This is a phase 2 study, designed as a European multicentre 6-month double blind random-ized controlled trial (RCT) of AZD0530 versus matched placebo, followed by a 12 month trial comparing open-label extended AZD0530 treatment with historical control data.
Study population: Male and female adult patients aged 18 years and older with a diagnosis of FOP who meet the inclusion (active disease) and exclusion criteria will be eligible for participation in this study. The total number of enrolled patients will be 20.
Intervention: Patients will be randomized to receive either AZD0530 100mg once daily or matched placebo, taken orally for the first 6 months, immediately followed by an open-label extension in which all patients will receive AZD0530 100mg once daily oral dose for a further 12 months.
Endpoints: Endpoints include objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) , [18F] NaF Positron Emission Tomography (PET) activity and patient reported outcome measures.

开始日期2020-08-05

申办/合作机构

Stichting Onderzoek Cancer Center Amsterdam

[+6]

NCT03661125 / Unknown status早期临床1期IIT

A Randomised, Balanced, Double-blind Two-way Crossover Design Study to Evaluate the Effects of SRC Kinase Inhibitor, Saracatinib, on Brain Activity Associated With Visual Processing in Patients With Parkinson's Disease Psychosis.

Parkinson's disease is often characterised by movement symptoms such as rigidity and bradykinesia, however, there are a number of non-motor symptoms that can have a significant impact on quality of life. One of the most common non-motor symptoms of Parkinson's disease is visual hallucinations (where someone sees things that don't exist outside their mind). . Recent findings led to the approval of a drug called Pimavanserin as a treatment for PD psychosis in the USA. Based on other recent studies, we believe that Saracatinib, a drug that interacts within the same system as Pimavanserin, is a potential treatment for PD psychosis. Saracatinib has shown to reduce the intensity of the psychedelic effect induced by psilocybin (a naturally occurring psychedelic found in psilocybe mushrooms) and attenuate social cognition and brain changes in healthy volunteers. The aim of this study is to test the effects of 14 days dosing of saracatinib or placebo on 30 volunteers with PD psychosis. We aim to to use neuroimaging combined with psychopharmacology to provide evidence that a putative new treatment approach can modulate abnormal visual cortex activation in patients with PD psychosis. If positive, this proof of mechanism study would provide a strong platform to pursue symptom modification studies with Saracatinib.

开始日期2019-04-11

申办/合作机构

King's College London

[+2]

NCT02955186 / Completed临床2期IIT

Fyn Kinase Inhibitors and Alcohol Drinking

The purpose of this study is to evaluate the effects of the study medication, saracatinib/AZD0530 (placebo or 125 mg/day) on alcohol drinking behavior in a laboratory setting in which participants are given an initial drink of alcohol followed by the choice to drink up to 12 more drinks over a three-hour period. The investigators hypothesize that saracatinib will reduce craving and number of drinks consumed prior to and after exposure to the initial drink of alcohol and during the three hour drinking period.

开始日期2017-05-09

申办/合作机构

Yale University

[+1]

100 项与塞卡替尼相关的临床结果

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100 项与塞卡替尼相关的转化医学

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100 项与塞卡替尼相关的专利（医药）

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293

项与塞卡替尼相关的文献（医药）

2024-10-01·Journal of Proteomics

Construction of a prognostic model for colon cancer by combining endoplasmic reticulum stress responsive genes

Article

作者: Yuan, Zhibin ; Tang, Jianjun ; Zhang, Meng ; Wang, Yi ; Xu, Song

Endoplasmic reticulum stress may affect the occurrence and development of cancer. However, its effect on the prognosis of colon cancer (CC) patients is not clear yet. Herein, based on TCGA database, we screened 15 endoplasmic reticulum stress responsive genes (ERSRGs) associated with the prognosis of CC patients by Cox regression. By LASSO and multivariate Cox regression analyses, a prognostic risk assessment model involving 12 genes (DNAJB2, EIF4A1, YPEL4, COQ10A, IRX3, ASPHD1, NTRK2, TRIM39, XBP1, GRIN2B, LRRC59, and RORC) was built. The survival curves indicated that patients in the low-risk group had good prognosis. ROC curves demonstrated a good performance of this 12-gene prognostic model, and the Riskscore could be considered as an independent prognostic factor. Patients in low-risk group benefit more from immune checkpoint inhibitor and immune checkpoint blockade (ICB) treatment. Besides, the enrichment analysis suggested a remarkable difference in Ca²⁺ signaling in both groups. Finally, based on the cMAP database, we identified several potential drugs that could target high-risk groups, such as Dasatinib, GNF-2, Saracatinib, and WZ-1-84. To sum up, our research constructed an ERSRGs-characteristic prognostic model. The model is a promising biomarker for prediction of clinical outcomes and immune therapy response of CC patients. SIGNIFICANCE: Based on the transcriptomic data of colon cancer in the TCGA database, this study screens 12 endoplasmic reticulum stress-related genes (ERSRGs), including DNAJB2, EIF4A1, YPEL4, COQ10A, IRX3, ASPHD1, NTRK2, TRIM39, XBP1, asphD1, NTRK2. GRIN2B, LRRC59, and RORC, and a prognostic model was constructed. This model can be used as a predictor of prognosis and immunotherapy response in colon cancer patients. At the same time, model-based prediction of drugs can also be a potential option for colon cancer treatment in the future.

