The main purpose of this study is to investigate the safety and efficacy of the study drug solanezumab in participants with prodromal Alzheimer's disease (AD).

开始日期2016-06-01

申办/合作机构

Eli Lilly & Co.

NCT02614131

/ Terminated临床1期

Single-Dose and Multiple-Dose, Dose-Escalation Study With LY2599666 to Evaluate the Safety, Pharmacokinetics, and Tolerability in Healthy Subjects and Patients With Mild Cognitive Impairment Due to Alzheimer's Disease and Mild-to-Moderate Alzheimer's Disease

The main purpose of this study is to evaluate the safety and tolerability of the study drug known as LY2599666 in different groups of people - those who are healthy, those who have mild cognitive impairment due to Alzheimer's Disease (AD), and those with mild-to-moderate AD. The study will measure how much LY2599666 gets into the bloodstream and how long it takes the body to get rid of it. It will also evaluate how LY2599666 affects the body. The study has three parts. Part A will last about 2 months. Parts B and C will each last about 23 weeks. Participants may only enroll in one part.

开始日期2015-12-01

申办/合作机构

Eli Lilly & Co.

100 项与苏兰珠单抗相关的临床结果

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100 项与苏兰珠单抗相关的转化医学

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100 项与苏兰珠单抗相关的专利（医药）

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298

项与苏兰珠单抗相关的文献（医药）

2026-03-04·NEUROLOGICAL RESEARCH

Alzheimer’s disease basics: we all should know

Review

作者: Das, Sayantan

BACKGROUND:

Alzheimer's disease (AD) is the most common cause of dementia worldwide, affecting over 55 million individuals and projected to rise drastically in the coming decades. Characterized by progressive cognitive decline and memory impairment, AD involves complex pathological mechanisms including amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles (NFTs) of hyperphosphorylated tau, and chronic neuroinflammation.

OBJECTIVE:

This comprehensive review aims to provide a foundational understanding of the molecular, genetic, and immunological underpinnings of AD, with a focus on pathogenic proteins, glial cell responses, and current monoclonal antibody (mAb)-based therapeutic strategies.

METHODS:

Literature on key pathological players such as Aβ, tau, microglia, and astrocytes was mentioned to explain their roles in neurodegeneration. The impact of key genetic mutations (APP, PSEN1, PSEN2, APOE, BACE1, MAPT) was outlined. Additionally, recent clinical trial data of anti-Aβ monoclonal antibodies (aducanumab, lecanemab, donanemab) were reviewed, with comparative analysis of efficacy, safety, and trial outcomes.

RESULTS:

Neuroinflammation, mediated by activated microglia and astrocytes, exacerbates Aβ and tau pathology, contributing to synaptic loss and neuronal death. Genetic mutations alter APP processing and promote plaque formation. Monoclonal antibodies show promise in reducing Aβ burden and slowing cognitive decline: donanemab achieved 60% slower decline in mild cognitive impairment, while lecanemab showed 27% cognitive benefit in early AD. Aducanumab, despite initial promise, was discontinued in 2024 due to limited efficacy and safety concerns. Adverse events like amyloid-related imaging abnormalities (ARIA), particularly in APOE-4 carriers, remain significant.

CONCLUSION:

AD pathology is multifactorial, involving an interplay between protein aggregation, immune dysregulation, and genetic risk. While mAb therapies mark progress in disease modification, their success depends on patient stratification, early intervention, and safety profiling. Future directions must emphasize combinatorial and personalized approaches incorporating early biomarkers, neuroimaging, and emerging technologies to effectively combat the rising global burden of AD.

2026-03-01·Psychogeriatrics

Eligibility for Anti‐Amyloid‐β Monoclonal Antibodies in Patients With Primary Progressive Aphasia due to Alzheimer's Disease in Japan

Article

作者: Inagawa, Shoya ; Ikeuchi, Takeshi ; Shimizu, Soichiro ; Tsugawa, Akito ; Kasuga, Kensaku ; Ishii, Kenji ; Inagawa, Yuta ; Takenoshita, Naoto ; Saito, Kazuhiro

ABSTRACT:

Background:

Primary progressive aphasia (PPA) is a clinical syndrome characterized by progressive language impairment. The logopenic variant (lvPPA) is frequently associated with Alzheimer's disease (AD) pathology. With the approval of anti‐amyloid‐β monoclonal antibodies, such as lecanemab and donanemab, for the treatment of AD, accurately differentiating lvPPA due to AD (lvAD) from the other PPA variants has become highly important.

Methods:

Thirteen patients with PPA who underwent cognitive testing, including the Standard Language Test of Aphasia (SLTA), brain magnetic resonance imaging, single‐photon emission computed tomography (SPECT), cerebrospinal fluid (CSF) biomarker analysis, and amyloid positron emission tomography (PET) imaging were enrolled in this study. Patients were classified into the lvPPA, semantic variant PPA (svPPA), and nonfluent/agrammatic variant PPA (nfaPPA) groups based on the results of clinical and neuropsychological assessments. We determined the proportion of PPA patients in each group who met the optimal use guidelines for anti‐amyloid monoclonal antibody therapy.

Results:

Six (86%) of the 7 lvPPA patients were amyloid positive (A+), and 5 (71%) were eligible for lecanemab or donanemab. In most lvPPA patients, SPECT displayed an AD‐typical pattern of hypoperfusion in the bilateral temporoparietal regions, posterior cingulate gyrus, and precuneus. One lvPPA patient was negative for AD biomarkers and demonstrated an atypical perfusion pattern for AD, and was subsequently rediagnosed as having frontotemporal lobar degeneration.

