A PHASE 1, OPEN-LABEL, FIXED SEQUENCE, 2-PERIOD, SINGLE-DOSE, CROSS-OVER STUDY TO ESTIMATE THE ABSOLUTE BIOAVAILABILITY OF VEPDEGESTRANT (ARV-471, PF-07850327) FOLLOWING ORAL AND INTRAVENOUS DOSING OF THE DRUG TO HEALTHY PARTICIPANTS

The purpose of this study is to learn how much of the study medicine called Vepdegestrant will reach the bloodstream when given orally compared to given intravenously.
This study is seeking participants who:
* are healthy males and healthy females who cannot have children.
* are 18 years or older.
* are healthy as decided by medical tests.
* have a body mass index (BMI) of 16 to 32 kilogram per meter squared.
* have a total body weight of more than 45 kilograms (99 pounds).
In Period 1, all participants will receive one dose of Vepdegestrant by IV. In Period 2, all participants will receive one dose of Vepdegestrant by mouth following a high-fat breakfast. The levels of Vepdegestrant in Period 1 will be compared to the levels of Vepdegestrant in Period 2 and the bioavailablility of the oral formulation of Vepdegestrant will be determined.
The study duration is 22 days and includes two periods. Participants will stay in the clinical research unit for 9 days (8 nights) during each period. A follow-up visit for each participant takes place at 28 to 35 days after taking the study medicine for the last time.

开始日期2025-04-03

申办/合作机构

Pfizer Inc.

[+1]

CTR20242782

/ Active, not recruiting临床2期

一项在 18 岁及以上 ER+/HER2- 晚期或转移性乳腺癌研究参与者中评估口服蛋白水解靶向嵌合体 Vepdegestrant（ARV-471/PF-07850327）联合 PF-07220060 治疗的耐受性、PK 和抗肿瘤活性的开放标签、干预性的安全有效性 Ib/II 期研究

II期主要目的：1. 评估 Vepdegestrant 联合 PF-07220060 治疗的临床抗肿瘤活性。II期次要目的：1. 确定 Vepdegestrant 联合 PF-07220060 治疗的其他抗肿瘤活性结局。2. 进一步评价 Vepdegestrant 与 PF-07220060 联合用药的总体安全性特征和耐受性。3. 评价 Vepdegestrant 与 PF-07220060 联合给药时，Vepdegestrant、ARV-473 和 PF-07220060 的血浆药物暴露量。4. 评估治疗后血浆 ctDNA 相对于基线水平的变化。II期探索性目的：1. 探索 PF-07220060 联合 Vepdegestrant 治疗对患者报告的症状和健康相关生命质量的影响。2. 了解乳腺癌的肿瘤生物学，确定潜在的敏感性和/或耐药性机制。3. 评价分子定义的研究参与者人群中突变状态与应答之间的关系。4. 探索药物基因组学对 PF-07220060 血浆药物暴露量的影响。

开始日期2024-11-18

申办/合作机构

Pfizer Inc.

[+2]

NCT06645938

/ Completed临床1期

A PHASE I, RANDOMIZED, OPEN-LABEL, 2-PERIOD, 2-TREATMENT, 2-SEQUENCE, CROSSOVER, SINGLE-DOSE STUDY IN HEALTHY ADULT PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF AN VARIANT (HIGH HARDNESS) TABLET OF VEPDEGESTRANT (ARV-471, PF-07850327) RELATIVE TO THE REGISTRATIONAL TABLET

The purpose of the study is to compare the amount vepdegestrant available from two different tablet formulations under fed conditions in healthy adult participants; 200 mg vepdegestrant alternative tablet formulation compared to 200 mg vepdegestrant standard tablet formulation.
This study is seeking male or female participants of non-childbearing potential age who:
* are 18 years or older
* are healthy as decided by medical tests.
* have a Body mass index (BMI) of 16 to 32 kilogram per meter squared; and a total body weight of more than 45 kilograms (99 pounds).
All participants will be put into groups to receive one of the 2 treatments in each period. This study will consist of 2 treatment sequences:
* Sequence 1: Single 200 mg dose of vepdegestrant registrational tablet in Period 1, followed by a single 200 mg dose of vepdegestrant variant tablet in Period 2.
* Sequence 2: Single 200 mg dose of vepdegestrant variant tablet in Period 1, followed by a single 200 mg dose of vepdegestrant registrational tablet in Period 2.
Participants will be in the study for about 11 weeks.

开始日期2024-10-16

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）

2025-06-01·EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS

A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats

Article

作者: Dahlgren, David ; Koziolek, Mirko ; Borchardt, Thomas ; Arendt, Nathalie ; Sjöblom, Markus ; Indulkar, Anura ; Hedeland, Mikael ; Niessen, Janis ; Dubbelboer, Ilse R ; Lennernäs, Hans

AIM:

Proteolysis targeting chimeras (PROTACs) exhibit a unique and promising pharmacology. However, this comes with molecular properties exceeding the 'drug-like' rule of five chemical space, which often limits gastrointestinal absorption. This in vivo study aimed to investigate the contribution of luminal and plasma stability, intestinal effective permeability, P-glycoprotein (P-gp) efflux, and bile excretion, on the rat intestinal absorption and systemic exposure of two PROTACs, ARV-110 (812 Da, LogD_7.4 4.8) and ARV-471 (724 Da, LogD_7.4 4.6).

METHODS:

Luminal stability and effective intestinal permeability were determined directly from luminal disappearance using single-pass intestinal perfusion, with and without a protease inhibitor, or a P-gp/Cytochrome P450 CYP3A inhibitor (ketoconazole) in rats. Plasma stability was tested by in vitro incubations. Intestinal absorption, systemic exposure, and biliary excretion were examined after intraduodenal and intravenous dosing with ketoconazole or the P-gp selective inhibitor (encequidar).

RESULTS AND DISCUSSION:

Both PROTACs were degraded in the intestinal lumen and in plasma by peptidases. The intestinal effective permeability in rats was moderate for ARV-110 (0.62 × 10^-4 cm/s) and low for ARV-471 (0.23 × 10^-4 cm/s). P-gp inhibition increased the permeability 1.6- and 2.3-fold for ARV-110 and ARV-471, respectively. After intraduodenal dosing with the P-gp inhibitors a corresponding increase in systemic exposure was observed for both PROTACs. There was only a minor difference in the increased systemic exposure induced by the two inhibitors, suggesting that the mechanisms were primarily P-gp inhibition, rather than gut-wall and hepatic extraction. Biliary excretion was a minor pathway and did not affect the absorption and systemic exposure of the PROTACs to a large extent.

CONCLUSION:

In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux.

2025-05-31·NEW ENGLAND JOURNAL OF MEDICINE

Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer.

Article

作者: Hu, Xichun ; Parameswaran, Janaki ; Mouret-Reynier, Marie-Ange ; Lu, Dongrui R ; Jerzak, Katarzyna J ; Hamilton, Erika P ; Patsouris, Anne ; Zhi, Xin ; Valota, Olga ; Cui, Jiuwei ; Guarneri, Valentina ; Sezer, Ahmet ; De Laurentiis, Michelino ; Jhaveri, Komal ; Fontana, Andrea ; Yoshinami, Tetsuhiro ; Zamagni, Claudio ; Cil, Timucin ; Martignoni, Marcella ; Molckovsky, Andrea ; Ladoire, Sylvain ; Rodriguez-Lescure, Alvaro ; Zhang, Yongqiang ; Fuentes, Christian ; Demirci, Umut ; Campone, Mario ; Cazzaniga, Marina

BACKGROUND:

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system.

METHODS:

In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to ESR1-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with ESR1 mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model.

RESULTS:

A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P = 0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively.

CONCLUSIONS:

Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.).

2025-05-08·JOURNAL OF MEDICINAL CHEMISTRY

In Vitro ADME Profiling of PROTACs: Successes, Challenges, and Lessons Learned from Analysis of Clinical PROTACs from a Diverse Physicochemical Space

Article

作者: Nash, Samuel ; Pike, Andy ; Swedrowska, Magda ; Srivastava, Abhishek ; Grime, Ken

Established in vitro assays for ADME properties often struggle with compounds outside of the rule-of-5 space such as PROTACs. These bifunctional molecules, due to high lipophilicity and molecular weight, frequently exhibit low solubility, high nonspecific binding, and poor translation of assay data, necessitating empirical validation. This study evaluates the performance of standard ADME screening assays exemplified by 10 PROTACs in clinical development, with varying lipophilicity, in the context of the AstraZeneca data set. Assessment of in vitro metabolic clearance, plasma protein and incubation binding, blood-to-plasma ratio, Caco-2 permeability, and efflux was performed. Additionally, due to the poor performance of the aqueous solubility assay, the impact of biorelevant media was investigated on solubility. The primary objective was to evaluate the suitability of traditional ADME assays for PROTACs and understand the lipophilicity limits. This work aims to guide discovery teams on assay reliability and performance and inform decision-making regarding compound progression in this challenging area.

