A Phase 1/2a, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HDP-101 in Patients With Plasma Cell Disorders Including Multiple Myeloma

This study will assess the safety, tolerability, pharmacokinetics (PK) and the therapeutic potential of HDP-101 in patients with plasma cell disorders including multiple myeloma.

开始日期2022-02-07

申办/合作机构

Heidelberg Pharma AG

EUCTR2020-003414-12-DE / Not yet recruiting临床1/2期

A Phase 1/2a, First-in-human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of HDP-101 in Patients with Plasma Cell Disorders Including Multiple Myeloma

开始日期2021-09-09

申办/合作机构

Heidelberg Pharma AG

100 项与 Pamlectabart tismanitin 相关的临床结果

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100 项与 Pamlectabart tismanitin 相关的转化医学

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100 项与 Pamlectabart tismanitin 相关的专利（医药）

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项与 Pamlectabart tismanitin 相关的文献（医药）

2021-02-01·Molecular cancer therapeutics2区 · 医学

HDP-101, an Anti-BCMA Antibody–Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells

2区 · 医学

Article

作者: Müller, Christoph ; Baumann, Anja ; Breunig, Christian ; Pahl, Andreas ; Lutz, Christian ; Raab, Marc S. ; Pálfi, Anikó ; Giesen, Nicola ; Hechler, Torsten ; Figueroa-Vazquez, Vianihuini ; Müller-Tidow, Carsten ; Goldschmidt, Hartmut ; Kulke, Michael ; Ko, Jonathan ; Krämer, Alwin

Abstract:

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti–B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

2018-12-01·Drug discovery today. Technologies

Amanitins and their development as a payload for antibody-drug conjugates

Review

作者: Pahl, Andreas ; Lutz, Christian ; Hechler, Torsten

Amanitin-based ADCs represent a new class of ADCs using a novel mode of action. This payload introduces a novel mode of action into oncology therapy, the inhibition of RNA Polymerase II. The high potency of the toxin leads to highly efficacious ADCs. The development of the technology around this toxin will be described. These developments support the clinical development of amanitin-based ADCs by using a toxin with a new mode of action and with a favorable therapeutic index. HDP-101 is an Amanitin based ADC directed against BCMA and will be advancing to the clinical phase in 2019.

Research square

Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models

作者: Shirazi, Fazal ; Lee, Hans C. ; Jones, Richard J. ; Pahl, Andreas ; Kuiatse, Isere ; Singh, Ram Kumar ; Qin, Li ; Orlowski, Robert Z. ; Zou, Jianxuan ; Hong, Samuel ; Patel, Krina K. ; Wan, Jie ; Wang, Hua ; Choudhary, Rajan Kumar

Abstract:

B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not -negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.

项与 Pamlectabart tismanitin 相关的新闻（医药）

2024-12-07

·医药魔方Info

国内首款！葛兰素史克BCMA ADC在华申报上市

12月7日，CDE网站显示，葛兰素史克（GSK）的Belantamab mafodotin（玛贝兰妥单抗）在华申报上市。今年10月，玛贝兰妥单抗已被纳入优先审评，用于联合硼替佐米和地塞米松治疗既往接受过至少一种治疗的多发性骨髓瘤成年患者。玛贝兰妥单抗是Seagen（已被辉瑞收购）开发的一款BCMA ADC。2009年12月，GSK与Seagen达成协议，获得该药物的研究、开发、生产和商业化权益。 2020年，玛贝兰妥单抗在美国和欧盟获批上市，用于治疗既往接受过至少4种治疗（包括抗CD38单抗、蛋白酶体抑制剂和免疫调节剂）的复发性或难治性多发性骨髓瘤成年患者。不过，因验证性III期DREAMM-3研究未能达到主要终点，GSK已分别于2022年和2023年在美国和欧盟撤回该适应症。为探索玛贝兰妥单抗作为多发性骨髓瘤患者的二线治疗方案的应用潜力，GSK此前还开展了两项III期研究（DREAMM-7和DREAMM-8）。这两项研究已分别于2023年11月和今年6月达到主要终点。 DREAMM-7研究旨在评估玛贝兰妥单抗+BorDex（硼替佐米+地塞米松）vs. 强生的CD38单抗达雷妥尤单抗+BorDex在复发或难治性多发性骨髓瘤二线及之后治疗中的疗效。在无进展生存期（PFS）的主要终点中，与达雷妥尤单抗联合用药组（n=251）相比，玛贝兰妥单抗联合治疗组（n=243）观察到具有统计学意义和临床意义的改善，显示疾病进展或死亡风险降低了59%。中位随访时间为28.2个月，玛贝兰妥单抗联合治疗组的中位PFS为36.6个月，而达雷妥尤单抗联合治疗组为13.4个月。也就是说，玛贝兰妥单抗联合治疗相较于标准疗法延长了近3倍PFS。目前，除玛贝兰妥单抗以外，全球仅HDP-101（Heidelberg Pharma/华东医药）一款BCMA ADC处于临床开发阶段。 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。精彩预告线上直播 ↑点击扫码，直达直播间↑

