A Phase 3 Randomized, Double-Blind, Active-Controlled Study of Palazestrant With Ribociclib Versus Letrozole With Ribociclib for the First-Line Treatment of ER+, HER2- Advanced Breast Cancer (OPERA-02)

This phase 3 clinical trial compares the efficacy and safety of palazestrant with ribociclib to letrozole and ribociclib in women and men who have not received prior systemic anti-cancer treatment for advanced breast cancer.

开始日期2025-10-31

申办/合作机构

Olema Pharmaceuticals, Inc.

[+1]

NCT07164976

/ Not yet recruiting临床1/2期IIT

Phase Ib/II Trial of Ribociclib Plus Anastrozole in Patients With Hormone Receptor-Positive, HER2-Negative Metastatic or Recurrent Breast Cancer

This document outlines an investigator-initiated Phase Ib/II clinical trial in Japan, focusing on the combination therapy of ribociclib and anastrozole for patients with hormone receptor-positive (HR-positive), HER2-negative metastatic or recurrent breast cancer. The trial aims to evaluate the efficacy (specifically, overall response rate) and safety of this combination in the Japanese patient population. Nagoya City University is the sponsor of this trial, with funding provided by Novartis Pharma K.K..
Study Design and Endpoints: The trial is structured into two parts:
* Phase Ib: The primary endpoint for this phase is tolerability, which is assessed by dose-limiting toxicities (DLT). Secondary endpoints include pharmacokinetics (PK) of the drugs, as well as the incidence of adverse events (AE) and serious adverse events (SAE).
* Phase II: The primary endpoint for Phase II is the Overall Response Rate (ORR), which will be determined by a blinded central imaging review based on RECIST version 1.1 criteria. Secondary endpoints encompass PK (for the initial 20 patients), ORR as assessed by the investigator, progression-free survival (PFS), overall survival (OS), and the overall incidence of adverse events

开始日期2025-10-01

申办/合作机构

Nagoya City University

[+1]

NCT07054190

/ Recruiting临床2期

A Phase II, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Neoadjuvant Treatment With Inavolisib Combinations in Patients With Untreated, Early-stage, PIK3CA-Mutated Breast Cancer

This study will evaluate the safety and efficacy of inavolisib combination therapies in participants with untreated, PIK3CA-mutated, Stage II-III, estrogen receptor (ER)-positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer (BC).

开始日期2025-08-29

申办/合作机构

Hoffmann-La Roche Ltd.

100 项与琥珀酸瑞波西利相关的临床结果

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100 项与琥珀酸瑞波西利相关的转化医学

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100 项与琥珀酸瑞波西利相关的专利（医药）

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1,324

项与琥珀酸瑞波西利相关的文献（医药）

2025-10-01·BREAST

Baseline neutrophil-lymphocyte ratio (NLR) predicts toxicity and survival in HR+/HER-2 breast cancer patients treated with CDK4/6 inhibitors

Article

作者: Sharif, Sireen ; Bar-Sela, Gil ; Darawshe, Ali ; Yosef, Samih ; Badran, Omar

METHODS:

This retrospective cohort study included 2218 patients with HR+/HER2- metastatic breast cancer treated with palbociclib or ribociclib between 2017 and 2024, using data from Israel's largest health maintenance organization. We compared baseline NLR values between patients who developed grade 4 neutropenia (absolute neutrophil count <0.5 × 10⁹/L) and those with higher counts during the first three months of treatment. Additional comparisons were conducted using different neutropenia thresholds. We also assessed the association between baseline NLR (cut-off 2.5), progression-free survival (PFS), and treatment-related adverse events.

RESULTS:

Patients with grade 4 neutropenia had significantly higher baseline NLR values compared to those with higher neutrophil counts. The effect size was large in all comparisons. Patients with an NLR of ≥2.5 had a shorter median progression-free survival (PFS) than those with an NLR of <2.5. Hepatotoxicity was more frequently observed in patients with NLR <2.5, while the incidence of dermatologic adverse events was similar across groups.

CONCLUSIONS:

Elevated baseline NLR is associated with an increased risk of severe neutropenia and shorter progression-free survival in patients treated with CDK4/6 inhibitors. These findings highlight a potential link between systemic inflammation and treatment outcomes, suggesting that NLR may be a valuable predictive biomarker in this setting.

2025-10-01·BREAST

Cancer outcomes in patients eligible for adjuvant cyclin-dependent kinase 4 and 6 inhibitors but spared adjuvant chemotherapy by Oncotype Dx: A multicenter retrospective GBECAM 0520 study

Article

作者: de Melo Gagliato, Debora ; Pereira de Araújo, Julio Antonio ; Megid, Thais Baccili Cury ; Argolo, Daniel ; Lopes, Mario Machado ; Cesca, Marcelle Goldner ; Moura, Larissa Matos Almeida ; Parisi Marlière, Júlia Leal Franco ; Linck, Rudinei ; Shimada, Andrea Kazumi ; Rosa, Daniela Dornelles ; Gaudêncio, Débora ; Silva de Souza, Zenaide ; Oliveira, Leandro Jonata de Carvalho ; Gomes, Daniel Musse ; Sales, Leticia Telles ; Beal, Juliana Rodrigues ; Batista, Daniel Negrini ; Kaliks, Rafael Aliosha ; Mano, Max Senna ; Testa, Laura ; Bines, José ; Dos Anjos, Carlos Henrique ; Assad-Suzuki, Daniele ; Katz, Artur ; Sanches, Solange Moraes ; Bonadio, Renata Colombo ; Barroso-Sousa, Romualdo ; Corrêa, Tatiana Strava

BACKGROUND:

In pivotal CDK4/6 inhibitor (CDK4/6i) adjuvant trials, most patients received chemotherapy (CT). However, the role of CDK4/6i in patients spared CT by a genomic signature remains unclear. We investigated the proportion of patients without genomic CT indication but eligible for adjuvant abemaciclib or ribociclib, and estimated their potential benefit from CDK4/6i.