296

项与 Vepdegestrant 相关的新闻（医药）

2025-07-04

·医学新视点

乳腺癌进展或死亡风险降低超40%，PROTAC迎来里程碑 | 2025上半年蛋白降解领域盘点

▎药明康德编者按：靶向蛋白降解剂（TPD）通过利用细胞自身的蛋白降解系统降解与疾病相关的靶蛋白。由于无需直接抑制靶蛋白的活性，这种治疗模式有望针对许多以往被认为“不可成药”的靶点，因而成为新药开发的热点领域之一。早在近10年前，这项技术刚刚起步时，药明康德就开始布局相关能力和技术，积累了丰富的成功经验，搭建起集发现、合成、分析纯化和测试等能力的一体化赋能平台。目前，该平台已成功支持超过120款TPD分子的开发，其中20余款顺利推进至临床阶段。本文将回顾2025年上半年TPD领域的最新进展。还将介绍药明康德的一体化CRDMO平台如何高效解决TPD药物开发过程中的诸多挑战，在短短12个月内完成IND申报所需的蛋白降解靶向嵌合体（PROTAC）候选药物的制备，并为首次人体临床研究提供临床试验用药。临床进展：首个PROTAC分子3期结果发布，细胞外蛋白降解疗法初步临床数据积极今年3月，辉瑞（Pfizer）和Arvinas联合公布了PROTAC药物vepdegestrant的首个关键性3期临床试验结果。在携带ESR1突变的HR阳性、HER2阴性乳腺癌患者中，vepdegestrant与活性对照相比，将患者的疾病进展或死亡风险降低超过40%（风险比低于0.60）。Arvinas和辉瑞近日已经向美国FDA递交vepdegestrant的新药申请（NDA）。此外，该公司的另一款在研PROTAC疗法ARV-102在1期临床试验中显著降低健康志愿者中枢神经系统（CNS）和外周的LRRK2蛋白水平。这一结果为后续在LRRK2相关神经退行性疾病中的进一步临床研究奠定了基础。Kymera Therapeutics公司的潜在“first-in-class”口服STAT6降解剂KT-621在1期健康受试者的临床试验中也获得积极结果。数据显示，每日一次口服KT-621，在所有高于1.5 mg剂量水平中实现了平均超过90%的血液STAT6降解；在所有≥50 mg的多剂量递增（MAD）组中，更在血液与皮肤中均达成STAT6完全降解。百时美施贵宝（Bristol Myers Squibb）在欧洲血液学协会（EHA）年会上，展示了其靶向蛋白降解平台的最新研究数据，包括其在研口服E3泛素连接酶cereblon调节剂（CELMoD）药物mezigdomide和iberdomide在多发性骨髓瘤（MM）患者中的更新临床研究结果，以及golcadomide在非霍奇金淋巴瘤（NHL）中的研究进展。此外，该公司也公布其潜在“first-in-class”的口服BCL6配体导向降解剂（LDD）BMS-986458在NHL中的初步研究结果。其中，golcadomide联合利妥昔单抗治疗复发/难治性滤泡性淋巴瘤患者展现出显著疗效，总缓解率（ORR）高达94%，完全缓解（CR）率为63%。BMS-986458的初步研究结果显示，在外周血和肿瘤组织中均观察到BCL6快速且持久的降解。从最低剂量起即观察到在弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤患者中的抗肿瘤活性。在21名可评估疗效的患者中，ORR为81%（N=17），CR率为23.8%（N=5）。Biohaven公司开发的靶向蛋白降解剂BHV-1300和BHV-1400近期在早期临床试验中表现出显著降低细胞外蛋白的能力。这两款在研药物均为双特异性分子，一端与靶蛋白结合，另一端与肝细胞表面的去唾液酸糖蛋白受体（ASGPR）结合。ASGPR可介导肝细胞通过内吞作用，将靶蛋白摄入细胞内并降解。临床试验数据显示，BHV-1300和BHV-1400注射入患者体内后，短短数小时内即介导了靶蛋白的快速降解，蛋白水平降幅达到70%~80%，凸显出这类药物迅速的起效速度与临床应用潜力。融资与合作：大药企持续布局分子胶药物在靶向蛋白降解领域，促进蛋白降解的双特异性分子之外，分子胶降解剂通过与单个靶蛋白或E3泛素连接酶结合，即可诱导或稳定它们之间的相互作用，从而实现蛋白降解。这一细分领域近年来不断升温。在2024年，诺华（Novartis）、渤健（Biogen）、辉瑞、武田（Takeda）、卫材（Eisai）与诺和诺德（Novo Nordisk）等多家跨国药企先后签署了单笔数额超过10亿美元的分子胶研发合作协议。进入2025年上半年，分子胶领域的布局热度依然持续。今年5月，基因泰克（Genentech）与Orionis Biosciences达成超过20亿美元的研发合作协议，致力于开发靶向难以成药靶点的小分子单价分子胶药物，用于癌症治疗。此前在今年2月，礼来（Eli Lilly and Company）也与Magnet Biomedicine公司签署一项近13亿美元的合作协议。双方合作的范围不仅涵盖基于分子胶的蛋白降解剂研发，还将探索利用分子胶促进蛋白质之间产生诱导接近和协同作用，精准靶向疾病相关组织的创新作用机制。此外，艾伯维（AbbVie）公司在1月也与Neomorph公司达成超16亿美元的分子胶蛋白降解剂研发合作。与此同时，2025年上半年，多家开发靶向蛋白降解剂的新锐公司也完成新一轮融资。具体融资及合作信息请参见下表：▲2025年上半年靶向蛋白降解领域的融资和研发合作信息（数据来源：公开资料）展望未来，靶向蛋白降解剂有着更为深远的意义。这一领域的权威，丹娜-法伯癌症研究所（Dana–Farber Cancer Institute）的Eric Fischer教授在接受Nature Medicine采访时指出，利用口服小分子药物来降解蛋白质，将改变过去受制于“可成药性”局限的研发模式，使科学家们能更自由地探索哪些靶点真正能够最大程度改变疾病的进程。期待未来有更多蛋白降解药物在临床研究中取得积极进展，造福广大患者。然而，TPD药物的广阔前景也伴随着独特的开发挑战。例如，由于分子量大、结构复杂，PROTAC类分子通常存在溶解度差和药代动力学性质不佳的问题。以下案例展示了药明康德旗下合全药业（WuXi STA）如何与合作伙伴携手，有效应对这些挑战。解决TPD药物开发痛点，加速创新疗法进入临床试验几年前，一家公司因PROTAC分子的生产难题，选择与合全药业合作，希望在14个月内完成候选药物的生产，以支持IND申请及首次人体临床试验。然而，该候选分子的初始合成路线非常复杂，需要多达24个步骤，且最终产率仅为0.3%。此外，PROTAC特定的分子结构进一步增加了产品结晶和纯化难度。同时，由于候选化合物分子量较大且水溶性低，其口服生物利用度只有0.9%。值得注意的是，在合成过程中还有三步涉及使用罕见金属钯（Pd）作为催化剂，这不仅带来潜在安全隐患，更显著提高了生产成本。针对上述问题，合全药业的工艺研发、生物催化及结晶工艺等团队协同攻关，重新设计了一条合成路线，将合成步骤从原来的24步缩减至16步，并在其中两个步骤中用生物催化剂替代了钯催化剂。为攻克结晶难题，团队采用高通量结晶筛选技术，迅速确定了符合纯度与产量要求的结晶工艺，并通过优化大幅提升了生产过程的总产率。这些改进不但极大提高了整体合成工艺的可放大性，也提升了合成效率并降低了成本。与此同时，合全药业的制剂研发团队针对药物口服生物利用度低的问题，进行了全面的生物利用度增强技术筛选，最终选定喷雾干燥制备固体分散体（SDD）技术进行制剂制备。这种技术将难溶药物以无定形状态高度分散在聚合物中，目前已成功应用于多种上市药物的制剂开发中。借助SDD技术，候选化合物药片制剂的口服生物利用度提高了约30倍，为后续临床应用奠定了坚实基础。合全药业一体化CRDMO平台的整合能力，使多个团队能够并行推进原料药与制剂开发，高效协作，加速破解PROTAC分子开发中的难题。最终，团队仅用了12个月就完成了支持IND申请所需的候选药物生产和制剂制备，顺利供应首次人体临床研究用药，比合作伙伴原定时间提前了2个月。作为赋能全球靶向蛋白降解药物开发的重要平台之一，药明康德一体化平台的能力不但涵盖PROTAC，还包括分子胶、以及多种新兴双功能性蛋白降解剂类型。例如，诱导细胞外或细胞膜蛋白进入溶酶体进行降解的溶酶体靶向嵌合体（LYTAC），将抗体与蛋白降解剂偶联产生的蛋白降解剂-抗体偶联药物（DAC），诱导靶蛋白被自噬体吞噬降解的自噬靶向嵌合小分子（AUTAC），以及靶向降解特定RNA的核糖核酸酶靶向嵌合体（RIBOTAC）等。展望未来，药明康德将继续秉持“让天下没有难做的药，难治的病”的愿景，依托全球研发基地与生产网络，以独特的一体化、端到端的CRDMO模式，助力靶向蛋白降解剂的开发，帮助合作伙伴将科学创新转化为惠及全球患者的变革性药物。CRDMO: H1 2025 Review of Targeted Protein Degraders Targeted protein degraders (TPDs) offer a novel therapeutic approach by leveraging the body’s own protein degradation systems to eliminate disease-associated target proteins. This strategy opens new avenues for addressing previously “undruggable” targets. Nearly a decade ago, when this technology was still in its infancy, WuXi AppTec began building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. To date, this platform has supported the development of more than 120 TPD molecules, with over 20 advancing to clinical stages. This article summarizes key developments in the TPD landscape during the first half of 2025. It also presents a case study demonstrating how WuXi AppTec’s integrated CRDMO platform efficiently overcomes TPD development challenges, including preparing IND-enabling materials for a proteolysis-targeting chimera (PROTAC) candidate within just 12 months for first-in-human (FIH) trials.Clinical Advances: First PROTAC Phase 3 Results and Progress in Extracellular Protein DegradersIn March 2025, Pfizer and Arvinas jointly announced top-line results from the first-ever Phase 3 clinical trial of a PROTAC therapy—vepdegestrant. In HR+, HER2- breast cancer patients with ESR1 mutations, vepdegestrant reduced the risk of disease progression or death by more than 40% compared to the active control (hazard ratio < 0.60). Arvinas and Pfizer have recently submitted a new drug application (NDA) for the drug.Arvinas' second PROTAC candidate, ARV-102, also showed promise in Phase 1 studies, achieving significant reductions in LRRK2 protein levels in both the central nervous system and peripheral tissues of healthy volunteers—laying the groundwork for future clinical trials in LRRK2-related neurodegenerative diseases.Meanwhile, Kymera Therapeutics reported positive Phase 1 results for KT-621, a potential first-in-class oral STAT6 degrader. Once-daily administration achieved over 90% average degradation of STAT6 in the blood at doses above 1.5 mg. Complete degradation in both blood and skin was observed in all multiple ascending dose (MAD) cohorts at doses ≥50 mg.Bristol Myers Squibb presented its latest research on targeted protein degradation at the European Hematology Association (EHA) 2025 Congress, highlighting progress across its protein degradation platform. This included updated clinical data on its investigational oral cereblon E3 ligase modulators (CELMoDs) mezigdomide and iberdomide in patients with multiple myeloma (MM), as well as developments in the study of golcadomide in non-Hodgkin lymphoma (NHL). Additionally, the company released initial data on BMS-986458, a potential first-in-class oral BCL6 ligand-directed degrader (LDD), in NHL.Among the findings, golcadomide in combination with rituximab demonstrated significant efficacy in patients with relapsed/refractory follicular lymphoma, with an overall response rate (ORR) of 94% and a complete response (CR) rate of 63%. Preliminary results for BMS-986458 showed rapid and sustained degradation of BCL6 in both peripheral blood and tumor tissue. Antitumor activity was observed from the lowest dose levels in patients with diffuse large B-cell lymphoma and follicular lymphoma. Among 21 evaluable patients, the ORR was 81% (N=17), with a CR rate of 23.8% (N=5).Biohaven’s BHV-1300 and BHV-1400 demonstrated rapid and robust reductions in target protein levels—achieving 70–80% decreases within hours. These molecules bind target proteins on one end and the asialoglycoprotein receptor (ASGPR) on the other, thereby facilitating internalization and degradation via endocytosis.Financing and Collaborations: Molecular Glues Attract Major DealsAlongside bifunctional degraders, molecular glues—small molecules that induce or stabilize interactions between E3 ligases and target proteins—continue to draw significant interest. In 2024, multiple major pharmaceutical companies signed R&D deals for molecular glue technologies worth over $1 billion.That momentum has carried into 2025, with several multinational pharmaceutical companies announcing collaborations focusing on molecule glue-based degraders, targeting undruggable targets in oncology, immunology, and more diseases with unmet medical needs. In addition, novel proximity-inducing mechanisms are being explored to target disease-relevant tissues with high precision. In parallel, several emerging companies in the TPD space completed new funding rounds during H1 2025. The potential of targeted protein degradation continues to expand. A recent article in Nature Medicine noted that the ability to degrade