A Randomized Phase 1/2 Trial Evaluating the Addition of Tolinapant to Weekly Paclitaxel With or Without Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer

This phase I/II trial tests the safety, best dose and effectiveness of adding tolinapant (ASTX660) to paclitaxel with or without bevacizumab in treating patients with ovarian cancer that has come back after a period of improvement (recurrent). Tolinapant may stop the growth of tumor cells by blocking proteins, such as XIAP and cIAP1, that promote the growth of tumor cells and increase resistance to chemotherapy. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to the tumor. This may slow the growth and spread of tumor cells. Adding ASTX660 to paclitaxel with or without bevacizumab may be safe, tolerable and/or effective in treating patients with recurrent ovarian cancer.

开始日期2025-05-02

申办/合作机构

National Cancer Institute

NCT06607458 / Not yet recruiting临床2期

An Open-label, Randomized, Multi-Center Study to Evaluate the Efficacy and Safety of Induction Treatment with Melphalan/HDS Followed by Consolidation Treatment with Trifluridine-Tipiracil Plus Bevacizumab Versus Trifluridine-Tipiracil Plus Bevacizumab Alone in Patients with Refractory Metastatic Colorectal Cancer with Liver Dominant Disease

The goal of this clinical trial is to learn if using a liver-directed therapy with high dose chemotherapy followed by approved cancer treatment to treat patients with colorectal cancer that has spread to the liver is safe and tolerable. The clinical trial will also learn if the liver-directed therapy with high dose chemotherapy works on the disease in the liver. Investigators will compare the use of the liver-directed therapy with high dose chemotherapy followed by approved cancer treatment or approved cancer treatment alone.
Participants will:
* Undergo up to two liver-directed therapy with high dose chemotherapy procedures followed by approved cancer treatment or take approved cancer treatment alone
* Visit clinic at least every two weeks for checkups and tests
* Complete scans approximately every two months

开始日期2025-05-01

申办/合作机构

Delcath Systems, Inc.

NCT06311851 / Not yet recruiting临床1/2期IIT

An Open-Label Pilot Study to Evaluate Efficacy and Safety of Bevacizumab Via Transarterial Chemoembolization (TACE) in Patients With Liver Metastases

Trans arterial chemoembolization (TACE) has emerged as a treatment option for chemotherapy-refractory diseases in Liver metastases. By delivering chemotherapy agents directly to the tumor site, TACE can maximize local drug concentrations and reduce systemic adverse reactions. Bevacizumab is a monoclonal antibody that functions as an angiogenesis inhibitor. It works by slowing the growth of new blood vessels by inhibiting vascular endothelial growth factor A (VEGF-A). The application of Bevacizumab during TACE has not been reported. In this study, we will evaluate the the overall survival (OS)、efficacy, and safety of the application of Bevacizumab during TACE in patients with Liver Metastases by designing an open, single-arm phase II clinical study.

开始日期2025-04-01

申办/合作机构-

100 项与贝伐珠单抗相关的临床结果

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100 项与贝伐珠单抗相关的转化医学

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100 项与贝伐珠单抗相关的专利（医药）

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21,100

项与贝伐珠单抗相关的文献（医药）

2025-01-01·Journal of Pharmaceutical and Biomedical Analysis

GC-MS and multivariate analysis reveal partial serum metabolome restoration by bevacizumab in a colon cancer rat model: An untargeted metabolomics investigation

Article

作者: Abduljabbar, Maram H. ; Althobaiti, Yusuf S ; Serag, Ahmed ; Althobaiti, Yusuf S. ; Almutairi, Farooq M ; Almalki, Atiah H ; Alnemari, Reem M ; Aldhafeeri, Muneef M ; Almalki, Atiah H. ; Abduljabbar, Maram H ; Aldhafeeri, Muneef M. ; Alnemari, Reem M. ; Almutairi, Farooq M.

Bevacizumab is an anti-angiogenic therapeutic agent that targets vascular endothelial growth factor (VEGF) and has been approved for the treatment of several types of cancer, including colon cancer. Herein, a GC-MS based metabolomics approach was employed to investigate the impact of bevacizumab on the serum metabolome of colon cancer rats. Multivariate chemometric analysis models such as PCA and PLS-DA showed a clear separation between the control, cancer and bevacizumab-treated groups, suggesting that bevacizumab administration induced significant metabolic alterations. Furthermore, pairwise comparisons between the studied groups using the OPLS-DA model in addition to univariate analysis identified several discriminatory metabolites belonged to various chemical classes including amino acids, organic acids and fatty acids that were perturbed between the studied groups. Interestingly, bevacizumab treatment was able to partially restore some of the cancer-induced metabolic disturbances, indicating its potential therapeutic efficacy via improving the tumor vasculature and nutrient delivery. Besides, pathway analysis of the differential metabolites identified key metabolic pathways affected by bevacizumab, which included valine, leucine and isoleucine metabolism, pyruvate metabolism and butanoate metabolism. However, little effects were observed on lipid metabolites such as palmitic acid and stearic acid and consequently their related metabolic pathways such as fatty acid biosynthesis metabolism suggesting that bevacizumab has more prominent effect on energy and amino acid metabolisms as compared to fatty acid metabolism in colon cancer rats. Overall, our study provided novel insights into the metabolic mechanisms underlying the therapeutic effects of bevacizumab in colon cancer rats via the use of a comprehensive GC-MS metabolomics approach.

