Phase 2, Multi-Center, Randomized, Open-Label Trial of BDC-1001 as a Single Agent and in Combination With Pertuzumab in Subjects With HER2-Positive Metastatic Breast Cancer Previously Treated With Trastuzumab Deruxtecan

This is an open-label, Phase 2 study to evaluate preliminary anti-tumor activity, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of BDC-1001 administered as a single agent and in combination with pertuzumab in subjects with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (Enhertu®).

开始日期2023-11-30

申办/合作机构

Bolt Biotherapeutics, Inc.

[+1]

NCT04278144 / Recruiting临床1/2期

Phase 1/2 Study of BDC-1001 as a Single Agent and in Combination With Nivolumab in Patients With Advanced HER2-Expressing Solid Tumors

A first-in-human study using BDC-1001 as a single agent and in combination with nivolumab in HER2 expressing advanced malignancies

开始日期2020-02-24

申办/合作机构

Bolt Biotherapeutics, Inc.

[+1]

100 项与 Trastuzumab Imbotolimod 相关的临床结果

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100 项与 Trastuzumab Imbotolimod 相关的转化医学

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100 项与 Trastuzumab Imbotolimod 相关的专利（医药）

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项与 Trastuzumab Imbotolimod 相关的新闻（医药）

2024-05-17

·佰傲谷BioValley

免疫激动ADC持续失败

日前，Bolt Biotherapeutics在2024年第一季度业绩报告中，表示将停止其核心管线trastuzumab imbotolimod (BDC-1001) 的开发，并裁员约50%。BDC-1001是一款TLR免疫激动抗体偶联物（ISAC），由靶向HER2的曲妥珠单抗生物类似药通过非可降解连接子与Bolt专有TLR 7/8双激动剂偶联。注意的是，BDC-1001是全球进度最快的免疫激动抗体偶联物之一、也是最具代表性的产品之一。放弃的原因根据Bolt公司报告，根据战略审查，BDC-1001计划不符合预定义的成功标准，因此将资源集中在下一代ISAC计划上。事实上，BDC-1001早在2021年12月就已经披露过一次令人失望的临床数据。来自于BDC-1001的1/2期研究中期数据显示，在40例疗效可评估患者中，客观缓解率（ORR）为2.5%，1例PR（部分缓解），12例SD（疾病稳定）。因此，尽管BDC-1001在所有剂量队列中显示出良好的安全性和耐受，以及临床响应的早期迹象，治疗后肿瘤活检的肿瘤微环境中的生物标志物发生变化。都未能挽回投资者的信心，Bolt公司的股票在披露BDC-1001的1/2期研究中期数据的当天大跌56%。根据报道，Bolt公司在放弃BDC-1001之后，将专注另外两个早期管线的开发，分别是Dectin-2激动抗体BDC-3042，处于1期临床阶段；以及Claudin 18.2靶向免疫激动抗体偶联物（ISAC）BDC-4182，处于临床前阶段。不过，Leerink Partners分析师Daina Graybosch在一份报告中下调了对Bolt公司股票的评级，认为新确定的两个优先级项目拥有较高的风险，因为其具有更新颖和早期性质。Bolt公司的免疫激动抗体偶联物（ISAC）计划将继续得到Genmab和Toray的合作支持，Genmab通过早期开发资助多达三个ISAC项目。Bolt公司目前的收入主要来自合作收入，分别来自Genmab、Toray和信达。预计将会获得约1.128亿美元的现金余额，以支持至2026年下半年的运营。持续失败的激动ADC免疫激动抗体偶联物（ISAC）是Magic Bullets(魔法子弹)理念延申下的一种抗体偶联药物（ADC）类型，但是与传统ADC偶联小分子毒素不同的是，ISAC偶联的是免疫激动剂（例如TLR、STING等）。