proteins with orally available small molecules is fundamentally reshaping drug discovery—liberating scientists from traditional “druggability” constraints and allowing them to focus on the targets that matter most in disease biology. As the field progresses, more TPD therapies are expected to achieve clinical milestones and ultimately bring benefits to patients worldwide.However, the promise of TPDs comes with unique development challenges. For example, due to their large molecular weight and structural complexity, PROTACs often suffer from poor solubility and suboptimal pharmacokinetics. The following case study illustrates how WuXi STA, an integral part of WuXi AppTec, collaborated with a partner to address these challenges effectively.Addressing Key Bottlenecks in TPD Drug DevelopmentSeveral years ago, a biotech company developing a PROTAC candidate faced synthetic challenges and turned to WuXi STA for support. The goal was to complete the production of drug substance and clinical trial material within 14 months to support an IND filing and FIH trial. However, the original synthesis route involved 24 steps and yielded only 0.3%. Crystallization and purification proved difficult due to the compound’s unique structure.Compounding the challenge, the candidate’s high molecular weight and poor solubility resulted in oral bioavailability of just 0.9%. Moreover, three steps in the synthesis relied on a palladium (Pd) catalyst, raising safety concerns and increasing production costs.To resolve these issues, WuXi STA’s process chemistry, biocatalysis, and crystallization teams worked in concert to redesign the synthesis route, reducing the number of steps from 24 to 16 and replacing palladium with biocatalysts in two steps. To tackle crystallization bottlenecks, high-throughput crystallization screening identified suitable conditions that met both purity and yield requirements. These changes significantly improved the scalability and efficiency of the synthetic route while reducing costs.Simultaneously, WuXi STA’s formulation team addressed the low oral bioavailability by exploring a range of enabling technologies and ultimately selected spray-dried dispersion (SDD) to prepare a solid dosage form. SDD disperses poorly soluble compounds in an amorphous state within a polymer matrix and has been successfully used in several approved drugs. With this approach, the candidate’s oral bioavailability improved by approximately 30-fold—supporting further clinical advancement.Thanks to WuXi STA’s integrated CRDMO model, API process development and formulation were advanced in parallel by multiple teams working seamlessly together. Ultimately, they delivered IND-enabling materials and clinical trial materials within just 12 months—two months ahead of schedule.As one of the industry’s leading platforms enabling targeted protein degradation, WuXi AppTec’s integrated services extend beyond PROTACs to a wide array of bifunctional modalities, including:• LYTACs (lysosome-targeting chimeras): for degrading extracellular or membrane proteins via lysosomes• DACs (degrader-antibody conjugates): combining antibodies with protein degraders• AUTACs (autophagy-targeting chimeras): small molecules inducing autophagic degradation• RIBOTACs (ribonuclease-targeting chimeras): targeting and degrading specific RNA sequencesAs targeted protein degradation continues to evolve, WuXi STA remains committed to leveraging its integrated CRDMO platform to empower the development of targeted protein degraders, helping partners translate scientific innovation into transformative medicines for patients around the world.参考资料（可上下滑动查看）[1] Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic. Retrieved May 15, 2025, from https://www.nature.com/articles/d41573-025-00037-7[2] Monte Rosa Therapeutics Announces Fourth Quarter 2024 Financial Results and Provides Corporate Update Including New Clinical Results from MRT-6160 and MRT-2359 Programs. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/20/3046104/0/en/Monte-Rosa-Therapeutics-Announces-Fourth-Quarter-2024-Financial-Results-and-Provides-Corporate-Update-Including-New-Clinical-Results-from-MRT-6160-and-MRT-2359-Programs.html[3] Magnet Biomedicine Enters into a Collaboration and License Agreement with Lilly to Discover and Develop Novel Molecular Glue Medicines. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/magnet-biomedicine-enters-into-a-collaboration-and-license-agreement-with-lilly-to-discover-and-develop-novel-molecular-glue-medicines-302387756.html[4] AbbVie and Neomorph Announce Collaboration to Develop Molecular Glue Degraders for Oncology and Immunology. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/abbvie-and-neomorph-announce-collaboration-to-develop-molecular-glue-degraders-for-oncology-and-immunology-302357741.html[5] Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/04/04/3055854/0/en/Arvinas-Presents-First-in-Human-Data-for-Investigational-Oral-PROTAC-ARV-102-Demonstrating-Blood-Brain-Barrier-Penetration-and-Central-and-Peripheral-LRRK2-Degradation.html[6] Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/11/3040386/0/en/Arvinas-and-Pfizer-Announce-Positive-Topline-Results-from-Phase-3-VERITAC-2-Clinical-Trial.html[7] Argobio and the Institut Pasteur launch Enodia Therapeutics: A biotech company with a new approach for Targeted protein Degradation. Retrieved May 15, 2025, from https://www.pasteur.fr/en/press-area/press-documents/argobio-and-institut-pasteur-launch-enodia-therapeutics-biotech-company-new-approach-targeted[8] Biohaven Reports Positive Degrader Data Achieving > 80% Sustained Reductions in Total IgG with Potential First-in-Class BHV-1300. Retrieved May 15, 2025, from https://ir.biohaven.com/news-releases/news-release-details/biohaven-reports-positive-degrader-data-achieving-80-sustained[9] Revolution Medicines Reports First Quarter 2025 Financial Results and Update on Corporate Progress. Retrieved May 15, 2025, from https://ir.revmed.com/node/11636[10] Photys Therapeutics Enters into Exclusive License Agreement with Polymed for Phase 1-Ready IRAK4 Degrader, Furthering its Proximity-based Pipeline and Mission. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/20/3029603/0/en/Photys-Therapeutics-Enters-into-Exclusive-License-Agreement-with-Polymed-for-Phase-1-Ready-IRAK4-Degrader-Furthering-its-Proximity-based-Pipeline-and-Mission.html[11] Nurix Licenses a Drug Discovery Program to Sanofi Targeting a Novel Transcription Factor for Autoimmune Diseases. Retrieved May 15, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-licenses-drug-discovery-program-sanofi-targeting-novel[12] PAQ Therapeutics Announces $39 Million Series B Financing and Initiates Phase 1 Trial to Advance Novel Approach Addressing KRAS-Driven Cancers with High Unmet Need. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/paq-therapeutics-announces-39-million-series-b-financing-and-initiates-phase-1-trial-to-advance-novel-approach-addressing-kras-driven-cancers-with-high-unmet-need-302447786.html[13] Fraser Therapeutics Secures $29 Billion Series B from J&J and 8 Others. Retrieved May 15, 2025, from http://prazertx.com/pages/board/view.php?menu_code=477&board_sid=16&data_sid=261&page_num=&skey=&sval=&category_code1=[14] TRIMTECH Therapeutics raises $31M seed funding to advance targeted protein degradation pipeline for treatment of neurodegenerative diseases. Retrieved May 15, 2025, from https://www.businesswire.com/news/home/20250305069531/en/TRIMTECH-Therapeutics-raises-%2431M-seed-funding-to-advance-targeted-protein-degradation-pipeline-for-treatment-of-neurodegenerative-diseases[15] Auron Therapeutics Announces FDA Clearance to Initiate Clinical Development of AUTX-703 and Completion of Series B Financing. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/04/3020131/0/en/Auron-Therapeutics-Announces-FDA-Clearance-to-Initiate-Clinical-Development-of-AUTX-703-and-Completion-of-Series-B-Financing.html[16] Advancing targeted protein degraders: leveraging CMC strategies for rapid IND submission and bioavailability solutions. Retrieved May 15, 2025, from https://sta.wuxiapptec.com/wp-content/uploads/2024/10/Advancing-targeted-protein-degraders.pdf免责声明：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：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，传递医学新知