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Bulk integrated single-cell-spatial transcriptomics reveals the impact of preoperative chemotherapy on cancer-associated fibroblasts and tumor cells in colorectal cancer, and construction of related predictive models using machine learning

Article

作者: Pan, Yuqin ; Qin, Jian ; Lou, Jinwei ; Ding, Muzi ; Gao, Rui ; Xiao, QianNi ; Wang, Shukui ; Chen, Yuhan ; Hu, Shangshang

BACKGROUNDPreoperative chemotherapy (PC) is an important component of Colorectal cancer (CRC) treatment, but its effects on the biological functions of fibroblasts and epithelial cells in CRC are unclear.METHODSThis study utilized bulk, single-cell, and spatial transcriptomic sequencing data from 22 independent cohorts of CRC. Through bioinformatics analysis and in vitro experiments, the research investigated the impact of PC on fibroblast and epithelial cells in CRC. Subpopulations associated with PC and CRC prognosis were identified, and a predictive model was constructed using machine learning.RESULTSPC significantly attenuated the pathways related to tumor progression in fibroblasts and epithelial cells. NOTCH3 + Fibroblast (NOTCH3 + Fib), TNNT1 + Epithelial (TNNT1 + Epi), and HSPA1A + Epithelial (HSPA1A + Epi) subpopulations were identified in the adjacent spatial region and were associated with poor prognosis in CRC. PC effectively diminished the presence of these subpopulations, concurrently inhibiting pathway activity and intercellular crosstalk. A risk signature model, named the Preoperative Chemotherapy Risk Signature Model (PCRSM), was constructed using machine learning. PCRSM emerged as an independent prognostic indicator for CRC, impacting both overall survival (OS) and recurrence-free survival (RFS), surpassing the performance of 89 previously published CRC risk signatures. Additionally, patients with a high PCRSM risk score showed sensitivity to fluorouracil-based adjuvant chemotherapy (FOLFOX) but resistance to single chemotherapy drugs (such as Bevacizumab and Oxaliplatin). Furthermore, this study predicted that patients with high PCRSM were resistant to anti-PD1therapy.CONCLUSIONIn conclusion, this study identified three cell subpopulations (NOTCH3 + Fib, TNNT1 + Epi, and HSPA1A + Epi) associated with PC, which can be targeted to improve the prognosis of CRC patients. The PCRSM model shows promise in enhancing the survival and treatment of CRC patients.

2024-12-31·Journal of Medical Economics

Budget impact of dostarlimab plus carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer from a third-party US payer perspective

Article

作者: Walder, Lydia ; Burton, Mark ; Lubinga, Solomon J. ; Shen, Qin

AIMDostarlimab plus carboplatin-paclitaxel (CP) significantly increased progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC) vs CP alone in the RUBY trial (NCT03981796). This analysis estimated the per-member-per-month (PMPM) costs of introducing dostarlimab + CP as a treatment alternative from a third-party US payer perspective.MATERIALS AND METHODSA budget impact model was developed to estimate the costs of introducing dostarlimab + CP into commercial and Medicare health plans over a 3-year time horizon (2023-2025). Costs were sourced from relevant literature and US-specific databases and were calculated using epidemiology data, clinical inputs, treatment costs, and market share estimates. Clinical inputs were sourced from primary clinical trials for each respective treatment (i.e. dostarlimab + CP, CP, pembrolizumab, pembrolizumab plus lenvatinib, bevacizumab + CP, and pembrolizumab + CP). Current and future market shares assumed dostarlimab + CP reduced the market share of CP only. Analyses were performed in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations using a US 2023 cost year.RESULTSFor a commercial plan, the model estimated (dMMR/MSI-H and overall populations) that 7 and 26 patients would be treated with dostarlimab + CP, respectively; average annual budget impacts per patient treated were $118,257 and $116,094; average budget impacts per patient treated per month (PPPM) were $9,855 and $9,675; average budget impacts PMPM were $0.02 and $0.06. For a Medicare plan, the model estimated that 28 and 93 patients, respectively, would be treated with dostarlimab + CP. Average annual budget impacts per patient treated and PPPM were the same as those for the commercial plan in both populations; average budget impacts PMPM were $0.07 and $0.22, respectively.CONCLUSIONSIntroducing dostarlimab + CP as a first-line treatment for patients with pA/rEC results in minimal budget impact PMPM from a US third-party payer's perspective. Together with the efficacy and safety results from RUBY, these results support the use of dostarlimab + CP as a treatment option.

