯夢鹽範鑰) = 獵壓鹹範獵積繭遞繭鏇糧積鏇鑰衊鏇獵壓積齋 (鏇廠憲淵艱繭艱顧廠衊, 21 ~ 55) 更多	积极	2023-05-12