蛋白降解靶向嵌合体临床3期临床1期临床结果临床申请

2025-07-04

·BiG生物创新社

从靶点抑制到蛋白降解，TAC技术群如何实现革命性突破？

作者｜YY 01 从“抑制”到“降解”PROTAC技术即将取得正果2025年6月，靶向蛋白降解（Targeted Protein Degradation, TPD）领域迎来关键性时刻。由 Arvinas 与辉瑞联合开发的口服降解剂 Vepdegestrant（ARV-471）正式向FDA 提交新药上市申请（NDA），用于治疗 ESR1 突变的 ER阳性/HER2阴性（ER+/HER2-）晚期或转移性乳腺癌患者。这一里程碑的意义，不仅在于它可能成为全球第一个获得监管批准的 PROTAC 药物，更在于它验证了 TPD 技术在复杂临床适应症中的可行性，标志着降解疗法登堂入室、取得正果的第一步。图1. Vepdegestrant化学结构。从分子结构看（图1），Vepdegestrant 是一个典型的双功能 PROTAC 嵌合体，明确分为三个关键模块：红色区域：E3 泛素连接酶招募模块（Recruiting Module）该部分负责特异性结合细胞内的 E3 泛素连接酶 cereblon（CRBN），将降解机器引入反应复合体中。其功能并非直接作用于目标蛋白，而是充当“引荐者，即将目标蛋白引导进入细胞自身的蛋白降解系统（图2）。蓝色区域：靶向模块（Targeting Ligand）该部分专一识别并结合雌激素受体（ER），是整个 PROTAC 分子的“定位系统”。通过高亲和力锁定 ER，使其成为被降解的目标蛋白（POI），为后续的泛素化反应奠定基础（图2）。绿色区域：连接子（Linker）连接子将 ER 配体与 CRBN 配体串联在一起，起到空间架桥作用。它的长度与柔性必须恰到好处，以便促进三元复合物的构建，使目标蛋白与 CRBN 在空间上充分靠近，触发泛素化与后续降解（图2）。图2. Vepdegestrant作用机制示意图。（图片来源：Expert Opinion on Pharmacotherapy）Vepdegestrant 的降解机制区别于传统抗雌激素药物如他莫昔芬（Tamoxifen）或氟维司群（Fulvestrant），后者只是竞争性拮抗 ER 功能，而 PROTAC 分子通过诱导 ER 蛋白泛素化并进入蛋白酶体，实现“清除”而非“抑制”。这种机制在应对 ESR1 突变所引发的激素治疗耐药中展现出特殊优势。Vepdegestrant的新药申请基于 III 期临床试验 VERITAC-2 的数据。研究纳入 624 例接受过 CDK4/6 抑制剂与内分泌治疗的 ER+/HER2- 晚期乳腺癌患者，并在其中重点分析了 43% ESR1 突变阳性亚组。结果显示，Vepdegestrant 在该人群中的无进展生存期（PFS）显著优于标准治疗氟维司群。这一成果不仅在 2025 年 ASCO 年会中发布，还发表于《新英格兰医学杂志》，并入选 ASCO“Best of”推荐，代表其在临床与学术界获得的双重认可。Vepdegestrant 的意义远不止于某一靶点或适应症的推进。作为 TPD 概念的首个临床转化代表，它验证了 PROTAC 药物在真实世界肿瘤治疗中的药效潜力，也开启了未来更多“不可成药靶点”被“靶向清除”的现实通道。 02 不止是 PROTAC靶向降解技术迈入多模态时代Vepdegestrant 的上市申请不仅象征着 PROTAC 概念的临床化突破，也在事实上揭示了靶向蛋白降解（TPD）技术的一条核心演化路径：从“连接 E3 和目标蛋白”的单一策略，走向围绕“诱导降解”这一目标的多模态、多路径拓展。过去两年，研究者不再局限于传统 PROTAC 所依赖的蛋白酶体/E3连接酶体系，而是开始探索更多“降解通道”的可能性，涵盖溶酶体、自噬体、内吞受体，甚至病毒相关机制。这些新的降解策略被统称为 “XX-TACs”（Targeting Chimeras），不仅极大地拓宽了靶点空间，也丰富了分子形式与给药方式，进一步推动了“不可成药蛋白”领域的药物发现。 2.1 PolyTACs：重构内吞通路，靶向难成药膜蛋白在靶向蛋白降解技术中，大多数传统策略（如PROTAC）依赖细胞内蛋白酶体系统，仅适用于胞内蛋白。而对于细胞膜蛋白或分泌型胞外蛋白，由于它们位于细胞膜外侧或细胞外空间，PROTAC 无法触及，因此长期被视为“不可成药”靶点。为解决这一难题，研究者提出了LYTAC（Lysosome-Targeting Chimera，溶酶体靶向嵌合体）技术。LYTAC 通过招募细胞表面的天然转运受体（如 ASGPR、CI-M6PR），将膜蛋白或胞外蛋白内吞入胞，并引导其进入溶酶体中降解。该机制开辟了面向胞外靶点的靶向降解新路径，但其局限在于对特定受体的高度依赖，导致适用范围受限（如 ASGPR 主要表达于肝组织）。PolyTAC（Polymeric Lysosome-Targeting Chimera）技术的出现，正是对这一瓶颈的突破。PolyTAC 可视为一种“非受体依赖型 LYTAC”，通过人工设计的聚合物支架，将目标膜蛋白与特定“辅助蛋白”配体同时结合，在细胞膜表面形成多价复合物，诱导内吞并导入溶酶体降解。其作用机制如图3所示。图3. PolyTACs作用机理示意图。（图片来源：bioRxiv）·抗体片段（深蓝色Y 形）：特异性识别目标膜蛋白（POI，黄色），如 PD-L1、EGFR、HER2 等；·聚合物主链（绿色链条）：作为支架结构，连接多个功能单元；·小分子配体：与细胞膜上的“辅助蛋白”（Helper protein，紫色）结合，触发内吞作用。当PolyTAC 同时结合目标蛋白与辅助蛋白后，会在膜表形成多位点聚集（multisite binding），触发细胞启动受体介导的内吞机制。整个复合体被内吞进入细胞，最终送入溶酶体中完成降解。这种机制打破了对天然转运机制的依赖，具有更强的组织适配性与降解普适性；利用“AND逻辑”控制降解门槛，提升靶向性；支持双靶点协同降解与模块化结构替换；有望广泛应用于免疫肿瘤、难成药膜蛋白调控等领域。2.2 VIPER-TACs：利用病毒“自毁武器”精准杀伤癌细胞要想让一个细胞失去生存能力，最有效的办法之一，就是让它体内的关键蛋白（essential protein）彻底消失。传统的靶向药物往往只是抑制这些蛋白的功能，而不能将它们彻底清除。靶向蛋白降解（TPD）技术则不同，它直接让蛋白在体内“被回收、被处理”，真正意义上实现功能清零。在PROTAC之外，新兴的VIPER-TACs （Viral E3 Pan-Essential Removing TACs）技术利用了一种精准的定位技术，让病毒的蛋白降解机制反过来为人类服务。VIPER-TACs核心设计是利用人乳头瘤病毒（HPV）中的一种蛋白vE3（viral E3 ligase，亦称E6），它是一种病毒自带的 E3 连接酶，天然能够降解多种人体蛋白。研究人员正是利用vE3这一能力，实现选择性地降解癌细胞中的关键蛋白。VIPER-TACs的作用机制如图4所示：图4. VIPER-TAC作用机制示意图。（图片来源：Cell Chemical Biology）图4可以分为上下两部分，分别对应正常细胞与病毒感染细胞对VIPER-TAC 的反应差异：·正常细胞（图4上）：在正常细胞中，VIPER-TAC 分子虽然可以与目标蛋白结合，但由于缺乏病毒特有的 E3 连接酶 vE3），无法启动降解过程，所以目标蛋白得以保留，细胞正常生存，无毒副作用。·病毒感染细胞（图4下）：当细胞被病毒感染（如HPV）时，病毒蛋白 vE3得以表达；VIPER-TAC 一端结合目标蛋白，一端通过vE3与病毒 E3 蛋白结合，从而构建起一个“病毒酶+目标蛋白+降解分子”的三元复合物，启动泛素化。