3,010

项与贝伐珠单抗相关的新闻（医药）

2024-11-19

·复宏汉霖

ESMO Asia 2024 | 复宏汉霖将携5项研究成果精彩亮相

2024年12月6日至8日，欧洲肿瘤学会亚洲分会（ESMO Asia）年会将于新加坡召开。复宏汉霖将在本次大会上分享抗PD-1单抗H药汉斯状®、抗EGFR单抗HLX07、达雷妥尤单抗生物类似药HLX15等3款产品的最新临床研究数据。 H药为复宏汉霖自主研发的重组人源化抗PD-1单抗注射液，目前已在中国和多个东南亚国家获批上市，也是全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。以临床需求为导向，公司围绕H药进行了差异化、多维度的适应症布局，覆盖肺癌、消化道肿瘤等高发大癌种。目前，H药已在中国获批4项适应症，惠及患者超过8.5万人。此外，探索H药在多项差异化适应症中疗效的创新联合疗法正在进行中，如H药联合贝伐珠单抗及化疗一线治疗转移性结直肠癌（mCRC），联合化疗用于胃癌的新辅助/辅助治疗，联合化疗同步放疗治疗局限期小细胞肺癌等。 HLX07是复宏汉霖自主研发的针对EGFR靶点的创新型生物药。基于公司成熟的抗体工程改造平台，复宏汉霖在西妥昔单抗的基础上，将HLX07的Fab区人源化，同时使该产品聚糖含量降至最低，以具备更低的免疫原性和良好的靶点亲和力。目前，公司围绕食管鳞癌、皮肤鳞癌、鼻咽癌等多个实体瘤适应症，正在积极开展HLX07单药或联合H药的II期临床探索。 HLX15是复宏汉霖自主开发的一款全人源抗CD38 IgG1κ单克隆抗体，有望用于治疗多发性骨髓瘤（Multiple myeloma，MM）。参照中国、欧盟和美国的生物类似药技术指导原则的要求，复宏汉霖采用逐步递进、比对及相似性评价原则，对HLX15与原研达雷妥尤单抗进行了头对头的药学分析和体内外药理学比对研究。2024年6月，HLX15的I期临床研究已成功完成，达到了所有预设的研究终点。以下为此次入选ESMO Asia的详细信息： ASTRUM-004R研究：斯鲁利单抗一线治疗局部晚期或转移性鳞状非小细胞肺癌的多中心、单臂、真实世界研究论文题目：First-Line Serplulimab for Advanced Squamous Non-Small Cell Lung Cancer: A Multicenter, Single-Arm, Real-World ASTRUM-004R Study 摘要编号：682P 主要研究者：沈波，江苏省肿瘤医院、江苏省肿瘤研究所、南京医科大学附属肿瘤医院展示时间：2024年12月7日下午17:50-18:45（新加坡时间）晚期非透明细胞肾细胞癌（nccRCC）一线治疗中，呋喹替尼联合斯鲁利单抗的疗效和安全性：单臂、多中心临床试验场次：Mini Oral session: Genitourinary tumours 论文题目：Efficacy and safety of fruquintinib combined with serplulimab as 1st line treatment in advanced non-clear cell renal cell carcinoma (nccRCC): A single-arm, multicentre clinical trial 摘要编号：274MO 报告人：黄吉玮，上海交通大学医学院附属仁济医院演讲时间：2024年12月8日上午9:42 – 9:47（新加坡时间） HLX07-NPC：HLX07联合斯鲁利单抗和化疗对比安慰剂联合斯鲁利单抗和化疗作为鼻咽癌一线治疗：一项随机、双盲、多中心II期研究场次：Mini Oral session: Head and neck cancers 论文题目：First-line HLX07 vs. Placebo Combined with Serplulimab and Chemotherapy for Nasopharyngeal Cancer: a Randomised, Double-blind, Multicentre Phase 2 study 摘要编号：LBA3 牵头主要研究者：张力，中山大学肿瘤防治中心演讲时间：2024年12月7日下午14:40-14:45（新加坡时间） HLX07-CSCC：HLX07单药治疗晚期皮肤鳞状细胞癌的有效性和安全性：一项开放标签、多中心II期研究论文题目：Efficacy and Safety of HLX07 Monotherapy in Advanced Cutaneous Squamous Cell Carcinoma: an Open-label, Multicentre Phase 2 Study 摘要编号：759P 牵头主要研究者：李常兴，南方医科大学南方医院展示时间：2024年12月7日下午17:50-18:45（新加坡时间） HLX15-001：一项在男性健康受试者中比较HLX15和达雷妥尤单抗注射液的药代动力学特征、安全性、耐受性和免疫原性的I期临床研究论文题目：A Randomised, Double-blind, Phase I Study to Compare the Pharmacokinetics, Safety, Tolerability, and Immunogenicity of HLX15 and Daratumumab in Healthy Male Participants 摘要编号：63P 牵头主要研究者：苏钰文，南京医科大学附属逸夫医院展示时间：2024年12月7日下午17:50-18:45（新加坡时间）关于复宏汉霖复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已有6款产品在中国获批上市，3款产品在国际获批上市，24项适应症获批，4个上市申请分别获中国药监局、美国FDA和欧盟EMA受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，公司商业化生产基地已相继获得中国、欧盟和美国GMP认证。复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖50多个分子，并全面推进基于自有抗PD-1单抗H药汉斯状®的肿瘤免疫联合疗法。截至目前，公司已获批上市产品包括国内首个生物类似药汉利康®（利妥昔单抗）、自主研发的中美欧三地获批单抗生物类似药汉曲优®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac®）、汉达远®（阿达木单抗）、汉贝泰®（贝伐珠单抗）以及汉奈佳®（奈拉替尼），此外，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴市场。 Henlius to Showcase Latest Results of 5 Clinical Trails at ESMO Asia 2024 From 6 to 8 December 2024, the European Society for Medical Oncology Asia (ESMO Asia) Congress will be held in Singapore. At this congress, Henlius will share the latest results of clinical trials of several products, including HANSIZHUANG (serplulimab), HLX07 (anti-EGFR mAb), and daratumumab biosimilar HLX15. HANSIZHUANG (serplulimab) is a recombinant humanised anti-PD-1 monoclonal antibody（mAb）injection independently developed by Henlius, and the world's first anti-PD-1 mAb approved for the first-line treatment of SCLC. It has been approved in China and multiple countries in Southeastern Asia. Underpinned by the patient-centric strategy, Henlius has carried out a differentiated and multi-dimensional layout in the field of gastrointestinal cancer and lung cancer, covering a wide variety of indications. Up to date, HANSIZHUANG has been approved by the National Medical Products Administration (NMPA) for the treatment of 4 indications, benefiting more than 85,000 patients. Moreover, a wide variety of clinical trials on immuno-oncology combination therapies in differentiated indications has been