ISAC的优势，通过抗体药物将免疫激动剂定向输送到肿瘤微环境中并局部释放，解决免疫刺激剂全身给药的障碍，提高抗肿瘤治疗的同时避免全身性的副作用。这种机制上的应用前景，吸引了大量药企的关注，一度成为研发热点。但是随着几款临床ISAC药物的数据出炉——极差的有效性数据，使得刚刚兴起的ISAC热潮被迫降温。诺华率先折戟ISAC诺华开发了一款靶向HER2的TLR免疫刺激抗体偶联物(ISAC)NJH395，是最早进入临床研究的ISAC药物。可惜的是，在NJH395的1期临床研究中，客观缓解率(ORR)为0%。此外，NJH395诱导快速而强大的全身免疫激活，高剂量给药会产生ADA和神经炎症。倒闭的ISAC先驱公司Silverback Therapeutics是开发ISAC药物的先驱企业，但是管线的失败，使得这家公司于2022年7月宣布终止运营，并剥离所有资产。2021年9月13日，Silverback在ESMO会议上公布了其ISAC新药SBT6050的I/Ib期临床的中期数据。14例可评估患者中，SBT6050的总缓解率ORR仅7%，疗效堪忧。该消息公布后，Silverback当天股价大跌25%，跌势难收。作为公司立足的核心技术的代表，SBT6050的失败造成了整个公司的崩塌。Silverback接连调整运营战略，但是依然未能挽回颓势，Silverback在2022年7月宣布终止在ISAC上继续探索的步伐。Bolt放弃核心ISAC2024年5月，在此前的临床数据惨淡的背景下，经Bolt公司审核，决定终止临床阶段的BDC-1001的开发。STING激动ADC也遭难2023年3月，Mersana Therapeutics的免疫激动ADC管线XMT-2056的1期临床试验被FDA叫停，原因是XMT-2056在剂量爬坡的第一个剂量组中就出现了5级（致命）严重不良事件（SAE），具体死亡原因仍在调查中。尽管XMT-2056在同年11月就被解除临床搁置，但同样为XMT-2056的开发蒙上了一层阴影。延伸阅读：降低剂量，免疫激动ADC解除临床搁置小结就整体开发进度来看，ISAC的开发处于非常早期的一个阶段，ISAC虽然理念清晰，但在临床试验中很难跨过剂量爬坡这一关。而TLRs、STING等激动剂本身开发常伴有治疗窗口窄、全身毒性的问题，在疗效提升的同时毒性也将增大，相较于ADC而言，ISAC的治疗窗口更难以把控。目前第一梯队几家企业的接连失利也给这类偶联组合药物的开发蒙上了一层阴影，未来ISAC能否转化为一种临床治疗手段仍待考察。延伸阅读：免疫激动ADC之殇参考资料：1.https://investors.boltbio.com/news-and-events/news-releases?a9d908dd_year%5Bvalue%5D=2020&op=%E6%BB%A4%E6%B3%A2%E5%99%A8&a9d908dd_widget_id=a9d908dd&form_build_id=form-8sb-vSKjxhpxkElLaIoCpWkzsMoZNbYuPxfVGHFurUs&form_id=widget_form_base2.https://www.biopharmadive.com/news/bolt-biotherapeutics-layoffs-ceo-change-restructuring-pipeline/716165/本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处········

抗体药物偶联物临床1期生物类似药

2024-05-15

·Endpoints

Bolt Biotherapeutics revamps as it drops lead cancer asset, changes CEO and trims headcount

Bolt Biotherapeutics is reshuffling to cut costs and extend its cash runway to the second half of 2026. The California biotech said Tuesday afternoon that it is dropping its lead oncology asset, as well as staging an executive team revamp and slashing its employee count in half. Bolt will cease development of an immune-stimulating antibody conjugate (ISAC), dubbed trastuzumab imbotolimod or BDC-1001, after the company found it was unlikely to meet a predefined success criteria. The candidate was in a Phase 1/2 trial in solid tumors, but had lackluster results in 2021. BDC-1001 comprises a HER2-targeting biosimilar of Herceptin conjugated with a TLR7/8 agonist.