最终，关键蛋白被送入蛋白酶体清除，感染细胞因关键功能丧失而死亡。这一机制的最大亮点是选择性极高，即只有在“携带病毒”的细胞中，VIPER-TAC 才能真正启动降解机制。因此，它尤其适合用来治疗HPV 阳性的癌症，如部分宫颈癌和头颈癌。相比化疗或靶向抑制剂，这种方式能够做到精准杀伤病毒感染细胞、最大限度保留正常组织、打击难以抑制的“核心依赖蛋白”，提升抗肿瘤效率。2.3 ByeTACs：让蛋白酶体“直通目标”的极简降解设计靶向蛋白降解技术的主流范式，如PROTAC，往往需要组装一个“三元复合体”：目标蛋白、PROTAC、E3 泛素连接酶。组装之后，E3 把泛素贴到目标蛋白上，蛋白酶体再接手完成清除。看似高效，但这个过程实则高度依赖于合适的 E3 酶“上线服务”。问题是，人类细胞中虽存在数百种 E3 酶，但它们的表达具有组织特异性，且可利用的泛素连接酶种类十分有限，这成了 TPD 技术进一步推广的一道“瓶颈”。ByeTACs（Bypassing E3 Ligase for Proteasomal Degradation）技术的开发，正是为了解决这个问题：既然招募 E3 太复杂，为什么不直接把目标蛋白送进蛋白酶体？图5展示了ByeTAC 分子如何直接连接目标蛋白（POI）与蛋白酶体上的“接收点”Rpn13。图5. ByeTAC作用机制示意图。（图片来源：J. Med. Chem.）·ByeTAC蓝色结构域是一个专门设计用于结合 Rpn13 的小分子配体。Rpn13 是 26S 蛋白酶体上的识别亚基；·ByeTAC黑色结构与是一个柔性 linker，用于调节空间构象；·ByeTAC粉色结构域是与目标蛋白（POI）结合的小分子配体；最终复合物形成后，整个目标蛋白就被“拉进”蛋白酶体，不需泛素标签也能被降解。ByeTAC技术平台的优势在于无需 E3 酶，简化分子设计；不需要泛素标记，理论上更快、更直接、更高效；特别适合在肿瘤、神经退行性疾病等 E3 酶表达缺陷的场景下使用；结构紧凑，可成药性强：分子更小、更稳定，利于口服与组织穿透。2.4 AUTOTACs：激活细胞“吃掉自己”的清道夫机制细胞并不总是依赖蛋白酶体来处理蛋白质垃圾。面对更大、更难清除、或发生聚集的蛋白，细胞会启动一条更强力的通道：自噬系统（Autophagy）。AUTOTAC（Autophagy-Targeting Chimera）正是沿着这条通路展开的创新降解策略，它通过诱导自噬机制，让目标蛋白主动“被打包”并送入溶酶体，从而被彻底分解清除。其结构与作用机制如图6所示：图6. ATUOTAC结构与作用机制示意图。（图片来源：Nature Communications）构建AUTOTAC 分子AUTOTAC 分子同样由三部分连接组成：·TBL（Target-binding ligand）：专门识别并结合目标蛋白；·ATL（Autophagy-targeting ligand）：结合细胞自噬受体 ·两者通过linker连接，构成双功能嵌合体（Chimeric ligand）。AUTOTAC作用机制AUTOTAC将目标蛋白与p62 结合在一起。p62 被称为自噬系统中的“桥梁蛋白”，能够与 LC3 （Microtubule-associated protein 1A/1B-light chain 3）结合，引导整个复合体进入自噬流程。目标蛋白在此过程中被聚合、隔离，失活并准备“打包运输”。当AUTOTAC 分子同时结合目标蛋白与 p62 后，就像贴上了“回收标签”。p62 本身是自噬系统的桥梁蛋白，它通过与 LC3 蛋白结合，将整个复合体引导至自噬小体膜上。这一步完成后，目标蛋白随即被打包进一个双层膜结构中，形成自噬体（autophagosome）。随后，自噬体与溶酶体融合，形成自噬溶酶体（autolysosome），其中包含的目标蛋白就会被各种水解酶彻底分解清除。值得一提的是，部分 AUTOTAC 分子本身可能不会被降解，有望实现持续降解作用。这一机制的最大亮点在于不依赖泛素或蛋白酶体；特别适合聚集蛋白、膜蛋白等“难清除目标”；可激活细胞本身的“回收系统”，具有较强的生理兼容性。随着对 p62–LC3–自噬体这一链路的深入研究，AUTOTAC 为复杂适应症（如神经退行性疾病、肿瘤）提供了一种“细胞内自毁程序”式的解决方案。 03 结语与展望从“成药性”走向“清除性”TPD技术迈入全能时代Vepdegestrant 的上市申请不仅为靶向蛋白降解（TPD）领域点亮了第一盏“监管绿灯”，更揭示出一个趋势日益明朗的未来：TPD 正在从一种新机制，演变为一个多路径、多通道、多适应症的药物开发平台。过去，我们以是否“可成药”来评估靶点的开发潜力；而今天，TPD技术正以“是否可清除”作为新的判断标准，把那些曾经被认为“不可成药”的蛋白重新纳入药物化学视野。在这个转变过程中，我们见证了从PROTAC到ByeTAC, VIPER-TAC, AUTOTAC, PolyTAC的范式裂变，每一种新策略，都是对蛋白降解边界的拓展。值得注意的是，这场“降解革命”的内核，并非简单的降解路径替换，而是一种更底层的药物开发逻辑转变：从功能拮抗，走向直接清除；从对蛋白功能的抑制，走向对蛋白本体的“处理”与“回收”。这将为诸多具有“成瘾性依赖”的癌症靶点、具有聚集特征的神经病变蛋白，乃至难以抑制的病毒关键蛋白，提供更加本质和彻底的解决方案。未来，随着 TPD 技术的进一步发展，将有更多靶点从“难以成药”转向“可以降解”；将有更多病种，从传统靶向疗法的边缘，纳入 TPD 的新范式之中；将有更多原创新药，从单点构想，走向以机制为支撑、以降解为核心的系统性开发。从“蛋白抑制”到“蛋白清除”，TPD 并非仅是机制创新，更是一次对疾病可治疗边界的重塑。而 Vepdegestrant，只是这场革命的开始。附表: TAC技术对比主要参考文献 Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer. Pfizer Press Release. 31. 05. 2025.Dutta, R. et al. Multivalent Ligand-Protein Interactions Using Polymeric Lysosome-Targeting Chimeras (PolyTACs) Leads to Lysosome-Targeting Receptor-Independent Degradation of Transmembrane Proteins. bioRxiv 2025.05.06.652519; doi: https://doi.org/10.1101/2025.05.06.652519Mangano, K. et al.VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation. Cell Chemical Biology. (2025) 32, 423 - 433.e9.Loy, C. A. et al. ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation. J. Med. Chem. (2025) 68, 9694-9705.Ji, C.H.et al. The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system. Nat Commun13, 904 (2022). https://doi.org/10.1038/s41467-022-28520-4共建Biomedical创新生态圈！如何加入BiG会员？