initiated by the company to further explore the efficacy of the product, such as HANSIZHUANG plus bevacizumab and chemotherapy as first-line treatment for patients with metastatic colorectal cancer (mCRC), HANSIZHUANG plus chemotherapy as neoadjuvant/adjuvant therapy for gastric cancer (GC), and HANSIZHUANG plus chemotherapy and concurrent radiotherapy in patients with limited-stage small cell lung cancer (LS-SCLC), etc. HLX07 is an innovative drug targeting EGFR independently developed by Henlius. Adopting the self-developed advanced antibody engineering platform, Henlius re-engineered cetuximab by humanising its Fab regions and minimizing its glycan contents to generate HLX07 to reduce immunogenicity and maintain a high binding affinity of the product. Currently, Henlius is conducting phase 2 clinical trials to explore HLX07 as monotherapy or in combination with HANSIZHUANG (serplulimab) for the treatment of solid tumours including esophageal squamous cell carcinoma (ESCC), cutaneous squamous cell carcinoma (CSCC), and nasopharyngeal carcinoma (NPC). HLX15 is a fully human anti-CD38 IgG1κ monoclonal antibody independently developed by Henlius. The indication to be developed for HLX15 is multiple myeloma (MM). In accordance with the biosimilar guidelines of NMPA, EMA, and FDA, HLX15 has been developed strictly following the principles of stepwise development, comparability and similarity assessment and has been compared head-to-head with reference daratumumab via analytical studies and preclinical studies. In June 2024, the phase 1 clinical trial of HLX15 met its primary endpoint. Results to be presented at the ESMO Asia 2024 are as follows: ASTRUM-004R Study Title: First-Line Serplulimab for Advanced Squamous Non-Small Cell Lung Cancer: A Multicenter, Single-Arm, Real-World ASTRUM-004R Study Presentation Number: 682P Speaker: Bo Shen, Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital, Nanjing Medical University Time: December 7, 2024, 17:50-18:45 PM SGT Session: Mini Oral session: Genitourinary tumours Title: Efficacy and safety of fruquintinib combined with serplulimab as 1st line treatment in advanced non-clear cell renal cell carcinoma (nccRCC): A single-arm, multicentre clinical trial Presentation Number: 274MO Speaker: Jiwei Huang, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Time: December 8, 2024, 9:42 – 9:47 AM SGT HLX07-NPC Session: Mini Oral session: Head and neck cancers Title: First-line HLX07 vs. Placebo Combined with Serplulimab and Chemotherapy for Nasopharyngeal Cancer: a Randomised, Double-blind, Multicentre Phase 2 study Presentation Number: LBA3 Leading PI: Li Zhang, Sun Yat-sen University Cancer Center Time: December 7, 2024, 14:40-14:45 PM SGT HLX07-CSCC Title: Efficacy and Safety of HLX07 Monotherapy in Advanced Cutaneous Squamous Cell Carcinoma: an Open-label, Multicentre Phase 2 Study Presentation Number: 759P Leading PI: Changxin Li, Southern Medical University Nanfang Hospital Time: December 7, 2024, 17:50-18:45 PM SGT HLX15-001 Title: A Randomised, Double-blind, Phase I Study to Compare the Pharmacokinetics, Safety, Tolerability, and Immunogenicity of HLX15 and Daratumumab in Healthy Male Participants Presentation Number: 63P Leading PI: Yu-wen Su, Sir Run Run Hospital, Nanjing Medical University Time: December 7, 2024, 17:50-18:45 PM SGT About Henlius Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable, and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases, and ophthalmic diseases. Up to date, 6 products have been launched in China, 3 have been approved for marketing in overseas markets, 24 indications are approved worldwide, and 4 marketing applications have been accepted for review in China, the U.S. and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP. Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI™ in the U.S., Zercepac® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab), HANBEITAI (bevacizumab) and HANNAIJIA (neratinib), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets. 联系方式媒体：PR@Henlius.com 投资者：IR@Henlius.com 喜欢本文内容点击下方按钮·分享 ·收藏 ·点赞 ·在看

