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更新于：2025-07-14

Bexobrutideg

更新于：2025-07-14

概要

概要

基本信息

药物类型

蛋白水解靶向嵌合体（PROTAC）

别名

3-((4-(1-((1-(6-(((S)-2,6-Dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide、NX 5948、NX-5948

+ [1]

靶点

BTK

作用方式

抑制剂

作用机制

BTK抑制剂(酪氨酸蛋白激酶BTK抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [6]

在研适应症

慢性淋巴细胞白血病弥漫性大B细胞淋巴瘤滤泡性淋巴瘤+ [13]

非在研适应症-

原研机构

Nurix Therapeutics, Inc.

在研机构

Nurix Therapeutics, Inc.

非在研机构-

权益机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评快速通道 (美国)、孤儿药 (美国)、孤儿药 (欧盟)、优先药物（PRIME） (欧盟)

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结构/序列

分子式C42H54N12O5

InChIKeyHPTPDBYCFHFWJG-CWTKIQHKSA-N

CAS号2649400-34-8

关联

项与 Bexobrutideg 相关的临床试验

NCT06717269

/ Recruiting临床1期

A Phase 1, Open-Label Study in Healthy Volunteers to Evaluate the Relative Bioavailability of NX-5948 Tablets Compared to Capsules, and the Effect of Food and an Acid-reducing Agent on the Pharmacokinetics of NX-5948

This is a 2-cohort, fixed-sequence, 3-period, relative bioavailability, food-effect, and drug-drug interaction study. It is an open-label study evaluating the relative bioavailability of NX-5948 tablets compared to capsules, and the effect of food and an acid-reducing agent on the pharmacokinetics (PK) of NX-5948.

开始日期2024-11-30

申办/合作机构

Nurix Therapeutics, Inc.

NCT06691828

/ Completed临床1期

A Phase 1, Open-Label, 2-Period, Fixed-Sequence Study to Assess the Absolute Bioavailability, Absorption, Metabolism, Excretion, and Mass Balance of [14C]-NX-5948 in Healthy Males

This is a Phase 1, 2-period, open-label, single-dose, fixed-sequence study to assess the absolute bioavailability, absorption, metabolism, excretion, and mass balance of [14C]-NX-5948. Period 1 will analyze PD (pharmacodynamics) and exploratory biomarkers. Period 2 will analyze total radioactivity and metabolite profiling.

开始日期2024-11-01

申办/合作机构

Nurix Therapeutics, Inc.

NCT06593457

/ Completed临床1期

A Phase 1, 2-Part, Placebo-Controlled, Double-Blinded Study to Assess the Effect of Food and Drug-Drug Interaction of Fluconazole on the Pharmacokinetics of NX-5948

This is a Phase 1, 2-part double-blinded (with respect to NX-5948/placebo), placebo-controlled study. Part 1 is a randomized, 3 period cross-over food-effect (FE) and drug-drug interaction (DDI) study. Part 2 is a single-period PK evaluation study.

开始日期2024-08-20

申办/合作机构

Nurix Therapeutics, Inc.

100 项与 Bexobrutideg 相关的临床结果

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100 项与 Bexobrutideg 相关的转化医学

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100 项与 Bexobrutideg 相关的专利（医药）

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项与 Bexobrutideg 相关的文献（医药）

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.

2025-05-01·AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS

Bruton Tyrosine Kinase Degraders

Review

作者: Sabakhtarishvili, Giorgi ; Tabbara, Imad A. ; Bajwa, Omer ; Alshebli, Mouza

Bruton tyrosine kinase (BTK) is a key enzyme involved in B-cell development and signaling, making it a crucial target in the treatment of B-cell malignancies, such as chronic lymphocytic leukemia and non-Hodgkin lymphoma. While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance—both intrinsic and acquired—poses a significant challenge, often associated with BTK mutations like C481S. To address this, novel BTK degraders have been developed, leveraging proteolysis-targeting chimeras to selectively degrade both wild-type and mutant BTK forms. This approach offers a promising strategy to overcome BTKi resistance.Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials. NRX-0492 demonstrated over 90% BTK degradation with sustained pharmacodynamic effects, whereas BGB-16673 achieved clinical responses in 67% of patients with relapsed/refractory B-cell malignancies. Similarly, NX-5948 and NX-2127 showed potent BTK degradation, with NX-2127, in addition, targeting immunomodulatory proteins, resulting in partial and stable responses in chronic lymphocytic leukemia and non-Hodgkin lymphoma patients. HZ-Q1060, a preclinical candidate, displayed rapid and sustained BTK degradation in vivo. Early-phase trials of ABBV-101 and AC676 are also showing promising results.These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

2025-03-01·BIOMEDICAL CHROMATOGRAPHY

A Validated Liquid Chromatography–Tandem Mass Spectrometry Assay for the Determination of NX‐5948 in Beagle Dog Plasma: Application to a Pharmacokinetic Study

Article

作者: Sun, Wenfei ; Wang, Fang ; Ma, Zheheng ; Chu, Furui

ABSTRACT:

Proteolysis targeting chimera (PROTAC) has been developed and currently enjoys widespread interest among the field of pharmaceutical manufacturing in recent decades. NX‐5948 is an orally active PROTAC Bruton tyrosine kinase degrader, which shows anti‐inflammatory and antitumor activities. In this study, a simple and fast bioanalytical method for the quantification of NX‐5948 in beagle dog plasma was developed using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). A full method validation was performed according to regulatory guidelines. For the quantification, [M + H]+ was formed using an electrospray ionization (ESI) source in the positive ion mode, and selective reaction monitoring (SRM) was employed using a triple quadrupole mass spectrometry. The monitored precursor‐to‐product transitions were m/z 807.5 > 790.5 for NX‐5948 and m/z 812.4 > 452.1 for internal standard. A linear response was obtained at the concentration range of 0.5–200 ng/mL, with correlation coefficient > 0.99. The interday accuracy ranged from −9.03% to 5.99% (RSD < 7.84%), and the intraday accuracy from −5.15% to 8.56% (RSD < 6.90%). NX‐5948 was demonstrated to be stable under the present storage conditions. After validation, the method was successfully applied for the quantification of NX‐5948 in beagle dog plasma after oral and intravenous administration of the NX‐5948.

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项与 Bexobrutideg 相关的新闻（医药）

2025-07-10

·GlobeNewswire-Health Care

European Medicines Agency Grants Bexobrutideg (NX-5948) Orphan Drug Designation for the Treatment of Lymphoplasmacytic Lymphoma, also Known as Waldenström Macroglobulinemia

July 07, 2025 -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, today announced that the European Medicines Agency (EMA) has granted Orphan Drug Designation (ODD) to bexobrutideg (NX-5948) for the treatment of lymphoplasmacytic lymphoma. Bexobrutideg is an orally bioavailable, brain penetrant degrader of Bruton’s tyrosine kinase (BTK) which is being evaluated in an ongoing Phase 1a/b clinical trial in adults with relapsed or refractory B-cell malignancies, including lymphoplasmacytic lymphoma, also known as Waldenström macroglobulinemia (WM). The EMA’s Orphan Drug Designation program grants orphan status to therapies intended for the treatment, diagnosis, or prevention of rare diseases that affect fewer than 5 in 10,000 people in the European Union. This designation provides several incentives to encourage the development of treatments for rare conditions, including 10 years of market exclusivity in the EU upon approval, access to protocol assistance, eligibility for centralized marketing authorization, and significant reductions in regulatory fees. “The EMA’s Orphan Drug Designation for bexobrutideg represents an important milestone in our regulatory strategy and underscores the significant unmet medical need for improved treatments for Waldenström macroglobulinemia,” said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. “Granting of the designation highlights bexobrutideg’s potential to provide patients with WM a promising new therapeutic option.” Waldenström macroglobulinemia is a rare type of blood cancer that affects B lymphocytes, a form of white blood cell. In this disease, B cells grow and survive abnormally, leading to their accumulation in the bone marrow, lymph nodes, and spleen. Early symptoms often include fatigue and weakness. It is characterized by the overproduction of IgM paraprotein—a blood protein that can cause the blood to thicken and lead to complications such as vision issues, heart problems, hemolytic anemia, and neurological symptoms. Bexobrutideg previously received the U.S. Food and Drug Administration’s Fast Track designation in December 2024 for the treatment of WM and Fast Track designation in January 2024 for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) after at least two lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 (BCL2) inhibitor. In November 2024, the EMA granted PRIME designation to bexobrutideg for the treatment of adult patients with relapsed or refractory CLL/SLL after treatment with at least a BTK inhibitor and a BCL2 inhibitor. Bexobrutideg is an investigational, orally bioavailable, brain penetrant, small molecule degrader of BTK currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Nurix previously has reported encouraging safety and efficacy data in patients with WM treated in the ongoing Phase 1a/b clinical trial of bexobrutideg, demonstrating early promise of clinical benefit with potential for durable outcomes. Nurix continues to enroll patients with WM in an ongoing Phase 1b expansion cohort and anticipates sharing additional clinical data in 2025. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022). Nurix is also developing bexobrutideg for the potential treatment of inflammatory diseases. Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, the next frontier in innovative drug design aimed at improving treatment options for patients with cancer and inflammatory diseases. Nurix’s wholly owned, clinical stage pipeline includes degraders of Bruton’s tyrosine kinase (BTK), a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B (CBL-B), an E3 ligase that regulates activation of multiple immune cell types including T cells and NK cells. Nurix also is advancing multiple potentially first-in-class or best-in-class degraders and degrader antibody conjugates (DACs) in its preclinical pipeline. Nurix’s partnered drug discovery pipeline consists of preclinical stage degraders of IRAK4 and STAT6, as well as multiple additional programs under collaboration agreements with Gilead Sciences, Inc., Sanofi S.A. and Pfizer Inc., within which Nurix retains certain options for co-development, co-commercialization and profit sharing in the United States for multiple drug candidates. Powered by a fully AI-integrated discovery engine capable of tackling any protein class, and coupled with unparalleled ligase expertise, Nurix’s dedicated team has built a formidable advantage in translating the science of targeted protein degradation into clinical advancements. Nurix aims to establish degrader-based treatments at the forefront of patient care, writing medicine’s next chapter with a new script to outmatch disease. Nurix is headquartered in San Francisco, California. The content above comes from the network. if any infringement, please contact us to modify.