蛋白降解靶向嵌合体ASCO会议临床结果临床3期

2025-07-01

·药明康德

2025年上半年蛋白降解领域盘点：PROTAC迎来里程碑 | 同行致远

▎药明康德编者按：靶向蛋白降解剂（TPD）通过利用细胞自身的蛋白降解系统降解与疾病相关的靶蛋白。由于无需直接抑制靶蛋白的活性，这种治疗模式有望针对许多以往被认为“不可成药”的靶点，因而成为新药开发的热点领域之一。早在近10年前，这项技术刚刚起步时，药明康德就开始布局相关能力和技术，积累了丰富的成功经验，搭建起集发现、合成、分析纯化和测试等能力的一体化赋能平台。目前，该平台已成功支持超过120款TPD分子的开发，其中20余款顺利推进至临床阶段。本文将回顾2025年上半年TPD领域的最新进展。还将介绍药明康德的一体化CRDMO平台如何高效解决TPD药物开发过程中的诸多挑战，在短短12个月内完成IND申报所需的蛋白降解靶向嵌合体（PROTAC）候选药物的制备，并为首次人体临床研究提供临床试验用药。临床进展：首个PROTAC分子3期结果发布，细胞外蛋白降解疗法初步临床数据积极今年3月，辉瑞（Pfizer）和Arvinas联合公布了PROTAC药物vepdegestrant的首个关键性3期临床试验结果。在携带ESR1突变的HR阳性、HER2阴性乳腺癌患者中，vepdegestrant与活性对照相比，将患者的疾病进展或死亡风险降低超过40%（风险比低于0.60）。Arvinas和辉瑞近日已经向美国FDA递交vepdegestrant的新药申请（NDA）。此外，该公司的另一款在研PROTAC疗法ARV-102在1期临床试验中显著降低健康志愿者中枢神经系统（CNS）和外周的LRRK2蛋白水平。这一结果为后续在LRRK2相关神经退行性疾病中的进一步临床研究奠定了基础。Kymera Therapeutics公司的潜在“first-in-class”口服STAT6降解剂KT-621在1期健康受试者的临床试验中也获得积极结果。数据显示，每日一次口服KT-621，在所有高于1.5 mg剂量水平中实现了平均超过90%的血液STAT6降解；在所有≥50 mg的多剂量递增（MAD）组中，更在血液与皮肤中均达成STAT6完全降解。百时美施贵宝（Bristol Myers Squibb）在欧洲血液学协会（EHA）年会上，展示了其靶向蛋白降解平台的最新研究数据，包括其在研口服E3泛素连接酶cereblon调节剂（CELMoD）药物mezigdomide和iberdomide在多发性骨髓瘤（MM）患者中的更新临床研究结果，以及golcadomide在非霍奇金淋巴瘤（NHL）中的研究进展。此外，该公司也公布其潜在“first-in-class”的口服BCL6配体导向降解剂（LDD）BMS-986458在NHL中的初步研究结果。其中，golcadomide联合利妥昔单抗治疗复发/难治性滤泡性淋巴瘤患者展现出显著疗效，总缓解率（ORR）高达94%，完全缓解（CR）率为63%。BMS-986458的初步研究结果显示，在外周血和肿瘤组织中均观察到BCL6快速且持久的降解。从最低剂量起即观察到在弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤患者中的抗肿瘤活性。在21名可评估疗效的患者中，ORR为81%（N=17），CR率为23.8%（N=5）。Biohaven公司开发的靶向蛋白降解剂BHV-1300和BHV-1400近期在早期临床试验中表现出显著降低细胞外蛋白的能力。这两款在研药物均为双特异性分子，一端与靶蛋白结合，另一端与肝细胞表面的去唾液酸糖蛋白受体（ASGPR）结合。ASGPR可介导肝细胞通过内吞作用，将靶蛋白摄入细胞内并降解。临床试验数据显示，BHV-1300和BHV-1400注射入患者体内后，短短数小时内即介导了靶蛋白的快速降解，蛋白水平降幅达到70%~80%，凸显出这类药物迅速的起效速度与临床应用潜力。融资与合作：大药企持续布局分子胶药物在靶向蛋白降解领域，促进蛋白降解的双特异性分子之外，分子胶降解剂通过与单个靶蛋白或E3泛素连接酶结合，即可诱导或稳定它们之间的相互作用，从而实现蛋白降解。这一细分领域近年来不断升温。在2024年，诺华（Novartis）、渤健（Biogen）、辉瑞、武田（Takeda）、卫材（Eisai）与诺和诺德（Novo Nordisk）等多家跨国药企先后签署了单笔数额超过10亿美元的分子胶研发合作协议。进入2025年上半年，分子胶领域的布局热度依然持续。今年5月，基因泰克（Genentech）与Orionis Biosciences达成超过20亿美元的研发合作协议，致力于开发靶向难以成药靶点的小分子单价分子胶药物，用于癌症治疗。此前在今年2月，礼来（Eli Lilly and Company）也与Magnet Biomedicine公司签署一项近13亿美元的合作协议。双方合作的范围不仅涵盖基于分子胶的蛋白降解剂研发，还将探索利用分子胶促进蛋白质之间产生诱导接近和协同作用，精准靶向疾病相关组织的创新作用机制。此外，艾伯维（AbbVie）公司在1月也与Neomorph公司达成超16亿美元的分子胶蛋白降解剂研发合作。与此同时，2025年上半年，多家开发靶向蛋白降解剂的新锐公司也完成新一轮融资。具体融资及合作信息请参见下表：▲2025年上半年靶向蛋白降解领域的融资和研发合作信息（数据来源：公开资料）展望未来，靶向蛋白降解剂有着更为深远的意义。这一领域的权威，丹娜-法伯癌症研究所（Dana–Farber Cancer Institute）的Eric Fischer教授在接受Nature Medicine采访时指出，利用口服小分子药物来降解蛋白质，将改变过去受制于“可成药性”局限的研发模式，使科学家们能更自由地探索哪些靶点真正能够最大程度改变疾病的进程。期待未来有更多蛋白降解药物在临床研究中取得积极进展，造福广大患者。然而，TPD药物的广阔前景也伴随着独特的开发挑战。例如，由于分子量大、结构复杂，PROTAC类分子通常存在溶解度差和药代动力学性质不佳的问题。以下案例展示了药明康德旗下合全药业（WuXi STA）如何与合作伙伴携手，有效应对这些挑战。解决TPD药物开发痛点，加速创新疗法进入临床试验几年前，一家公司因PROTAC分子的生产难题，选择与合全药业合作，希望在14个月内完成候选药物的生产，以支持IND申请及首次人体临床试验。然而，该候选分子的初始合成路线非常复杂，需要多达24个步骤，且最终产率仅为0.3%。此外，PROTAC特定的分子结构进一步增加了产品结晶和纯化难度。同时，由于候选化合物分子量较大且水溶性低，其口服生物利用度只有0.9%。值得注意的是，在合成过程中还有三步涉及使用罕见金属钯（Pd）作为催化剂，这不仅带来潜在安全隐患，更显著提高了生产成本。针对上述问题，合全药业的工艺研发、生物催化及结晶工艺等团队协同攻关，重新设计了一条合成路线，将合成步骤从原来的24步缩减至16步，并在其中两个步骤中用生物催化剂替代了钯催化剂。为攻克结晶难题，团队采用高通量结晶筛选技术，迅速确定了符合纯度与产量要求的结晶工艺，并通过优化大幅提升了生产过程的总产率。这些改进不但极大提高了整体合成工艺的可放大性，也提升了合成效率并降低了成本。与此同时，合全药业的制剂研发团队针对药物口服生物利用度低的问题，进行了全面的生物利用度增强技术筛选，最终选定喷雾干燥制备固体分散体（SDD）技术进行制剂制备。这种技术将难溶药物以无定形状态高度分散在聚合物中，目前已成功应用于多种上市药物的制剂开发中。借助SDD技术，候选化合物药片制剂的口服生物利用度提高了约30倍，为后续临床应用奠定了坚实基础。合全药业一体化CRDMO平台的整合能力，使多个团队能够并行推进原料药与制剂开发，高效协作，加速破解PROTAC分子开发中的难题。最终，团队仅用了12个月就完成了支持IND申请所需的候选药物生产和制剂制备，顺利供应首次人体临床研究用药，比合作伙伴原定时间提前了2个月。作为赋能全球靶向蛋白降解药物开发的重要平台之一，药明康德一体化平台的能力不但涵盖PROTAC，还包括分子胶、以及多种新兴双功能性蛋白降解剂类型。例如，诱导细胞外或细胞膜蛋白进入溶酶体进行降解的溶酶体靶向嵌合体（LYTAC），将抗体与蛋白降解剂偶联产生的蛋白降解剂-抗体偶联药物（DAC），诱导靶蛋白被自噬体吞噬降解的自噬靶向嵌合小分子（AUTAC），以及靶向降解特定RNA的核糖核酸酶靶向嵌合体（RIBOTAC）等。展望未来，药明康德将继续秉持“让天下没有难做的药，难治的病”的愿景，依托全球研发基地与生产网络，以独特的一体化、端到端的CRDMO模式，助力靶向蛋白降解剂的开发，帮助合作伙伴将科学创新转化为惠及全球患者的变革性药物。CRDMO: H1 2025 Review of Targeted Protein Degraders Targeted protein degraders (TPDs) offer a novel therapeutic approach by leveraging the body’s own protein degradation systems to eliminate disease-associated target proteins. This strategy opens new avenues for addressing previously “undruggable” targets. Nearly a decade ago, when this technology was still in its infancy, WuXi AppTec began building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. To date, this platform has supported the development of more than 120 TPD molecules, with over 20 advancing to clinical stages. This article summarizes key developments in the TPD landscape during the first half of 2025. It also presents a case study demonstrating how WuXi AppTec’s integrated CRDMO platform efficiently overcomes TPD development challenges, including preparing IND-enabling materials for a proteolysis-targeting chimera (PROTAC) candidate within just 12 months for first-in-human (FIH) trials.Clinical Advances: First PROTAC Phase 3 Results and Progress in Extracellular Protein DegradersIn March 2025, Pfizer and Arvinas jointly announced top-line results from the first-ever Phase 3 clinical trial of a PROTAC therapy—vepdegestrant. In HR+, HER2- breast cancer patients with ESR1 mutations, vepdegestrant reduced the risk of disease progression or death by more than 40% compared to the active control (hazard ratio < 0.60). Arvinas and Pfizer have recently submitted a new drug application (NDA) for the drug.Arvinas' second PROTAC candidate, ARV-102, also showed promise in Phase 1 studies, achieving significant reductions in LRRK2 protein levels in both the central nervous system and peripheral tissues of healthy volunteers—laying the groundwork for future clinical trials in LRRK2-related neurodegenerative diseases.Meanwhile, Kymera Therapeutics reported positive Phase 1 results for KT-621, a potential first-in-class oral STAT6 degrader. Once-daily administration achieved over 90% average degradation of STAT6 in the blood at doses above 1.5 mg. Complete degradation in both blood and skin was observed in all multiple ascending dose (MAD) cohorts at doses ≥50 mg.Bristol Myers Squibb presented its latest research on targeted protein degradation at the European Hematology Association (EHA) 2025 Congress, highlighting progress across its protein degradation platform. This included updated clinical data on its investigational oral cereblon E3 ligase modulators (CELMoDs) mezigdomide and iberdomide in patients with multiple myeloma (MM), as well as developments in the study of golcadomide in non-Hodgkin lymphoma (NHL). Additionally, the company released initial data on BMS-986458, a potential first-in-class oral BCL6 ligand-directed degrader (LDD), in NHL.Among the findings, golcadomide in combination with rituximab demonstrated significant efficacy in patients with relapsed/refractory follicular lymphoma, with an overall response rate (ORR) of 94% and a complete response (CR) rate of 63%. Preliminary results for BMS-986458 showed rapid and sustained degradation of BCL6 in both peripheral blood and tumor tissue. Antitumor activity was observed from the lowest dose levels in patients with diffuse large B-cell lymphoma and follicular lymphoma. Among 21 evaluable patients, the ORR was 81% (N=17), with a CR rate of 23.8% (N=5).Biohaven’s BHV-1300 and BHV-1400 demonstrated rapid and robust reductions in target protein levels—achieving 70–80% decreases within hours. These molecules bind target proteins on one end and the asialoglycoprotein receptor (ASGPR) on the other, thereby facilitating internalization and degradation via endocytosis.Financing and Collaborations: Molecular Glues Attract Major DealsAlongside bifunctional degraders, molecular glues—small molecules that induce or stabilize interactions between E3 ligases and target proteins—continue to draw significant interest. In 2024, multiple major pharmaceutical companies signed R&D deals for molecular glue technologies worth over $1 billion.That momentum has carried into 2025, with several multinational pharmaceutical companies announcing collaborations focusing on molecule glue-based degraders, targeting undruggable targets in oncology, immunology, and more diseases with unmet medical needs. In addition, novel proximity-inducing mechanisms are being explored to target disease-relevant tissues with high precision. In parallel, several emerging companies in the TPD space completed new funding rounds during H1 2025. The potential of targeted protein degradation continues to expand. A recent article in Nature Medicine noted that the ability to degrade proteins