生物类似药上市批准临床1期

2024-11-19

·PRNewswire

RiDYMO® Platform Drives New Breakthroughs in highly potent PLK1 Inhibitors Development

BEIJING, Nov. 19, 2024 /PRNewswire/ -- With the support of the RiDYMO® platform, we are able to comprehensively explore various potential targets in drug development, including protein-protein interactions, kinases, GPCRs, ion channels, and transcription factors. Continue Reading Figure: Screening process for novel scaffold lead compound Figure A: Optimization and FEP prediction for R1, R2, and R3, with dark gray areas indicating a 1 kcal error range and light gray areas representing a 2 kcal error range; B: Overall molecular optimization process based on the DP101 scaffold Figure: Antitumor effects of DP226 on HCT116 xenograft model Polo-like kinase 1 (PLK1) is a highly conserved serine/threonine protein kinase that plays a crucial role during cellular mitosis[1]. It is overexpressed in various malignancies, including colorectal cancer[2], pancreatic cancer[3], and breast cancer, and its high expression is associated with poor prognosis. Consequently, PLK1 has emerged as a promising target in cancer drug development, with numerous candidates currently in the pipeline worldwide. Among these, Cardiff Oncology's onvansertib (PCM-075) has shown the most significant progress, displaying encouraging efficacy results in clinical treatment for patients with metastatic colorectal cancer (mCRC). The RiDYMO® platform, a next-generation computational drug design platform developed by DP Technology, based on AI for Science, provides robust end-to-end support for hit discovery and optimization by integrating multiple artificial intelligence techniques, physical algorithms, and experimental validation. In this study, we referred to the co-crystal complex of PLK1 and PCM075 (2YAC) and utilized the RiDYMO platform's comprehensive capabilities to synthesize and test under 100 compounds, leading to the identification of preclinical candidate compounds with potential clinical value and significantly accelerating the drug development process. We first conducted an in-depth analysis of the interactions between PCM-075 and the PLK1 protein. Preserving key interactions, we applied molecular generation, evaluation, and screening techniques to obtain a novel scaffold, the lead compound DP101, which exhibited an activity of 56 nM. Next, during the optimization process based on the structure of DP101, we modified several sites on the scaffold, including hydrogen bonding networks (R3) and hydrophobic group encapsulation zones (R1 & R2). Experimental data showed a high consistency between computational predictions and experimental results, demonstrating the platform's practicality in optimizing kinase inhibitors. Leveraging the RiDYMO® platform's activity prediction ranking and physicochemical property forecasting, we underwent multiple rounds of testing and optimization, ultimately obtaining several compounds with enhanced in vitro activity and pharmacokinetic properties. Notably, the activity of DP226 (0.19 nM) improved nearly 300-fold compared to DP101, surpassing PCM075, with an oral bioavailability (F = 76.8%) significantly higher than that of PCM075 (F = 24%). At low doses, DP226 exhibited superior anti-tumor effects compared to PCM075, and in combination with bevacizumab, it led to tumor regression, positioning it as a potential PCC molecule for further studies. Dr. Dongdong Li, Director of Medicinal Chemistry at DP Technology and Project Leader, stated, "With the support of the RiDYMO® platform, we are able to comprehensively explore various potential targets in drug development, including protein-protein interactions, kinases, GPCRs, ion channels, and transcription factors. The use of the RiDYMO® platform for activity predictions, rankings, and experimental validations significantly enhances the efficiency of activity optimization, effectively shortening optimization cycles and accelerating the overall project development timeline. The integrated capabilities of the RiDYMO® platform hold promise for providing high-efficiency support in early-stage drug discovery. As a potential PCC molecule, we look forward to collaborating with experienced pharmaceutical companies in this field to advance this project to the next milestone." About the RiDYMO® Hit Discovery and Optimization Platform RiDYMO® is a state-of-the-art hit discovery and optimization platform developed by DP Technology, leveraging the principles of AI for Science. It employs the proprietary Hermite® computational drug design software to elucidate the dynamics of "undruggable" targets and explores a broader chemical space encompassing small molecules, macrocycles, and cyclic peptides. By integrating advanced artificial intelligence, physical algorithms, and high-throughput experimentation, the platform excels in designing oral macrocyclic compounds and rapidly delivers innovative drug candidates. As one of its core algorithms, Reinforced Dynamics (RiD)[4] has a significant advantage in the sampling efficiency of molecular dynamics simulation. By fully leveraging the high-dimensional representation capabilities of neural networks, RiD can efficiently capture dynamic conformational changes in complicated biomolecular systems. Previously, the core RiD algorithm of the platform was published in Nature Computational Science. The study demonstrated that RiD could achieve a more comprehensive free energy surface within 1.86 μs, compared to 100 μs required by traditional MD methods, representing nearly a hundredfold increase in efficiency. RiDYMO® has been successfully employed in various projects, including the development of c-Myc small molecules, GPX4 small molecules, and β-catenin cyclic peptides, demonstrating its strong potential in innovative drug discovery. For more information, please visit our website. (). About Hermite Hermite® is a next-generation computational drug design platform developed by DP Technology, powered by AI for Science, to provide a comprehensive solution for drug design. Hermite® integrates industry-leading tools such as the Free Energy Perturbation module, Uni-FEP, and the ultra-high-throughput virtual screening tool, Uni-VSW, supporting key stages of drug discovery, from protein structure prediction and target validation, to hit discovery and lead optimization. The platform offers an interactive, web-based molecular visualization experience, with detailed management of projects, teams, and data. It features full compliance certification, multi-tier security measures, and supports both cloud-based and private deployment options. Hermite® is trusted by over 60% of leading pharmaceutical companies in China, applied across more than 50 drug pipelines. To date, industry users have performed over 200,000 Uni-FEP calculations on the Hermite® platform. For more information, please visit: About DP Technology At DP Technology, we're at the forefront of integrating artificial intelligence into scientific research and industrial R&D. Our "AI for Science" initiative is redefining how we tackle complex scientific challenges, making groundbreaking discoveries more accessible and actionable. We've developed the "DP Particle Universe," a suite of advanced pre-trained models that seamlessly connect cutting-edge research with real-world industrial applications. Our software suite includes: Bohrium® Scientific Computing Space Station, Hermite® Computational Drug Design Platform, RiDYMO® Hit Discovery Platform, and Piloteye® Battery Design Automation Platform. Together, these platforms form a robust foundation for industrial innovation and an open ecosystem for AI in science, fostering advancements in key areas such as drug discovery, energy, materials science and information technology. SOURCE DP Technology WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

蛋白降解靶向嵌合体

2024-11-18

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四款出海PD-(L)1/VEGF双抗比较：BD背后的商业逻辑是？