2024-06-01·Heliyon

Identification of a Macrophage marker gene signature to evaluate immune infiltration and therapeutic response in hepatocellular carcinoma

Article

作者: Li, Tong ; Ren, Zhenggang ; Xu, Xin ; Guo, Mengzhou ; Zhang, Lan ; Nakayama, Kiyoko ; Guo, Jing

Background:

Only a minority of hepatocellular carcinoma (HCC) patients can benefit from systemic regimens. Macrophages, which abundantly infiltrate in HCC, could mediate tumour microenvironment remodelling and immune escape, proving to be powerful weapons in combating HCC. Thus, a deeper understanding of macrophages is necessary for improving existing antitumour treatments.

Methods:

With a series of bioinformatic approaches, we comprehensively explored the role of macrophage-related genes in human HCCs from multiple single-cell and bulk RNA sequencing datasets. Unsupervised clustering was performed to cluster the macrophage marker genes (MMGs). GSVA and functional enrichment analysis were used to elucidate the functional differences among the MMG-associated clusters. Subsequently, a component analysis algorithm was used to construct a Macrosig score, and the prognosis, biological characteristics, mutation profile, TME cell infiltration status and drug response of patients with different Macrosig scores were further analysed.

Results:

We identified 13 MMGs in 574 HCC samples, based on which three MMG-associated clusters were defined. Overall survival time, clinicopathological features and immune infiltration scores differed among the different clusters. On this basis, 12 hub genes were identified among these clusters; subsequently, a scoring system was constructed to determine the Macrosig score. Importantly, patients with low-Macrosig scores, characterized by increased immune infiltration, increased mutation frequency and increased immune checkpoint expression, including CTLA-4, LAG3, PDCD1 and TIGIT, exhibited enhanced efficacy of immunotherapy when validated in an external database. Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244.

Conclusions:

A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients.

2024-05-02·Cancer research

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations

Article

作者: Kim, Sunshin ; Lee, Seonjeong ; Lee, Sang-Jin ; Lee, Geon Kook ; Yoon, Byoung-Ha ; Park, Kyung Chan ; Kim, Seon-Young ; Lee, Wonyeop ; Goh, Sung-Ho ; Lee, Cheolju ; Ju, Shinyeong ; Park, Seung-Jin ; Park, Seog Yun ; Kim, Jeong-Hwan ; Kwon, Yumi ; Park, Jong-Lyul ; Han, Ji-Youn

Abstract:

Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies.

Significance::

The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

项与塞卡替尼相关的新闻（医药）

2024-07-30

·Business Wire

New Study Describes a Functional, Aged, Human Cell-Based Platform That Examines the Contribution of Senescence in Alzheimer’s Disease Progression, and Response to Therapeutics