with orally available small molecules is fundamentally reshaping drug discovery—liberating scientists from traditional “druggability” constraints and allowing them to focus on the targets that matter most in disease biology. As the field progresses, more TPD therapies are expected to achieve clinical milestones and ultimately bring benefits to patients worldwide.However, the promise of TPDs comes with unique development challenges. For example, due to their large molecular weight and structural complexity, PROTACs often suffer from poor solubility and suboptimal pharmacokinetics. The following case study illustrates how WuXi STA, an integral part of WuXi AppTec, collaborated with a partner to address these challenges effectively.Addressing Key Bottlenecks in TPD Drug DevelopmentSeveral years ago, a biotech company developing a PROTAC candidate faced synthetic challenges and turned to WuXi STA for support. The goal was to complete the production of drug substance and clinical trial material within 14 months to support an IND filing and FIH trial. However, the original synthesis route involved 24 steps and yielded only 0.3%. Crystallization and purification proved difficult due to the compound’s unique structure.Compounding the challenge, the candidate’s high molecular weight and poor solubility resulted in oral bioavailability of just 0.9%. Moreover, three steps in the synthesis relied on a palladium (Pd) catalyst, raising safety concerns and increasing production costs.To resolve these issues, WuXi STA’s process chemistry, biocatalysis, and crystallization teams worked in concert to redesign the synthesis route, reducing the number of steps from 24 to 16 and replacing palladium with biocatalysts in two steps. To tackle crystallization bottlenecks, high-throughput crystallization screening identified suitable conditions that met both purity and yield requirements. These changes significantly improved the scalability and efficiency of the synthetic route while reducing costs.Simultaneously, WuXi STA’s formulation team addressed the low oral bioavailability by exploring a range of enabling technologies and ultimately selected spray-dried dispersion (SDD) to prepare a solid dosage form. SDD disperses poorly soluble compounds in an amorphous state within a polymer matrix and has been successfully used in several approved drugs. With this approach, the candidate’s oral bioavailability improved by approximately 30-fold—supporting further clinical advancement.Thanks to WuXi STA’s integrated CRDMO model, API process development and formulation were advanced in parallel by multiple teams working seamlessly together. Ultimately, they delivered IND-enabling materials and clinical trial materials within just 12 months—two months ahead of schedule.As one of the industry’s leading platforms enabling targeted protein degradation, WuXi AppTec’s integrated services extend beyond PROTACs to a wide array of bifunctional modalities, including:• LYTACs (lysosome-targeting chimeras): for degrading extracellular or membrane proteins via lysosomes• DACs (degrader-antibody conjugates): combining antibodies with protein degraders• AUTACs (autophagy-targeting chimeras): small molecules inducing autophagic degradation• RIBOTACs (ribonuclease-targeting chimeras): targeting and degrading specific RNA sequencesAs targeted protein degradation continues to evolve, WuXi STA remains committed to leveraging its integrated CRDMO platform to empower the development of targeted protein degraders, helping partners translate scientific innovation into transformative medicines for patients around the world.参考资料：[1] Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic. Retrieved May 15, 2025, from https://www.nature.com/articles/d41573-025-00037-7[2] Monte Rosa Therapeutics Announces Fourth Quarter 2024 Financial Results and Provides Corporate Update Including New Clinical Results from MRT-6160 and MRT-2359 Programs. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/20/3046104/0/en/Monte-Rosa-Therapeutics-Announces-Fourth-Quarter-2024-Financial-Results-and-Provides-Corporate-Update-Including-New-Clinical-Results-from-MRT-6160-and-MRT-2359-Programs.html[3] Magnet Biomedicine Enters into a Collaboration and License Agreement with Lilly to Discover and Develop Novel Molecular Glue Medicines. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/magnet-biomedicine-enters-into-a-collaboration-and-license-agreement-with-lilly-to-discover-and-develop-novel-molecular-glue-medicines-302387756.html[4] AbbVie and Neomorph Announce Collaboration to Develop Molecular Glue Degraders for Oncology and Immunology. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/abbvie-and-neomorph-announce-collaboration-to-develop-molecular-glue-degraders-for-oncology-and-immunology-302357741.html[5] Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/04/04/3055854/0/en/Arvinas-Presents-First-in-Human-Data-for-Investigational-Oral-PROTAC-ARV-102-Demonstrating-Blood-Brain-Barrier-Penetration-and-Central-and-Peripheral-LRRK2-Degradation.html[6] Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/11/3040386/0/en/Arvinas-and-Pfizer-Announce-Positive-Topline-Results-from-Phase-3-VERITAC-2-Clinical-Trial.html[7] Argobio and the Institut Pasteur launch Enodia Therapeutics: A biotech company with a new approach for Targeted protein Degradation. Retrieved May 15, 2025, from https://www.pasteur.fr/en/press-area/press-documents/argobio-and-institut-pasteur-launch-enodia-therapeutics-biotech-company-new-approach-targeted[8] Biohaven Reports Positive Degrader Data Achieving > 80% Sustained Reductions in Total IgG with Potential First-in-Class BHV-1300. Retrieved May 15, 2025, from https://ir.biohaven.com/news-releases/news-release-details/biohaven-reports-positive-degrader-data-achieving-80-sustained[9] Revolution Medicines Reports First Quarter 2025 Financial Results and Update on Corporate Progress. Retrieved May 15, 2025, from https://ir.revmed.com/node/11636[10] Photys Therapeutics Enters into Exclusive License Agreement with Polymed for Phase 1-Ready IRAK4 Degrader, Furthering its Proximity-based Pipeline and Mission. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/20/3029603/0/en/Photys-Therapeutics-Enters-into-Exclusive-License-Agreement-with-Polymed-for-Phase-1-Ready-IRAK4-Degrader-Furthering-its-Proximity-based-Pipeline-and-Mission.html[11] Nurix Licenses a Drug Discovery Program to Sanofi Targeting a Novel Transcription Factor for Autoimmune Diseases. Retrieved May 15, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-licenses-drug-discovery-program-sanofi-targeting-novel[12] PAQ Therapeutics Announces $39 Million Series B Financing and Initiates Phase 1 Trial to Advance Novel Approach Addressing KRAS-Driven Cancers with High Unmet Need. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/paq-therapeutics-announces-39-million-series-b-financing-and-initiates-phase-1-trial-to-advance-novel-approach-addressing-kras-driven-cancers-with-high-unmet-need-302447786.html[13] Fraser Therapeutics Secures $29 Billion Series B from J&J and 8 Others. Retrieved May 15, 2025, from http://prazertx.com/pages/board/view.php?menu_code=477&board_sid=16&data_sid=261&page_num=&skey=&sval=&category_code1=[14] TRIMTECH Therapeutics raises $31M seed funding to advance targeted protein degradation pipeline for treatment of neurodegenerative diseases. Retrieved May 15, 2025, from https://www.businesswire.com/news/home/20250305069531/en/TRIMTECH-Therapeutics-raises-%2431M-seed-funding-to-advance-targeted-protein-degradation-pipeline-for-treatment-of-neurodegenerative-diseases[15] Auron Therapeutics Announces FDA Clearance to Initiate Clinical Development of AUTX-703 and Completion of Series B Financing. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/04/3020131/0/en/Auron-Therapeutics-Announces-FDA-Clearance-to-Initiate-Clinical-Development-of-AUTX-703-and-Completion-of-Series-B-Financing.html[16] Advancing targeted protein degraders: leveraging CMC strategies for rapid IND submission and bioavailability solutions. Retrieved May 15, 2025, from https://sta.wuxiapptec.com/wp-content/uploads/2024/10/Advancing-targeted-protein-degraders.pdf免责声明：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：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

