Phase I Study with Dose-escalation and Expansion Evaluating the Safety and Efficacy of Oral Arsenic (ATO) in Low-risk Myelodysplastic Syndromes Failing Erythropoiesis Stimulating Agents and Luspatercept (or Ineligible for the Latter)

Phase I study with dose-escalation and expansion evaluating the safety and efficacy of oral Arsenic (ATO) in low-risk Myelodysplastic Syndromes having failed to Erythropoiesis Stimulating Agents and Luspatercept (or ineligible for the latter).

开始日期2025-02-01

申办/合作机构

Groupe Francophone des Myélodysplasies

ChiCTR2400093196 / Suspended临床4期IIT

Efficacy and safety of arsenic trioxide-based sequential chemotherapy in patients with relapsed/refractory ovarian cancer: a randomized controlled, open-label, multi-center clinical trial

开始日期2024-12-01

申办/合作机构

北京大学人民医院

NCT06088030 / Recruiting临床2期IIT

Clinical Research on Efficacy and Safety of Arsenic Trioxide Combined With Chemotherapy in p53-mutated Pediatric Cancer Patients：A Prospective，Single-arm, Multi-center Study

This prospective, single-arm, multi-center clinical trial aims to explore and evaluate the efficacy and safety of arsenic trioxide combined with chemotherapy for pediatric cancer with p53 mutation.

开始日期2023-12-13

申办/合作机构

中山大学孙逸仙纪念医院

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100 项与三氧化二砷相关的临床结果

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100 项与三氧化二砷相关的转化医学

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100 项与三氧化二砷相关的专利（医药）

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5,849

项与三氧化二砷相关的文献（医药）

2025-01-01·JOURNAL OF ETHNOPHARMACOLOGY

Targeting Nrf2/HO-1 signaling by crocin: Role in attenuation of arsenic trioxide-induced neurotoxicity in mice

Article

作者: Wang, Hefei ; Zhao, Yawei ; Chu, Xi ; Xu, Hao ; Wu, Zhonglin ; Li, Chen ; Hao, Yiwei ; Zhang, Shi ; Han, Xue ; Dong, Chunhui ; Shi, Jing

ETHNOPHARMACOLOGY RELEVANCE:

Saffron is a valued herb, obtained from the stigmas of the C.sativus Linn (Iridaceae). Pharmacopoeias have described it as having a variety of actions, such as stimulant, anti-carcinogen, and anti-depressant. As a folk medicine, crocin has been reported to have anti-cardiotoxicity and anti-hepatotoxicity effects. This paper focuses on crocin, one of the bioactive molecules found in saffron that are known to have therapeutic effects. Crocin has been shown in numerous experimental studies to be beneficial in treating depression, however, there aren't many studies on its neurotoxicity.

AIM OF THE STUDY:

Applications of arsenic trioxide (ATO) in medical settings is limited by its side effects. This study aims to examine crocin's protective effect against ATO-induced neurotoxicity and understand its potential molecular mechanism. Materialandmethods: A neurotoxicity model was created by administering ATO (4 mg/L/d). To counteract this, mice were intraperitoneally injected with crocin (100, 200 mg/kg/d). After 60 days, biochemical, histopathological, transmission electron microscopy, ELISA, and western blotting analyses were then performed.

RESULTS:

Our results indicated that crocin decreased neuronal death and loss caused by ATO, countered oxidative stress damage, and mitigated pro-inflammatory cytokines. Mice treated with crocin also displayed positive signs of brain tissue recovery. Additionally, crocin reduced the protein expressions of NLRP1, apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, GRP78, CHOP, and ATF4.

CONCLUSIONS:

This study attests that crocin can reduce ATO-induced neurotoxicity by safeguarding nerves from oxidative stress, inflammation, and apoptosis, possibly through the activation of the Nrf2/HO-1 signaling pathway.

2024-12-31·Hematology (Amsterdam, Netherlands)

Prognosis influence of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia with t(15;17)(q24;q21)

Article

作者: Xu, Huan ; Wang, Lu ; Zhao, Shuqi ; Tong, Hongyan ; Wang, Huanping ; Jin, Jie ; Huang, Jiansong ; Liu, Lin ; Wang, Jinghan

OBJECTIVES:

In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs.

METHODS:

268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs.

RESULTS:

APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable.

CONCLUSIONS:

Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.

2024-12-31·Nucleus (Austin, Tex.)

PML Nuclear bodies: the cancer connection and beyond

Review

作者: Abou-Ghali, Majdouline ; Lallemand-Breitenbach, Valérie

Promyelocytic leukemia (PML) nuclear bodies, membrane-less organelles in the nucleus, play a crucial role in cellular homeostasis. These dynamic structures result from the assembly of scaffolding PML proteins and various partners. Recent crystal structure analyses revealed essential self-interacting domains, while liquid-liquid phase separation contributes to their formation. PML bodies orchestrate post-translational modifications, particularly stress-induced SUMOylation, impacting target protein functions. Serving as hubs in multiple signaling pathways, they influence cellular processes like senescence. Dysregulation of PML expression contributes to diseases, including cancer, highlighting their significance. Therapeutically, PML bodies are promising targets, exemplified by successful acute promyelocytic leukemia treatment with arsenic trioxide and retinoic acid restoring PML bodies. Understanding their functions illuminates both normal and pathological cellular physiology, guiding potential therapies. This review explores recent advancements in PML body biogenesis, biochemical activity, and their evolving biological roles.

193

项与三氧化二砷相关的新闻（医药）

2024-11-30

·医药魔方

p53药物研发“深刻反思”