Conclusions:

These results suggest that SPECT may play a supportive role in differentiating lvAD from PPA. In the current clinical era of anti–amyloid‐β monoclonal antibody therapy, accurate identification of lvAD among patients with language‐predominant symptoms is increasingly important. Larger studies should be performed in the near future to validate these findings.

2026-02-19·CURRENT TOPICS IN MEDICINAL CHEMISTRY

Antibody Therapies Targeting Amyloid-β and Tau in Alzheimer’s Disease with Insights on Mechanisms, Clinical Trials, and Challenges

Article

作者: Kumar, Ajay ; Gasmi, Amin ; Wal, Pranay ; Jawaid, Talha ; Ashesh, Astik Manju ; Gupta, Sanjana ; Bhise, Manish R.

Abstract::

Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) deposits and neurofibrillary tangles containing phosphorylated tau protein. Around 57 million people worldwide were estimated by the World Health Organization to have dementia in 2021, with AD being the most prevalent type. The burden of AD is still rising. By 2036, there will likely be close to 20 million AD cases worldwide, according to projections that show a sharp increase brought on by population aging. Normal neural transmission is disrupted with Aβ plaques and hyperphosphorylated tau tangles, eventually resulting in the death of neurons and cognitive impairment. Currently, no therapies provide a cure; available treatments are symptomatic. The main focus of scientists has been on targeting Aβ and tau proteins. A number of anti-Aβ and anti-tau monoclonal antibody therapies targeting the buildup of Aβ and tau in the brain have been discovered recently. An announcement was made in September 2022 regarding the phase 3 research, suggesting Lecanemab had achieved its main objective of slowing the progression of clinical dementia. The CLARITY AD Phase 3 trial, which was published in the New England Journal of Medicine on January 5, 2023, assessed lecanemab, a monoclonal antibody, in patients with early-stage Alzheimer's disease or Mild Cognitive Impairment (MCI) brought on by Alzheimer's disease who had biomarker evidence of amyloid pathology. Lecanemab showed a statistically significant, although clinically modest, slowing of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the 18-month double-blind, placebocontrolled trial. Clinical worsening was reduced by 27% when compared to placebo (mean difference of -0.45; 95% CI: -0.67 to -0.23). Similar modest benefits were observed across quality of life and daily functioning measures, and all primary and secondary cognitive and functional endpoints were met. The change in CDR-SB fell short of the minimal clinically significant difference that is frequently mentioned for this patient population, and the observed clinical benefit is typically characterized as small to moderate. Crucially, lecanemab-treated participants had a higher incidence of amyloidrelated imaging abnormalities (ARIA) such as edema and microhemorrhages (about 21.5%) than the placebo group (about 9%). Although the majority of ARIA events were controllable, there were a few documented instances of severe consequences, especially when anticoagulation was used. On 9th June 2023, an FDA advisory group unanimously decided that Lecanemab demonstrates clinical benefits for therapy of early Alzheimer's disease, marking the opening door for full approval. The results demonstrate lower Aβ and tau, a real therapeutic advantage, going beyond simple alterations in biomarkers, representing a major breakthrough in the treatment of AD. This review provides a summary of mechanisms, results of the clinical trials of anti-tau and anti-Aβ antibody treatments up to February 2024, as well as recommendations for their future developments.

206

项与苏兰珠单抗相关的新闻（医药）

2026-03-19

·GlobeNewswire-Health Care

NetraMark Unveils AI-Discovered Treatment-Responsive Subgroups in A4 Alzheimer’s Trial at AD/PD Conference