ORLANDO, Fla.--( BUSINESS WIRE )--Researchers from Hesperos and the University of Central Florida have developed a groundbreaking model using human induced pluripotent stem cell (iPSC)-derived cortical neurons to better understand and combat Alzheimer’s disease (AD). Their study, “ A functional aged human iPSC-cortical neuron model recapitulates Alzheimer’s disease, senescence, and the response to therapeutics ," has been published in the prestigious journal Alzheimer's & Dementia ® : The Journal of the Alzheimer's Association. doi.org/10.1002/alz.14044 AD affects an estimated 6.2 million Americans aged 65 and older, with projections suggesting this number could reach 14 million by 2050. Current treatments, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only temporary relief. The high failure rate of AD clinical trials highlights the need for a better understanding of the pathophysiology and drug mechanisms. The study addresses a critical challenge in Alzheimer’s research: the degeneration of cortical layers associated with cognitive decline. Despite substantial efforts to date, few current AD therapies are not disease-modifying. The team accurately reproduced key biological aspects of aging and senescence in a multi-cellular microphysiological system (MPS), also known as a Human-on-a-Chip. This new approach reveals how cellular aging, also known as senescence, contributes to disease progression and therapy resistance, providing researchers with an accurate, human platform to further understand the disease and potential therapeutics in a living context. Further, since other platforms at Hesperos, based on neurodegenerative diseases, have been accepted by the Food and Drug Administration (FDA) for efficacy data, it provides a new method to accelerate development and regulatory submissions of new treatments. This model provides an invaluable tool for real-time measurement of neuronal activity and aging biomarkers, facilitating drug screening and the development of AD therapies. It also reveals complex disease mechanisms, such as the role of inflammatory factors in neuronal senescence and how it differs from non-disease age-related controls, offering new targets for intervention. Researchers cultured human iPSC-derived cortical neurons on patterned microelectrode arrays to measure long-term potentiation (LTP) noninvasively. LTP, a quantifiable metric for learning and memory, is directly impacted by central nervous system neurodegeneration. By treating these neurons with pathogenic amyloid-β (Aβ), a peptide that plays a central role in development of AD, to mimic disease pathophysiology, the team was able to analyze senescence and therapeutic responses. The study demonstrates that this novel human iPSC-cortical neuron model of aging, cultured in serum-free, defined conditions, accurately recapitulates hallmarks of AD showing the following: Pathological Insights : Aβ42 induced synaptic damage, accelerated neuronal senescence, impaired mitochondrial potential, and increased reactive oxygen species (ROS), leading to oxidative stress and inflammation. Therapeutic Responses : Drugs such as memantine, rolipram, saracatinib, and donepezil improved neuronal function and viability, though they did not completely halt Aβ42-driven senescence. The study underscores the potential of biomimetic MPS systems in translational research. By integrating clinically relevant neuronal function with proteome responses, this platform is poised to accelerate the discovery of novel neuroprotective compounds for AD and other neurological disorders. “This marks a significant step forward in Alzheimer's research by providing a deeper understanding of AD pathophysiology in a human aged MPS platform. We are excited about the potential of this model to transform drug discovery in AD, providing hope for patients,” said J. Hickman, PhD, co-founder and Chief Scientist of Hesperos and Professor of Chemistry at UCF. This research was supported by grants from the National Institutes of Health (R44TR001326, R44AG058330). Research Article : doi.org/10.1002/alz.14044 Nanoscience Technology Center (NSTC) at the University of Central Florida (UCF) The mission of the NSTC is to establish a cutting-edge research program in materials and nanotechnology, provide high quality training for students and facilitate the advance of innovations to solve real world technology challenges. https://nanoscience.ucf.edu/ Hesperos, Inc. Hesperos is a global contract research organization (CRO) providing drug development services using its Human-on-a-Chip ® platform - the most advanced, multi-organ microphysiological systems available today. https://hesperosinc.com