抑癌蛋白p53在约50%的癌症患者中发生突变，是生物医学历史上被研究最多的蛋白之一。过去25年，有至少71个p53突变体恢复剂被报道，相关临床试验超过20个，涉及1000多名癌症患者。然而，这些化合物在实验室中的活性大多数无法被检测到，在临床上尚未观察到统计学显著的患者获益。上海交通大学医学院附属瑞金医院卢敏团队早期揭示了癌症中p53功能丧失的新机制[1-3]，近年来设计了p53功能恢复策略并揭示了结构学机制[4]，获得了唯一有效的p53恢复剂三氧化二砷（ATO）[5]，之后首次在人体内（first-in-human）实现了p53突变体功能恢复[6]。图片来源：Cancer Discovery 2024年11月1日，卢敏研究员为独立通讯作者，宋花歆、肖淑君、吴嘉祺为共同第一作者，在Cancer Discovery发表评述文章[7]，以“Drugging p53: Barriers, Criteria, and Prospects”为题提出了p53恢复剂的研究规范。文章重点讨论了p53恢复剂研究的科学逻辑，长期以来对p53突变体的误解，p53恢复剂的研发障碍、有效性评估标准、临床转化规范、经验教训以及未来前景。在OncoKB数据库中收录的数百种明确的癌症驱动基因中，约一半编码肿瘤抑制因子（抑癌蛋白），四分之一编码癌蛋白。目前已有大量癌蛋白已经成药，而靶向抑癌蛋白的药物研发成果有限。开发p53恢复剂的科学挑战在于：用药物靶向抑癌蛋白需要恢复（而非常规地抑制）蛋白功能。如果用小分子结合至抑癌蛋白的活性位点，那么预计会是抑制（而非恢复）蛋白功能；如果用小分子结合至抑癌蛋白的非活性位点，这种结合又如何能实现蛋白功能恢复？这篇最新综述以p53作为抑癌蛋白的一个典型例子，剖析靶向抑癌蛋白所面临的困境。（A）p53突变导致蛋白失去功能的多种机制（蓝色框）、研发p53恢复剂面临的4个障碍（粉色框）、p53恢复剂研究的经验教训和成药前景（黄色框）。下方灰色框依次列出4项领域内误区、恢复剂的有效性评估标准、将恢复剂推进至临床试验的规范。（图片来源：Cancer Discovery&卢敏团队）唯一的科学策略：靶向蛋白折叠 p53主要通过与DNA结合并转录激活其下游的靶基因来发挥抑癌功能。癌症中至少存在数千种不同的p53突变，这些突变通过各种不同的机制削弱p53与DNA的结合能力，从而削弱其抑癌功能（图A，蓝色框）。一些突变正好发生于p53的DNA结合氨基酸（通常是带正电的精氨酸），导致这些突变体无法结合DNA，从而失去抑癌功能，这一类突变体被称为“DNA结合型突变体”。迄今为止，尚不存在恢复p53“DNA结合型突变体”功能的可行策略。作为一个重要的转录因子，p53进化出的DNA结合氨基酸可以与DNA的大沟和小沟在形状、电荷、朝向上完美匹配。很难想象一个小分子可以在形状、电荷、朝向上弥补因突变而缺失的精氨酸，此外还可以消除因突变而出现的新氨基酸所带来的负面影响。虽然已有研究报道某些化合物可以插入p53与DNA的结合面，但预期这些化合物只会削弱p53的DNA结合能力。总体而言，DNA结合型突变体不太可能通过药物恢复功能，而只能通过基因工程手段进行功能恢复，例如通过基因突变重新引入可以结合DNA的精氨酸。（B）胶连蛋白内部的多个氨基酸的作用力，促进了蛋白折叠。这些作用力包括自发生成的作用力如疏水相互作用、氢键、二硫键等等，也包括小分子与口袋结合时导入的作用力。（图片来源：Cancer Discovery&卢敏团队）另一些突变则发生于维持p53三级结构的氨基酸，导致p53不能折叠出三级结构，进而不能结合DNA并失去功能，这类突变被称为“结构型突变体”。蛋白质的折叠由“氨基酸胶水”（例如疏水作用、氢键、二硫键等）驱动，这些“氨基酸胶水”将蛋白内部的两个或多个氨基酸胶联在一起（图B）。在癌症中，造成p53内部空腔化的突变（如F270L和V143A等突变在p53内部从大尺寸氨基酸变成小尺寸氨基酸）和扰乱L2-L3结构的突变（如R175H、R249S和C242S等使L2和L3相互作用丢失的突变）都导致p53中某些关键“氨基酸胶水”的丢失，进而导致p53从折叠状态转变为非折叠状态。反过来，当一个小分子结合到某个蛋白内部的口袋中时，它通常会提高蛋白的热稳定性（亦即结构稳定性）和折叠能力（亦即蛋白复性），因为它在口袋中创造了新的“氨基酸胶水”，将蛋白内部的多个氨基酸胶连到一起（图B）。卢敏团队将促进蛋白折叠并恢复蛋白功能的靶向策略取名为靶向蛋白折叠（Targeted Protein Folding，TPF），类比于已经得到广泛应用的靶向癌蛋白的靶向蛋白抑制（Targeted Protein Inhibition，TPI）和新兴的靶向蛋白降解（Targeted Protein Degradation，TPD）。据称，TPF是目前唯一具有科学逻辑的p53功能恢复策略，但该策略只适用于结构型p53突变体。四大“误解” 关于p53突变体，有四个普遍存在的误解（图A，第一个灰色框），这些误解长期以来阻碍了领域发展。第一个常见的误解是相信存在一种“万能”p53恢复剂，可以恢复所有不同p53突变体的抑癌功能。然而，基于p53突变体多样的失活机制（图A，蓝色框），很容易得出结论：任何一个p53恢复剂，只可能适用于失活机制与该恢复剂的工作机制一致的p53突变体。遗憾的是，当前许多基础研究仍然随意选择一个p53突变体进行研究。这种误解进一步导致临床医生在开展临床试验时，未对患者的p53突变类型进行分类。第二个误解是认为可以通过传统的低温实验条件来评估结构型p53突变体的折叠情况。蛋白的折叠和不折叠状态由其熔解温度（Tm）决定。当环境温度（Tambient）高于蛋白的Tm时，蛋白会趋向不折叠，反之则趋向折叠。野生型p53的Tm值约为42°C，因此在人体中（37°C）趋向折叠状态。而结构型突变体由于缺失若干“氨基酸胶水”，Tm值通常在20–37°C之间，因而在人体中处于非折叠状态并失去功能。需要注意的是，这些结构型突变体的Tm值仍远高于4°C，这意味着它们在传统4°C实验条件（注：为防止抗体失活，一般涉及抗体的实验都在4℃下开展）下仍保持折叠状态，不能真实反映它们在人体内的非折叠状态。因此，评估结构型p53突变体折叠状态的实验（如特异性识别折叠p53的PAb1620抗体相关实验、特异性识别非折叠p53的PAb240抗体相关实验）应在室温或更高温度下开展，以准确反映其在体内的非折叠状态。第三个误解是认为“用小分子修饰p53表面的一个半胱氨酸可以促进p53折叠（亦即可以提高p53的Tm值）”。如前文所述，蛋白的折叠主要由“氨基酸胶水”胶连蛋白内部的2个或多个氨基酸所驱动（图B）。这一概念得到了数百种临床阶段和获批小分子药物的支持——这些靶向小分子结合在靶蛋白内部的口袋，提供了“氨基酸胶水”，进而导致Tm值增加。然而，目前大量p53突变体恢复剂被设计通过修饰p53表面的单个半胱氨酸来起作用（图B）。目前还没有科学依据来解释这类修饰是如何增加p53 Tm值的。（C）p53靶向折叠策略（TPF）对不同结构型p53突变体具有不同的功能恢复效率及机制。