METHODS:

This retrospective, real-world study included patients with T1-T3, N0-N1, HR+/HER2- early breast cancer (eBC) who underwent Oncotype DX (ODX) testing (2005-2024) at nine Brazilian institutions. Genomic CT indication followed TAILORx and RxPONDER; CDK4/6i eligibility followed MonarchE and NATALEE. Primary endpoints were 5-year invasive disease-free survival (iDFS) and distant disease-free survival (DDFS) among patients eligible for CDK4/6i, without genomic CT indication, treated with endocrine therapy (ET) alone.

RESULTS:

Among 922 patients, ODX showed low (<11), intermediate (11-25), and high (>25) genomic risk in 170 (18.4 %), 585 (63.5 %), and 167 (18.1 %), respectively. Overall, 24 (2.6 %) and 120 (13 %) were eligible for abemaciclib and ribociclib, respectively, had no CT indication, and received ET alone. In these patients (median follow-up: 57.8 and 66.4 months), 5-year iDFS and DDFS were 100 %.

CONCLUSIONS AND RELEVANCE:

HR+/HER2- eBC patients eligible for CDK4/6i but spared CT by ODX are a minority and have excellent outcomes with ET alone. This highlights the potential benefits of integrating genomic and clinical risk stratification to refine therapeutic decision-making regarding the need for CDK4/6i.

2025-10-01·TOXICOLOGY AND APPLIED PHARMACOLOGY

Ribociclib derivative Rib-CA suppresses breast cancer progression via p53-dependent apoptosis

Article

作者: Jiang, Yongyuan ; Ji, Jing ; Mou, Yi ; Wang, Jian ; Yang, Zihao ; Asan, Kadirya ; Chen, Si ; Song, Xiaoxue ; Lin, Haiyan ; Song, Mengwei ; Wang, Sen ; Zhou, Ying ; Yu, Xudong ; XiujunWang ; Zhang, Boyu

Breast cancer is a major global health challenge with high incidence and mortality. CDK4/6 inhibitors like Ribociclib have shown clinical benefits, but drug resistance remains a limitation. We designed and synthesized a novel Ribociclib derivative, Rib-CA, and evaluated its antitumor effects using in vitro assays (MTT, colony formation, EdU incorporation, cell adhesion, Transwell invasion, and wound healing) and in vivo models (CAM assay, xenografts). Transcriptomics, Western blotting, and machine learning were employed to explore its mechanism. Pharmacokinetics and safety were assessed via ADMETlab 2.0. Rib-CA exhibited enhanced anti-proliferative and anti-metastatic effects in MDA-MB-231 and MCF-7 cells compared to Ribociclib. Mechanistically, it activated p53 signaling, induced apoptosis, and triggered G2/M arrest. Machine learning identified CACHD1 and LAGE3 as potential biomarkers linked to p53 and immune regulation. In vivo, Rib-CA suppressed tumor growth and angiogenesis more effectively than Ribociclib, with favorable pharmacokinetics. Rib-CA demonstrates enhanced antitumor activity through p53 pathway activation and metastasis suppression, suggesting its therapeutic potential for breast cancer treatment.