Results illustrate how NetraMark’s advanced AI can potentially support precision enrichment strategies in future trialsTORONTO, March 19, 2026 (GLOBE NEWSWIRE) -- NetraMark Holdings Inc. (the “Company” or “NetraMark”) (TSX: AIAI) (OTCQB: AINMF) (Frankfurt: PF0), a company developing advanced artificial intelligence solutions for clinical trial optimization and precision medicine, today announced new findings illustrating the ability of its proprietary explainable AI platform, NetraAI, to uncover clinically meaningful responder subgroups within the landmark Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial. The results, were presented in a poster titled, “Decoding Heterogeneity in A4: Explainable ML Identifies Solanezumab-Responsive Subgroups in Preclinical AD,” which highlight how NetraMark’s technology has the potential to reveal therapeutic signals that may be obscured in conventional clinical trial analyses. The poster was presented at the Alzheimer’s Disease & Parkinson’s Diseases (AD/PD) 2026 International Conference, taking place March 17 - 21, 2026, in Copenhagen, Denmark during the poster sessions. Explainable AI Identifies Hidden Treatment Response Using a dynamical-systems-based explainable machine learning approach, NetraAI analyzed multimodal baseline variables including imaging, cognitive assessments, demographics, and biomarkers from participants in the A4 study. Although the original Phase 3 A4 trial showed no statistically significant overall benefit for solanezumab (a humanized monoclonal antibody designed to treat Alzheimer’s disease by binding to and clearing soluble amyloid-beta), NetraAI identified two distinct patient subgroups suggesting meaningful treatment effects relative to placebo. Key findings include: Identification of two biologically interpretable responder subgroups characterized by higher regional brain volume and stronger baseline cognitive performance.Large treatment effects, within these subgroups, with effect sizes reaching Cohen’s d up to 1.52.Participants within subgroups showing treatment effects were associated with greater baseline limbic and temporal network integrity, including higher right amygdala or right superior temporal cortex volume, alongside stronger psychomotor speed and attention scores on the Digit Symbol Substitution Test. These findings suggest that preserved neural reserve may be an important determinant of anti-amyloid treatment response in preclinical Alzheimer’s disease. Implications for Alzheimer’s Drug Development The results underscore a significant challenge in Alzheimer’s clinical development: being patient heterogeneity can mask meaningful drug response within overall trial populations. By identifying explainable, model-derived subgroups defined by only a small number of baseline variables, NetraAI illustrates how advanced AI can potentially support precision enrichment strategies in future trials. For the pharmaceutical industry, this approach could: Improve trial design by identifying patients most likely to respond to investigational therapiesEnable retrospective re-analysis of historical trials to extract new insightsReduce development risk and cost through data-driven patient stratification Timely Advances for the Alzheimer’s Research Community The upcoming presentation comes at a pivotal time for the Alzheimer’s field, as therapeutic development increasingly focuses on earlier disease stages and precision-guided treatment strategies. NetraMark’s explainable AI methodology aligns with this shift by supporting researcher efforts aimed at understanding not only whether a therapy demonstrates an effect, but also which patients may be most likely to benefit and why. "These findings suggest that patient heterogeneity may be masking treatment effects in Alzheimer’s trials, underscoring the need for approaches such as NetraAI that may identify interpretable patient subpopulations most likely to benefit from emerging therapies,” said Dr. Joseph Geraci, Chief Technical Officer and Founder of NetraMark. “Technologies capable of identifying biologically meaningful responder subgroups could fundamentally reshape how Alzheimer’s clinical trials are designed.” As the industry continues to explore disease-modifying treatments targeting amyloid and other pathways, technologies capable of interpretable patient segmentation have the potential to play a critical role in unlocking therapeutic signals that traditional analyses fail to detect. About NetraAI In contrast to other AI-based methods, NetraAI is uniquely engineered to include focus mechanisms that separate small datasets into explainable and unexplainable subsets. Unexplainable subsets are collections of patients that can lead to suboptimal overfit models and inaccurate insights due to poor correlations with the variables involved. NetraAI uses explainable subsets to derive insights and hypotheses (including factors that influence treatment and placebo responses and adverse events), potentially increasing the likelihood of a clinical trial's success. Many other AI methods lack these focus mechanisms and assign every patient to a class, often leading to "overfitting", which drowns out critical information that could have been used to improve a trial's chance of success. About NetraMark NetraMark is a company focused on being a leader in the development of Generative Artificial Intelligence (Gen AI)/Machine Learning (ML) solutions targeted at the Pharmaceutical industry. Its product offering uses a novel topology-based algorithm that has the ability to parse patient data sets into subsets of people that are strongly related according to several variables simultaneously. This allows NetraMark to use a variety of ML methods, depending on the character and size of the data, to transform the data into powerfully intelligent data that activates traditional AI/ML methods. The result is that NetraMark can work with much smaller datasets and accurately segment diseases into different types, as well as accurately classify patients for sensitivity to drugs and/or efficacy of treatment. For further details on the Company please see the Company’s publicly available documents filed on the System for Electronic Document Analysis and Retrieval+ (SEDAR+). Forward-Looking Statements This press release contains "forward-looking information" within the meaning of applicable Canadian securities legislation including statements regarding the potential of NetraMark’s NetraAI platform and analyses to reveal therapeutic signals that may not be apparent in conventional clinical trial analyses; the potential application of NetraAI to support precision enrichment strategies in future clinical trials; the potential to improve clinical trial design, enable retrospective analyses of historical trials, and reduce development risk and cost through data‑driven patient stratification; and the potential role of interpretable patient segmentation technologies in identifying treatment‑responsive subgroups, which are based upon NetraMark’s current internal expectations, estimates, projections, assumptions and beliefs, and views of future events. Forward-looking information can be identified by the use of forward-looking terminology such as "expect", "likely", "may", "will", "should", "intend", "anticipate", "potential", "proposed", "estimate" and other similar words, including negative and grammatical variations thereof, or statements that certain events or conditions "may", "would" or "will" happen, or by discussions of strategy. Forward-looking information includes estimates, plans, expectations, opinions, forecasts, projections, targets, guidance, or other statements that are not statements of fact. The forward-looking statements are expectations only and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results of the Company or industry results to differ materially from future results, performance or achievements. Any forward-looking information speaks only as of the date on which it is made, and, except as required by law, NetraMark does not undertake any obligation to update or revise any forward-looking information, whether as a result of new information, future events, or otherwise. New factors emerge from time to time, and it is not possible for NetraMark to predict all such factors. When considering these forward-looking statements, readers should keep in mind the risk factors and other cautionary statements as set out in the materials we file with applicable Canadian securities regulatory authorities on SEDAR+ at www.sedarplus.com including our Annual Information Form for the year ended September 30, 2025. These risk factors and other factors could cause actual events or results to differ materially from those described in any forward- looking information. The Toronto Stock Exchange does not accept responsibility for the adequacy or accuracy of this release. Contact Information: Swapan Kakumanu - CFO | swapan@netramark.com | 403-681-2549 Or Adam Peeler – Investor Relations | adam.peeler@loderockadvisors.com | 416-427-1235 LodeRock Advisors