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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/ESR1突变乳腺癌	申请上市	美国	Arvinas, Inc.	2025-06-06
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	美国	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	中国	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	日本	Pfizer 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	Arvinas Estrogen Receptor, Inc.	2023-03-03

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适应症

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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


NCT05654623 (VERITAC-2, Pubmed \| N Engl J Med)	临床3期	晚期乳腺癌	624	Vepdegestrant 200 mg	繭襯積窪醖糧襯夢獵範(積憲艱鏇範蓋蓋觸範選) = in 2.9% and 0.7% of the patients, respectively 壓觸獵繭襯築淵範壓製 (窪醖廠鏇繭鑰窪憲糧範 ) 更多	积极	2025-05-31
				Fulvestrant 500 mg
NCT05654623 (VERITAC-2, ASCO2025 \| Company_Website) 人工标引	临床3期	ER阳性/HER2阴性乳腺癌 ER Positive \| HER2 Negative	624	Vepdegestrant	鏇餘繭網齋築夢鏇顧繭(壓範衊顧網糧鑰選鏇餘) = 選衊鏇選餘窪餘糧築醖蓋鏇衊憲網獵襯製憲範 (廠顧壓醖衊衊淵願餘鹹, 3.6–5.3) 更多	积极	2025-05-30
				fulvestrant	鏇餘繭網齋築夢鏇顧繭(壓範衊顧網糧鑰選鏇餘) = 遞築鏇膚窪鏇壓築膚壓蓋鏇衊憲網獵襯製憲範 (廠顧壓醖衊衊淵願餘鹹, 2.2–3.8) 更多
NCT05654623 (VERITAC-2, Company_Website) 人工标引	临床3期	ER阳性/HER2阴性乳腺癌 ESR1 Mutation	-	Vepdegestrant (ESR1 mutant)	夢鏇鬱獵齋鏇淵構製顧(淵網選顧窪窪選鑰網鑰) = The results exceeded the pre-specified target hazard ratio of 0.60 in the ESR1m population. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population. 餘鹹構糧簾築積選衊窪 (憲顧壓壓鹽夢鹹衊餘夢 )	不佳	2025-03-11
				fulvestrant (ESR1 mutant)
NCT05548127 (TACTIVE-U, GlobeNewswire) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌三线	16	Vepdegestrant + Abemaciclib	構壓齋鑰獵製襯淵鬱鹹(齋夢鑰鑰鹹膚構範鹹鬱) = None 窪壓範廠淵構衊餘鏇衊 (憲顧鏇積顧廠壓壓選齋 ) 更多	积极	2024-12-10
				Vepdegestrant + Abemaciclib (mutant ESR1)
NCT05463952 (Pubmed \| Int J Clin Oncol)	临床1期	局部晚期不能切除的乳腺癌 \| 乳腺癌 \| ER阳性乳腺癌 ... estrogen receptor (ER) 更多	6	Vepdegestrant 200 mg QD	顧鏇糧簾窪鬱醖製蓋壓(壓廠齋膚顧網簾遞鹹鬱) = Four (66.7%) patients experienced adverse events; none led to dose reduction or discontinuation 鹹夢構糧鹹鹹繭築鹽繭 (願壓壓鹽齋遞鹽鑰餘醖 ) 更多	-	2024-11-20
NCT05538312 (CTgov)	临床1期	-	12	ARV-471 (Period 1: ARV-471 200 mg)	餘獵鹹夢艱餘遞廠艱鏇(觸願繭構簾鹽淵襯糧願) = 衊範糧鏇積衊願築夢鹽廠獵齋衊製憲淵廠觸壓 (夢簾鑰獵廠夢廠壓願簾, 23) 更多	-	2024-09-23
				Itraconazole+ARV-471 (Period 2: ARV-471 200 mg + Itraconazole 200 mg)	餘獵鹹夢艱餘遞廠艱鏇(觸願繭構簾鹽淵襯糧願) = 餘窪簾鏇醖觸繭淵觸鑰廠獵齋衊製憲淵廠觸壓 (夢簾鑰獵廠夢廠壓願簾, 24) 更多
NCT05463952 (CTgov)	临床1期	局部晚期不能切除的乳腺癌 \| 乳腺癌 \| ER阳性乳腺癌 ... 更多	6	ARV-471	遞積選齋膚築簾窪選製 = 觸鑰觸餘網顧鹹衊鹽構願鏇簾襯糧膚廠積憲膚 (鹽鑰齋夢窪範醖積範糧, 醖網鑰壓壓艱艱選觸遞 ~ 齋願觸醖餘鏇鬱齋選衊) 更多	-	2024-09-23
NCT05673889 (CTgov)	临床1期	-	24	Dabigatran (Period 1: Dabigatran 75 mg)	糧觸壓鹹觸鏇夢範顧壓(遞遞餘簾艱鑰選窪醖積) = 鬱築鑰觸齋蓋襯淵衊鏇網網壓遞鬱餘夢網網觸 (鑰網鏇觸築網網範顧憲, 94) 更多	-	2024-08-16
				ARV-471+Dabigatran (Period 2: Dabigatran 75 mg + ARV-471 200 mg)	糧觸壓鹹觸鏇夢範顧壓(遞遞餘簾艱鑰選窪醖積) = 簾觸膚鏇淵製獵鬱築艱網網壓遞鬱餘夢網網觸 (鑰網鏇觸築網網範顧憲, 66) 更多
NCT05652660 (CTgov)	临床1期	-	12	Rosuvastatin (Period 1: Rosuvastatin)	襯顧簾蓋壓網齋繭網廠(憲餘積範鬱醖築鹹製鏇) = 衊願鹹餘繭觸餘範鏇衊選構鏇鏇鹽憲餘製襯壓 (積艱齋選製鑰糧鑰網糧, 53) 更多	-	2024-07-26
				Rosuvastatin+ARV-471 (Period 2: ARV-471 + Rosuvastatin)	襯顧簾蓋壓網齋繭網廠(憲餘積範鬱醖築鹹製鏇) = 構選繭廠繭憲觸齋構簾選構鏇鏇鹽憲餘製襯壓 (積艱齋選製鑰糧鑰網糧, 48) 更多
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)	鑰窪積淵觸鹹衊蓋醖蓋(獵齋願願膚淵積範鑰憲) = ≥10% to either vepdegestrant or palbo were neutropenia (91%) and decreased white blood cell count (15%). 鹹壓夢齋艱窪構構製構 (獵獵積壓鹽簾糧顧積積 )	积极	2024-05-16
				Vepdegestrant+palbociclib (Mutant ESR1)