快速通道孤儿药

2025-06-15

·药明康德

总缓解率达90%的抗癌组合疗法；有望加速肝脏再生的小分子疗法进入临床…… | 一周盘点

本期看点1. 强生（Johnson & Johnson）公司口服menin抑制剂bleximenib联用venetoclax和azacitidine（VEN+AZA）治疗新确诊但不适合强化化疗的急性髓系白血病（AML），在一项早期临床试验中的总缓解率（ORR）达90%，复合完全缓解（cCR）率达75%。2. 布鲁顿酪氨酸激酶（BTK）降解剂bexobrutideg单药治疗复发/难治性慢性淋巴细胞白血病（CLL）和华氏巨球蛋白血症（WM）患者的1a/1b期临床试验结果积极，在两类患者中的客观缓解率均超80%。3. 有望加速和增强肝脏再生过程的小分子疗法HRX-215进入临床试验阶段，其针对因结直肠癌肝转移而接受部分肝切除术的患者开展的1b期临床试验已完成首例患者给药。Bleximenib（JNJ-75276617）：公布1b期临床试验的新数据强生公司公布了其在研药物bleximenib的1b期临床试验的积极数据。Bleximenib是一种口服menin抑制剂，通过阻断menin与KMT2A融合蛋白之间的致癌相互作用，抑制携带KMT2A基因重排或NPM1基因突变的白血病细胞生长。该研究评估了bleximenib联用VEN+AZA在复发/难治性（R/R）AML和新确诊但不适合强化化疗的AML患者中的安全性和有效性。该研究共纳入125名患者，其中52例携带KMT2A重排，73例携带NPM1突变。在推荐的2期剂量（RP2D）下，R/R AML患者的ORR为82%，cCR率为59%。新确诊但不适合强化化疗的AML患者的ORR为90%，cCR率为75%。安全性方面，数据显示分化综合征的发生率低，且无QTc间期延长的心脏安全信号。Bexobrutideg（NX-5948）：公布1a/1b期临床试验的新数据Nurix Therapeutics公司公布了其布BTK降解剂bexobrutideg单药治疗复发/难治性CLL和WM患者的1a/1b期临床试验的新数据。Bexobrutideg是一种口服、可穿越血脑屏障的小分子BTK蛋白降解剂。截至2025年3月12日，中位随访时间为9.0个月，大多数患者仍在接受治疗。在疗效可评估的47名CLL患者中，客观缓解率为80.9%，首次缓解的中位时间为1.9个月。许多患者在更长的时间内经历了缓解加深，多次从病情稳定转变为部分缓解（PR），一名接受治疗两年多的患者经历了完全缓解。中位缓解持续时间尚未达到，有18名患者接受了一年多的治疗。在所有CLL患者群体中观察到缓解，无论既往治疗、基线突变或中枢神经系统（CNS）受累如何。在疗效可评估的19名WM患者中，客观缓解率为84.2%，包括2例非常好的部分缓解（VGPR）、11例PR和3例轻微缓解（MR）患者，3名患者获得疾病稳定（SD）。无论基线时MYD88突变和CXCR4突变的情况如何，患者均观察到缓解。此外，从4周的第一次评估开始就观察到关键疗效指标IgM水平的稳步下降，随后继续加深，3例患者的IgM水平降低超过90%。安全性方面，bexobrutideg耐受性良好，在较长的研究持续时间或更高的剂量下未观察到新的安全信号。Tuspetinib：公布1/2期联合治疗试验的新数据Aptose Biosciences公司公布了其针对新确诊的AML患者开展的1/2期TUSCANY试验的新数据。这些患者接受了不同剂量的tuspabetinib联用标准剂量的venetoclax和azacitidine（TUS+VEN+AZA三联疗法）。该三联疗法正在被开作发为一种安全且不依赖于特定突变的一线治疗方案，用于治疗那些无法接受诱导化疗的新确诊AML患者，这些患者具有多样的突变。此次公布的结果显示，携带不同突变（包括TP53突变/复杂核型、FLT3野生型）的AML患者安全地达到了CR和最小残留病（MRD）阴性。40毫克剂量组（n=4）中有3名患者达到CR且MRD状态为阴性。80毫克剂量组（n=3）中所有3名患者均达到了CR和伴有血液学不完全恢复的完全缓解（CRi）。120毫克剂量组（n=3）的患者仍在接受治疗。安全性方面，该三联疗法的安全性良好，无治疗相关死亡，迄今为止接受治疗的所有10名患者均存活。MP0533：公布1/2a期临床试验数据Molecular Partners公司公布了其四特异性T细胞接合器MP0533用于治疗R/R AML患者的1/2a期临床试验的最新积极数据。MP0533是一种新型多特异性蛋白分子，可同时靶向CD33、CD123、CD70和CD3四个靶点。截至2025年4月14日的数据，队列8中8名可评估的R/R AML患者中，有3人（超过30%）在第一个治疗周期后达到临床缓解，其中包括1例CR和2例伴有部分血液学恢复的完全缓解（CRh）。两名患者的缓解持续时间超过3个月，一名患者仍在接受治疗，缓解已维持超过6个月。安全性方面，MP0533在所有队列中均显示出可接受的安全性特征。SGR-1505：公布1期临床试验的初步数据Schrödinger公司宣布其候选药物SGR-1505在针对复发/难治性B细胞恶性肿瘤患者的1期临床试验中展现出积极的初步数据。SGR-1505是一种口服MALT1抑制剂，靶向NF-κB信号通路中的关键节点MALT1，旨在阻断癌细胞的存活与增殖。在临床前研究中，观察到SGR-1505具有高效性和选择性，并且在临床前模型中作为单一疗法以及与BTK抑制剂和BCL-2抑制剂联用均显示出抗肿瘤活性。截至2025年5月13日，49名患者进行了安全性评估，SGR-1505整体安全且耐受性良好，未出现剂量限制毒性或因治疗伴发不良事件（TEAE）导致的死亡，常见不良事件包括皮疹和疲劳。45名疗效可评估的患者中，ORR为22%，并在多个B细胞肿瘤类型中观察到缓解，包括CLL/小淋巴细胞白血病（SLL）、WM和边缘区淋巴瘤（MZL）。值得注意的是，一些曾接受过BTK和BCL-2抑制剂治疗失败的患者也出现了缓解。目前，该研究正扩展至侵袭性淋巴瘤患者，并观察到1名患者达到PR。HRX-215：1b期临床试验完成首例患者给药HepaRegeniX公司宣布其候选药物HRX-215的1b期临床试验已完成首例患者给药。该试验旨在评估HRX-215在因结直肠癌肝转移而接受部分肝切除术的患者中的安全性和有效性。HRX-215是一种口服的小分子抑制剂，靶向肝脏再生过程中的关键调节因子丝裂原活化蛋白激酶激酶4（MKK4）。通过选择性地抑制MKK4，HRX-215已在临床前模型中被证明可以稳定和保护肝细胞，并加速和增强肝脏再生过程，即使是在受损或患病的肝脏中也同样有效。参考资料（可上下滑动查看）[1] Metsera Announces Positive Phase 1 Data of First-in-Class Once-Monthly Amylin Candidate MET-233i. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/09/3095726/0/en/Metsera-Announces-Positive-Phase-1-Data-of-First-in-Class-Once-Monthly-Amylin-Candidate-MET-233i.html[2] Avidity Biosciences Announces Positive Topline Phase 1/2 FORTITUDE™ Data Demonstrating Consistent Improvement Across Multiple Functional Measures Compared to Placebo in Del-Brax Treated FSHD Participants. Retrieved June 13, 2025, from https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-topline-phase-12-fortitude-data-demonstrating-consistent-improvement-across-multiple-functional-measures-compared-to-placebo-in-del-brax-treated-fshd-participants-302476040.html[3] Eluminex Biosciences Announces Phase 1b Single Ascending Dose Study Results of a Novel Pentavalent Trispecific Fusion Antibody (EB-105) in Patients with Diabetic Macular Edema (DME). Retrieved June 13, 2025, from https://www.prnewswire.com/news-releases/eluminex-biosciences-announces-phase-1b-single-ascending-dose-study-results-of-a-novel-pentavalent-trispecific-fusion-antibody-eb-105-in-patients-with-diabetic-macular-edema-dme-302476053.html[4] 큐어버스, 자가면역 ‘S1P1 작용제’ 美 1상 “IND 승인”. Retrieved June 13, 2025, from https://www.biospectator.com/news/view/25347[5] Myosin Therapeutics Receives FDA Clearance to Initiate First-in-Human Trial of MT-125 in Glioblastoma. Retrieved June 13, 2025, from https://www.prnewswire.com/news-releases/myosin-therapeutics-receives-fda-clearance-to-initiate-first-in-human-trial-of-mt-125-in-glioblastoma-302475329.html[6] Nuevocor Announces FDA Clearance of IND for NVC-001 for LMNA-Related Dilated Cardiomyopathy. Retrieved June 13, 2025, from https://www.prnewswire.com/news-releases/nuevocor-announces-fda-clearance-of-ind-for-nvc-001-for-lmna-related-dilated-cardiomyopathy-302477505.html[7] Monte Rosa Therapeutics Announces FDA Clearance of IND Application for MRT-8102, a NEK7-Directed Molecular Glue Degrader for the Treatment of Multiple Inflammatory Diseases. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/10/3096463/0/en/Monte-Rosa-Therapeutics-Announces-FDA-Clearance-of-IND-Application-for-MRT-8102-a-NEK7-Directed-Molecular-Glue-Degrader-for-the-Treatment-of-Multiple-Inflammatory-Diseases.html[8] HepaRegeniX Doses First Patient in Phase Ib Trial with Small Molecule Inhibitor HRX-215 to Promote Liver Regeneration. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/10/3096394/0/en/HepaRegeniX-Doses-First-Patient-in-Phase-Ib-Trial-with-Small-Molecule-Inhibitor-HRX-215-to-Promote-Liver-Regeneration.html[9] BioInvent Announces Promising Phase 1 Data of BI-1206 in Combination with KEYTRUDA® (pembrolizumab) in Solid Tumors. Retrieved June 13, 2025, from https://www.bioinvent.com/en/press/bioinvent-announces-promising-phase-1-data-bi-1206-combination-keytrudar-pembrolizumab-solid[10] Capsida is initiating the Phase 1/2 study for CAP-003, with the first patient expected to be dosed in the third quarter of this year. Retrieved June 13, 2025, from https://capsida.com/capsida-receives-fda-ind-clearance-for-its-iv-administered-gene-therapy-for-parkinsons-disease-associated-with-gba-mutations/[11] Molecular Partners presents positive data from ongoing Phase 1/2a trial of MP0533 in AML at EHA 2025. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/11/3097923/0/en/Molecular-Partners-presents-positive-data-from-ongoing-Phase-1-2a-trial-of-MP0533-in-AML-at-EHA-2025.html[12] ImmuneWalk Therapeutics Announces Positive Topline Phase 1 SAD Data for Immunology and Inflammation Drug Candidate IW-601. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/11/3097503/0/en/ImmuneWalk-Therapeutics-Announces-Positive-Topline-Phase-1-SAD-Data-for-Immunology-and-Inflammation-Drug-Candidate-IW-601.html[13] Capstan Therapeutics Announces Initiation of Phase 1 Trial of Lead In Vivo CAR-T Therapy, CPTX2309, for Treating Autoimmune Disease. Retrieved June 13, 2025, from https://www.capstantx.com/press-releases/capstan-therapeutics-announces-initiation-of-phase-1-trial-of-lead-in-vivo-car-t-therapy-cptx2309-for-treating-autoimmune-disease/[14] Vanda Pharmaceuticals Announces First Patient Dosed in a Trial Evaluating VCA-894A in Charcot-Marie-Tooth disease Type 2S. Retrieved June 13, 2025, from https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-first-patient-dosed-in-a-trial-evaluating-vca-894a-in-charcot-marie-tooth-disease-type-2s-302477600.html[15] Silence Therapeutics Presents Additional Phase 1 Data Highlighting Promise of Divesiran as the Potential First-in-Class siRNA Treatment for Polycythemia Vera. Retrieved June 13, 2025, from https://silence-therapeutics.com/investors/press-releases/press-releases-details/2025/Silence-Therapeutics-Presents-Additional-Phase-1-Data-Highlighting-Promise-of-Divesiran-as-the-Potential-First-in-Class-siRNA-Treatment-for-Polycythemia-Vera/default.aspx[16] Schrödinger Reports Encouraging Initial Phase 1 Clinical Data for SGR-1505 at EHA Annual Congress. Retrieved June 13, 2025, from https://ir.schrodinger.com/press-releases/news-details/2025/Schrdinger-Reports-Encouraging-Initial-Phase-1-Clinical-Data-for-SGR-1505-at-EHA-Annual-Congress/default.aspx[17] New results for Johnson & Johnson's bleximenib demonstrate promising antileukemic activity in combination with venetoclax and azacitidine for acute myeloid leukemia. Retrieved June 13, 2025, from https://www.investor.jnj.com/news/news-details/2025/New-results-for-Johnson--Johnsons-bleximenib-demonstrate-promising-antileukemic-activity-in-combination-with-venetoclax-and-azacitidine-for-acute-myeloid-leukemia/default.aspx[18] Nurix Therapeutics Presents Updated Positive Data Demonstrating Durable, Deepening Responses in Ongoing Clinical Trial of Bexobrutideg (NX-5948) Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Waldenström Macroglobulinemia (WM). Retrieved June 13, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-presents-updated-positive-data-demonstrating[19] Angitia Biopharmaceuticals Announces Topline Results from First in Human Study of AGA2115, A Bispecific Antibody for the Treatment of Osteogenesis Imperfecta. Retrieved June 13, 2025, from https://www.globenewswire.com/news-release/2025/06/12/3098209/0/en/Angitia-Biopharmaceuticals-Announces-Topline-Results-from-First-in-Human-Study-of-AGA2115-A-Bispecific-Antibody-for-the-Treatment-of-Osteogenesis-Imperfecta.html[20] Fate Therapeutics Announces Updated Clinical Data for FT819 Off-the-shelf CAR T-cell Product Candidate Demonstrating Durability of Drug-free Remission for Severe Lupus Nephritis at EULAR 2025 Congress. Retrieved June 13, 2025, from https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-announces-updated-clinical-data-ft819-shelf#:~:text=All%20three%20patients%20treated%20with%20FT819%20following%20fludarabine-free,in%20drug-free%20Definition%20of%20Remission%20in%20SLE%20%28DORIS%29tients-with-squamous-non-small-cell-lung-cancer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：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2