临床3期临床结果

2026-03-09

·阿尔茨海默病研究

从多奈哌齐到乐意保：卫材四十年AD守望，一家日本药企如何书写阿尔茨海默病治疗史

关键词：卫材，渤健，BioArctic，仑卡奈单抗，lecanemab，Leqembi，乐意保，Aricept，多奈哌齐，aducanumab，Aduhelm，elenbecestat，CLARITY AD，BAN2401，E2609，AHEAD 3-45，皮下注射，AD疾病修饰治疗，抗Aβ原纤维单抗「开拓性文章信息：期刊：New England Journal of Medicine，影响因子（IF）：158.5，JCR Q1 标题： Lecanemab in Early Alzheimer's Disease（中文：仑卡奈单抗在早期阿尔茨海默病中的研究）第一作者及单位： Christopher H. van Dyck，美国耶鲁大学医学院（Yale School of Medicine）神经病学系发表时间： 2023年1月5日 DOI： 10.1056/NEJMoa2212948 主要结论概要：本文是卫材×渤健×BioArctic三方合作的核心成果——CLARITY AD Phase III研究完整数据的正式发表。n=1795名早期AD患者，18个月治疗后lecanemab使主要终点CDR-SB恶化减缓27%（p<0.001），所有关键次要终点全部达成，淀粉样蛋白PET清除-59.1 Centiloid。这是人类历史上第一篇在NEJM以"早期阿尔茨海默病疾病修饰治疗完整Phase III正面结果"发表的文章，直接推动FDA于2023年7月完全批准Leqembi®，中国NMPA于2024年1月批准乐意保®，标志着卫材历经40年、渤健历经数十亿美元投入后在AD领域的历史性突破[1]。」一、总论：两家公司的AD战略交汇卫材株式会社（Eisai Co., Ltd.，东证一部：4523）与渤健公司（Biogen Inc.，NASDAQ：BIIB）是当前AD疾病修饰治疗赛道最具代表性的战略合作伙伴。两家公司在AD领域的合作跨越十余年，历经重大失败与历史性突破，共同构建了迄今全球AD治疗领域最完整的上市产品线[2][3]。卫材是一家以神经科学为核心战略的日本制药公司，以"hhc（human health care）"理念著称，是全球最早投入AD药物研发的制药公司之一。其1996年上市的多奈哌齐（Aricept®）是迄今全球销售规模最大的AD对症治疗药物，全球累计销售额超200亿美元[4]。渤健是一家以神经科学为核心的美国生物技术公司，拥有深厚的抗体工程和临床运营能力，aducanumab（Aduhelm®）的开发失败曾使其遭遇严峻的公司信誉危机，而lecanemab（Leqembi®）的成功则成为其战略重生的核心支柱[5]。 BioArctic是一家总部位于瑞典斯德哥尔摩的神经科学生物技术公司，以Lars Lannfelt教授（乌普萨拉大学）发现的"arctic APP突变体产生大量Aβ原纤维"这一科学发现为基础，成为lecanemab原始抗体的发现者和核心科学提供方[6]。三方合作的完整科学与商业路径，是本综述系统梳理的核心内容。二、卫材AD布局第一阶段：多奈哌齐与AChEI时代（1983—2003）2.1 多奈哌齐的研发与划时代获批卫材在AD领域的战略布局，最早可追溯至1983年。卫材研发团队受胆碱能假说（cholinergic hypothesis）驱动，启动乙酰胆碱酯酶抑制剂（AChEI）的系统性筛选项目，目标是开发比他克林（tacrine）更安全、更有效的AD对症治疗药物[4]。经历超过10年的化学合成与临床前优化，卫材最终确定了多奈哌齐（donepezil hydrochloride，研发代号E2020）这一化合物。多奈哌齐具有高选择性AChE抑制活性（对BuChE的选择性远低于tacrine），半衰期约70小时，每日一次给药，肝毒性极低[4]。 1993年，卫材就多奈哌齐与辉瑞（Pfizer）签署全球联合推广协议，由辉瑞负责北美、欧洲等主要市场的商业化推广，卫材负责亚太区及研发，形成强强联合的商业模式[4]。 1996年11月25日，FDA批准Aricept®（donepezil hydrochloride）5mg和10mg剂型，适应症为轻至中度AD，这是全球第二款获批的AChEI类AD药物（他克林于1993年首批），但因其安全性和依从性的优越性，很快成为全球最广泛处方的AD药物[4][7]。 2003年10月，FDA进一步批准Aricept®用于重度AD，使多奈哌齐成为唯一获批覆盖AD**全阶段（轻度、中度、重度）**的处方药[7]。Aricept在其专利保护期内（2001—2010年）的全球年销售额一度突破30亿美元，是卫材公司收入的最重要支柱，也为其后续投入AD疾病修饰治疗研发提供了资金基础[4]。 2010年多奈哌齐专利到期后，仿制药浪潮使Aricept销售额大幅下滑，但其作为"20世纪AD对症治疗奠基性药物"的历史地位无可撼动——迄今发表的多奈哌齐相关论文已超过2000篇[7][8]。三、合作伙伴BioArctic与BAN2401的科学起源（2005—2007）3.1 "北极突变"与Aβ原纤维毒性假说 BioArctic公司的科学基础来自乌普萨拉大学Lars Lannfelt教授团队2001年在Nature Neuroscience发表的研究——"arctic APP突变体（E693G）"揭示了一种特殊的家族性AD突变，其核心特征是该突变导致Aβ前体蛋白产生大量可溶性Aβ原纤维（protofibrils），而这些原纤维比Aβ单体或不溶性斑块对突触的毒性更强[6]。这一发现促使BioArctic开发了一系列专门针对Aβ原纤维的单克隆抗体，其中BAN2401（后来的lecanemab）是最具临床开发价值的候选抗体。BAN2401是一种人源化IgG1单抗，对Aβ原纤维的亲和力约是Aβ单体的1000倍，提供了高度特异的靶向能力[6][9]。3.2 卫材与BioArctic的许可协议（2007） 2007年12月，卫材与BioArctic签署BAN2401许可协议，卫材获得BAN2401的全球开发权和商业化权，并向BioArctic支付特许权使用费和里程碑款项[10]。BioArctic保留瑞典/北欧地区的共同推广权利，并持续提供科学支持。这一协议是整个lecanemab开发历程的法律与商业起点[10]。 2012年，卫材启动BAN2401的Phase IIb研究（201研究），这是lecanemab首个规模化人体临床试验，为后续的突破奠定基础[9]。四、卫材×渤健战略合作的建立与演进（2012—2014）4.1 2012年aducanumab合作的背景 2012年，渤健从苏黎世大学（Neurimmune公司）获得aducanumab（BIIB037）的全球许可。aducanumab是一种靶向Aβ聚集体（包括可溶性寡聚体和不溶性斑块）的人源化IgG1单抗，来源于长寿健康老年人的记忆B细胞（"逆向翻译医学"策略）[5]。同年，渤健开始与卫材就aducanumab的临床开发进行合作讨论，两家公司意识到在AD领域各有互补优势——渤健拥有神经科学临床运营能力，卫材拥有日本及亚洲市场准入网络和多奈哌齐的AD临床经验[11]。4.2 2014年联合开发协议：BAN2401与E2609的双线布局 2014年3月，卫材与渤健正式签署联合开发与商业化协议，合作标的包含两项资产[10][11]： ① BAN2401（lecanemab）：卫材将BAN2401的全球共同开发权授予渤健，双方50/50分担开发成本，渤健负责北美及欧洲商业化，卫材负责日本及亚洲区商业化。这是整个lecanemab故事从实验室走向全球的关键协议。 ② E2609（elenbecestat）：卫材自主研发的口服BACE1抑制剂，渤健同步纳入联合开发，启动Phase II/III研究。两款药物代表了"清除已有Aβ斑块（BAN2401）"与"从源头减少Aβ生成（E2609）"的双线战略[11]。