800

项与琥珀酸瑞波西利相关的新闻（医药）

2025-09-06

·ioncology

全球品质中国证据丨欧江华教授：来罗西利助推CDK4/6i升级优化，期待尽快纳入医保、惠及更多中国患者

点击蓝字，关注我们来罗西利PI访谈记扫描二维码查看更多内容编者按：CDK4/6抑制剂已经成为HR+/HER2-乳腺癌的重要治疗选择，但其疗效和安全性仍有更多优化提升的空间。近期，中国NMPA正式批准新型CDK4/6i来罗西利（Lerociclib）治疗局部晚期或转移性HR+/HER2-乳腺癌成人患者的两个适应症：与芳香化酶抑制剂（AI）联合使用作为初始内分泌治疗；与氟维司群联合用于既往接受内分泌治疗后疾病进展的患者。本期采访中，新疆医科大学附属肿瘤医院欧江华教授从CDK4/6i类药物的优化升级层面，解读来罗西利的药物机制优势和循证医学证据。 01 《肿瘤瞭望》：CDK4/6i是HR+/HER2-乳腺癌的重要治疗药物，但仍存在特定的毒副作用或疗效瓶颈。目前主要有哪些新型药物研发机制有望达到增效减毒的效果？欧江华教授新疆医科大学附属肿瘤医院 CDK4/6抑制剂联合内分泌治疗（CDK4/6i＋ET）已经成为HR+/HER2-乳腺癌患者系统治疗的重要选择，贯穿于早期高危患者的强化辅助治疗，晚期患者的一线、二线治疗；且PI3K抑制剂等新型靶向药物也正在联合CDK4/6i＋ET，进一步改变HR+/HER2-晚期乳腺癌的治疗格局。针对晚期患者，我们知道治疗的基本原则是延长患者生存期以及维持或改善生活质量。目前临床所应用的CDK4/6i总体上疗效和安全性均已得到验证，但仍存在特定的毒副作用，包括较为显著的中性粒细胞减少、贫血等血液毒性，以及腹泻、静脉血栓栓塞（VTE）、间质性肺病（ILD）、心电图QT间期延长、肝酶升高等。尽管这些不良事件发生率不一定很高，但一定程度上也会影响患者生活质量，临床医生需要平衡抗肿瘤药物的“两面性”，即权衡治疗获益和毒副作用，这些对临床评估和诊疗成本也有影响。此外，对于一些肿瘤负荷较高的患者（如内脏转移危象），内分泌治疗起效缓慢，化疗仍是临床更为经常使用的解救治疗方案。 CDK4/6i可谓当前HR+/HER2-乳腺癌领域的“明星药”，但不同药物的作用靶点效果、毒副反应有所差异。一方面，临床需要规范化、个体化地选择CDK4/6i，比如结合患者是否有心脏疾病、胃肠道症状等选择适宜的CDK4/6i。此外，临床仍需结合已上市产品的痛点和临床需求，对CDK4/6i进行优化升级。 02 《肿瘤瞭望》：近期，中外合作研发的新型CDK4/6i来罗西利在国内获批上市，这种CDK4/6i在药物机制方面有哪些创新和优势？欧江华教授新疆医科大学附属肿瘤医院来罗西利是新一代CDK4/6激酶抑制剂，该药物的首个临床关键III期研究是由徐兵河教授在2023年ASCO大会报道的。从已报道研究来看，来罗西利具有以下药物特征。首先，来罗西利创新性的采用三并环及螺环结构，激酶谱研究显示来罗西利对CDK4具有高选择性抑制，而且来罗西利的半数抑制浓度（IC50）非常低，提示对CDK4和CDK6靶点有较强的抑制作用。再者，来罗西利具有高渗透性，其在肿瘤组织高度富集，肿瘤组织暴露是血浆暴露的18倍。给药24小时后，在血浆浓度降到极低水平时，肿瘤组织浓度是其100倍以上。第三是临床获益高，在两项III期研究中的无进展生存期（PFS）HR仅为0.4左右。第四是停药率低，LEONARDA系列研究中因不良事件导致的来罗西利停药率仅为0.7%。来罗西利的高选择性、高组织渗透性、高临床获益、低停药率四大特征，主要得益于其药物结构的改进，是当前中国已获批的CDK4/6i中一款非常有效的治疗方案。 03 《肿瘤瞭望》：此次来罗西利获批用于HR+/HER2-晚期乳腺癌初治和经治患者的相关适应症，主要基于哪些重要的循证医学证据？这些研究中来罗西利表现了怎样的疗效和安全性特征？欧江华教授新疆医科大学附属肿瘤医院来罗西利在今年5月份于国内获批2个适应症，分别基于专为国内患者设计的两项Ⅲ期随机对照临床试验所提供的循证医学证据，包括初治人群的LEONARDA-2研究和内分泌经治人群的LEONARDA-1研究。两项试验均纳入绝经前、绝经后以及多项高危临床病理特征，比如内脏转移、肿块较大、转移部位较多（如3-4个以上）等高肿瘤负荷患者，更贴近中国的临床实践情况，适用性非常广，因为我国乳腺癌中位发病年龄相较于欧美国家约提前10年，不少年轻患者具有高危特征，这些研究提供了非常适合中国患者的新型CDK4/6i方案。此次国内获批也表明国家药监部门对这些循证医学证据的认可，再次印证了来罗西利的高选择性、高组织渗透性、高临床获益、低停药率的四大特征。 LEONARDA系列研究结果显示了来罗西利作为晚期一线或二线治疗均有显著的PFS获益，且PFS HR值在同类报道研究中处于非常低的水平；而且来罗西利对内脏转移、转移部位数较多的这些难治性患者，也显示出非常好的PFS获益，总体上的HR值低于0.5。此外，来罗西利的安全性很好、停药率很低，4 级中性粒细胞减少均为 5.1%；≥3级的腹泻事件几乎没有发生（仅在LEONARDA-2研究中发生1例），并且没有报告ILD、VTE 等特殊事件，心电图QT间期延长的发生率则与对照组相当。 △LEONARDA-2研究：研究者评估来罗西利＋来曲唑对比来曲唑用于初治晚期患者的中位PFS分别是未达到（NR）和16.56 个月，来罗西利组的疾病进展或死亡风险显著下降 53.6%（HR 0.464；95%CI 0.293–0.733；P=0.0004） △LEONARDA-1研究：来罗西利＋氟维司群对比安慰剂＋氟维司群用于ET耐药患者的中位PFS分别是11.07个月和5.49 个月，疾病进展或死亡风险显著下降54.9%（HR 0.451；95%CI 0.311–0.656；P＜0.0001） △LEONARDA-2研究：常见（≥10%）治疗期间不良事件（TEAE） △LEONARDA-1研究：常见TEAE 04 《肿瘤瞭望》：鉴于上述循证医学证据，您认为来罗西利有怎样的临床应用优势？