临床3期抗体药物偶联物引进/卖出并购优先审批

2024-11-06

·米内网

中美华东发威！13亿品种国产首家获批，重磅注射剂大涨1270%，10款新药、2个首仿药冲刺

精彩内容 11月6日，华东医药发布公告称，子公司中美华东的乌司奴单抗注射液获批上市，为国产首家，刚过去的10月公司再有3款新药获批临床，公司的新药矩阵越来越丰富。据米内网预测，中美华东4款报产在审的新药中（含合作项目），索米妥昔单抗注射液有望在今年年底前获批，还有6款新药已在III期临床阶段，未来几年公司将进入新药上市爆发期。仿制药方面，公司今年已拿下了他克莫司颗粒的国内首仿，还有两大新品将参与首仿争夺战。公司已过评产品达28个，3个口服药将参与第十批国采。 13亿品种国产首家获批，4款新药加速冲刺中美华东一直深耕内分泌、自身免疫及肿瘤等治疗领域，近几年持续加大研发投入，不断丰富新药研发管线布局，积极推进临床工作进度，陆续取得了多项重大阶段性成果。图1：中美华东最新获批的产品来源：国家药监局官网 2023年在中国三大终端六大市场（统计范围见文末），乌司奴单抗的销售额已超过13亿元，中美华东（新药3.3类）为国产首家获批，同时该产品也是公司第二款获批的生物药，用于治疗成年中重度斑块状银屑病。公司公告中提到，中美华东在该项目的研发直接投入总金额已超过1.5亿元。表1：2024年10月中美华东获批临床的新药情况（含合作项目）来源：公司公告、米内网整理公司与重庆派金生物在2022年4月联合提交了司美格鲁肽注射液糖尿病适应症的临床申请并于同年6月获批，III期临床已于今年10月完成。2024年7月，该新药体重管理适应症的临床试验申请获受理并于10月获得临床批件。 HDP-101是中美华东的合作开发项目，该新药是一种新型ADC药物，由人源化抗BCMA抗体与蘑菇毒素α-鹅膏蕈碱肽衍生物偶联而成，用于治疗B细胞成熟抗原（BCMA）阳性克隆性血液学疾病（如复发/难治性多发性骨髓瘤）。 HDM2006片是公司自主研发的小分子抗肿瘤药物HPK-1 PROTAC（造血祖激酶1蛋白降解靶向嵌合体），临床前研究结果显示，该新药在多个肿瘤模型中表现出显著的抗肿瘤效果，与PD-1/PD-L1抗体联用具有协同抗肿瘤作用。表2：中美华东部分重磅新药的最新情况（含合作项目）注：已终止项目不纳入统计来源：公司三季报、米内网综合数据库据米内网预测，中美华东报产在审的4款新药中，索米妥昔单抗注射液有望在2024年年底前获批，而瑞玛吡嗪注射液、迈华替尼片、注射用利纳西普或将在2025年上半年迎来好消息。 6款已在III期临床的新药中，QX005N注射液已于今年5月分别完成结节性痒疹和特应性皮炎2个适应症的首例受试者入组，德谷门冬双胰岛素注射液也于今年8月完成首例受试者入组，德谷胰岛素注射液预计在今年四季度获得主要终点数据，司美格鲁肽注射液糖尿病适应症预计在今年四季度获得主要终点数据并递交pre-BLA沟通。稳坐三大百亿市场国内龙头，首款生物药大涨1270% 2023年在中国三大终端六大市场（化+生），免疫抑制剂、糖尿病用药、抗血栓形成药的销售规模均在百亿以上，中美华东已成为这3个亚类市场的国内龙头企业。 2024上半年在中国三大终端六大市场，免疫抑制剂的销售额达169亿元，增长率为8.16%。中美华东排在TOP2企业，与TOP1企业诺华的份额差距在6%左右。公司的他克莫司胶囊2024上半年销售额超12亿元，环孢素软胶囊、吗替麦考酚酯分散片、吗替麦考酚酯片的销售额分别为4.2亿元、2.0亿元、1.1亿元左右。 2024上半年在中国三大终端六大市场，糖尿病用药的销售额达331亿元，增长率为5.41%。中美华东排在TOP6企业，前五名被跨国药企包揽，分别是诺和诺德、阿斯利康、默沙东、赛诺菲、默克。公司的吡格列酮二甲双胍片(15mg/500mg)2024上半年销售额超6.6亿元，阿卡波糖片、二甲双胍恩格列净片(Ⅰ)的销售额分别为2.5亿元、1.7亿元左右。 