A Safety, Tolerability and Pharmacokinetic Dose Escalation and Expansion, Phase I/Ib Study of AMC303 as Monotherapy in Patients With Advanced or Metastatic, Malignant Solid Tumour of Epithelial Origin

This is a two part Phase I/Ib, open-label, non-randomized and multi-center, dose escalation study with a 3+3 design (Part 1) and an expansion cohort at the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) (Part 2). If MTD is not reached in Part 1, RP2D will be determined after completion of Part 1 considering safety and tolerability, also beyond the dose limiting toxicity (DLT) period, pharmacokinetic (PK) and pharmacodynamic (PD) results.

开始日期2016-12-01

申办/合作机构

amcure GmbH

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项与 amcure GmbH 相关的文献（医药）

2020-01-01·Advances in Cancer Research2区 · 医学

The diverse and complex roles of atypical chemokine receptors in cancer: From molecular biology to clinical relevance and therapy

2区 · 医学

Review

作者: Szpakowska, Martyna ; Chevigné, Andy ; Sjöberg, Elin ; Augsten, Martin ; Östman, Arne ; Meyrath, Max

Chemokines regulate directed cell migration, proliferation and survival and are key components in cancer biology. They exert their functions by interacting with seven-transmembrane domain receptors that signal through G proteins (GPCRs). A subgroup of four chemokine receptors known as the atypical chemokine receptors (ACKRs) has emerged as essential regulators of the chemokine functions. ACKRs play diverse and complex roles in tumor biology from tumor initiation to metastasis, including cancer cell proliferation, adherence to endothelium, epithelial-mesenchymal transition (EMT), extravasation from blood vessels, tumor-associated angiogenesis or protection from immunological responses. This chapter gives an overview on the established and emerging roles that the atypical chemokine receptors ACKR1, ACKR2, ACKR3 and ACKR4 play in the different phases of cancer development and dissemination, their clinical relevance, as well as on the hurdles to overcome in ACKRs targeting as cancer therapy.

2019-07-01·Cancer Research

Abstract 4855: AMC303 inhibits tumor growth and metastasis in animal models by targeting CD44v6, a co-receptor of multiple oncogenic receptor tyrosine kinases

作者: Läufer, Thorsten ; Al-Rawi, Vanessa ; Coutelle, Oliver ; Heumann, Tina ; Matzke-Ogi, Alexandra ; Augsten, Martin

AbstractIntroduction: CD44v6, a member of the CD44 family, is an essential co-receptor for c-MET, RON and VEGFR-2. The receptor tyrosine kinases (RTKs) c-MET and RON, are key players in tumorigenic pathways, are activated by the ligands HGF and MSP, respectively and homo- or heterodimerize with each other or can be autoactivated due to amplification. The RTK VEGFR-2 is critical for angiogenesis in solid epithelial tumors. The peptidergic inhibitor AMC303, which allosterically and selectively binds to CD44v6, was investigated for its inhibitory effects on ligand-induced and autophosphorylated c-MET activation, and its impact on tumor growth and metastases in vivo.Methods: In vitro, tumor cells were incubated with AMC303 for 30 min prior to induction with an RTK-ligand. Analysis of RTK activation was carried out by Western blotting. For in vivo xenotransplantation human pancreatic tumor cells (L3.6pl) were orthotopically injected. Animals were treated with AMC303 i.p. at 0.1, 1, 10 mg/kg QOD or QWK for 3 weeks to address dose-dependency, the optimal treatment schedule was investigated with one, three or five times weekly administrations. Regression of metastases was investigated at 1 mg/kg QOD. Survival was evaluated with a dose of 1 mg/kg QOD. Immunohistochemical (IHC) analysis was performed for cleaved caspase 6, smooth muscle actin and CD31. Reduction of vessel permeability was assessed in Balb/C mice with the Miles assay and quantification of intra-tumoral FITC dextran after i.v. injection.Results: In vitro, AMC303 inhibited c-MET, VEGFR2 and RON phosphorylation induced by their respective ligands. Notably, AMC303 inhibited c-MET activation in cells with enhanced c-MET signaling caused by the exon 14 skipping mutation, but not c-MET auto-phosphorylation due to gene amplification. In vivo, AMC303 treatment attenuated primary xenograft tumor growth and metastasis and significantly prolonged survival. IHC on treated xenograft-tumors revealed an increase in apoptosis and necrosis along with a reduction in myofibroblast infiltration, angiogenesis and vessel permeability. Pharmacokinetic properties after i.p. administration of AMC303 revealed an terminal half-life of 6h. Administration schedules of AMC303 (1mg/kg) given one, three or five times per week had no significant impact on tumor growth attenuation. AMC303 treatment could be paused for 10 days without incurring significant tumor regrowth.Conclusions: AMC303 inhibits c-MET in vitro in a ligand-dependent fashion and in vivo significantly improved overall survival in an orthotopic pancreatic xenograft mouse tumor model. AMC303 effectively attenuated both primary and metastatic tumor growth by increasing apoptosis, reduction of angiogenesis and vascular normalization. These findings demonstrate the benefit of targeting multiple oncogenic RTK signaling pathways by AMC303.Citation Format: Tina Heumann, Vanessa Al-Rawi, Thorsten Läufer, Martin Augsten, Alexandra Matzke-Ogi, Oliver Coutelle. AMC303 inhibits tumor growth and metastasis in animal models by targeting CD44v6, a co-receptor of multiple oncogenic receptor tyrosine kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4855.