未来将在我国HR+/HER2乳腺癌治疗中发挥怎样作用？欧江华教授新疆医科大学附属肿瘤医院从上述循证医学证据可见，来罗西利的优势诸多。首先是疗效确切且获益人群广泛。众所周知，我国乳腺癌中位发病年龄更加靠前，绝经前患者比例较高，往往伴有内脏转移、高肿瘤负荷等高风险疾病特征，LEONARDA-1和LEONARDA-2研究均纳入了这些临床病理特征的患者，且获得了一致的PFS改善，而且HR值普遍低于0.5，显示了来罗西利非常广泛而强效的治疗获益。再者，来罗西利的安全性优势非常突出，尤其是血液学毒性低，4级中性粒细胞减少仅为5%，≥3级的腹泻几乎没有发生，并且没有发生ILD、VTE、QT 延长等特殊不良事件。这些安全性优势使得来罗西利非常适合作为晚期患者的长期维持治疗方案，而且能够减少剂量调整或停药的情况发生，使治疗获益最大化；同时也能够节省患者治疗过程中对不良事件的监测管理成本。这些临床优势表明来罗西利有望在我国HR+/HER2-乳腺癌的治疗中发挥巨大的作用。对于这么一款高效、低毒的治疗方案，我们也非常希望能够尽快进入国家医保目录，提高治疗可及性，从而使更多中国HR+/HER2-乳腺癌患者获益于来罗西利治疗。参考文献：（滑动查看） [1]国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性乳腺癌临床应用专家共识(2023版)[J]. 中华肿瘤杂志, 2023, 45(12):1003-1017.DOI: 10.3760/cma.j.cn112152-20230428-00188. [2]Morrison L, Loibl S, Turner NC. The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nat Rev Clin Oncol. 2024;21(2):89-105. doi:10.1038/s41571-023-00840-4 [3]Braal CL, Jongbloed EM, Wilting SM, Mathijssen RHJ, Koolen SLW, Jager A. Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences. Drugs. 2021;81(3):317-331. doi:10.1007/s40265-020-01461-2 [4]葛睿, 王碧芸, 江泽飞, 等. 乳腺癌CDK4/6抑制剂相关性不良反应管理共识[J]. 中华肿瘤杂志, 2022, 44(12):1296-1304.DOI: 10.3760/cma.j.cn112152-20220825-00578 [5]Bisi JE, Sorrentino JA, Jordan JL, et al. Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget. 2017;8(26):42343-42358. doi:10.18632/oncotarget.16216 [6]Yu Q, Sicinska E, Geng Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23-32. doi:10.1016/j.ccr.2005.12.012 [7]Kim S, Tiedt R, Loo A, et al. The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models [published correction appears in Oncotarget. 2020 Apr 07;11(14):1289. doi: 10.18632/oncotarget.27407.]. Oncotarget. 2018;9(81):35226-35240. Published 2018 Oct 16. doi:10.18632/oncotarget.26215 [8]Xichun Hu, et al. LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/ HER2- advanced or metastatic breast cancer.. J Clin Oncol 42, 2024 (suppl 16; abstr 1052). [9]Xu B, Zhang Q, Luo Y, et al. Lerociclib plus fulvestrant in patients with HR+/HER2- locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial. Nat Commun. 2025;16(1):716. Published 2025 Jan 16. doi:10.1038/s41467-025-56096-2 欧江华教授新疆医科大学附属肿瘤医院乳腺外科二病区主任主任医师教授博士生导师医学博士（授予国：荷兰）中国老年医学会肿瘤康复常委乳腺专家委员会主任委员中国抗癌协会肿瘤微创专业委员会乳腺学组副主任委员中国抗癌协会肿瘤整形专业委员会常委中华医学会肿瘤学分会乳腺学组委员自治区卫健委职称专业组评审专家（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