2024上半年在中国三大终端六大市场，抗血栓形成药的销售额达177亿元，降幅在6.72%。中美华东排在TOP4企业，销售额增长率为12.42%，前三名分别是拜耳、赛诺菲、勃林格殷格翰。表3：2024上半年中美华东部分销售额正增长的产品情况来源：米内网中国三大终端六大市场药品竞争格局图2：中美华东的二甲双胍恩格列净片(Ⅰ)的销售情况（单位：万元）来源：米内网中国三大终端六大市场药品竞争格局 2024上半年在中国三大终端六大市场，中美华东TOP20产品中有8个销售额有正增长。公司的二甲双胍恩格列净片(Ⅰ)是2021年获批的新品，2023年销售额突破2亿元，2024上半年再有85.26%的增长。公司的利拉鲁肽注射液在2023年获批，是公司首款上市的生物药。在中国三大终端六大市场，中美华东的利拉鲁肽注射液2024上半年销售额增速高达1269.71%，公司已成为利拉鲁肽注射液的TOP2企业（国内龙头）。 28个产品已过评，两大新品冲击国内首仿图3：2024年至今中美华东获批的仿制药新品来源：米内网中国上市药品（MID）数据库今年以来，中美华东已陆续获批了3个仿制药新品，其中他克莫司颗粒为国内首仿。目前公司还有6个仿制药新品报产在审，有望继续扩大公司在免疫抑制剂、抗肿瘤药、全身用抗真菌药市场的产品矩阵，还将在血脂调节剂市场迎来新突破。图4：中美华东报产在审的仿制药新品来源：米内网中国申报进度（MED）数据库西罗莫司片和注射用卡非佐米均为免疫抑制剂，目前仅有原研企业获批进口，中美华东有望参与国内首仿争夺。2023年在中国三大终端六大市场，西罗莫司片和注射用卡非佐米均是亿元级别的畅销产品，市场潜力可期。中美华东已上市的产品暂无血脂调节剂，二十碳五烯酸乙酯软胶囊若顺利获批，将为公司打开新市场大门，2023年在中国三大终端六大市场，血脂调节剂的销售额在220亿元以上，2024上半年再有2.57%的增长，百亿市场将迎来新的掘金者。截至2024年11月5日，中美华东过评（含视同过评）的产品有28个，公司积极参与国家集中带量采购，第三批至第七批（不含胰岛素专项）共5个产品中标。表4：中美华东国采中标产品的市场情况来源：米内网中国公立医疗机构药品终端竞争格局随着各批次国采陆续落地执行，助力中美华东的中标产品提升市场占有率，2024上半年在中国城市公立医院、县级公立医院、城市社区中心及乡镇卫生院（简称中国公立医疗机构）终端，中美华东已成为了吗替麦考酚酯胶囊的TOP2企业（国内龙头）、注射用泮托拉唑钠的TOP3企业。 11月1日，第十批国采相关药品信息填报工作正式展开，中美华东的西格列汀二甲双胍片(Ⅰ)、西格列汀二甲双胍片(Ⅱ)和马昔腾坦片或将参与竞标，上述3个产品均为公司近五年获批的新产品。资料来源：国家药监局官网、米内网数据库、公司公告等注：米内网《中国三大终端六大市场药品竞争格局》，统计范围是：城市公立医院和县级公立医院、城市社区中心和乡镇卫生院、城市实体药店和网上药店，不含民营医院、私人诊所、村卫生室，不含县乡村药店；上述销售额以产品在终端的平均零售价计算。数据统计截至11月5日，如有疏漏，欢迎指正！本文为原创稿件，转载请注明来源和作者，否则将追究侵权责任。投稿及报料请发邮件到872470254@qq.com稿件要求详询米内微信首页菜单栏商务及内容合作可联系QQ：412539092 【分享、点赞、在看】点一点不失联哦

抗体药物偶联物临床3期蛋白降解靶向嵌合体上市批准申请上市

2024-10-24

·heidelberg-pharma.com

PR: Heidelberg Pharma to Participate in Leading Scientific and Financial Conferences in November 2024