在人体内，结构型p53突变体的Tm小于环境温度环境温度（37℃），因此处于非折叠状态（图i）。当使用图示的三种TPF策略实现“Tm大于环境温度Tambient”时，结构型突变体会重新折叠，要么重新折叠成和野生型完全一样的结构（子图ii），要么还额外具有一个无序的L3环（子图 iii）。在子图ii中，高温敏型突变如β-sandwich突变、V272M、R282W因为远离与DNA结合有关的L3环，使得这些突变体在重新折叠时能重新组装出野生型的L3 ，从而可以被TPF高效恢复功能；在子图iii中，非/低温敏型突变如G245S和R249S位于L3环并破坏了L3环，导致这些突变体在整体重新折叠后组装出无序的L3环，从而不能被高效恢复功能。（图片来源：Cancer Discovery&卢敏团队）第四个误解是认为结构型p53突变体会错误折叠（misfolded）。结构型p53突变体的Tm值低于人体体温37°C，因此，它们在人体内处于非折叠状态（unfolded），没有三级结构（图C，子图i）。在特定条件下，当Tm值重新大于环境温度时（例如通过小分子结合p53的口袋以提高p53的Tm值、通过基因工程方法在第二位点导入促进结构稳定的突变来提高p53的Tm值、降低环境温度），这些突变体会重新折叠，折叠后会出现两种情况：第一种是重新折叠成和野生型p53完全一样的三级结构（图C，子图ii），第二种是重新折叠成在整体上和野生型p53一致但在局部区域包含一个无序的L3环（图C，子图iii）。第二种情况往往是领域内认为p53突变体会错误折叠的原因。“Misfolded conformation”这个术语通常用于描述一种非野生型的、固定的、对应于某种特定新功能的构象，而结构型p53突变体在重新折叠以后，其L3环在第二种情况下既不固定、也不对应特定的新功能。因此，领域内的研究方向应该是“使不折叠的p53蛋白重新折叠”，而非“纠正p53的错误折叠”。四大障碍截至目前，绝大多数已报道的p53恢复剂都是广谱性恢复剂，少数为特异性靶向Y220C 单突变体的p53恢复剂，该综述归纳了研发广谱性p53恢复剂的四大障碍（图 1A，粉色框）。第一个障碍是缺乏可理解的作用机制（MoA），这是确定化合物是否为靶向化合物的基石。如前所述，通过修饰单个暴露的半胱氨酸来恢复p53 DNA结合型突变体或结构型突变体的功能还缺乏明显的作用机制。不过，值得关注的是，在众多广谱性p53恢复剂中，ATO及其类似物在恢复p53结构型突变体方面具有可解释的MoA——这类化合物通过将蛋白内部的Cys124、Cys135和Cys141氨基酸胶联在一起，从而促进结构型p53突变体折叠。第二个障碍是缺乏对构效关系（structure-activity relationship，SAR）的理解。理解SAR对于药理学家验证其所提出的结构学模型、挑选出最具潜力的候选化合物以开展昂贵的临床试验至关重要。目前，绝大多数广谱性p53恢复剂都缺乏这些至关重要的SAR研究，进而阻碍了对所提出的结构模型与SAR之间相容性的进一步研究。ATO及其类似物是例外。在它们的结构模型中，它们释放出砷（As）或锑（Sb）原子来结合突变的p53。在SAR研究中，不能在细胞中释放As/Sb原子的As/Sb化合物对恢复p53突变体无效，这与它们的结构模型一致。第三个障碍是缺乏对细胞中靶点特异性的研究——这是靶向化合物在人体内与其靶蛋白结合以调控其功能的先决条件。一般来说，靶点特异性主要取决于小分子与其结合口袋的互补性（图B）。然而，当前大多数广谱性p53恢复剂与暴露在p53上的半胱氨酸的某个巯基结合，而不与任何口袋结合。这类化合物应该缺乏靶点选择性。事实上，确实，在p53的10个半胱氨酸中，这些恢复剂与所有5个暴露的半胱氨酸（C124/C182/C229/C275/C277）混杂结合。此外，据报道，这些化合物还可以与多种多样含有暴露巯基的蛋白以及含有巯基的谷胱甘肽（GSH）相互作用。相比之下，ATO及其类似物在细胞模型中显示出靶向p53的特异性。这种特异性源于砷更倾向于结合三巯基（trithiol，而且这三个巯基之间的相互距离必须刚好合适，以便能和砷原子形成3根共价键）而不是单巯基或二巯基，以及结合未被锌占据的半胱氨酸三联体口袋。细胞中适合砷结合的半胱氨酸三联口袋的数量可能是有限的。据称，迄今为止，p53是唯一具有这种口袋的共晶结构证据的蛋白质。第四个障碍是缺乏用于在临床试验中筛选匹配患者的明确的可适用突变体的清单。如前文所述，目前还没有能够恢复所有p53突变体功能的是广谱性p53恢复剂。例如，通过靶向蛋白折叠策略（TPF）所研发的p53恢复剂，仅能恢复结构型p53突变体的功能。更复杂的是，即使在这些结构型突变体中，TPF策略对不同突变体的恢复效率也存在差异（图 1C）。温度敏感（temperature sensitive，TS）亚型结构型突变体通常是最容易被TPF策略恢复功能的突变体。温敏型突变体的定义是：能够在环境温度（Tambient）降低时恢复功能的突变体。由于降低Tambient使“Tm > Tambient”成立，这将促进结构型p53突变体的重新折叠，因此可以推断TS型p53突变体是一类重新折叠以后能够组装出完整DNA结合面（从而恢复DNA结合能力和肿瘤抑制功能）的p53突变体（图 1C，子图 ii）。典型的温敏型突变（如β-sandwich突变、V272M、R282W）通常发生在离DNA结合表面相对较远的地方，这使得在p53重新折叠过程中能够组装出完整的DNA结合面。因此，任何能够促进“Tm > Tambient”这个不等式成立的策略，包括ATO及其类似物的药理学策略、遗传学策略、降低环境温度的策略，都具有恢复TS亚型结构型p53突变体功能的潜能。反过来，非温敏型的结构型突变体是那些即使（被低温诱导）重新折叠也无法组装出完整DNA结合面的突变体（图 1C，子图 iii），支持证据包括：典型的非温敏亚型或低温敏亚型的结构型突变体（如R249S、G245S）通常发生于结合DNA的L2-L3 motif，这些突变体在重新折叠以后不能组装出完整的DNA结合面，解释了为什么它们在满足“Tm > Tambient”蛋白整体重新折叠以后仍难以被TPF策略恢复功能。有效性评估标准 P53药物研发领域亟需可靠且简便的标准来评估现有及未来的p53恢复剂的有效性。在靶向治疗领域，用于评估新发现的靶向小分子的核心标准包括：具有可以解释MoA的结构模型、SAR与结构模型具有相容性，但并不是所有细胞生物学实验室都能轻易开展相关评估。鉴于此，该综述提出了4项普通细胞生物学实验室都可以轻易测试的有效性评估标准（图A，第二个灰色框）。第一项标准是采用确认有效的、敏感的p53活性分析实验系统，评定标准如，p53野生型样品的信号强度比p53缺失和p53突变型样品高一百或几百倍，例如荧光素酶报告基因检测实验（luciferase reporter assay）、使用PAb1620抗体的特异性免疫沉淀实验（PAb1620只识别折叠状态下的p53）。