申请上市核酸药物

2025-09-05

·生物制品圈

为何又是它？诺华再押舶望siRNA，合计交易额近百亿

9月3日，舶望制药（下称“舶望”）宣布与诺华达成一项新的战略合作，双方共同开发针对心血管疾病的siRNA药物。此次合作是双方在去年1月首次合作基础上的再度深化，根据协议，舶望将获得1.6亿美元的预付款，总潜在里程碑高达52亿美元。加上此前合作的41.65亿美元，两次交易潜在总金额已近百亿，再创“天价”BD。而就在9月2日，诺华才刚宣布以22亿美元（2亿美元预付款）与Arrowhead Pharmaceuticals达成合作，将后者的临床前siRNA药物ARO-SNCA的全球独家开发、生产和商业化权益收入囊中，用于治疗帕金森等突触核疾病，次日便继续加码，选择扩大与舶望的合作范围，力指多款、多阶段心血管领域资产。背后折射出的，既是舶望技术平台与管线的备受青睐，也是诺华紧密加码siRNA的战略意图。 01 从“买鱼”到“认渔” 本次交易的核心标的主要包括一款Ⅱ期siRNA药物的优先谈判权、两款早期分子中国以外权益的选择权以及一款临床前siRNA药物中国以外独家许可。首先，双方将共同探索BW-00112（ANGPTL3）联合用药，用于治疗血脂异常。该产品目前在美国和中国处于 II 期临床试验阶段，后续联合用药的临床试验将由舶望主导开展，诺华则将获得该产品的优先谈判权。同时，舶望还将授予诺华两款处于早研阶段分子的中国以外权益的选择权，用于治疗重度高甘油三酯血症 (sHTG) 和混合型血脂异常。而针对另一款处于临床前研究阶段的 siRNA 候选药物，诺华将获得中国地区以外的独家许可，并包含在美国和中国分享损益 (P&L) 的互惠选择权，预计 2026 年将启动 I 期临床试验。合作范围打包式涵盖多阶段，意味着在现有成果的基础上，舶望持续开发和发现优质候选的平台能力同样获得了MNC的认可，而不乏亮点的交易模式也为双方共进提供了极大支撑。通过选择权和优先谈判权，诺华保留了决策灵活性，以相对可控的成本提前锁定多个未来选项，而在中美两地的P＆L互惠选择权，也帮助舶望保留了参与两个最大医药市场商业化和分享利润的可能性。回看两家的初次结缘，彼时舶望授予诺华两款心血管siRNA药物的海外权益，包括一款I期临床产品的全球权益和一款I/IIa期产品的大中华区外权益，协议中特别约定诺华保留“针对心血管疾病的最多额外2个靶点化合物的选择权”。而今新协议涉及的siRNA候选分子正属于该选择权覆盖范围。据了解，首次合作中的核心管线BW-00163（高血压siRNA）已于今年6月进入Ⅱ期临床，顺利触发里程碑付款，为此次深化合作奠定了基础。值得注意的是，相较于常见的预付款+阶段性里程碑付款+销售分成的模式，本次交易在研发合作的基础上，还纳入了股权投资意向，进一步深化双方利益绑定和战略认可。据舶望官网新闻披露，诺华已初步意向参与其下轮股权融资，具体参与（包括投资金额与时间）仍需履行例行尽职调查、并由双方协商并签署正式协议来确定。可以看出，经过初次试水，双方已建立良好互信，舶望的技术实力与研发潜力得到了诺华的持续看好，实实在在地为其赢来了再度青睐和深化合作。 02 为什么是舶望？小核酸药物（寡核酸药物，oligonucleotide）指长度小于30nt的寡核苷酸序列，包括多种机制和类型，如小干扰RNA（siRNA）、微小RNA（microRNA或miRNA）、ASO（反义寡核苷酸）、Aptamer（核酸适配体）和CpG寡核苷酸（CpG ODN），通过RNA干扰（RNA interference, RNAi）发挥药效，可对靶点进行限制性选择，具有较高的特异性，不受限于传统蛋白靶点的可成药性，理论上可靶向任何致病基因。但早期因易被核酸酶降解、肾清除率高，小核酸药物一度陷入开发难的局面。其中，siRNA药物虽然凭借更高效率和精准度的基因调控潜力吸引了更多资本与研发投入，其技术临床转化却在Alnylam、Ionis等biotech的迅速崛起与行业首次迎来热潮的背景下很快遭遇瓶颈。对于以RNA为基础的siRNA药物来说，递送系统至关重要，克服系统循环、外渗、组织渗透、细胞摄取以及内涵体逃逸等重大挑战的递送平台既是小核酸领域的“卡脖子”技术，也是此类药物获得成功的必要条件。如何将易降解的siRNA安全、有效地递送至特定组织或器官（除肝脏外），成为了一大关键障碍。彼时，以Alnylam、Arrowhead、Dicerna等企业为关键代表，多家药企持续改进递送系统和化学修饰技术，推动GalNac（N-乙酰半乳糖胺）偶联技术成熟，利用干细胞表面高度表达的ASGPR受体实现高效肝脏靶向，一举突破了肝内递送难题，推动siRNA领域自2016年起步入收获期。近年更是逐渐覆盖更加广泛的疾病谱，在某些领域替代或补充现有疗法，应用领域从早期的罕见病拓展到心血管代谢等常见慢性病——对于这种需长期管理的疾病来说，长效、低频次给药的siRNA药物可谓优势尽显。目前，肝外递送（如针对中枢神经系统、肾脏、肌肉等组织）仍是待攻克的关键挑战。整体来说，递送系统也仍是siRNA领域的核心壁垒。可以说，增强递送能力、掌握递送平台，就是实现技术护城河的关键。