五、elenbecestat（E2609）：BACE抑制剂的挫折（2014—2019）5.1 临床开发历程 elenbecestat是卫材自主研发的选择性口服BACE1抑制剂，通过抑制BACE1酶（β-位点APP切割酶1）从源头阻断Aβ肽的生成。Phase IIb研究（Study 202）显示elenbecestat可使CSF Aβ显著降低，支持其生物学效应[12]。 2016—2017年，卫材与渤健联合启动两项Phase III研究：MISSION AD1 （NCT02956486）：针对早期AD患者MISSION AD2 （NCT03036280）：针对早期AD患者，与MISSION AD1设计相同，双盲平行进行两项研究合计入组超过3000名早期AD患者，是当时规模最大的BACE抑制剂Phase III试验之一[12][13]。5.2 2019年安全性终止 2019年9月13日，卫材与渤健发表联合声明：独立数据安全监察委员会（IDMC）审查MISSION AD1和MISSION AD2研究的数据后，建议立即终止两项研究。终止原因为：接受elenbecestat治疗的患者出现不良的风险获益比，具体表现为神经精神相关不良事件（包括焦虑、抑郁、异常梦境等）发生率显著高于安慰剂组[12][13]。这一结果与同期BACE抑制剂领域的整体失败（默克verubecestat、罗氏umibecestat等均告失败）相互印证，从根本上动摇了"抑制Aβ生成"作为AD治疗策略的近期可行性，并促使整个行业资源向"清除已有Aβ"的抗体策略进一步集中[14]。六、aducanumab：争议性获批与历史性退市（2019—2024）6.1 EMERGE与ENGAGE：戏剧性的Phase III历程 aducanumab的Phase III故事是制药史上最具戏剧性的案例之一。两项Phase III研究（EMERGE，n=1638；ENGAGE，n=1647）在2019年3月被渤健/卫材联合宣布以无效性为由中期终止，震惊业界[5]。然而，仅数月后，2019年10月，渤健宣布重新分析扩充后的数据集后发现：EMERGE研究高剂量亚组达到主要终点（CDR-SB减缓22%，p=0.01），而ENGAGE研究高剂量亚组呈中性结果。渤健据此向FDA提交BLA申请[5][15]。6.2 争议性加速批准与FDA顾问委员会的反对 2021年6月7日，FDA以"加速批准"路径批准aducanumab（商品名：Aduhelm®），批准依据为淀粉样蛋白清除这一替代终点，而非直接的认知功能改善[15]。然而，这一批准极具争议： FDA肿瘤学和神经科学顾问委员会曾以10:0（反对）：0（赞成）：1（不确定）的投票结果明确建议不批准 3名顾问委员因不满FDA无视建议而辞职美国国会介入调查FDA与渤健的"不寻常互动" 多数医疗中心和保险公司拒绝使用和报销初始定价每年56,000美元，随后在压力下降至28,200美元，但CMS（美国医疗保险和医疗救助服务中心）最终决定将aducanumab的报销范围限定于参与临床试验的患者[15][16]。6.3 主动退市：2024年1月的战略重组随着lecanemab的成功使渤健无需aducanumab维持AD产品线，渤健于2024年1月31日宣布：主动终止aducanumab的开发与商业化，将aducanumab的权利归还给原许可方Neurimmune，公司资源全面向lecanemab重新聚焦[16][17]。现有患者可继续使用至2024年11月1日，临床试验参与者可获得药物直至2024年5月。aducanumab从加速批准到完全退市，仅历时约2年半，成为制药史上最短命的重磅AD药物[17]。七、lecanemab的完整开发历程与历史性突破（2016—2024）7.1 Phase IIb研究（201研究，2016—2020）卫材于2016年正式启动BAN2401的Phase IIb研究（201研究，NCT01767311），与渤健联合运营。该研究采用贝叶斯自适应设计（Bayesian adaptive randomization），n=856名早期AD患者，探索5个剂量组，主要终点为淀粉样蛋白PET和认知功能评估，研究持续18个月[9][18]。 2018年7月，卫材公布Phase IIb期中分析结果：高剂量lecanemab（10mg/kg双周）使CDR-SB减缓30%（p=0.034，贝叶斯分析），同时显著降低淀粉样蛋白PET负荷和多项血浆生物标志物（pTau181、Aβ42/40等）。FDA于2018年12月授予lecanemab快速通道资格（Fast Track Designation）[18]。 2020年，Phase IIb完整数据在Alzheimer's Research & Therapy发表（Swanson等，2021），结果全面支持进入确证性Phase III[9]。7.2 CLARITY AD Phase III（2021—2022）设计：n=1795名早期AD患者（MCI至轻度AD痴呆，均经PET或CSF确认淀粉样蛋白阳性），随机1:1分配至lecanemab（10mg/kg，每2周静脉输注）或安慰剂组，治疗持续18个月，在全球约30个国家270个研究中心开展[1]。 2022年9月27日：卫材宣布CLARITY AD达到主要终点，CDR-SB减缓具有高度统计学显著性[19]。 2023年1月5日：van Dyck等在NEJM发表完整结果：CDR-SB减缓27%（p<0.001），iADRS减缓26%，ADAS-Cog14减缓26%，ADCS-MCI-ADL减缓37%，淀粉样蛋白PET -59.1 Centiloid[1]。7.3 FDA批准历程2023年1月6日：FDA基于Phase IIb生物标志物数据，加速批准lecanemab（商品名：Leqembi®）[19]2023年7月6日：FDA基于CLARITY AD完整数据，完全批准Leqembi®，成为2003年以来首款获FDA完全批准的AD药物。同日，卫材宣布在美国定价为每年26,500美元[20]2024年1月9日：中国NMPA批准lecanemab（商品名：乐意保®），成为在中国获批的第一款AD疾病修饰治疗药物[21]7.4 长期OLE数据与皮下注射新剂型（2025） 36个月OLE数据（AAIC 2025发布）：早期治疗组与延迟治疗组（原安慰剂交叉组）相比，CDR-SB减缓51%，证实越早开始治疗长期获益越大[22]。 Leqembi IQLIK（皮下注射维持剂型）：在完成18个月静脉输注初始治疗后，患者可转换为每周一次皮下注射（360mg/mL，SC）维持治疗。2025年8月，FDA正式批准Leqembi IQLIK，这是全球首款获批的皮下注射AD单克隆抗体维持剂型，将使患者可在家自行注射，大幅提升便利性和依从性[22][23]。八、症状前AD预防研究：AHEAD 3-45（2020年至今） AHEAD 3-45研究是卫材×渤健与美国NIH/ADCS（阿尔茨海默病合作研究）合作开展的全球最大规模症状前AD预防随机对照试验[24]，旨在证明lecanemab能否在无认知症状但已有Aβ积累的中年人群中预防AD进展。研究包含两个并行亚研究：A45研究：针对中度Aβ积累人群（55—80岁），接受lecanemab 10mg/kg每2周静脉输注A3研究：针对轻度Aβ积累人群（55—80岁），接受lecanemab较低剂量方案主要终点为tau PET变化（A45）和脑淀粉样蛋白积累速率（A3），持续治疗约4年，预计在2026—2028年有初步认知终点数据读出[24][25]。AHEAD 3-45是继A4研究（solanezumab失败）之后，AD症状前预防领域最被寄予期望的大型RCT。