Ladenburg, Germany, 24 October 2024 – Heidelberg Pharma AG (FSE: HPHA), a clinical-stage developer of innovative Antibody Drug Conjugates (ADCs), announces it will present its ADC candidates and ADC technology platforms at leading scientific and financial conferences throughout November. The Company’s most advanced Amanitin-based ADC product candidate, HDP-101, is currently in a Phase I/IIa trial for the treatment of relapsed or refractory multiple myeloma. In late September, Heidelberg Pharma presented clinical data from the fifth patient cohort, demonstrating a case of complete remission in a patient who had been treated multiple times. This patient showed a partial response after the second treatment cycle, with a complete remission observed after 11 cycles. In addition, several patients exhibited promising biological activity and objective improvements, underscoring the potential of HDP-101 as a treatment option for patients with this disease. HDP-201, Heidelberg Pharma’s first Exatecan-based ADC candidate, is a topoisomerase I inhibitor that has proven success in cancer therapy and is already used in two approved ADCs. Its distinct mode of action from Amanitin broadens the Company’s portfolio of active ingredients. HDP-201 targets guanylyl cyclase-C (GCC), a receptor expressed on the surface of intestinal cells and cancer cells in various gastrointestinal tumors. Preclinical data suggest that the tolerability and efficacy of HDP-201 is at least on a par with existing, approved Exatecan-based ADCs. Following extensive preclinical testing, the final development candidate for HDP-201 was determined in recent weeks, with colorectal cancer identified as the target indication for its clinical development. World ADC San Diego 2024 Date & location: 4 – 7 November 2024 San Diego, California, USA Workshop: 2nd Biomarker & Patient Selection Day Date: 4 November, 10:30 am PST Title of presentation: Leveraging 17p Deletion as a Biomarker & Patient Selection Tool for Amanitin Payload ADCs Presenter: Anikó Pálfi, Director Biochemistry & Cell Biology Stream: Discovery Chemistry Date: 6 November, 2:00 pm PST Title of presentation: HDP-201, a Multimeric Linker-Exatecan-based ADC as Novel Therapeutic Modality for Treatment of Solid Tumors Presenter: Professor Andreas Pahl, CEO Plenary: BCMA Breakdown: Exploring Case Studies of ADC Development for Targets Without an Approved Therapy Date: 6 November, 4:00 pm PST Title of presentation: ATACs: A New Payload Provides New Options for Cancer Therapy Presenter: Dr. Torsten Hechler, Senior Vice President ADC Research Deutsches Eigenkapitalforum Date & location: 25 – 27 November 2024, Frankfurt, Germany Panel: Company Presentations (Room Zurich) Date: 26 November, 11:15 am MEZ Title of presentation: Leader in Next Generation ADC Payloads Presenter: Walter Miller, Chief Financial Officer Walter Miller will be available for one-on-one meetings, which can be arranged via the online conference system.

临床结果抗体药物偶联物临床1期

100 项与 Pamlectabart tismanitin 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
难治性多发性骨髓瘤	临床2期	美国	Heidelberg Pharma AG	2022-02-07
难治性多发性骨髓瘤	临床2期	德国	Heidelberg Pharma AG	2022-02-07
难治性多发性骨髓瘤	临床2期	匈牙利	Heidelberg Pharma AG	2022-02-07
难治性多发性骨髓瘤	临床2期	波兰	Heidelberg Pharma AG	2022-02-07
多发性骨髓瘤	临床2期	美国	Heidelberg Pharma AG	2021-05-01
副蛋白血症	临床2期	德国	Heidelberg Pharma AG	2021-05-01
慢性淋巴细胞白血病	临床1期	德国	Heidelberg Pharma Research GmbH	2022-01-30
弥漫性大B细胞淋巴瘤	临床1期	德国	Heidelberg Pharma Research GmbH	2022-01-30
BCMA阳性多发性骨髓瘤	临床申请批准	中国	Heidelberg Pharma AG	2024-10-15

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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


NCT04879043 (HDP-101-01, PipelineReview) 人工标引	临床1/2期	难治性多发性骨髓瘤	12	HDP-101	艱蓋獵膚簾獵製獵構膚(鹽繭衊鹽餘遞憲鑰構醖) = The Safety Review Committee's (SRC) evaluation of patient data concluded that no dose-limiting toxicities have occurred to date. 構簾鏇壓鬱蓋範淵憲選 (鑰糧積鬱築餘憲製選繭 )	积极	2023-09-19
NCT04879043 (HDP-101-01, ASH2022) 人工标引	临床1/2期	复发性多发性骨髓瘤	4	HDP-101	淵壓繭衊醖網築衊壓齋(齋憲鏇顧艱廠範糧鹽壓) = 積淵膚窪鑰鹹觸選齋遞窪廠淵網構壓願襯製製 (鹽網網憲糧製鏇壓餘窪 )	积极	2022-11-15