上周有2笔中国Biotech的重磅出海交易引起业内广泛关注与热议。 11月13日，普米斯宣布与BioNTech达成股权收购协议。根据协议条款，BioNTech将以8亿美元预付款收购普米斯100%已发行股本。此外，BioNTech将在普米斯达到双方约定的里程碑条件时，额外支付最高1.5亿美元的里程碑付款。 11月14日，默沙东（MSD）宣布与礼新医药达成全球独家许可，获得礼新医药PD-1/VEGF双抗LM-299的全球开发、生产和商业化独家许可。礼新医药将获得5.88亿美元的首付款，基于LM-299多项适应症的技术转让、开发、获批和商业化进展，礼新医药还将获得最高27亿美元的里程碑付款。尽管普米斯临床管线丰富，但目前真正具有商业价值的恐怕只有PM8002（PD-L1/VEGF）双抗项目。因此上述2项交易实际上都是围绕PD-(L)1/VEGF双抗项目的。结合之前已经出海的另2款PD-(L)1/VEGF双抗项目（康方生物的AK112及宜明昂科的IMM2510），本文将对4款双抗进行横向比较以分析近期交易背后的商业逻辑。 01 立项从PD-(L)1/VEGF双抗的研发历史（图1）来看，AK112毫无疑问是First-in-Class，早在2018年8月就递交了专利申请，由此猜测立项可能追溯到2016年。图1. PD-(L)1/VEGF双抗的研发历史在《创新药Fast Follow策略的未来》文中曾经推测，AK112的立项是基于罗氏于2014年起陆续开展的Atezolizumab联合Bevacizumab用于治疗多个实体瘤的临床试验。 2款PD-L1/VEGF双抗（IMM2510及PM8002）的专利申请时间分别为2019年12月及2020年8月，推测他们的立项是基于罗氏在2018年ASCO年会上首次公布了Atezolizumab+Bevacizumab的临床1期结果并于同年7月获FDA突破性疗法认证。而LM-299的专利申请时间为2022年12月，结合其分子设计（详见下）及当时AK112已公布的临床数据，推测其立项很可能在2021年并且是针对AK112的Fast-follow。 02 分子设计从分子设计来看，4款PD-(L)1/VEGF双抗都选择了2+2对称结构的Format，而其中的3款双抗（AK112、PM8002、LM-299）结构高度相似，均以Bevacizumab为骨架而在重链C端连接PD-(L)1 scFv或VHH（图2）。图2. 双抗结构示意图 (A)AK112; (B)PM8002; (C)IMM2510; (D)LM-299 IMM2510以PD-L1单抗为骨架，在重链N端连接VEGFR1的D2 domain作为VEGF trap。在Fc功能方面，AK112、PM8002、LM-299均采用了LALA突变以去除ADCC功能，而IMM2510则引进了ADCC功能增强型突变（表1）。表1. 4款PD-(L)1/VEGF双抗横向比较 03 临床结果作为First-in-Class的AK112已经积累了丰富的临床数据，并于今年5月获NMPA批准用于用于经表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗后进展的EGFR基因突变阳性的局部晚期或转移性非鳞状非小细胞肺癌（NSCLC）患者的治疗。特别是今年9月在WCLC会议上公布的HARMONi-2试验结果显示，AK112治疗的患者无进展生存期（PFS）为11.1个月，而Keytruda组患者的PFS仅为5.8个月。头对头研究结果表明，与Keytruda相比，AK112单抗将进展或死亡风险降低了49%（HR=0.51，P<0.0001），并实现了5.3个月的无进展生存期中位数改善，达到了该研究的主要目标。在2024年ESMO大会上公布的PM8002联合化疗治疗EGFR突变NSCLC的临床2期试验结果显示，64例患者接受了PD-L1 TPS检测：28例为TPS<1%，23例为TPS 1%-49%，13例为TPS≥50%。所有患者均可评估安全性和疗效。研究结果表明：总体ORR为54.7%（35/64），DCR为95.3%（61/64）。在PD-L1 TPS<1%组，ORR为35.7%，DCR为92.9%；在TPS 1%-49%组，ORR为56.5%，DCR为100%；在TPS≥50%组，ORR为92.3%，DCR为92.3%。尽管IMM2510在2021年8月就已进入临床，但目前公布的临床结果非常有限。而LM-299则于今年9月刚刚进入临床，目前还看不到任何结果。 04 交易首付款在中国创新药出海已常态化的今天，很多交易总额动不动就在10亿美元以上，但我们其实更应该以首付款金额来评价交易的价值。这是因为：1、首付款最能体现出买方对于项目的信心，因为首付款通常是无法追回的，因此对于买方来说往往是最大的风险；2、往往有更多临床数据的项目其交易的首付款占总交易金额的比例也更高；3、相当多的交易最终会在某个阶段因为各种原因终止而无法拿到全部里程碑付款。 2022年12月，康方生物宣布与Summit Therapeutics达成合作协议，后者获得康方生物PD-1/VEGF双抗AK112在美国、加拿大、欧洲、加拿大和日本的权益，Summit支付5亿美元预付款，以及最高50亿美元的总交易金额，包括开发、注册、商业化里程碑金额。当时AK112在中国的临床3期试验基本完成，这个价格算是合理。 PM8002及IMM2510在临床2期的时候出海，首付款金额分别为5500万美元及不到1000万美元，这个价格是明显偏低的，可能与卖方资金短缺急于促成交易有关。而刚刚进入临床1期的LM-299能拿到5.88亿美元首付款，不得不说是一个天价了，很大程度上是得益于AK112击败Keytruda的临床数据。 05 BioNTech/普米斯交易背后的逻辑从普米斯角度来看，其临床管线众多（图3），手头上的现金可能无法支撑如此规模的临床管线开发。图3. 普米斯研发管线此外，普米斯临床管线上除PM8002及PM1080（中国权益已授权给翰森制药）项目外，几乎都是负资产（烧钱但短期内无法带来理想的临床结果）。比如PM8001（PD-L1/TGFb双抗）项目，尽管恒瑞在胃癌上取得突破，但普米斯还需要相当的投入才能成功。TIGIT相关项目（PM1009及PM1022）、CD73相关项目（PM1015及PM1086）、4-1BB相关项目（PM1003、PM1032及PM1030）均不被业界看好，因此普米斯在一级市场的估值在5亿美元左右，进一步融资相当困难。从BioNTech角度来看，作为“新冠暴发户”手握几百亿美元现金并急于转型，疫情后一直在全球范围（特别是中国）扫货。从其公布管线可以看到，通过引进已经搭建起较丰富的ADC及双抗临床管线（图4），结合其自身的肿瘤疫苗管线，未来可以进行一系列临床联用开发。图4. BioNTech临床管线但可以想象BioNTech内部的研发能力，特别是大分子的研发能力较弱。通过并购普米斯获得其抗体（特别是双抗）研发的“Know-how"，能够快速提升BioNTech在大分子领域的研发能力。因此以不到10亿美元的价格收购普米斯对于BioNTech来说是捡漏，而对于普米斯来说则是无奈的选择。 06 默沙东/礼新交易背后的逻辑在今年ASCO会议前夕，康方生物宣布在非小细胞肺癌的 3 期临床试验中AK112击败了默克公司的 Keytruda。这一消息犹如一颗重磅炸弹在业内及资本市场引起巨大反响，因为在此结果之前，还没有任何一种药物在 3 期 NSCLC 头对头试验中击败过 Keytruda。尽管在ASCO会议期间，默沙东首席医学官Eliav Barr 博士在接受采访时表现得云淡风轻，“这对患者来说是个好消息，或者可能是另一种（治疗）选择”，但想必自那时起，默沙东高层已是翻江倒海。站在默沙东的角度，从内心可能希望AK112治疗NSCLC的总体生存率（OS）相较Keytruda没有优势，但也不得不面对未来AK112在OS上也击败Keytruda这种可能性。因此，对于默沙东来说引进一款PD-(L)1/VEGF双抗从投资角度更像是在股市中利用对冲策略来进行风险规避。同时，默沙东需要一款与AK112在临床表现上高度一致的PD-(L)1/VEGF双抗以规避买到me-worse的风险。但由于临床数据有限，即使是PM8002也很难保证与AK112表现一样。在这种情况下，就不难理解默沙东为什么会选择了一款在设计上及临床前功能上与AK112几乎一样的一款PD-1/VEGF双抗LM-299，两者在分子设计上几乎一模一样，都是以Bevacizumab作为骨架在重链C端连接PD-1 scFv或VHH（图2A&D）。至于为什么首付款给到了5.88亿美元，可能是参考了今年8月默沙东以7亿美元首付款收购已完成临床1期的CN201这一交易（详见CN201天价交易背后的天时地利人和）。还有另一种可能是默沙东一直在与AK112海外权益拥有者Summit进行BD谈判，但由于价格太贵（Summit市值曾达231亿美元）还没有谈拢，而通过引进一款PD-1/VEGF双抗可以增加默沙东在谈判桌上的筹码。值得一提的是，这一交易的另一大赢家是金斯瑞，因为LM-299中的PD-1 VHH是从金斯瑞引进得到的，根据协议金斯瑞可以得到预付款的40%，其他里程碑付款的25%和特许使用权费用的25%，也就是说金斯瑞可以得到2.35亿美元预付款和高达6.75亿美元的里程碑付款。不知道面对这一大笔钱，Frank是高兴呢还是遗憾呢？高兴的是仅凭PD-1 VHH授权就能收获2.35亿美元对于任何CRO来说都是天文数字：1、中国有能力产出相似PD-1 VHH的CRO至少在10家以上；2、金斯瑞孵化的传奇生物在2017年及2023年的2笔出海交易的首付款分别为3.5及1亿美元。遗憾在哪里呢？很少有人知道Frank在孵化了传奇生物不久后还孵化了一家专注于大分子药物的Biotech：Qragen。但在2017年12月传奇生物与强生的巨额合作后，为了加大在细胞治疗方面的研发，Qragen的全体人员并入了传奇生物。很遗憾，7年后传奇生物的下一款Carvykti仍遥遥无期，而中国Biotech在双抗领域却迎来了大爆发。假如当年Qragen没有解散并且在2018年启动PD-1/VEGF双抗项目，那将是紧跟AK112的全球第二款PD-1/VEGF双抗，因为根据BioNTech披露，PM8002项目是2019年9月启动的。如果那样Qragen很可能成就另一个传奇。当然，这些都是事后诸葛亮的假设，世上没有后悔药，创新药领域机会一直都有，让我们向前看。共建Biomedical创新生态圈！如何加入BiG会员？