2019-06-01·Cancer Immunology, Immunotherapy2区 · 医学

An immunosuppressive macrophage profile attenuates the prognostic impact of CD20-positive B cells in human soft tissue sarcoma

2区 · 医学

Article

作者: Tobin, Nicholas P ; Li, Tian ; Bergh, Jonas ; Zhang, Yifan ; Augsten, Martin ; Ehnman, Monika ; Tsagozis, Panagiotis ; Haglund, Felix ; Hesla, Asle

BACKGROUNDImmune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized.METHODSMarker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics.RESULTSB cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10^low, PTGS2^low or CD163^low tumor microenvironment according to the transcriptomic data. IL10 levels consistently correlated with the M2-like macrophage marker CD163, which also defined the majority of macrophages. A polarization of these cells toward a pro-tumoral phenotype was further supported by lack of correlation between CD163 and M1 markers like NOS2, as well as by low abundance of CD80 positive cells in tissue.CONCLUSIONSAnalysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages.

项与 amcure GmbH 相关的新闻（医药）

2023-02-21

·药渡Daily

成立十周年，海创药业即将步入商业化元年？

2013年2月5日，怀揣着中国创新药的使命感，陈元伟与其海归团队创立了海创药业，“海归创业”即是公司名字的由来。如今，十年之期已至，海创药业交出了怎样的成绩单？氘代药物商业化开局十年，被认为是一款创新药研发所需要的时间周期，海创药业首先给出的是一款氘代药物。所谓氘代药物是指含有氘原子的药物，而氘代技术是指用氘原子替换小分子化合物上的氢原子，以相同的结构、不同的组成来完美规避原研药的专利封锁。氘代原理图来源：参考资料1海创药业首个即将进入商业化的产品——德恩鲁胺（HC-1119）就是第二代雄激素受体（AR）拮抗剂恩扎卢胺的氘代化合物，用于前列腺癌治疗。2022年6月26日，海创药业发布公告，HC-1119中国III期临床研究已经完成。该中国III期临床试验采取差异化策略，解决阿比特龙和多西他赛治疗失败的晚期前列腺癌患者未满足的临床需求。海创药业已向国家药品监督管理局药品审评中心递交中国上市前的沟通交流申请，目前相关事项正在按照药品审评中心要求顺利推进中。临床结果显示，与恩扎卢胺相比，HC-1119有效性更高，80mg HC-1119与160mg恩扎卢胺疗效相当，病人依从性更好；安全性更好，已有临床受试者中尚未有癫痫发生，有望成为临床上用于前列腺癌治疗更好的选择。市场潜力方面，前列腺癌是世界范围内最常见的恶性肿瘤之一，在全球位列男性恶性肿瘤发病率第二、死亡率第五；中国前列腺癌患者数量已从2015年的8.8万人增长到2019年10.8万人，年复合增长率5.3%，预计到2030年，新发病例数将达到约20万人，中国前列腺癌药物市场规模也从2015年的人民币22亿元增长到2019年的人民币53亿元，年复合增长率为24.5%，并且预计到2024年，其市场规模将达到人民币155亿元，年复合增长率为24.1%。竞争方面，原研药恩扎卢胺早在2012年就已上市，2019年在国内获批，并进入医保目录，2020年全球销售额约43.9亿美元，占AR抑制剂全球市场份额77.8%。但恩扎卢胺专利面临挑战，2021年8月，豪森药业的恩扎卢胺仿制药获批首仿上市，而四川科伦、沈阳红旗、齐鲁制药等也已递交了仿制药上市申请。面对原研药和仿制药的双重竞争，HC-1119选择从转移性去势抵抗性前列腺癌（mCRPC）二、三线治疗切入，目前该领域尚未有获批的治疗药物，HC-1119上市后将具备差异化竞争优势。为了迎接首个商业化产品上市，海创药业也在着手准备生产和销售团队。一方面委托有资质的CDMO/CMO、药物生产企业生产临床药物；同时开始建设符合国际GMP标准的研发生产基地，以满足HC-1119等产品后续商业化生产需要。另一方面积极组建商业化团队。1月31日，海创药业宣布聘任唐刚为营销中心副总裁，负责公司产品商业化推广相关事宜。