2024-06-15

·生物谷

针对非吸烟肺癌新突破！Cancer Res | 雌激素信号通路成非吸烟肺癌新靶标

肺癌发生的主要原因是吸烟，然而，在不吸烟人群中，尤其是不吸烟女性的肺癌发生率一直在稳步上升。尽管在不吸烟的肺癌患者中，大约有80%的患者接受了靶向性治疗，主要针对诸如EGFR和ALK等蛋白的突变，其余的患者通常会接受细胞毒性的化疗手段来治疗，这种疗法的副作用较高且患者的反应率较低，这就凸显了其对靶向性疗法的迫切需求。近日，一篇发表在国际杂志Cancer Research上题为“Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations”的研究报告中，来自韩国科学技术研究院等机构的科学家们利用多组学分析技术阐明了韩国不吸烟肺癌患者机体中雌激素信号通路的过表达机制，并提出了抗癌药物塞卡替尼（saracatinib）或能作为一种靶向性的治疗制剂。多组学整合了多种分子信息，其中，蛋白质组学面临着特殊的挑战——要求研究人员在微克级的微量水平上精确解析未降解的蛋白质信息。在过去10年里，研究人员从韩国国家癌症研究中心就诊的1597名未确定疗法靶点的不吸烟肺癌患者中收集了101份组织样本，并将其临床信息、基因组、转录组、蛋白质组和磷酸化蛋白质组数据分发到每一种组学分析方法，彼此互为参照。本研究创新利用同位素标记技术，使得蛋白质组学检测能够以仅百微克的蛋白量，实现高效解析，平均每份样本可鉴定出超过9000种蛋白质和约5000种磷酸化修饰蛋白质，该水平是常规蛋白质分析所需量的10%左右。图片来源：https://aacrjournals.org/cancerres/article-abstract/84/9/1491/745069/Proteogenomic-Characterization-Reveals-Estrogen?redirectedFrom=fulltext 通过对基因突变和细胞信号通路进行分析后，研究人员在不吸烟肺癌患者的组织中观察到了已知与肺癌相关的基因驱动突变，比如STK11和ERBB2基因。此外，研究人员发现，尽管雌激素信号通路表现为过表达，但雌激素受体并未发生明显改变。基于此，塞卡替尼作为一种亚雌激素信号转导蛋白抑制剂，当其用于携带STK11和ERBB2基因突变的细胞时，相比未携带这些突变的对照组而言，在细胞死亡效应上表现出明显的统计学意义（p<0.01）。在此基础上，研究人员目前正在开发一种分子诊断技术，其能用来在不吸烟肺癌患者中区分携带雌激素信号通路特殊表达的患者，目前研究人员计划通过联合研究开展临床前试验分析塞卡替尼对不吸烟肺癌患者动物模型的治疗效应。 Lee Cheolju教授强调，本次借助多组学策略成功识别难治性肺癌治疗新靶点的案例，是国内研究与医疗机构及科研单位精诚合作的结晶，其意义非凡。这一里程碑式的成果不仅加深了我们对非EGFR/ALK突变非吸烟肺癌发病机制的认知，还为开发塞卡替尼作为治疗此类患者的新希望提供了科学依据，填补了当前靶向治疗缺口。展望未来，我们将以此为契机，拓宽多组学方法在更多人类疾病研究中的应用边界，持续深化对疾病复杂性的理解与应对策略。参考文献： Seung-Jin Park，Shinyeong Ju，Sung-Ho Goh, et al. Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations, Cancer Research (2024). DOI:10.1158/0008-5472.CAN-23-1551 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