九、综合总结表：卫材×渤健AD产品线·合作伙伴·重要节点序号产品/项目类型靶点/机制合作方关键里程碑时间节点结局/现状 1Aricept®（多奈哌齐）5/10mg AChEI对症 AChE抑制辉瑞（全球推广） FDA批准，全球首批安全性AChEI 1996年11月 ✅持续上市 2Aricept®（多奈哌齐） AChEI对症 AChE抑制 — FDA批准重度AD适应症，覆盖全程 2003年10月 ✅持续上市 3Aricept 23mg AChEI高剂量 AChE抑制辉瑞 FDA批准中重度AD高剂量剂型 2010年 ✅上市 4BAN2401许可协议科学授权 Aβ原纤维单抗BioArctic （授权方）卫材获得BAN2401全球开发权 2007年12月 ✅协议持续有效 5BAN2401 Phase IIb（201研究）临床研究可溶性Aβ原纤维渤健（联合运营）贝叶斯自适应设计，CDR-SB减缓30% 2016—2020年 ✅支持进入Phase III 6elenbecestat（E2609）口服小分子 BACE1抑制渤健（联合开发）卫材×渤健2014年协议纳入，启动MISSION AD Phase III 2014—2016年 ❌终止 7elenbecestat MISSION AD1/2 Phase III BACE1 渤健 IDMC安全性终止：神经精神不良事件 2019年9月 ❌终止 8aducanumab（BIIB037）抗Aβ聚集体单抗 Aβ寡聚体+斑块渤健（原研）×卫材（联合商业化） FDA加速批准（争议性批准） 2021年6月 ❌已退市 9Aduhelm® 退市 — — 渤健×卫材渤健宣布主动放弃aducanumab，权利归还Neurimmune 2024年1月 ❌全面终止 10CLARITY AD Phase III 确证性RCT 可溶性Aβ原纤维渤健×BioArctic 主要终点CDR-SB减缓27%，n=1795 2021—2022年 ✅成功 11Leqembi®（lecanemab）加速批准抗Aβ原纤维单抗可溶性Aβ原纤维渤健×BioArctic FDA加速批准，全球首款抗Aβ原纤维单抗上市 2023年1月 ✅上市 12Leqembi®（lecanemab）完全批准抗Aβ原纤维单抗可溶性Aβ原纤维渤健×BioArctic FDA完全批准，2003年以来首款完全批准AD药 2023年7月 ✅完全批准 13乐意保®（仑卡奈单抗）中国抗Aβ原纤维单抗可溶性Aβ原纤维渤健×BioArctic 中国NMPA批准，第一款中国AD靶向单抗 2024年1月 ✅中国上市 14Leqembi IQLIK（SC皮下注射）皮下注射维持剂型可溶性Aβ原纤维渤健 FDA批准，全球首款皮下注射AD单抗维持剂型 2025年8月 ✅上市 15AHEAD 3-45 症状前预防RCT lecanemab预防 NIH/ADCS×卫材×渤健全球最大症状前AD预防RCT，tau PET为主要终点 2020—进行中 🔄Phase III进行中参考文献 [1] van Dyck, C. H. et al. "Lecanemab in Early Alzheimer's Disease." New England Journal of Medicine vol. 388 (2023): 9–21. doi:10.1056/NEJMoa2212948. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948 [2] Cummings, J. et al. "Alzheimer's disease drug development pipeline: 2025." Alzheimer's & Dementia: Translational Research & Clinical Interventions vol. 11 (2025): e70098. doi:10.1002/trc2.70098. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70098 [3] Cummings, J. et al. "Alzheimer's disease drug development pipeline: 2024." Alzheimer's & Dementia: Translational Research & Clinical Interventions vol. 10 (2024): e12465. doi:10.1002/trc2.12465. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.12465 [4] Birks, J. S. & Harvey, R. J. "Donepezil for dementia due to Alzheimer's disease." Cochrane Database of Systematic Reviews Issue 6 (2018): CD001190. doi:10.1002/14651858.CD001190.pub3. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD001190.pub3/abstract [5] Knopman, D. S. et al. "Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019." Alzheimer's & Dementia vol. 17 (2021): 696–701. doi:10.1002/alz.12213. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12213 [6] Lannfelt, L. et al. "Amyloid-β protofibrils as Alzheimer's disease drug target: preclinical and clinical studies with the mAb158 antibody." Alzheimer's Research & Therapy vol. 6 (2014): 16. doi:10.1186/alzrt246. https://alzres.biomedcentral.com/articles/10.1186/alzrt246 [7] Rogers, S. L. et al. "A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease." Neurology vol. 50 (1998): 136–145. doi:10.1212/WNL.50.1.136. https://www.neurology.org/doi/10.1212/WNL.50.1.136 [8] Mohs, R. C. et al. "Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope." Alzheimer Disease and Associated Disorders vol. 11 Suppl 2 (1997): S13–21. doi:10.1097/00002093-199700112-00003. https://pubmed.ncbi.nlm.nih.gov/9236949/ [9] Swanson, C. J. et al. "A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody." Alzheimer's Research & Therapy vol. 13 (2021): 80. doi:10.1186/s13195-021-00813-8. https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00813-8 [10] Eisai Co., Ltd. "The commercialization agreement on the lecanemab antibody was signed in December 2007." Eisai News Release (2022). https://www.eisai.com/news/2022/news202232.html [11] Eisai