也正因此，凭借其创新型递送平台，以及团队在核酸序列设计、化学修饰、GalNAc递送技术、肝外递送技术等全流程环节的丰富经验，专注siRNA药物开发的舶望虽然成立不足5年，却在短时间内快速赶上，成功构筑了一定的技术壁垒，并在初次合作后，凭借研发实力再获MNC青睐。舶望建立了完整的核酸药物开发平台，并基于此开发了覆盖多种疾病的多元化药物研发管线。其搭建的自主创新siRNA技术平台名为 RADS（RNA with superior Activity, Durability, Safety），即具备“更强活性、更持久效力、更高安全性”的RNA分子平台。迅速搭建完成后，每隔2-3个月左右，即完成针对特定靶点的siRNA，例如AGT、HBV、LPA、PKK、C3、XDH的siRNA，筛选及优化能力十分出色。通过对siRNA序列设计、化学修饰和递送方式的优化，该平台大幅提升了siRNA药物的药效和稳定性，降低给药频率和副作用，能够开发出更低剂量下疗效更好、持续时间更长的药物，在某些适应症上有望实现一年一次给药，已在多项临床试验中取得积极成果。更关键的是，对siRNA药物来说，一旦搭建成熟的技术平台，开发类似药物的速度便会明显加快，可实现较短的药物研发周期（通常为3-5年）和较高的成功率，有望接连迎来重要突破，收获持续看好态度，不难想见。聚焦心血管代谢疾病领域，虽然Alnylam、Arrowhead等企业已较早布局PCSK9、ANGPTL3、LPA、AGT等靶点的RNAi药物（部分项目已进入后期临床或上市），舶望凭借自身技术平台，针对相同靶点实现了快速跟进甚至同步开发。图1 舶望制药RANi技术平台RADS 此外，其核心团队也是本次合作的关键因素。董事长兼CEO舒东旭博士曾任职于Arrowhead，主导肝外递送平台开发，拥有北京大学化学专业及海外博士后科研背景；首席科学官邵鹏程博士在默克有近17年药物化学经验，曾任Arrowhead药物化学总监，参与心血管、糖尿病、肿瘤、中枢神经等多个领域项目；首席医学官金建军博士曾担任诺华中国临床开发负责人，主导过全球首款获批用于慢性疾病治疗的siRNA药物Inclisiran（Leqvio）的亚洲III期研究；首席商务官Patrick Gallagher拥有25年投资经验，累计完成约10亿美元资金募集，曾主导多项国际并购与合作项目。这支国际化团队为舶望快速建立技术平台、推进管线和达成国际合作提供了坚实基础。目前，舶望已有6款RNAi候选药物进入临床研究，涵盖心脑血管疾病、病毒感染、代谢疾病及罕见病等多个治疗领域。表1 舶望制药临床管线统计 03 诺华的迫切与布局而对于诺华来说，豪掷千金的背后原因，正是看中siRNA药物对其心血管领域管线的强大助力。 2024年，心血管领域为诺华贡献了21％的销售额，高达78亿美元，成为除肿瘤外的另一大业绩主力，而其中高达15％来自于其重磅产品Entresto。然而，Entresto专利于今年7月到期，FDA仿制药批准下，多家欧美药企早已准备吞食市场份额，而中国药企如信立泰、石药欧意和正大天晴等，也已提早布局、伺机而动。有机构预测称，仿制药上市3个月内将瓜分85％-90％的市场的份额，造成数十亿损失。同时，2019年诺华斥巨资以97亿美元收购的Leqivo（首个且唯一上市的降血脂siRNA药物）销量仍未达预期，虽然贡献了一定业绩，却无法填补Entresto专利保护丧失造成的业绩空白，且爬坡速度已经见缓。而除Entresto外，诺华的其他几款重要产品也将在2030年前迎来专利悬崖，包括2027年到期的Promacta（升血小板）和Kisqali（CDK4/6），2029年到期的Cosentyx（IL-17）和2030年到期的Kesimpta（CD20）。由此，寻找下一个能支撑数十亿美元销售的心脑血管药物、填补心血管领域的增长接力空缺，已经成为诺华迫切妥善解答的关键问题，而借助siRNA药物的广阔前景扩充管线、长远布局其他核心领域也是不可忽视的重要考量。近年来，诺华聚焦心血管、神经科学和免疫学等优势方向，对内侧重推进核心项目，对外着重获取储备技术和新分子实体，积极推进从内部研发向外部引进转型，48 小时内连续两笔“闪电交易”便很好地佐证了这一策略动向。与Arrowhead就临床前管线达成合作，不仅是为了押注优质管线，也旨在利用其TRiM平台的研发潜力，推进帕金森病等难治性神经退行性疾病的整体进展，而通过与舶望达成合作，诺华则能够在灵活决策的基础上获得多阶段极具潜力的心血管siRNA药物，快速强化现有布局的同时，提前锁定未来优质管线。结语这一合作不仅是一次双赢，也标志着中国创新药研发在RNAi前沿达到了国际水平。当前，行业已形成以Alnylan、Ionis、Sarepta为核心的鼎力竞争格局，持续引领行业创新，诺华、辉瑞、罗氏等MNC则通过合作与收购，先手布局、深度参与。即便如此，凭借过硬的技术平台创新和持续的研发投入，中国药企新兴力量仍能迎头赶上，走出产品简单交易模式，主导后续试验、成为创新源泉，参与全球市场竞争，实在令人欣喜。引用： 1.舶望制药官网新闻及公开资料 2.Arrowhead官网新闻 3.https://mp.weixin.qq.com/s/qicDfsHRm-tQhbyNmgMiIA 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