值得注意的是，广泛使用的PAb1620免疫荧光染色法可能不能灵敏地区分野生型p53、p53缺失和结构突变p53，这可能是由于在细胞固定过程中p53不可避免地发生变性，导致不能被PAb1620抗体识别。此外，温敏亚型的结构型突变体如 R282W和V272M即使已经完全重新折叠，也不能被PAb1620抗体高效识别，这可能是由于p53的DNA结合域的拓扑结构限制。第二项标准是需加入野生型p53作为对照，这经常被忽视。加入这个对照样品有助于评估恢复剂离完全恢复p53功能还有多远。例如，尽管ATO上百倍地促进p53-R175H这一低温敏亚型结构型突变体的蛋白折叠，实现了蛋白折叠的完全恢复；但它仅仅3-4倍地提高p53-R175H的转录活性，远远不足以实现转录活性的完全恢复。第三项标准是引入一组功能恢复潜力明确的p53突变体作为内部对照。结构学机制以及大规模实验都表明，靶向蛋白折叠（TPF）策略对不同p53突变体的恢复效力由突变体固有的突变特性预先决定。研究表明，三种p53靶向折叠方法（低温组织培养、ATO处理、PAT处理）恢复800种常见p53错义突变体的转录活性效力排序是一致的：高温敏亚型结构型突变体（如V272M/R282W）> 非/低温敏亚型结构型突变体（如R175H/G245S/R249S）> 非结构型突变体（如R273H/R248Q）（图C）。因此，如果一种新发现的p53恢复剂对这些不同类型突变体展现出相同程度的恢复效果，那它可能不是直接靶向p53突变体。第四项标准是评估恢复剂对p53靶基因上调能力的时候，必须评估足够多的p53靶基因（理想情况是评估所有p53靶基因），而非只评估或只展示少数几个靶基因。有效的p53恢复剂应该诱导p53靶基因整体上调，且特异性上调。经验总结临床转化四项规范尽管过去已有多款p53恢复剂进入临床，但尚未发现任何统计学显著的患者获益。该综述总结了有望推动实验室发现的p53恢复剂进入临床试验的4项规范：1）需要具有可解释的结构模型（MoA）以明确分子的靶向模式；2）SAR与提出的结构学模型需相互兼容以确保结构学模型的正确性；3）需要具备靶点特异性；4）需有明确的可适用突变体的清单以便进行精准患者入组。适应症选择由于p53在几乎所有癌症类型中都会发生突变，因此，p53恢复剂的临床试验还需考虑癌症类型。在血液系统恶性肿瘤中，TP53突变是一个明确的驱动突变，一些证据包括TP53突变与患者预后不良相关，复发患者TP53突变频率增加，共同发生的驱动突变有限等。因此，血液系统恶性肿瘤可能是p53恢复剂开展临床试验理想的癌种选择。首次在人体内（First-in-human）实现p53突变体功能恢复就是利用ATO在血液系统肿瘤患者中取得的。经验总结回首靶向p53突变体的数十年的研究，科学家们也总结了一些经验教训，包括在药物发现阶段，需选择有功能恢复潜力的p53突变体（如结构型突变体），并采用具有科学逻辑的功能恢复策略（如TPF策略）。此外，在临床试验阶段，需选择合适的p53恢复剂（如满足上述4项有效性评估标准及临床转化规范的恢复剂），并招募最可能产生临床获益的匹配患者（如携带温敏亚型的结构型p53突变体的患者）。未来展望该综述提出，当前该领域的一个重要任务应该是利用前文提到的4项评估标准来评估现有和未来的p53恢复剂的有效性，并选择符合上述4项临床转化规范的恢复剂进行临床试验。尽管ATO符合所有这些评估标准和临床规范，但作为一种已获批的老药，缺乏显著的商业价值，因此，需要科学家、临床医生、制药公司之间更紧密的合作，以验证其用于治疗TP53突变癌症患者的疗效。该领域的另一个“任务”是在p53上鉴定新的配体结合口袋（见图A，黄色框）。在癌症靶向治疗领域，一个蛋白的可成药性（druggability）在很大程度上取决于其深层疏水口袋的存在（供小分子紧密结合）。这一原则同样适用于p53。p53-Y220C上的Cys220口袋的发现，在过去几十年中极大地促进了众多Y220C单突变体特异性恢复剂的研究；然而，Cys220口袋是Y220C突变体特有的，而癌症相关的p53突变体有超过1000种。卢敏团队2021年发现的砷结合口袋（As-binding pocket, ABP）在几乎所有p53突变体中都存在，但由于该口袋空间较小，开发靶向ABP口袋的新型p53恢复剂具有较高挑战。因此，该领域中的一个主要挑战是在p53中鉴定更多的配体结合口袋，无论是变构口袋，还是被掩埋因而难以被发现的口袋。自1979年被发现以来，围绕p53的研究已经走过了45年。期待在对历史研究的充分总结和思考下，p53药物研发能够早日取得实质性突破，迎来诸如KRAS赛道的曙光。 -上下滑动查看参考资料- [1]Lu, M., M.R. Muers, and X. Lu, Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding. Nat Rev Mol Cell Biol, 2016. 17(8): p. 523-32. [2]Lu, M., et al., A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway. Cell, 2014. 157(5): p. 1130-45. [3]Lu, M., et al., Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell, 2013. 23(5): p. 618-33. [4]Chen, S., et al., Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site. Cancer Cell, 2021. 39(2): p. 225-239 e8. [5]Xiao, S., et al., Characterization of the generic mutant p53-rescue compounds in a broad range of assays. Cancer Cell, 2024. 42(3): p. 325-327. [6]Song, H., et al., Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties. Sci Transl Med, 2023. 15(690): p. eabn9155. [7]Song, H., et al., Drugging tumor suppressor p53: barriers, criteria, and prospects. Cancer Discovery, 2024. 14(11). [8]https://www.nature.com/articles/d41573-020-00130-z [9]https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00133-8 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1期临床终止临床结果引进/卖出