临床2期临床1期临床结果

2025-06-09

·医药观澜

辉瑞联合开发，明星PROTAC新药申报上市！针对乳腺癌

编者按：今日，Arvinas和辉瑞（Pfizer）公司宣布已为其联合开发的明星PROTAC分子vepdegestrant向美国FDA提交新药申请（NDA），用于治疗既往接受过内分泌治疗的雌激素受体阳性（ER+）/人表皮生长因子受体2阴性（HER2-）、ESR1突变的晚期或转移性乳腺癌患者。根据新闻稿，若获批，vepdegestrant将成为首个获美国FDA批准的PROTAC雌激素受体降解剂。值得一提的是，近10年前，在此类技术刚刚起步之时，药明康德就开始布局相关的能力和技术，并积累了大量成功经验。随着近年来对PROTAC了解的逐步深入，公司针对这类创新分子已搭建了完善的一体化赋能平台，集发现、合成、分析纯化和测试等能力于一体，目前已成功支持超过100款PROTAC分子的开发，其中超过20个分子顺利推进至临床阶段。今天这篇文章里，药明康德内容团队将从vepdegestrant的最新监管进展出发，与读者分享PROTAC药物的研发历史与未来的潜在进展。上市申请的主要依据Vepdegestrant是一款潜在“first-in-class”的口服PROTAC降解剂，利用人体天然的蛋白质降解系统特异性地靶向并降解雌激素受体。它已经获得美国FDA授予的突破性疗法认定，用于治疗经治ER阳性、HER2阴性乳腺癌。这次vepdegestrant上市申请的递交，主要基于VERITAC-2临床3期试验的积极结果。试验分析显示，在携带ESR1突变的激素受体（HR）阳性、HER2阴性乳腺癌患者群体中，vepdegestrant与活性对照相比，为患者的无进展生存期（PFS）带来统计显著并具有临床意义的改善。这些患者在此前接受CDK4/6抑制剂和内分泌治疗后疾病出现进展。在携带ESR1突变的患者群体中，患者的疾病进展或死亡风险降低43%（HR=0.57；95% CI：0.42–0.77，P<0.001），vepdegestrant组患者的PFS达5.0个月，对照组患者则仅有2.1个月。在携带ESR1突变的所有患者亚群当中，vepdegestrant的获益情形一致。次要终点总生存期（OS）数据尚不成熟，仍需要研究继续评估。Arvinas董事长、首席执行官兼总裁John Houston博士表示：“我们期待新药申请的审评结果，也期待这个潜在首个获FDA批准的PROTAC ER降解剂有望为有需要的患者带来一种新治疗选择。”PROTAC演化史说到PROTAC分子的历史，还要追溯到Arvinas公司的联合创始人，耶鲁大学的Craig Crews教授与其合作伙伴，在2001年发表的一篇具有里程碑意义的论文。研究人员设计了一种人造双功能性分子，它的一端能够结合目标蛋白，另一端则是能结合E3连接酶的多肽。研究发现，这种分子能将目标蛋白拉到E3连接酶附近，让E3连接酶给目标蛋白打上泛素标签，标记它们送入细胞的蛋白酶体系统进行降解。 “未来，这一方法有望用于让蛋白出现有条件失活，以及降解导致疾病的蛋白。”该论文的摘要里写道。这一分子也被命名为蛋白靶向嵌合分子-1（protein-targeting chimeric molecule 1），缩写为Protac-1。在2008年，Crews教授团队的科学家更近一步，开发出一种双功能小分子药物。这款小分子的一端可选择性结合雄激素受体，另一端结合叫做MDM2的E3连接酶。这种能够靶向蛋白进行降解的双功能分子也被命名为PROTAC（PROteolysis TArgeting Chimera）。我们如今常用来指代靶向蛋白降解疗法的“PROTAC”正是由此而来。2013年，Crews教授联合创办了Arvinas公司，加速推进这一技术的科学转化。为了测试此类分子的成药可行性，该公司优先选择雄激素受体和雌激素受体这两个比较成熟的靶点。其中靶向雌激素受体的PROTAC分子，就是这次递交上市申请的vepdegestrant（曾名为ARV-471）。由于它在前期临床试验中表现出选择性降解野生型和突变型雌激素受体的出色能力，辉瑞公司在2021年与Arvinas达成超20亿美元的研发合作，共同打造这款PROTAC分子成为治疗ER阳性乳腺癌患者的支柱性内分泌疗法。除了vepdegestrant之外，Arvinas公司的其他PROTAC降解剂也取得了显著进展。去年，Arvinas与诺华（Novartis）就其针对雄激素受体的第二代PROTAC降解剂ARV-766达成了超过10亿美元的研发合作协议。此外，Arvinas针对LRRK2的蛋白降解剂ARV-102已进入1期临床试验，旨在治疗帕金森病。初步分析显示，单次口服剂量≥60 mg，或每日重复口服剂量≥20 mg时，患者脑脊液中LRRK2降解率超过50%，外周单核细胞中LRRK2降解率超过90%，表明ARV-102可实现中枢神经系统及外周LRRK2蛋白的显著降解。新靶点、新模式，靶向蛋白降解走向多元化Arvinas之外，还有多家公司正在开发与PROTAC分子具有类似作用机制的新药。例如，Kymera Therapeutics公司和赛诺菲（Sanofi）联合开发的IRAK4靶向蛋白降解剂KT-474（SAR444656）已处于2期临床开发阶段，用于治疗化脓性汗腺炎（HS）和特应性皮炎（AD）。该公司靶向STAT6的蛋白降解剂KT-621处于1期临床开发阶段，潜在治疗与2型炎症相关的多种免疫和炎症性疾病。日前公布的数据显示，KT-621在每日一次口服给药下，于所有高于1.5 mg剂量水平中实现了超过90%的平均血液STAT6降解；在所有≥50 mg的多剂量递增组中，更在血液与皮肤中均达成完全降解。