AACR会议临床结果临床研究

2024-01-16

·药渡Daily

展望2024 | 阿尔兹海默症治疗将全面迈进新时代

阿尔茨海默症患者的脑海中，仿佛有一块橡皮擦，擦去了记忆和时光。这是一件多么可怕的事情，意味着你的成就、你的经历、你的所爱，全部都离你而去，那么活着，也仅仅只是活着而已。多年来，全球药企投入了巨大的经费进行阿尔茨海默症药物的研发，但大部分以失败告终，前路茫茫似乎看不到希望。所幸，我们生活在一个不断进取的时代，随着近期阿尔茨海默症新药在中国的获批，这一长久未曾进展的领域正在不断透进光来。重磅新药仑卡奈单抗（Lecanemab）的获批，似乎正在成为治疗阿尔兹海默症的一个里程碑。作为2003年来首获美国FDA完全批准的治疗阿尔兹海默症新药，仑卡奈单抗确实十分优秀。2022年11月，仑卡奈单抗针对早期阿尔兹海默症的III期试验结果发表在国际权威医学期刊《新英格兰医学杂志》上。这项被称为Clarity AD研究的试验共在北美、欧洲、亚洲的235个研究点入组1795名患者，主要终点为治疗18个月后临床痴呆评分总和（CDR-SB）相较于基线的变化，该评分越高意味着患者临床功能越低。来源：卫材官微试验结果显示，接受治疗18个月后，仑卡奈单抗组和安慰剂组的CDR-SB评分分别为1.21和1.66。相较安慰剂组，仑卡奈单抗组CDR-SB评分低0.45，评分增速降低了27%。此外，接受治疗6个月后，仑卡奈单抗组CDR-SB评分就开始出现显著性差异，且两组评分的绝对差异随着时间的推移而扩大。基于观察到的数据和外推至30个月的CDR-SB进行的斜率分析，接受仑卡奈单抗治疗25.5个月相当于安慰剂治疗18个月时的水平，这表明仑卡奈单抗可以延缓疾病进展达7.5个月。仑卡奈单抗使患者CDR-SB的临床下降减少了27%来源：华福证券研报这项临床试验也成为仑卡奈单抗在此次中国获批的依据。仑卡奈单抗成功上市，也为后来者在阿尔茨海默症治疗药物的研发注入了一剂强心剂。不过，也不能过于乐观，因为到目前为止，阿尔茨海默症的发病机制对人类来说，还是个迷。未解之谜1907年，德国医生Alois Alzheimer发表了一个病例，他持续跟踪一名女性患者的病程进展直至她在发病后四年半死亡，并在患者脑组织中发现大量神经炎性斑和神经原纤维缠结。1910年，德国著名精神病学家Emil Kraepelin首次将由此种病理改变引起的临床症状与体征命名为“阿尔茨海默症”。在中国，该疾病也被称为“老年痴呆”。对于阿尔茨海默症的研究迄今已过百年，但依然未取得突破性进展。阿尔茨海默症的发病机制复杂，至今仍未完全破译具体机制，通常认为是老化、遗传和环境多种因素的共同结果。患者中普遍存在神经元丢失、突触障碍、胞外淀粉样蛋白β（Aβ）沉积形成淀粉样斑块、异常磷酸化Tau蛋白形成胞内神经元纤维缠结。目前致病机制主要存在三大主流假说：Aβ类淀粉样蛋白级联假说Aβ沉积形成淀粉样斑块是阿尔茨海默症的主要病理特征之一。Aβ由淀粉样前体蛋白（APP）经分泌酶降解生成，在淀粉样途径中，APP被BACE剪切产生sAPPβ蛋白，sAPPβ蛋白被γ-secretase继续剪切，生成包括Aβ1-42、Aβ1-40等Aβ多肽并释放到胞外，最终聚集形成淀粉样蛋白斑，导致阿尔茨海默症发生。渤健的Aducanumab、Lecanemab和礼来的Donanemab都是靶向Aβ淀粉样蛋白的阿尔茨海默症药物，为Aβ假说提供坚定支撑。β类淀粉样蛋白的级联反应和主要治疗方法来源：西南证券研报Tau蛋白异常磷酸化假说病理状态下，胞内Tau蛋白过度或异常磷酸化使其丧失促微管组装的生物学活性，微管解聚、轴突运转出现障碍，进而引起神经细胞的凋亡，导致阿尔茨海默症发生。Tau蛋白的磷酸化与阿尔茨海默症患者病程中认知功能缺失密切相关。以Tau蛋白为靶点的阿尔茨海默症药物正在研发中，根据药渡数据，进入临床试验的有Tideglusib、Saracatinib、Nilotinib等小分子抑制剂。