加入海创药业前，唐刚担任荣昌生物副总裁，从0到1完成市场营销体系搭建及商业推广团队建立，负责首个国产ADC药物的商业化推广，主导RC48上市并列入国家医保目录。PROTAC 革命性技术与氘代技术及氘代药物相比，海创药业更受关注的是其PROTAC技术。PROTAC，即蛋白降解靶向嵌合体。PROTAC技术利用双功能小分子靶向降解目标蛋白（TPD），被认为是生物医药领域的革命性技术，可靶向不可成药靶点及解决药物耐药性问题，背后对应的市场价值高达万亿。与传统小分子药物相比，PROTAC的优势包括：◆高选择性、高活性由于PROTAC 分子降解蛋白后能被循环利用因此催化活性大大提高，通常小分子抑制剂抑制活性IC50在nmol级，而PROTAC分子DC50能达到单位数的nmol级甚至pmol级。因此，PROTAC药物只需很低的剂量就可以有更好、更长久的药效。◆靶点更多与传统小分子或抗体局限于单个可识别的活性位点不同，PROTAC靶向蛋白质降解可以通过靶蛋白表面上的任何结合位点介导，更容易开发简单有效和选择性高的配体，作用于一些传统意义上的不可成药的靶点。◆克服耐药性传统小分子抑制剂产生耐药性的常见原因是发生了靶蛋白的代偿性增加或突变。PROTAC分子通过降解靶蛋白，完全消除其功能，可以解决小分子抑制剂常出现的耐药性问题。PROTAC工作原理来源：参考资料1目前，全球范围内尚未有PROTAC药物上市，进入临床的PROTAC药物约20个（国产7个），且都处于临床早期。进展最快的是Arvinas的ARV-110和ARV-471，均已进入Ⅱ期临床。在这场PROTAC技术的竞速赛中，海创药业是国内最早一批探索相关领域的企业。截至2022年上半年，公司已获得PROTAC 技术相关授权发明专利 3 项，通过PCT申请4项。依靠PROTAC技术平台，海创药业已合成多个目标蛋白配体、数百个Linker，在PROTAC分子结构设计、化合物合成已具备丰富经验。在海创药业的研发管线中，有三款PROTAC产品。其中，HP518是一款靶向降解AR的治疗前列腺癌的口服PROTAC药物，目前正在澳大利亚开展I期临床试验，是中国首款进入临床试验阶段的口服AR PROTAC药物。2023年2月1日，HP518用于治疗转移性去势抵抗性前列腺癌（mCRPC）的临床试验申请已正式获得FDA批准，继其在澳大利亚开展I期临床试验之后，现于美国也已进入临床阶段。与Arvinas的ARV-110类似，HP518靶向难以成药的AR剪切突变体以治疗耐药性前列腺癌，目前这一领域存在极大未满足的临床需求，市场前景广阔。从小分子靶向药到单抗、双抗、ADC药物，再到核酸药物、细胞疗法，谁能率先掌握最新技术，就能引领行业发展。在PROTAC药物领域，海创药业与全球领头羊Arvinas差距并不大，未来如能获得突破性进展，前景或将不可估量。三年亏11亿距离商业化有多远由于没有一款药品上市，主要产品仍处于研发状态，2020年-2022年，海创药业分别亏损4.9亿元、3.06亿元及3.03亿元，三年累计亏损11亿元。亏损的主要原因是巨额的研发投入。2020年-2022年，海创药业的研发费用分别为4.29亿元、2.65亿元及2.55亿元。高额的研发投入，换取的是多款产品进入临床。海创药业目前拥有 10 项在研产品，其中 4 项产品进入临床试验的不同研究阶段。除了前文的HC-1119及HP518，还有一款引进自amcure GmbH一款First-in-class的特异性靶向CD44v6的抑制剂HP558、以及一款针对高尿酸血症、痛风等代谢性疾病的URAT1抑制剂HP501。海创药业研发管线来源：参考资料1对于何时能够盈利，海创药业预测需要等到核心产品HC-1119及HP501上市，并实现10至12亿元的销售收入，才有望在2025年实现盈亏平衡。在此之前，海创药业预计10项在研产品还需要至少再投入10.8亿元研发费用。再加上海创药业才刚刚开始建立商业化团队，未来产品上市推广、构建销售网络也将是一笔不菲的费用。为了维持高额的研发支出，IPO前，海创药业就已完成多轮融资，其中B轮融资4000万美元，C轮融资近10亿元人民币，投资方包括：海思科、上海复星、深圳投控、成都高投、泰格医药等多家投资机构。2022年4月12日，海创药业成功登陆科创板，发行价格为42.92元/股，募集资金10.6亿元。值得关注的是，虽然2022年海创药业长期处于破发状态，但自2023年以来，截至2月6日，A股股价已上涨42.27%，尤其是2月2日实现20%涨停，创下历史新高。海创药业股市走势来源：百度股市通从现金流来看，截至三季报，海创药业有现金2.76亿元，交易性金融资产14.21亿元，合计16.97亿元，以每年亏损3.5亿元计，还可支撑四年多时间。因此，在2026年前，海创药业必须成功实现商业化。总结2023年，是海创药业的关键年，首款氘代药物即将上市，如能顺利实现商业化，将为后续氘代技术及PROTAC技术转化为商业价值奠定基础。参考资料1.海创药业招股书，官网2. https://www.nbd.com.cn/articles/2023-02-01/2651468.html3.https://baijiahao.baidu.com/s?id=1729985073538783020&wfr=spider&for=pcEND👇关注药渡数据媒体矩阵

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