Nurix Therapeutics公司可穿越血脑屏障的布鲁顿氏酪氨酸激酶（BTK）蛋白降解剂NX-5948目前处于1b/2期临床开发阶段，去年公布的早期临床试验数据显示，在治疗复发/难治性华氏巨球蛋白血症（WM）患者时，NX-5948达到77.8%的客观缓解率，其中两例患者已接受治疗超过1年。该公司的另一款蛋白降解剂NX-2127可同时降解BTK和IKZF蛋白，已进入治疗B细胞恶性肿瘤的首个人体临床试验。PROTAC分子之外，基于诱导接近（induced proximity）的创新蛋白降解模式也不断涌现。分子胶蛋白降解剂领域近两年来得到多家大型药企的关注。诺华（Novartis）、渤健（Biogen）、辉瑞、艾伯维（AbbVie）、武田（Takeda）、卫材（Eisai）与诺和诺德（Novo Nordisk）等公司纷纷达成分子胶相关的研发合作。专注于蛋白降解的新锐持续涌现，也进一步扩展了创新蛋白降解模式。例如，Pinetree Therapeutics开发多特异性靶向蛋白质降解剂，A轮融资1700万美元，且与阿斯利康（AstraZeneca）达成总额超5亿美元合作；Draupnir Bio和Booster Therapeutics基于溶酶体机制开发蛋白降解剂，种子轮融资逾千万美元；Firefly Bio由诺贝尔化学奖得主Carolyn Bertozzi教授联合创立，开发蛋白降解剂-抗体偶联药物（DAC）。Bertozzi教授联合创建的Lycia Therapeutics在去年也完成超1亿美元的C轮融资，推进其可降解细胞外和细胞膜蛋白的溶酶体靶向嵌合体（LYTAC）技术进入临床开发。此外，Automera公司则致力于开发自噬靶向嵌合小分子（AUTACs）。Expansion Therapeutics开发的核糖核酸酶靶向嵌合体（RIBOTAC）技术，可以实现对特定RNA的靶向降解。Vicinitas则是一家针对癌症与遗传疾病，以专有靶向蛋白稳定平台开发创新疗法的公司，其靶向去泛素化酶嵌合体（DUBTAC）平台生成的小分子可以促进蛋白质上的泛素链移除，进而避免蛋白质的降解。▲药明康德快速构建双功能性降解剂的平台能力作为业内靶向蛋白降解药物开发的重要赋能平台之一，药明康德早在此类药物的浪潮刚刚兴起之际，就快速搭建了综合性的赋能平台，能力涵盖PROTAC、分子胶、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS、以及DAC等主要分子类型。根据去年投资者开放日公布的信息，自2021年起，该平台已为靶向蛋白降解领域中66%的活跃公司提供了赋能合作。展望未来，靶向蛋白降解剂有着更为深远的意义。正如这一领域的权威，丹娜-法伯癌症研究所（Dana–Farber Cancer Institute）的Eric Fischer教授指出的那样，利用口服小分子去降解蛋白质，可以让科学家摆脱“可成药性”的束缚，真正思考哪些靶点能够最大程度地改变疾病进程。我们也期待看到更多蛋白降解药物能在临床上获得积极进展，造福广大患者。参考资料：[1] Arvinas Announces Submission of New Drug Application to U.S. FDA for Vepdegestrant for Patients with ESR1-Mutated ER+/HER2- Advanced or Metastatic Breast Cancer. Retrieved June 6, 2025 from https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-submission-new-drug-application-us-fda[2] Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Retrieved March 11, 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[3] 2024 WuXi AppTec Investor Day. Research Enabling Platforms Enhance CRDMO Model. Retrieved March 11, 2025, from https://static.wuxiapptec.com/6f/20240926/2024%20WuXi%20AppTec%20Investor%20Day%20-%20Research%20Enabling%20Platforms.pdf[4] PROTAC protein degraders to drug the undruggable enter phase 3 trials. Retrieved March 11, 2025, from https://www-nature-com.libproxy1.nus.edu.sg/articles/d41591-024-00072-8[5] Nurix Corporate Presentation. Retrieved March 11, 2025, from https://ir.nurixtx.com/static-files/ee8cb2f8-e482-486e-a861-ececbd15f703[6] Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer. Retrieved June 6, 2025 from https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-significantly-improves版权说明：本文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。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