Co., Ltd. & Biogen Inc. "Since March 2014, Eisai and Biogen have been jointly developing BAN2401." Eisai News Release (2017). https://www.eisai.com/news/news201773.html [12] Eisai Co., Ltd. & Biogen Inc. "Eisai and Biogen to Discontinue Phase III Clinical Studies of BACE Inhibitor Elenbecestat in Early Alzheimer's Disease." Eisai News Release, September 13, 2019. https://www.eisai.com/news/2019/news201965.html [13] Wessels, A. M. et al. "Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials." JAMA Neurology vol. 77 (2020): 199–209. doi:10.1001/jamaneurol.2019.3988. https://jamanetwork.com/journals/jamaneurology/fullarticle/2755347 [14] Egan, M. F. et al. "Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease." New England Journal of Medicine vol. 378 (2018): 1691–1703. doi:10.1056/NEJMoa1706441. https://www.nejm.org/doi/full/10.1056/NEJMoa1706441 [15] Sevigny, J. et al. "The antibody aducanumab reduces Aβ plaques in Alzheimer's disease." Nature vol. 537 (2016): 50–56. doi:10.1038/nature19323. https://www.nature.com/articles/nature19323 [16] Knopman, D. S. et al. "Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019." Alzheimer's & Dementia vol. 17 (2021): 696–701. doi:10.1002/alz.12213. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12213 [17] Biogen Inc. "Biogen to Realign Resources for Alzheimer's Disease Franchise." Investor News Release, January 31, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise [18] van Dyck, C. H. et al. "Lecanemab in Early Alzheimer's Disease." New England Journal of Medicine vol. 388 (2023): 9–21. doi:10.1056/NEJMoa2212948. https://www.nejm.org/doi/full/10.1056/NEJMoa2212948 [19] Eisai Co., Ltd. & Biogen Inc. "Eisai and Biogen Announce Positive Topline Results of the Final Analysis for CLARITY AD Study of Lecanemab." Investor News Release, September 27, 2022. https://investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-announce-positive-topline-results-final [20] U.S. Food and Drug Administration. "FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval." FDA Press Announcement, July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval [21] Biogen Inc. & Eisai Co., Ltd. "LEQEMBI® (Lecanemab) Approved for the Treatment of Alzheimer's Disease in China." Investor News Release, January 9, 2024. https://investors.biogen.com/news-releases/news-release-details/leqembir-lecanemab-approved-treatment-alzheimers-disease-china [22] Eisai Co., Ltd. "FDA Approves LEQEMBI® IQLIK™ (lecanemab-irmb) Subcutaneous Injection for Maintenance Dosing for the Treatment of Early Alzheimer's Disease." Eisai News Release, August 29, 2025. https://media-us.eisai.com/2025-08-29-FDA-Approves-LEQEMBI-R-IQLIK-TM-lecanemab-irmb-Subcutaneous-Injection-for-Maintenance-Dosing-for-the-Treatment-of-Early-Alzheimers-Disease [23] BioArctic AB. "Latest data presented at AAIC 2025 reinforces lecanemab's clinical effect with consistent safety profile." BioArctic Press Release, 2025. https://www.bioarctic.com/en/latest-data-presented-at-aaic-2025-reinforces-lecanemabs-clinical-effect-with-consistent-safety-profile/ [24] Rafii, M. S. et al. "The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease." Alzheimer's & Dementia vol. 19 (2023): 1227–1233. doi:10.1002/alz.12748. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12748 本文内容来自公开信息及研究文献，不代表临床建议。如需投稿、转载、商务合作后台留言，回复有一定延迟敬请谅解。辅助编辑：腾讯元宝or（GPT、Gemini、Claude等）扫码加入ima知识库，获取本公众号所有文献全文资料，AI问答了解更多信息，文献实时更新