ASCO会议并购引进/卖出临床1期临床结果

100 项与贝伐珠单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06409	贝伐珠单抗	L01XC07	DB00112

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
非小细胞肺癌	挪威	Roche Registration GmbH	2005-01-12
非小细胞肺癌	冰岛	Roche Registration GmbH	2005-01-12
非小细胞肺癌	列支敦士登	Roche Registration GmbH	2005-01-12
非小细胞肺癌	欧盟	Roche Registration GmbH	2005-01-12
铂敏感性卵巢上皮癌	欧盟	Roche Registration GmbH	2005-01-12
铂敏感性卵巢上皮癌	挪威	Roche Registration GmbH	2005-01-12
铂敏感性卵巢上皮癌	列支敦士登	Roche Registration GmbH	2005-01-12
铂敏感性卵巢上皮癌	冰岛	Roche Registration GmbH	2005-01-12
铂敏感性原发性腹膜癌	欧盟	Roche Registration GmbH	2005-01-12
铂敏感性原发性腹膜癌	列支敦士登	Roche Registration GmbH	2005-01-12
复发性铂耐药性卵巢癌	冰岛	Roche Registration GmbH	2005-01-12
复发性铂耐药性卵巢癌	列支敦士登	Roche Registration GmbH	2005-01-12
复发性铂耐药性卵巢癌	欧盟	Roche Registration GmbH	2005-01-12
复发性铂耐药性卵巢癌	挪威	Roche Registration GmbH	2005-01-12
肾细胞癌	冰岛	Roche Registration GmbH	2005-01-12
肾细胞癌	欧盟	Roche Registration GmbH	2005-01-12
肾细胞癌	挪威	Roche Registration GmbH	2005-01-12
肾细胞癌	列支敦士登	Roche Registration GmbH	2005-01-12
结肠癌	美国	Genentech, Inc.	2004-02-26
直肠癌	美国	Genentech, Inc.	2004-02-26

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
转移性乳腺癌	临床3期	美国	National Cancer Institute	2002-01-29
晚期结直肠腺癌	临床3期	美国	National Cancer Institute	2001-09-01
直肠腺癌	临床3期	美国	National Cancer Institute	2001-09-01
复发性结肠癌	临床3期	美国	National Cancer Institute	2001-09-01
III期结肠癌	临床3期	美国	National Cancer Institute	2001-09-01
转移性乳腺癌	临床前	加拿大	National Cancer Institute	2002-01-29
晚期结直肠腺癌	临床前	美国	National Cancer Institute	2001-09-01
直肠腺癌	临床前	美国	National Cancer Institute	2001-09-01
复发性结肠癌	临床前	美国	National Cancer Institute	2001-09-01
III期结肠癌	临床前	美国	National Cancer Institute	2001-09-01

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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