Tau蛋白异常磷酸化路线和主要治疗方法来源：西南证券研报胆碱能假说该假说认为阿尔茨海默症产生是由于患者脑内的神经递质存在缺陷，导致胆碱能神经元受到损伤。乙酰胆碱酯酶（AChE）和乙酰胆碱转移酶（ChAT）的活性下降是乙酰胆碱（Ach）浓度下降、胆碱能活性下降的主要原因。根据药渡数据，截至目前全球共有141种阿尔茨海默症治疗方法或药物研发管线，其中与神经递质调节以及突触功能改善上相关的药物管线有15个。阿尔茨海默症胆碱能神经元的化学变化来源：西南证券研报根据世界卫生组织《2023年世界社会报告》数据显示，2021年全球65岁以上老年人口数约为7.6亿，预计2050年全球老年人口数将增至16亿以上，人口老龄化背景下痴呆及轻度认知损害患者数将持续增加。截至2018年全球约3310万人患有阿尔茨海默症，2050年这一数字将增至2.42亿。而在中国，据Frost&Sullivan数据，2020年中国阿尔茨海默症患者数为1250万人，预计将在2030年增至1950万人；1990年阿尔茨海默症的死亡顺位处于第10位，20年后已跃升至第5位。不论是年龄标化患病率，还是年龄标化死亡率均高于全球平均水平。根据《中国阿尔茨海默症诊治指南》，胆碱酯酶抑制剂中的多奈哌齐、卡巴拉汀、加兰他敏是目前治疗轻中度阿尔茨海默症推荐用药，中重度患者则推荐使用谷氨酸受体拮抗剂中的美金刚。但这些推荐用药疗效普遍不足，只能短期控制症状，难以针对明确病因机制入手延缓疾病进程。根据《阿尔茨海默病患者需求洞察报告》，在接受调查的1000名受访患者中（75.7%接受了药物治疗），其中有近半数接受药物治疗患者反馈了对现有药物治疗效果的不满意。因此，市场急需治疗阿尔茨海默症新药。但由于发病机制不明确，关于阿尔茨海默症的新药研发可谓屡战屡败。根据美国药物生产与研发协会数据显示，全球累计在阿尔兹海默病上的研发投入超过6000亿美元，失败的临床药物超过300种，失败率超过99%。2012年，强生/辉瑞的单抗药物Bapineuzumab在III期临床惨遭失败；2014年，罗氏的Gantenerumab的III期临床宣告失败；2016年，新加坡生物技术公司TauRx的LMTX宣布III期临床试验未能改善患者的认知功能宣告失败；2017年，默沙东宣布停止开发BACE抑制剂药物Verubecestat；2018年，强生宣布其终止了BACE抑制剂Atabecestat II/III期临床试验等。直到2021年6月，美国FDA批准了Aducanumab的上市，才终结了2003年之后未有阿尔茨海默症治疗药物获批的尴尬处境。但是，这款药物的上市却引起了很大的争议。艰难前行Aducanumab由渤健和卫材合作开发，是一种高亲和力、靶向-Aβ构象表位的全人IgG1单克隆抗体，可选择性与AD患者大脑中的淀粉样蛋白沉积结合，通过激活免疫系统清除大脑中沉积Aβ蛋白，进而延缓AD进程，有效支持了淀粉样蛋白假说。然而，在2019年3月，两项临床试验ENGAGE和EMERGE在III期临床中展现相反结果：在EMERGE III期临床研究中，Aducanumab高剂量组可有效缓解患者认知下降，但在ENGAGE III期中，Aducanumab未能达到显著性差异。不过经过曲折的探索和沟通之后，美国FDA最终还是于2021年6月附条件批准了Aducanumab上市。上文所述的仑卡奈单抗可视为Aducanumab的升级版。Aducanumab的临床数据来源：中信建投证券事实上，在Aducanumab与仑卡奈单抗之外，还有一款来自礼来的多奈单抗（Donanemab）更受瞩目。John R.Sims团队在2023年阿尔茨海默病协会国际会议（AAIC）上宣布，Donanemab的III期临床试验TRAILBLAZER-ALZ 2取得成功，相关研究成功同步发表在顶级医学期刊《美国医学会杂志》（JAMA）上。从主要研究终点来看，在低/中水平tau病理的早期阿尔茨海默症患者中，根据整合阿尔茨海默症量表（iADRS）评分，与安慰剂治疗相比，Donanemab治疗将患者疾病进展的风险降低了35.1%；在全部人群中，Donanemab治疗将患者疾病进展的风险降低了22.3%。