抗体药物偶联物临床结果临床1期

2024-05-15

·BioPharmaDive

Bolt Biotherapeutics to lay off staff, abandon lead ADC candidate

San Francisco-based Bolt Biotherapeutics on Tuesday said it is ending development of its lead cancer drug, laying off half its staff and changing up its leadership.Alongside announcing first quarter earnings, the biotechnology company revealed it will no longer advance its antibody-drug conjugate trastuzumab imbotolimod, or BDC-1001, after concluding the program was unlikely to meet its high bar for advancement.Instead, the company will focus on two earlier-stage candidates: BDC-3042, an agonist antibody now in Phase 1 testing, and BDC-4182, currently in preclinical evaluation. The latter is a product of Bolts immune-stimulating antibody conjugate, or ISAC, platform, which is meant to trigger anti-tumor immune responses. Its aimed at a protein called Claudin 18.2 thats becoming an increasingly popular target among cancer drug developers.The companys ISAC research will continue to be supported by collaborations with Genmab and Toray. The former is funding up to three ISAC candidates through early-stage development, while the latter is funding one ISAC candidate through Phase 1 testing.In a client note downgrading her rating on Bolts stock, Leerink Partners analyst Daina Graybosch described the two newly prioritized programs as at the high end of risk, given novelty and early nature of development. While Graybosch expressed confidence in the promise of Bolts platform, she expects multiple surprises and restarts to come.Bolt is laying off 50% of its workforce, or approximately 50 people, as part of its pipeline reprioritization. The company expects the cuts to extend its cash runway into the second half of 2026.Additionally, Willie Quinn, who was previously Bolts chief financial officer, has replaced Randal Schatzman as CEO. Chief Business Officer Grant Yonehiro will be promoted to chief operating officer, and Chief Medical Offier Edith Perez will move into an advisory role.Shares for Bolt fell around 34% in Wednesday morning trading. The company is now worth about $33 million. '

抗体药物偶联物高管变更临床1期

100 项与 Trastuzumab Imbotolimod 相关的药物交易

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研发状态

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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


NCT04278144 (ESMO2023) 人工标引	临床1/2期	实体瘤 HER2 Expression	131	BDC-1001	鹽製簾膚艱繭製糧齋積(構鹹蓋網願獵鏇淵膚鹹) = 選膚網鏇壓廠願繭觸壓齋醖網觸憲膚選繭網獵 (夢觸膚蓋襯鹹淵範齋鏇 ) 更多	积极	2023-10-23
				BDC-1001+nivolumab	鹽製簾膚艱繭製糧齋積(構鹹蓋網願獵鏇淵膚鹹) = 憲顧獵構蓋憲廠築廠製齋醖網觸憲膚選繭網獵 (夢觸膚蓋襯鹹淵範齋鏇 ) 更多
NCT04278144 (ASCO2023) 人工标引	临床1/2期	HER2阳性实体瘤 HER2 Expressing	118	BDC-1001	夢遞構遞糧鑰構獵壓簾(簾繭繭鏇積鑰顧鹽鏇糧) = A related SAE (Gr4, bronchopulmonary hemorrhage) was seen in 1 pt (mono, 1.1%). 蓋憲鹹餘鑰網築醖鹽餘 (鹽鏇築憲齋製窪蓋觸構 ) 更多	积极	2023-05-26
				Nivolumab+BDC-1001
NCT04278144 (ASCO2021)	临床1/2期	HER2阳性实体瘤	20	BDC-1001	窪遞夢襯獵積繭窪鬱範(鹹築鹹遞繭鬱醖簾膚淵) = mild to moderate 積網顧遞夢膚膚遞餘獵 (鹽遞製淵壓廠衊齋製鬱 )	-	2021-05-28