siRNA引进/卖出临床1期临床2期临床申请

2025-09-03

·GlobeNewswire-Health Care

Olema Oncology Announces New Clinical Trial Agreement with Pfizer to Combine Palazestrant with Atirmociclib in ER+/HER2- Metastatic Breast Cancer

Study to explore the palazestrant-atirmociclib combination in approximately 35 patients with initiation anticipated in H2 2025 Results to inform potential pivotal Phase 3 trial of novel combination in frontline metastatic breast cancer setting Sept. 02, 2025 -- Olema Pharmaceuticals, Inc. (“Olema” or “Olema Oncology”, Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, today announced a new clinical trial collaboration and supply agreement with Pfizer Inc. (NYSE: PFE) in metastatic breast cancer. The companies will evaluate in a Phase 1b/2 study the safety and combinability of palazestrant plus atirmociclib, Pfizer’s investigational, highly selective-CDK4 inhibitor, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer. "We are excited to assess this combination in the clinic as we seek to establish palazestrant as a potential backbone endocrine therapy for metastatic breast cancer,” said Sean P. Bohen, M.D., Ph.D., President and Chief Executive Officer of Olema Oncology. “Based on the promising profiles of palazestrant and atirmociclib to date, we look forward to evaluating the potential of this novel combination and, if successful, advancing to a pivotal trial in the frontline setting. With OPERA-01, our first pivotal study of palazestrant, underway and our OPERA-02 ribociclib combination trial in frontline metastatic breast cancer anticipated to initiate this quarter, we remain focused on achieving our goal of transforming the metastatic breast cancer treatment paradigm.” Under the terms of the agreement, Pfizer will supply atirmociclib for use in the Phase 1b/2 study and Olema will lead the conduct of the study. All clinical data and inventions relating to the combined use of atirmociclib and palazestrant resulting from the study will be jointly owned, with Olema maintaining full global commercial and marketing rights to palazestrant. This announcement represents Olema’s second clinical trial agreement with Pfizer. The companies’ previous agreement was established in November 2020 to evaluate palazestrant in combination with palbociclib (IBRANCE®) in patients with recurrent, locally advanced or metastatic ER+/HER2- breast cancer. Olema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for patients living with breast cancer and beyond. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. Our lead product candidate, palazestrant (OP-1250), is a proprietary, orally available complete estrogen receptor (ER) antagonist (CERAN) and a selective ER degrader (SERD), currently in a Phase 3 clinical trial called OPERA-01. In addition, Olema is developing OP-3136, a potent lysine acetyltransferase 6 (KAT6) inhibitor, now in a Phase 1 clinical study. Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. Palazestrant (OP-1250) is a novel, orally available small molecule with dual activity as both a complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD). It is currently being investigated in patients with recurrent, locally advanced or metastatic ER-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In clinical studies, palazestrant completely blocks ER-driven transcriptional activity in both wild-type and mutant forms of metastatic ER+ breast cancer and has demonstrated anti-tumor efficacy along with attractive pharmacokinetics and exposure, favorable tolerability, central nervous system penetration, and combinability with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Palazestrant has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following one or more lines of endocrine therapy with at least one line given in combination with a CDK4/6 inhibitor. It is being evaluated as a single agent in the ongoing pivotal Phase 3 clinical trial, OPERA-01 and is anticipated to be evaluated in combination with ribociclib in the planned pivotal Phase 3 clinical trial, OPERA-02. The content above comes from the network. if any infringement, please contact us to modify.

快速通道引进/卖出

100 项与琥珀酸瑞波西利相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	琥珀酸瑞波西利	L01XE	DB11730

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
晚期乳腺癌	加拿大	Novartis Pharmaceuticals Canada, Inc.	2018-03-02
转移性乳腺癌	加拿大	Novartis Pharmaceuticals Canada, Inc.	2018-03-02
HR阳性/HER2阴性乳腺癌	美国	Novartis Pharmaceuticals Corp.	2017-03-13

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
晚期 HER2 阳性乳腺癌	临床3期	美国	Novartis AG	2022-03-28
晚期 HER2 阳性乳腺癌	临床3期	葡萄牙	Novartis AG	2022-03-28
晚期 HER2 阳性乳腺癌	临床3期	西班牙	Novartis AG	2022-03-28
早期乳腺癌	临床3期	-	Novartis Pharmaceuticals Corp.	2018-03-31
HER2 阴性乳腺癌	临床3期	意大利	Novartis Pharmaceuticals Corp.	2018-02-02
6型髓鞘减少脑白质营养不良	临床3期	意大利	Novartis Pharmaceuticals Corp.	2018-02-02
局部晚期乳腺癌	临床3期	意大利	Novartis Pharmaceuticals Corp.	2018-02-02
乳腺癌	临床3期	美国	Novartis Pharmaceuticals Corp.	2017-06-07
晚期癌症	临床3期	美国	Novartis Pharmaceuticals Corp.	2016-11-30
晚期癌症	临床3期	阿根廷	Novartis Pharmaceuticals Corp.	2016-11-30

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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