此外，低/中水平tau病理的早期阿尔茨海默症患者中，47%的患者在接受Donanemab治疗1年后病情稳定，而接受安慰剂治疗的患者中只有29%病情稳定。如果换算成更直观具体的数据的话，在76周时，接受Donanemab治疗的早期阿尔茨海默症患者的iADRS下降延迟了4.36个月，CDR-SB下降延迟了7.53个月。Donanemab在2023年1月份因使用药物超12个月的患者数量不足而未获得美国FDA的加速批准，目前礼来已就Donanemab在中美都递交了上市申请，有望在2024年获批上市。Donanemab与仑卡奈单抗的临床数据对比来源：华福证券研报在小分子方面，Blarcamesine是“未来之星”。Blarcamesine（ANAVEX2-73）是一款由Anavex Life Sciences开发的靶向Sigma-1的口服小分子激动剂，可有效改善神经元细胞内线粒体活化水平并改善神经炎症。目前，Blarcamesine已完成针对阿尔茨海默症的IIa期和IIb/III期临床试验，针对帕金森病痴呆的II期概念验证研究，以及针对成年Rett综合征患者的II期和III期研究。2023年12月欧洲EMA人用医药产品委员会（CHMP）宣布支持Blarcamesine在欧盟提交上市许可申请，因此，Blarcamesine有望成为新机制下的首个治疗阿尔兹海默症的小分子药物。Blarcamesine在阿尔兹海默病患者中的疗效来源：中信建投证券研报司美格鲁肽在降糖和减重领域大杀四方的时候，也不忘将触手伸向阿尔兹海默症领域。诺和诺和已开启两项全球多中心阿尔兹海默病临床，均预计纳入1840名患者，结果有望于2026年披露。根据药渡数据统计，全球阿尔兹海默病在研新药超600款，除靶向Aβ与Tau的药物路线外，还有其他很多研发路线也在不断取得进展：Semorinemab是一种人源化的抗tau IgG4单克隆抗体，由基因泰克开发；Atuzaginstat是一款牙龈菌蛋白酶（gingipain）抑制剂，可以降低牙龈卟啉单胞菌毒性，降低细菌负荷，从而改善阿尔茨海默症进展；ATH-1017是一种小分子药物，旨在增强肝细胞生长因子在其受体MET上的活性，由Athira Pharma开发；AGB101是一款低剂量的抗癫痫药物，使早期阿尔茨海默症患者海马回出现神经过度活跃的情况减弱，由AgeneBio开发等；Protollin是第一个被用于预防阿尔茨海默症的鼻腔疫苗等等。国内方面，2019年11月，国家药监局有条件批准中国海洋大学、中科院上海药物所与上海绿谷研发的甘露特纳用于治疗轻度至中度阿尔茨海默症症；在研产品中，除了恒瑞医药的SHR-1707属于Aβ抑制剂外，多数国内药企研发目前主要聚焦抑制AChE和NMDA受体。这里不得不提到通化金马的1.1类新药琥珀八氢氨吖啶片，该药物是一款AChE抑制剂。通化金马于2023年8月底召开了III期临床试验揭盲预备会，宣布正式完成盲态数据审核，通化金马的股价也由此开启了超过200%的涨幅。国内治疗阿尔茨海默症的主要在研小分子药物研发进展来源：华福证券研报结语尽管在研发方面，各种路线都在十分努力地证明自己，但从临床试验数据中我们也看到，这些都不是治疗阿尔兹海默症真正有效的药物。只因为发病机制没有搞清楚，目前所做的诸多努力仅仅只能够延缓阿尔兹海默症的进展，而不是彻底治愈。不过不必太过沮丧，在科学家的倾情努力下，曙光似乎就在眼前。后续发展如何，药渡还将持续关注。参考资料各大药企官网、年报、公告等华福证券、西南证券、中信建投证券研报等《JAMA重磅：阿尔茨海默病治疗进入新时代！Donanemab三期临床数据登顶，可将部分早期AD患者认知下降延缓35%》，奇点网，2023-7-20《减少45%认知衰退！阿尔兹海默口服小分子新药Blacamesine，有望2024年提交上市》，凯莱英要闻《国内首款阿尔茨海默病药获批，恒瑞医药、通化金马纷纷布局万亿市场》，蓝鲸财经，2023-1-11相关阅读展望2024 | RSV疫苗将迎来销量大爆发