2024-11-15

·佰傲谷BioValley

Ⅲ期临床失败，触发贷款违约

近日，Syros Pharmaceuticals公司宣布，tamibarotene治疗新诊断RARA基因过表达高危骨髓增生异常综合征（HR-MDS）患者的III期临床SELECT-MDS-1未能达到主要终点目标，与对照组相比，Tamibarotene+Azacitidine联合疗法未能显著提高某些MDS患者的完全缓解率。 tamibarotene是全司押注希望的管线，先前公司停止在新诊断RARA过表达AML患者招募已经大大刺激了市场的神经，经历了70%的大跌。 MDS是tamibarotene目前推的最快的适应症，Syros指望着靠着这个临床成功来摆脱财务困境。 SELECT-MDS-1临床的失败再次加剧了市场的失望情绪，该临床结果公布后，公司股价急剧下跌，跌幅高达92%。希望管线破灭 tamibarotene是一款口服视黄酸受体α (RARα)激动剂，最早日本由Nippon Shinyaku公司开发，2005年6月就已在日本被批准上市，用于治疗急性早幼粒细胞白血病。视黄酸受体α是一种核受体，由RARA基因编码，大约50%的MDS患者和30%的AML患者表现出RARA基因的过表达。当RARA的表达量超过其严格控制的天然配体时，骨髓中的细胞可能无法分化成健康的髓细胞，从而导致血液恶性肿瘤。 Tamibarotene通过与过表达的RARA结合，帮助恢复髓细胞分化。2023年，Tamibarotene获得了FDA快速通道指定，用于治疗RARA过表达的高风险MDS患者。 SELECT-MDS-1主要评估Tamibarotene+Azacitidine对比Azacitidine+安慰剂在新诊断RARA过表达高危骨髓增生异常综合征（HR-MDS）患者中的安全性和有效性。结果显示，接受Tamibarotene+Azacitidine治疗的患者CR率为23.8%，而对照组（Azacitidine+安慰剂）的CR率为18.8%，虽然CR率前者更高，但是没有达到统计学显著差异。公司首席执行官Conley Chee在一份声明中表示了对这一结果的深感失望，公司将停止SELECT-MDS-1临床试验，在完成对后期临床数据的审查后评估下一步方案。此外，Tamibarotene在另一项适应症—AML中的临床疗效更加不理想。针对40名新诊断RARA过表达AML患者的预先设定分析结果显示(SELECT-AML-1)，Tamibarotene三联疗法组患者的CR/CRi率不及对照组（65% VS 70%)，公司认为在最终分析中，Tamibarotene三联疗法组显示出优势的可能性不大。在2024年8月，Syros宣布计划停止SELECT-AML-1的患者招募。该消息公布后，公司股价暴跌70%。从公司两次的股价反应看出，Tamibarotene连个临床试验挫折对公司打击之大，尤其是公司把已经十分紧张的资金都押注Tamibarotene上。 35%的裁员重组 Syros Pharmaceuticals由知名风险投资公司Flagship Pioneering孵化，成立于2011年，专注于基因调控疗法的开发。2022年9月收购了TYME公司后在纳斯达克交易市场上市。在公司去年重组前，共有8条管线在研，包括共2个临床后期管线和6个早期临床/临床前管线。然而去年，两个合作方的相继离开给公司打击很大。 2023年7月和8月，辉瑞（镰状细胞病和β-地中海贫血）和Incyte（骨髓增殖性肿瘤）相继终止与公司的合作协议，里程碑款项已经泡汤。同时公司Syros财务状况也堪忧，截至2023年9月30日，现金、现金等价物和有价证券为1.12亿美元。去年10月，Syros进行了重组来消减开支，临床前管线一律砍掉，只剩下Tamibarotene在内的三条管线在研，其中还暂停了SY-2101在急性早幼粒细胞白血病的临床开发。作为重组的一部分，还裁员了35%，公司的首席执行官、首席科学官也在此次人事变动之列。触发违约条款更加雪上加霜的是，SELECT-MDS-1临床失败还构成与Oxford Finance LLC贷款协议的违约。早在2020年，公司与Oxford Finance LLC签订了一项贷款和担保协议，该协议中协定了一些违约条款，其中就包括SELECT-MDS-1未达到临床主要终点。 Tamibarotene的失败也基本阻断了公司的再融资能力，2025年11月1日起，公司就要开始偿还本金。截至2024年9月30日，Syros现金及其现金等价物只有0.58亿美元。参考出处 https://www.biospace.com/drug-development/syros-crashes-over-90-on-late-stage-mds-fail-loan-default https://ir.syros.com/press-releases/detail/311/syros-reports-third-quarter-2024-financial-results-and https://www.nasdaq.com/press-release/syros-reports-third-quarter-2023-financial-results-and-provides-a-corporate-update 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 · · · · · · · ·

临床3期临床失败临床结果并购

2024-11-13

·PRNewswire

75+ Key Companies Charting New Frontiers in Multiple Sclerosis Therapeutic Space | DelveInsight