NCT03829410 (CRDF-004, GlobeNewswire) 人工标引	临床2期	KRAS 突变结直肠癌二线	-	Onvansertib with FOLFIRI and bevacizumab (bev-naïve patients)	(範衊衊築淵簾築鏇築憲) = 膚衊鹹觸遞壓襯糧艱鹽鹽醖醖選廠餘糧艱膚壓 (襯醖餘願廠膚壓製選窪 ) 更多	积极	2024-10-30
				onvansertib with FOLFIRI and bevacizumab (bev-exposed patients)	(範衊衊築淵簾築鏇築憲) = 觸齋蓋鹹築願夢醖齋糧鹽醖醖選廠餘糧艱膚壓 (襯醖餘願廠膚壓製選窪 ) 更多
NCT04091217 (ML41186, CTgov)	临床2期	黏膜黑色素瘤	43	Atezolizumab+Bevacizumab	獵願鹽簾蓋鏇膚鹹鹹繭(鹽簾蓋襯繭艱襯構艱窪) = 鑰構鏇齋餘鑰網齋餘鹹餘鏇鑰餘獵鏇蓋廠遞窪 (廠艱簾選餘願夢網積選, 鹽選範簾願廠繭積積鹹 ~ 網築繭獵構鬱鬱醖糧積) 更多	-	2024-10-24
GlobeNewswire 人工标引	临床2期	转移性微卫星稳定结直肠癌一线	104	GRANITE+ immune checkpoint inhibitors + fluoropyrimidine+bevacizumab	(齋蓋願壓憲鹹襯餘繭憲) = 衊願蓋鹽憲壓築膚鑰窪壓廠夢廠壓鹹願製繭憲 (鹹蓋繭遞糧網醖蓋選積 ) 更多	积极	2024-09-30
				Fluoropyrimidine+bevacizumab	(齋蓋願壓憲鹹襯餘繭憲) = 齋憲醖觸蓋構窪觸醖淵壓廠夢廠壓鹹願製繭憲 (鹹蓋繭遞糧網醖蓋選積 )
HEPATORCH (PRNewswire) 人工标引	临床3期	肝细胞癌	326	特瑞普利单抗+贝伐珠单抗	(顧鹽範艱願積醖遞製觸) = 積憲選願製觸顧鬱艱齋齋網鏇壓鬱製餘選築憲 (構襯齋願製壓製積鑰構 ) 更多	积极	2024-09-29
				索拉非尼	(顧鹽範艱願積醖遞製觸) = 製餘觸蓋願觸遞糧鬱鏇齋網鏇壓鬱製餘選築憲 (構襯齋願製壓製積鑰構 ) 更多
NCT06233994 (ZG005-IIT-001, NEWS) 人工标引	N/A	晚期肝细胞癌一线	10	ZG005 10 mg/kg + Bevacizumab 15 mg/kg	(憲餘窪蓋簾簾夢壓鏇願) = 構鹹積顧蓋繭築構鏇蓋鹹糧蓋鹽襯築簾願積簾 (顧繭簾糧獵襯壓膚夢蓋 ) 更多	积极	2024-09-25
EURETINA2024	N/A	-	-	Avastin (30 G Needle)	淵積壓艱範夢鬱鏇齋顧(齋顧膚網蓋淵觸繭選衊) = 鬱築構鹹構壓夢網簾簾壓簾膚糧齋憲鏇淵鏇鑰 (壓蓋獵襯餘齋蓋齋糧選 )	-	2024-09-19
				Avastin (23/26/30 gauge needles with and without APAD)	淵積壓艱範夢鬱鏇齋顧(齋顧膚網蓋淵觸繭選衊) = 築願網蓋壓膚構鏇淵網壓簾膚糧齋憲鏇淵鏇鑰 (壓蓋獵襯餘齋蓋齋糧選, 1 ~ 10 μm)
EURETINA2024	N/A	视网膜动脉闭塞	-	Intravitreal combined with intravenous tPA	鑰蓋廠鹹觸憲鏇鬱觸艱(襯繭選糧顧構遞繭夢壓) = happened in the treatment group 鹽簾繭範製鹹鹹膚窪襯 (構夢範糧艱願遞選淵衊 ) 更多	-	2024-09-19
				Intravitreal injection (Conservative treatment)
The Submarine Study (EURETINA2024)	N/A	-	123	Subretinal Aflibercept	(鹹憲網糧齋獵鬱醖積願) = 襯餘壓襯鏇夢鹽夢願範鏇夢觸鹹夢願顧艱艱繭 (餘觸鹽範觸鹽簾糧壓網 ) 更多	积极	2024-09-19
				Subretinal Ranibizumab	(鹹憲網糧齋獵鬱醖積願) = 齋醖蓋願觸鬱鏇窪願繭鏇夢觸鹹夢願顧艱艱繭 (餘觸鹽範觸鹽簾糧壓網 ) 更多
EURETINA2024	N/A	湿性年龄相关性黄斑变性	-	MVASI	(簾構夢鹽糧觸餘齋廠餘) = 積繭鹽鹽簾夢繭夢醖淵獵襯獵夢構醖簾廠糧衊 (網襯鹽淵鏇廠網簾遞選 ) 更多	-	2024-09-19
				Avastin	(簾構夢鹽糧觸餘齋廠餘) = 構衊窪壓構積範觸糧簾獵襯獵夢構醖簾廠糧衊 (網襯鹽淵鏇廠網簾遞選 ) 更多
EURETINA2024	N/A	湿性年龄相关性黄斑变性	-	Intravitreal Bevacizumab	艱蓋製鹹觸願襯齋遞鹹(獵選簾鏇膚構齋窪網網) = No serious ocular adverse events were reported 夢衊壓鬱齋鬱鑰艱膚獵 (築膚衊廠鬱鑰壓觸醖築 )	-	2024-09-19
				Intravitreal Ranibizumab