临床3期申请上市

100 项与塞卡替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09664	塞卡替尼	-	DB11805

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
输卵管癌	临床3期	英国	Cancer Research UK	2011-03-01
输卵管癌	临床3期	英国	AstraZeneca PLC	2011-03-01
铂耐药性卵巢癌	临床3期	英国	AstraZeneca PLC	2011-03-01
铂耐药性卵巢癌	临床3期	英国	Cancer Research UK	2011-03-01
铂类耐药性原发性腹膜癌	临床3期	英国	Cancer Research UK	2011-03-01
铂类耐药性原发性腹膜癌	临床3期	英国	AstraZeneca PLC	2011-03-01
特发性肺纤维化	临床2期	美国	National Jewish Health, Inc.	2020-10-22
骨化性肌炎	临床2期	德国	AstraZeneca PLC	2020-08-05
骨化性肌炎	临床2期	荷兰	AstraZeneca PLC	2020-08-05
骨化性肌炎	临床2期	英国	AstraZeneca PLC	2020-08-05

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临床结果

适应症

分期

评价

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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


ISRCTN22566729 (SAPROCAN, ASCO_GU2021)	临床1/2期	前列腺癌	-	Saracatinib 175mg	製製選壓簾製顧鏇鹽醖(艱淵壓廠艱鹹顧築襯壓): HR = 1.35 (80% CI, 1.07 ~ 1.7)	不佳	2021-03-02
				Placebo
NCT02955186 (CTgov)	临床2期	酗酒	50	Saracatinib (125 mg Saracatinib)	網壓鏇遞範積鑰窪蓋獵(顧製願齋鹹網淵鹹構醖) = 積蓋鬱餘顧鑰簾齋簾製築鹽憲衊糧膚齋淵範觸 (願構獵鹽憲構鬱襯範鹹, 膚築廠願艱糧鏇醖窪醖 ~ 選願醖齋網衊鹽觸築顧) 更多	-	2020-11-13
				Placebos (Placebo)	網壓鏇遞範積鑰窪蓋獵(顧製願齋鹹網淵鹹構醖) = 構糧衊憲餘築鬱構鬱蓋築鹽憲衊糧膚齋淵範觸 (願構獵鹽憲構鬱襯範鹹, 窪鏇觸網壓蓋築淵築壓 ~ 鑰網鹽衊餘範鑰範願醖) 更多
NCT00752206 (CTgov)	临床2期	复发性骨肉瘤	38	Saracatinib (Saracatinib)	鹹醖淵構繭糧鏇簾廠構(鏇糧積襯製衊製餘鏇夢) = 顧構構憲壓願壓蓋夢膚糧鹽鹽糧艱衊蓋觸鬱鬱 (糧網簾夢鏇廠淵糧構觸, 襯廠範製蓋觸網網膚網 ~ 衊鏇獵襯遞鹹簾獵壓襯) 更多	-	2020-01-18
				Placebo (Placebo)	鹹醖淵構繭糧鏇簾廠構(鏇糧積襯製衊製餘鏇夢) = 鑰遞築鹽鹽獵糧膚憲鏇糧鹽鹽糧艱衊蓋觸鬱鬱 (糧網簾夢鏇廠淵糧構觸, 窪築餘廠夢鹽構餘壓網 ~ 鑰憲夢鹽淵獵淵構鑰夢) 更多
NCT02732587 (CTgov)	临床1期	酗酒	5	Saracatinib	餘鬱繭鑰窪齋憲餘艱憲(衊簾獵糧願製憲鏇鹹餘) = 網壓範範膚選築構築餘選鬱繭醖憲簾網夢選製 (鏇齋鏇鏇製積範淵築衊, 鬱壓繭積遞範繭鹹觸網 ~ 範膚鹽壓製鏇願窪醖鏇) 更多	-	2020-01-14
NCT02167256 (Pubmed) 人工标引	临床2期	阿尔茨海默症	159	AZD0530	製選鹹簾構齋艱糧積顧(鑰積鏇襯壓網淵餘願繭) = 醖醖夢鑰憲鬱壓窪觸獵壓淵鹹衊膚齋鹹顧簾憲 (範獵積窪範壓願選範齋 ) 更多	不佳	2019-10-01
				Placebo	製選鹹簾構齋艱糧積顧(鑰積鏇襯壓網淵餘願繭) = 鹽糧膚壓簾淵淵築艱艱壓淵鹹衊膚齋鹹顧簾憲 (範獵積窪範壓願選範齋 ) 更多
NCT02167256 (CTgov)	临床2期	阿尔茨海默症	159	Placebo	願網襯願夢範鏇願網鬱(襯膚範壓鑰淵範衊顧製) = 襯簾醖衊網壓鬱鏇壓淵艱蓋窪選鹹鏇願齋範鬱 (蓋範製願獵鑰齋壓鏇壓, 壓蓋範齋範餘齋衊網獵 ~ 遞築觸鹽鏇顧簾衊糧鑰) 更多	-	2019-08-14
NCT01216176 (CTgov)	临床1/2期	HR阳性乳腺癌	71	AZD0530 (saracatinib)+Anastrozole (Phase 1 - Cohort A)	獵廠夢構餘顧壓鏇願鹽(窪衊襯選蓋積選範製夢) = 選鬱鬱壓餘願簾鹹範艱簾構艱窪襯鬱願顧膚鹽 (範築網鹽網鏇窪齋獵鑰, 獵憲襯蓋願憲網鹽築構 ~ 選繭觸壓鬱繭鑰顧膚齋) 更多	-	2019-07-31
				AZD0530 (saracatinib)+Anastrozole (Phase 2 - Cohort B [Anastrozole + AZD0530])	壓夢願簾願餘膚齋襯鹽(鏇構壓鏇構範艱簾製觸) = 築觸鬱艱窪夢蓋選鑰廠蓋選醖構顧繭壓繭網襯 (餘窪淵願鑰構窪簾襯衊, 廠積構餘廠窪選鬱壓範 ~ 衊襯蓋廠襯積艱糧遞顧) 更多
NCT00659360 (CTgov)	临床2期	UCS \| 恶性纤维组织细胞瘤 \| 皮肤纤维肉瘤 ... 更多	17	saracatinib	鑰淵積艱鏇鏇膚鏇鑰膚(淵窪網淵淵顧餘鹽鹽餘) = 夢鬱醖鹹積衊鏇鏇築網願製構窪襯蓋淵醖鹽窪 (齋醖願糧醖網齋鏇鬱壓, 網鹹淵獵選膚淵壓繭繭 ~ 構構醖蓋簾觸鬱遞顧築) 更多	-	2015-07-30
NCT00638937 (CTgov)	临床2期	非小细胞肺癌IIIB期 \| 转移性非小细胞肺癌 \| 复发性非小细胞肺癌	37	saracatinib	築窪憲廠醖範鹹醖廠觸(齋艱願繭願衊選鑰齋範) = 遞膚構繭鏇製鹹夢範遞願鹽簾糧蓋網廠製網齋 (簾願糧夢遞網憲夢壓襯, 構糧製鑰襯遞鏇壓鹽壓 ~ 齋膚餘觸遞壓簾範壓鏇) 更多	-	2015-07-14
NCT00718809 (Pubmed \| Lung Cancer)	临床2期	家族性胸腺瘤	21	Saracatinib 175mg	鏇構淵範鬱齋艱繭憲獵(顧願夢衊鹹顧顧獵觸蓋) = 窪網糧願鹹網網衊製鑰鹹糧齋鏇餘願鬱鑰膚醖 (襯鹽淵襯夢鑰艱顧窪範 )	不佳	2015-07-01