Multiple sclerosis (MS) is a chronic neurological disorder affecting the central nervous system (CNS), particularly the brain, spinal cord, and optic nerves. Continuous research has led to new drug developments, particularly disease-modifying therapies (DMTs) that slow MS progression. Monoclonal antibodies, oral therapies, and infusion treatments are among the most promising options and drives the multiple sclerosis market. LAS VEGAS, Nov. 13, 2024 /PRNewswire/ -- DelveInsight's ' Multiple Sclerosis Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline multiple sclerosis therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the multiple sclerosis pipeline domain. Key Takeaways from the Multiple Sclerosis Pipeline Report DelveInsight's multiple sclerosis pipeline report depicts a robust space with 75+ active players working to develop 80+ pipeline therapies for multiple sclerosis treatment. Key multiple sclerosis companies such as Mapi Pharma, Novartis, Immunic, Biocad, Apimeds, Genentech (Roche), AB Science, Celltrion, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, BrainStorm Cell Therapeutics, NeuroSense Therapeutics, Denali Therapeutics Inc., Sanofi, MediciNova, Biogen, Tiziana Life Sciences, Antisense Therapeutics, RemeGen, Atara Biotherapeutics, Contineum Therapeutics, Eli Lilly and Company, Axsome Therapeutics, Accure therapeutics, Stem Cell Medicine Ltd., Ever Supreme Bio-Technology Co., Ltd., ImCyse, Lucid Psycheceuticals, Immune Response BioPharma, Guangzhou Lupeng Pharmaceutical, Kyowa Kirin, Nura Bio, Bristol-Myers Squibb, ImStem Biotechnology, Hoffmann-La Roche, LAPIX Therapeutics, Motric Bio, Immunophage Biotech, NervGen, FibroBiologics, Kyverna Therapeutics, GlaxoSmithKline, PolTREG, Cyxone, Biohaven Pharmaceuticals, HuniLife Biotechnology, GlobeStar Therapeutics, Anokion, Medsenic, ZyVersa Therapeutics, Alumis Inc., Axoltis Pharma, Barricade Therapeutics, BioNxt Solutions, Eikonoklastes Therapeutics, 4D Pharma, Gossamer Bio, Pasithea Therapeutics, Synaptogenix, Monte Rosa Therapeutics, Immix Biopharma, f5 Therapeutics, Autobahn Therapeutics, Biosenic, Polpharma Biologics, Find Therapeutics, TeraImmun, AptaTargets, Trethera, Aditxt, SetPoint Medical, Sarepta Therapeutics, Nucleome Therapeutics, Vaccinex Inc., and others are evaluating new multiple sclerosis drugs to improve the treatment landscape. Promising multiple sclerosis pipeline therapies such as GA Depot, Remibrutinib, Tolebrutinib, IMU 838, BCD-132, Apitox, Fenebrutinib, SAR 441344, CT-P53, CNM-Au8, Orelabrutinib, Vafidemstat, Temelimab, Elezanumab, NurOwn (MSC-NTF cells), PrimeC, SAR4433820, Ibudilast, BIIB091, Foralumab, ATL1102, RC18, ATA188, PIPE-307, Pirtobrutinib, LY3541860, Solriamfetol, Act-01, SCM-010, UMSC01, IMCY-0141, Lucid-MS, NeuroVax, LP-168, NB-4746, CC-97540, IMS-001, RO7121932, BMS-986196, LPX-TI641, MTR-601, IPG-11406, IPG-1094, NVG-291, CYMS-101, KYV-101, PIPE-791, GSK 3888130B, PTG-007, T 20K, BHV-8000, HuL001, Amethyst™, ANK 700, Arscimed, A-005, NX210c, Research programme: CAR-TREG, TASIN-1, Cladribine ODF, ET-101, MRx0002, GB7208, PAS-002, Bryostatin-1, MRT-6160, NXC-201, Research Program: Cytokine reduction, ABX-002, Arsenic trioxide, LL-341070, PB018, FTX 101, TI-235, TRE 515, NT-0007, NT-0002, NVG300, and others are under different phases of multiple sclerosis clinical trials. In October 2024, Immunic, Inc. reported favorable results from the non-binding interim futility analysis of its Phase 3 ENSURE trial, which is evaluating its lead candidate, vidofludimus calcium (IMU-838), a nuclear receptor-related 1 (Nurr1) activator, for the treatment of relapsing multiple sclerosis (RMS). In October 2024, Immunic, Inc. announced a positive outcome of the non-binding, interim futility analysis of its Phase III ENSURE program, investigating lead asset, nuclear receptor related 1 (Nurr1) activator, vidofludimus calcium (IMU-838), for the treatment of relapsing multiple sclerosis (RMS). Based on the outcome of the interim futility analysis, an unblinded Independent Data Monitoring Committee (IDMC) has recommended that the trials are not futile and should continue as planned. In September 2024, Roche, secured FDA approval for an injectable form of its blockbuster multiple sclerosis treatment, Ocrevus, reducing patient treatment time and potentially helping the company stay ahead of increasing competition. In September 2024, Sanofi announced the outcomes of Phase III clinical trials of its investigational oral brain-penetrant BTK inhibitor, tolebrutinib, aimed at treating multiple sclerosis (MS). These studies, namely HERCULES, GEMINI 1, and GEMINI 2, have provided mixed results, with the HERCULES trial meeting its primary endpoint while the GEMINI trials did not. The HERCULES study focused on the efficacy and safety of tolebrutinib in individuals with non-relapsing secondary progressive MS (nrSPMS) compared to a placebo. In August 2024, Abata Therapeutics announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for ABA-101 for the treatment of patients with progressive multiple sclerosis (MS). The FDA recently cleared ABA-101's Investigational New Drug (IND) application, and initiation of a first-in-human (FIH) Phase I study is imminent. In August 2024, TG Therapeutics announced that the FDA has cleared an investigational new drug (IND) application submitted by TG Therapeutics for azercabtagene zapreleucel (azer-cel), an investigational allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, for a phase 1 clinical trial in patients with progressive multiple sclerosis (MS). In January 2024, Kyverna Therapeutics, Inc. announced it received fast-track designation by the U.S. Food and Drug Administration (FDA) for its autologous, fully human CD19 chimeric antigen receptor (CAR) T-cell product candidate, KYV-101, to be used for the treatment of multiple sclerosis (MS). Request a sample and discover the recent advances in multiple sclerosis treatment drugs @ Multiple Sclerosis Pipeline Report The multiple sclerosis pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage multiple sclerosis drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the multiple sclerosis clinical trial landscape. Multiple Sclerosis Overview Multiple sclerosis is a chronic autoimmune disorder that affects the central nervous system, leading to the deterioration or permanent damage of myelin, the protective sheath surrounding nerve fibers. While the exact cause of multiple sclerosis remains unclear, it is believed to involve a combination of genetic predisposition, environmental factors, and possibly viral