蛋白降解靶向嵌合体临床结果临床3期突破性疗法

100 项与 Bexobrutideg 相关的药物交易

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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
慢性淋巴细胞白血病	临床1期	美国	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	法国	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	意大利	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	荷兰	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	波兰	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	西班牙	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	瑞士	Nurix Therapeutics, Inc.	2022-04-13
慢性淋巴细胞白血病	临床1期	英国	Nurix Therapeutics, Inc.	2022-04-13
弥漫性大B细胞淋巴瘤	临床1期	美国	Nurix Therapeutics, Inc.	2022-04-13
弥漫性大B细胞淋巴瘤	临床1期	法国	Nurix Therapeutics, Inc.	2022-04-13

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临床结果

适应症

分期

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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


NX-5948 (EHA2025)	临床1期	复发性慢性淋巴细胞白血病 TP53 \| BTK \| PLCG2 ... 更多	48	Bexobrutideg 50 mg	餘淵壓窪襯壓餘襯鏇選(製獵獵觸蓋範觸積築齋) = 29.2% 鑰鬱齋獵鑰築鹽鬱繭簾 (範鑰鹽淵齋觸鏇憲鑰壓 ) 更多	-	2025-05-14
NX-5948 (EHA2025)	临床1期	复发性慢性淋巴细胞白血病 TP53 \| BTK \| PLCG2 ... 更多	48	Bexobrutideg 100 mg	餘淵壓窪襯壓餘襯鏇選(製獵獵觸蓋範觸積築齋) = 29.2% 鑰鬱齋獵鑰築鹽鬱繭簾 (範鑰鹽淵齋觸鏇憲鑰壓 ) 更多	-	2025-05-14
PS1883 (EHA2025)	临床1期	巨球蛋白血症 MYD88 \| CXCR4	18	Bexobrutideg 600 mg	餘獵簾顧築築衊衊範窪(膚壓蓋襯齋艱獵鹽窪範) = 27.8% 觸顧鬱構餘憲鏇積壓遞 (鬱壓繭鏇繭繭網繭簾艱 ) 更多	积极	2025-05-14
NCT05131022 (NX-5948-301, ASH2024) 人工标引	临床1期	慢性淋巴细胞白血病末线 \| 三线	34	NX-5948	選顧構窪鏇糧鹹顧衊獵(淵獵壓鏇選鏇糧觸齋醖) = Most common TEAEs were: purpura/contusion (44.1%, no Gr≥3); thrombocytopenia (23.5%, 2.9% Gr≥3); petechiae (29.4%, no Gr≥3); fatigue (20.6%, no Gr≥3); neutropenia (17.6%, 14.7% Gr≥3; pts with up to Gr 4 cytopenias were eligible for study participation); rash (23.5%, no Gr≥3, 2.9% SAE); headache (23.5%, no Gr≥3).There was no new onset atrial fibrillation/flutter or hypertension. 鏇遞糧餘顧蓋範顧廠憲 (鹹廠齋艱蓋齋積構襯鹹 ) 更多	积极	2024-12-09
NCT05131022 (GlobeNewswire) 人工标引	临床1期	巨球蛋白血症	79	NX-5948	衊糧醖繭製鹽憲鹽鹹選(衊鑰顧衊網廠蓋膚構築) = 鹹觸範廠廠鑰築醖鹹壓鑰窪憲廠願築願繭餘鬱 (構範蓋膚遞積鏇鹽築齋 ) 更多	积极	2024-10-19
NCT05131022 (EHA 12024 \| EHA 22024) 人工标引	临床1期	慢性淋巴细胞白血病 \| B细胞恶性肿瘤	46	NX-5948	網窪齋願鏇襯蓋積齋鬱(範製鏇廠襯糧憲觸選製) = none 簾鏇鹽簾憲遞窪夢餘遞 (觸顧構餘製簾襯壓鑰夢 ) 更多	积极	2024-05-14
NCT05131022 (Biospace) 人工标引	临床1期	慢性淋巴细胞白血病	7	NX-5948	鬱鑰顧鹽鬱顧選網範鹹(夢醖觸築憲遞積築淵膚) = 窪廠蓋鹹衊夢膚糧築積窪網壓遞窪鬱願夢膚壓 (齋蓋構壓願鏇選鑰膚夢 ) 更多	积极	2024-01-16
NCT05131022 (NX-5948-301, ASH2023) 人工标引	临床1期	B细胞淋巴瘤三线	14	NX-5948	襯餘憲選廠築繭淵鏇製(鑰糧廠構憲窪鑰襯糧繭) = 廠糧觸鏇願窪觸觸膚觸構膚艱廠衊築憲糧鏇遞 (積廠範夢齋網膚範窪襯 ) 更多	积极	2023-12-11