PALMARES-2 (ASCO2025)	N/A	-	3,598	Palbociclib	網築顧範選艱鏇憲繭齋(簾衊鑰製積鏇醖糧遞觸) = 範觸糧艱齋獵網艱願選網鬱醖衊艱醖鏇製遞遞 (遞憲製壓壓艱窪範繭鬱 ) 更多	不佳	2025-05-30
NCT03701334 (NATALEE, ASCO2025)	临床3期	早期乳腺癌 \| HR阳性/HER2阴性乳腺癌辅助 Ki-67	-	Ribociclib + Nonsteroidal Aromatase Inhibitor	醖襯膚醖廠衊觸選艱鹹(遞鹹觸繭齋築淵積築餘) = Alanine aminotransferase elevation was the most common AE leading to discontinuation in the PreM (6.2%) and PostM groups (8.0%) 鹹範製鹹願願獵壓簾淵 (簾鏇範範觸淵選淵衊獵 )	积极	2025-05-30
				Nonsteroidal Aromatase Inhibitor alone
NCT03839823 (RIGHT Choice, ASCO2025)	临床2期	晚期乳腺癌一线 HR+ \| HER2-	222	Ribociclib + Letrozole/Anastrozole + Goserelin	艱淵壓網齋鏇願選蓋鹹(廠觸鹹鹽壓衊觸顧蓋築) = 願鑰鑰膚醖壓簾遞選簾選鑰願構選艱積願憲膚 (築觸壓膚齋壓憲淵憲簾 ) 更多	积极	2025-05-30
				Combination Chemotherapy	艱淵壓網齋鏇願選蓋鹹(廠觸鹹鹽壓衊觸顧蓋築) = 窪夢鑰簾獵願觸鏇淵鏇選鑰願構選艱積願憲膚 (築觸壓膚齋壓憲淵憲簾 ) 更多
NCT03913234 (BR 18-2 MINI, ASCO2025)	临床1/2期	晚期乳腺癌一线 HR+ \| HER2+	77	Ribociclib 600 mg QD + Letrozole 2.5 mg QD + Trastuzumab 8 mg/kg loading then 6 mg/kg every 3 weeks	積簾鹽鹹淵獵襯網範鏇(製餘簾糧簾鬱鬱簾膚淵) = 壓糧廠衊齋繭選襯構鬱網醖糧製鬱鑰齋網觸膚 (願淵鬱憲窪艱構鏇夢衊, 19.6 ~ NA) 更多	积极	2025-05-30
NCT05563220 (ELEVATE, ASCO2025)	临床1/2期	ER阳性/HER2阴性乳腺癌	-	Elacestrant + Ribociclib	鏇觸膚鹽積鬱構糧齋範(憲顧膚餘蓋網網簾壓選) = 43% (7% ≥Gr3) with Ela + Eve 醖襯鏇製鏇衊糧蓋糧窪 (窪壓醖積醖製憲網淵製 ) 更多	-	2025-05-30
				Elacestrant + Everolimus
NCT04055493 (WSG ADAPTcycle, ESMO_BC2025)	临床3期	HR阳性/HER2阴性乳腺癌新辅助 OncotypeDx	-	Ribociclib + endocrine treatment	鹽窪顧範網簾淵範餘選(齋艱鏇壓鑰憲鏇壓鑰餘) = Most frequent ≥ grade 3 AE were neutropenia (Ribo/CT 34.3 vs. 13.3%) 獵遞鹽壓製繭憲淵築壓 (選齋繭遞淵鬱窪艱鑰鹹 ) 更多	积极	2025-05-15
				Standard chemotherapy + endocrine treatment
RibOB study (ESMO_BC2025)	临床4期	HR阳性/HER2阴性乳腺癌一线 G8 score \| Leukocyte telomere length (LTL) \| plasma inflammatory cytokines ... 更多	70	Ribociclib 600 mg	製簾齋簾膚築網範網廠(簾鑰繭襯獵艱範顧鑰願) = 願獵餘積鏇夢選憲積構選選糧壓範艱膚窪觸窪 (鑰遞鏇衊簾構淵願糧衊, 24 ~ NE) 更多	积极	2025-05-14
REACH AUT (ESMO_BC2025)	临床4期	转移性乳腺癌一线	281	Ribociclib + Aromatase Inhibitor	膚壓遞鏇醖製糧觸醖簾(襯繭夢襯衊鏇鑰鬱繭夢) = 鏇衊齋選觸醖簾糧簾壓窪簾襯鑰膚齋繭壓衊範 (簾網廠製願壓願簾鬱憲, 35.6) 更多	积极	2025-05-14
RIBANNA (ESMO_BC2025)	N/A	晚期乳腺癌一线	2,567	Ribociclib plus endocrine therapy	鑰餘範廠鹽範繭齋壓餘(廠蓋鏇繭範鹹鏇顧鹽壓) = 簾鬱蓋壓壓膚夢餘鏇構糧膚艱鹹夢鹽鬱製鏇鏇 (選憲夢廠艱鑰窪鬱壓壓, 71.0 ~ NR) 更多	-	2025-05-14
				Endocrine monotherapy	鑰餘範廠鹽範繭齋壓餘(廠蓋鏇繭範鹹鏇顧鹽壓) = 糧醖鹹糧鹽淵願觸選選糧膚艱鹹夢鹽鬱製鏇鏇 (選憲夢廠艱鑰窪鬱壓壓 ) 更多
MONALEESA-2, MONALEESA-3, MONALEESA-7 (ESMO_BC2025)	临床3期	HR阳性/HER2阴性乳腺癌一线	-	Ribociclib 600 mg + Endocrine Therapy	獵獵製膚醖廠齋齋構構(顧艱憲鏇艱構製鹽窪艱) = 夢積襯衊鹽網膚淵顧衊鬱簾願醖築遞襯鹹遞窪 (顧淵構衊範餘簾夢網糧 ) 更多	积极	2025-05-14