infections. Common symptoms of multiple sclerosis include fatigue, difficulty walking, numbness or tingling in the limbs, muscle weakness, and vision problems, which can vary significantly among individuals and may evolve over time. Diagnosis typically involves a combination of neurological examinations, magnetic resonance imaging (MRI) to detect lesions in the brain and spinal cord, and sometimes lumbar puncture to analyze cerebrospinal fluid for inflammatory markers. While there is no cure for multiple sclerosis, treatment options aim to manage symptoms, reduce the frequency and severity of relapses, and slow disease progression. This may include disease-modifying therapies (DMTs), corticosteroids for acute exacerbations, and symptomatic treatments such as physical therapy, pain management, and lifestyle modifications. Early diagnosis and a tailored treatment plan are crucial for improving the quality of life for those living with multiple sclerosis. Find out more about multiple sclerosis treatment drugs @ Drugs for Multiple Sclerosis Treatment A snapshot of the Multiple Sclerosis Pipeline Drugs mentioned in the report: Learn more about the emerging multiple sclerosis pipeline therapies @ Multiple Sclerosis Clinical Trials Multiple Sclerosis Therapeutics Assessment The multiple sclerosis pipeline report proffers an integral view of the multiple sclerosis emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Multiple Sclerosis Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Intravenous, Subcutaneous, Parenteral, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Immunomodulators, MHC class II gene modulators, Agammaglobulinaemia tyrosine kinase inhibitors, Dihydroorotate dehydrogenase inhibitors, Nuclear receptor subfamily 4 group A member 2 agonists, CD20 antigen inhibitors, Energy metabolism stimulants; Immunomodulators, Lysine-specific demethylase 1 inhibitors, Monoamine oxidase B inhibitors, Protein-arginine deiminase inhibitors, Immunostimulants Key Multiple Sclerosis Companies: Mapi Pharma, Novartis, Immunic, Biocad, Apimeds, Genentech (Roche), AB Science, Celltrion, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, BrainStorm Cell Therapeutics, NeuroSense Therapeutics, Denali Therapeutics Inc., Sanofi, MediciNova, Biogen, Tiziana Life Sciences, Antisense Therapeutics, RemeGen, Atara Biotherapeutics, Contineum Therapeutics, Eli Lilly and Company, Axsome Therapeutics, Accure therapeutics, Stem Cell Medicine Ltd., Ever Supreme Bio-Technology Co., Ltd., ImCyse, Lucid Psycheceuticals, Immune Response BioPharma, Guangzhou Lupeng Pharmaceutical, Kyowa Kirin, Nura Bio, Bristol-Myers Squibb, ImStem Biotechnology, Hoffmann-La Roche, LAPIX Therapeutics, Motric Bio, Immunophage Biotech, NervGen, FibroBiologics, Kyverna Therapeutics, GlaxoSmithKline, PolTREG, Cyxone, Biohaven Pharmaceuticals, HuniLife Biotechnology, GlobeStar Therapeutics, Anokion, Medsenic, ZyVersa Therapeutics, Alumis Inc., Axoltis Pharma, Barricade Therapeutics, BioNxt Solutions, Eikonoklastes Therapeutics, 4D Pharma, Gossamer Bio, Pasithea Therapeutics, Synaptogenix, Monte Rosa Therapeutics, Immix Biopharma, f5 Therapeutics, Autobahn Therapeutics, Biosenic, Polpharma Biologics, Find Therapeutics, TeraImmun, AptaTargets, Trethera, Aditxt, SetPoint Medical, Sarepta Therapeutics, Nucleome Therapeutics, Vaccinex Inc., and others are evaluating new multiple sclerosis drugs to improve the treatment landscape. Key Multiple Sclerosis Pipeline Therapies:GA Depot, Remibrutinib, Tolebrutinib, IMU 838, BCD-132, Apitox, Fenebrutinib, SAR 441344, CT-P53, CNM-Au8, Orelabrutinib, Vafidemstat, Temelimab, Elezanumab, NurOwn (MSC-NTF cells), PrimeC, SAR4433820, Ibudilast, BIIB091, Foralumab, ATL1102, RC18, ATA188, PIPE-307, Pirtobrutinib, LY3541860, Solriamfetol, Act-01, SCM-010, UMSC01, IMCY-0141, Lucid-MS, NeuroVax, LP-168, NB-4746, CC-97540, IMS-001, RO7121932, BMS-986196, LPX-TI641, MTR-601, IPG-11406, IPG-1094, NVG-291, CYMS-101, KYV-101, PIPE-791, GSK 3888130B, PTG-007, T 20K, BHV-8000, HuL001, Amethyst™, ANK 700, Arscimed, A-005, NX210c, Research programme: CAR-TREG, TASIN-1, Cladribine ODF, ET-101, MRx0002, GB7208, PAS-002, Bryostatin-1, MRT-6160, NXC-201, Research Program: Cytokine reduction, ABX-002, Arsenic trioxide, LL-341070, PB018, FTX 101, TI-235, TRE 515, NT-0007, NT-0002, NVG300, and others are under different phases of multiple sclerosis clinical trials. Dive deep into rich insights for new drugs for multiple sclerosis treatment, visit @ Multiple Sclerosis Drugs Table of Contents For further information on the multiple sclerosis pipeline therapeutics, reach out @ Multiple Sclerosis Treatment Drugs Related Reports Multiple Sclerosis Market Multiple Sclerosis Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key multiple sclerosis companies including Immune Response BioPharma, Inc., Clene Nanomedicine, Genzyme, ImStem Biotechnology, Rho, Inc., Bristol-Myers Squibb, TG Therapeutics, Inc., Hoffmann-La Roche, Atara Biotherapeutics, Immunic AG, Celgene, Anokion SA, Sanofi, Actelion, Biogen, Supernus Pharmaceuticals, Inc., GeNeuro SA, HuniLife Biotechnology, Inc., Emerald Health Pharmaceuticals, RemeGen Co., Ltd., Antisense Therapeutics, Biocad, AB Science, Genentech, Novartis, Pipeline Therapeutics, ASLAN Pharmaceuticals, GlaxoSmithKline, Lucid Psycheceuticals, Voronoi, Hanmi Pharmaceutical, Mapi Pharma, f5 Therapeutics, Autobahn Therapeutics, AstraZeneca, ZyVersa Therapeutics, RedHill Biopharma, Gossamer Bio, Sarepta Therapeutics, BrainStorm Cell Limited, CytoDyn, Pear Therapeutics, Solstice Neurosciences, ProJenX, among others. Multiple Sclerosis Epidemiology Forecast Multiple Sclerosis Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted multiple sclerosis epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Relapsing Multiple Sclerosis Pipeline Relapsing Multiple Sclerosis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key relapsing multiple sclerosis companies, including ASLAN Pharmaceuticals, GlaxoSmithKline, Lucid Psycheceuticals, Voronoi, Hanmi Pharmaceutical, among others. Relapsing-Remitting Multiple Sclerosis Pipeline Relapsing-Remitting Multiple Sclerosis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key RRMS companies, including TG Therapeutics, Novartis, Sanofi, Cinnagen, Polpharma Biologics, Immunic, Mapi Pharma, Biocad, Apimeds, Genentech (Roche), Merck, Immune Response BioPharma, Clene Nanomedicine, InnoCare Pharma, Oryzon Genomics, GeNeuro SA, AbbVie, Emerald Health Pharmaceuticals, GlaxoSmithKline, RedHill Biopharma, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期临床结果快速通道细胞疗法免疫疗法

100 项与三氧化二砷相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D02106	三氧化二砷	L01XX27	DB01169

研发状态

批准上市

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适应症	国家/地区	公司	日期
急性早幼粒细胞白血病	美国	Cephalon, Inc.	2000-09-25

未上市

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床3期	美国	Cephalon, Inc.	2007-10-01
急性髓性白血病	临床3期	加拿大	Cephalon, Inc.	2007-10-01
系统性红斑狼疮	临床2期	法国	Medsenic SAS	2013-07-01
小细胞癌	临床2期	美国	Cephalon, Inc.	2011-08-01
小细胞癌	临床2期	美国	Teva Pharmaceuticals USA, Inc.	2011-08-01
小细胞肺癌	临床2期	美国	Cephalon, Inc.	2011-08-01
小细胞肺癌	临床2期	美国	Teva Pharmaceuticals USA, Inc.	2011-08-01
转移性子宫内膜恶性肿瘤	临床2期	美国	Cephalon, Inc.	2010-03-01
胶质瘤	临床2期	美国	Cephalon, Inc.	2005-05-01
胶质瘤	临床2期	美国	CTI BioPharma Corp.	2005-05-01

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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


ASH2024	N/A	急性早幼粒细胞白血病	-	Standard-dose ATO (10mg IV daily for 28 days)	襯鏇糧蓋襯齋鹽蓋廠積(獵範構壓選鏇獵鏇淵範) = Patients receiving ATO treatment have a high rate of adverse events in both groups, reducing the total ATO dosage at induction treatment may reduce the adverse event rate and help patients achieve the same long-term survival. 願遞鏇觸繭衊製壓鹹衊 (繭構獵製願鏇獵艱遞艱 )	-	2024-12-09
				Low-dose ATO (10mg IV daily for less than 28 days)
EHA2024	N/A	急性早幼粒细胞白血病一线	-	ATO-based chemotherapy-free regimens	願築廠構廠選選壓簾齋(衊壓衊簾壓鑰選鏇齋範) = 鏇鏇築壓衊襯鏇觸鏇憲築鏇繭鹽願簾餘壓窪積 (蓋夢夢範糧衊鹹齋繭鏇, 0.06‒0.47)	不佳	2024-05-14
				ATO-containing chemotherapy-based regimens	願築廠構廠選選壓簾齋(衊壓衊簾壓鑰選鏇齋範) = 製憲壓蓋鹽憲壓網製鬱築鏇繭鹽願簾餘壓窪積 (蓋夢夢範糧衊鹹齋繭鏇, 0.70‒1.43)
EHA2024	N/A	急性早幼粒细胞白血病	-	Arsenic Trioxide (ATO)	遞築積窪壓觸壓糧顧廠(蓋範願遞憲範憲餘膚願) = 餘廠構膚獵鬱遞憲膚憲網廠廠壓願壓製糧獵憲 (鑰鹹襯願獵構襯簾鬱鏇 ) 更多	-	2024-05-14
				Chemotherapy	艱糧觸網醖構遞鬱糧夢(憲積鬱廠鬱廠壓選餘繭) = 衊衊廠衊顧製壓鹹鏇艱鬱範築膚觸憲壓壓鹹壓 (鑰構鏇醖鹽構膚膚觸觸 )
ASH2023	N/A	急性早幼粒细胞白血病	-	Oral-Arsenic Trioxide	範簾網醖築憲獵窪鏇觸(獵繭遞構顧鏇網餘範選) = 網糧範鏇夢鏇齋窪鑰選獵夢網醖鏇網蓋壓鑰淵 (餘顧鹹餘憲艱範鏇壓觸 ) 更多	-	2023-12-09
				All-Trans Retinoic Acid	範簾網醖築憲獵窪鏇觸(獵繭遞構顧鏇網餘範選) = 繭窪壓鑰襯餘顧選廠網獵夢網醖鏇網蓋壓鑰淵 (餘顧鹹餘憲艱範鏇壓觸 ) 更多
ASH2023	N/A	急性早幼粒细胞白血病	135	ATRA-ATO	鏇鑰廠廠醖鏇築鬱簾廠(壓淵鬱願壓遞願鹹選鹹) = 壓襯壓齋窪夢鹹積遞齋願製繭顧醖艱廠願觸齋 (艱夢鏇鹹簾顧鬱窪遞憲 ) 更多	积极	2023-12-09
				ATRA+chemotherapy	鏇鑰廠廠醖鏇築鬱簾廠(壓淵鬱願壓遞願鹹選鹹) = 鹽鹽壓鑰窪夢簾選膚網願製繭顧醖艱廠願觸齋 (艱夢鏇鹹簾顧鬱窪遞憲 ) 更多
NCT00045565 (ASCO2023)	临床1期	胶质母细胞瘤	30	Arsenic Trioxide once weekly	艱構繭糧艱簾夢網觸壓(窪構廠膚夢獵鹹鹽糧蓋) = Major dose limiting toxicities were increased aspartate and alanine aminotransferases and one case of hyperkalemia 築製鬱襯蓋觸憲遞顧鏇 (構遞製選蓋蓋襯獵夢鏇 )	-	2023-05-31
				Arsenic Trioxide twice weekly
NCT02966301 (Pubmed) 人工标引	临床2期	慢性移植物抗宿主病一线	21	Corticosteroids+Arsenic Trioxide	範鹽顧鬱獵廠構襯夢鏇(憲獵製繭淵鑰衊膚蓋觸) = 製鹹製鏇夢餘夢膚遞夢夢窪餘構製範繭襯觸願 (鬱鹹艱壓構淵醖艱顧鏇, 50.9 ~ 91.3) 更多	积极	2022-07-10
NCT02966301 (GvHD-ATO, CTgov)	临床2期	慢性移植物抗宿主病	21	Arsenic Trioxide Injectable Solution	鹽蓋齋積夢積糧鑰淵窪(衊蓋鹽繭顧壓選範蓋齋) = 積鹽餘獵網衊願鬱餘鹽糧淵醖糧糧觸夢遞遞鏇 (製鹹淵夢鑰壓製齋壓蓋, 膚艱夢衊衊艱網築膚願 ~ 獵鹽願齋鏇鑰獵鏇淵糧) 更多	-	2022-05-09
NCT01404949 (CTgov)	临床2期	急性早幼粒细胞白血病	17	Tretinoin+Arsenic Trioxide	艱獵衊窪餘製顧鹽淵廠(簾範糧艱繭積夢製襯願) = 醖觸艱憲襯觸艱鑰齋廠艱膚獵鹹選觸遞壓範獵 (糧夢遞廠齋鏇鹽醖夢艱, 蓋窪簾網蓋鬱築範積構 ~ 鬱網網選蓋觸觸餘築製) 更多	-	2021-11-30
NCT02339740 (AAML1331, Pubmed \| JAMA Oncol)	临床3期	急性早幼粒细胞白血病	154	ATRA and arsenic trioxide-based regimen	艱築鏇淵鹽廠願鏇餘獵(簾鹽窪遞鹽選鬱襯鬱窪) = 膚鑰顧鏇網醖遞鏇壓選蓋膚鹹憲網簾淵衊膚窪 (襯鏇築願衊蓋衊壓獵糧 )	积极	2021-11-11
				Chemotherapy	艱築鏇淵鹽廠願鏇餘獵(簾鹽窪遞鹽選鬱襯鬱窪) = 選齋選鑰選鹽糧範糧齋蓋膚鹹憲網簾淵衊膚窪 (襯鏇築願衊蓋衊壓獵糧 )