临床3期申请上市引进/卖出并购上市批准

2026-03-09

·生物通

构建人类二维大脑类器官解离细胞模型：高通量研究阿尔茨海默病神经炎症的定量新方法平台

阿尔茨海默病（Alzheimer's disease, AD）是一种困扰全球的神经退行性疾病，其典型病理特征包括脑内β-淀粉样蛋白（Amyloid-β, Aβ）斑块沉积和过度磷酸化的Tau蛋白（p-Tau, pTau）形成的神经原纤维缠结。越来越多的证据表明，神经炎症是驱动AD发生与发展的重要推手。其中，病毒等病原体感染，特别是单纯疱疹病毒1型（Herpes Simplex Virus 1, HSV-1），被发现与AD患病风险及病理变化存在关联，提示病原体触发的免疫反应可能参与了AD的发病过程。为了更深入地理解这种关联并开发新的治疗策略，科学家们需要能够模拟人脑复杂微环境的实验模型。传统的小鼠模型在物种间存在差异，而近年来兴起的三维（3D）人脑类器官（cerebral organoids）虽能高度模拟脑结构，但在进行高通量药物筛选时面临通量低、细胞感染/药物处理不均一等挑战。那么，能否建立一个既保留人脑细胞多样性，又适用于大规模、标准化检测的实验平台呢？针对上述挑战，这项发表于《npj Dementia》的研究报道了一个创新的解决方案。研究人员构建了一个基于二维（2D）培养的人脑类器官解离细胞（dissociated cells from cerebral organoids, dcOrgs）的高通量定量平台，用于模拟和研究AD相关的神经炎症。这个平台巧妙地结合了人脑类器官的细胞复杂性（包含神经元、星形胶质细胞、小胶质细胞等）和2D细胞培养的通量优势，为研究HSV-1感染如何诱发AD样病理变化，以及测试潜在治疗药物（如抗病毒药阿昔洛韦 Acyclovir, ACV）的效果，提供了一个强有力的工具。本研究主要运用了以下几项关键技术方法：首先，利用人诱导多能干细胞（human induced pluripotent stem cells, hiPSCs）分化生成三维大脑类器官，随后将其解离并在二维条件下培养，形成包含多种神经细胞类型（包括自发产生的小胶质细胞）的dcOrgs模型。其次，通过携带绿色荧光蛋白（GFP）标签的重组HSV-1病毒株感染dcOrgs，建立神经炎症模型。再者，结合流式细胞术（Flow Cytometry），使用多种特异性抗体（如识别Aβ聚集体的阿杜卡单抗Aducanumab、识别Aβ单体的索拉珠单抗Solanezumab，以及识别不同磷酸化位点的Tau抗体等），在单细胞水平上定量检测细胞内Aβ、pTau等AD相关蛋白的丰度及其与病毒蛋白的共定位。此外，研究还通过酶联免疫吸附测定（ELISA）检测细胞培养上清液中分泌的Aβ亚型（Aβ40, Aβ42, Aβ38）水平。最后，利用批量RNA测序（Bulk RNA-seq）和单细胞RNA测序（scRNA-seq）技术，全面解析HSV-1感染前后dcOrgs的转录组变化，并通过基因集富集分析（Gene Set Enrichment Analysis, GSEA）探究差异表达基因与AD等疾病相关基因的关联。研究结果 HSV-1感染在二维大脑类器官解离细胞中成功建立研究人员成功从hiPSCs分化出包含神经元、星形胶质细胞和小胶质细胞（约7.1%的细胞表达小胶质细胞标记物P2RY12）的dcOrgs。用HSV-1-GFP病毒感染后，超过50%的细胞在23小时后显示GFP阳性，表明感染成功。而用抗病毒药物ACV处理或紫外线灭活（UV-inactivated）的病毒作为对照，则几乎看不到感染迹象。RNA测序数据显示，不同处理的dcOrgs样本间具有高度可重复性，且HSV-1感染引发了显著的转录组扰动。细胞内Aβ聚集物与HSV-1高度共现，且主要由细胞自主效应驱动通过多色流式细胞术分析发现，在HSV-1感染的dcOrgs中，识别Aβ聚集体的抗体（阿杜卡单抗）信号与病毒蛋白（GFP）信号呈强正相关，其相关性高于识别Aβ单体的抗体（索拉珠单抗）。这种强共定位主要出现在死亡细胞中。进一步分析同一感染样品内GFP阳性（HSV-1+）和GFP阴性（HSV-1-）的活细胞发现，HSV-1+细胞内的Aβ（无论聚集态还是单体）信号均显著高于HSV-1-细胞，表明Aβ的增多主要是由细胞自主（cell intrinsic）因素，即病毒在细胞内的活动所驱动，而非旁观者效应。作为对照，用甲型流感病毒（IAV）感染dcOrgs也观察到了Aβ与病毒的共定位，但其相关性模式与HSV-1不同（在活细胞中相关性更强），提示不同病毒可能通过不同机制影响Aβ代谢。 HSV-1感染导致Tau磷酸化增加并改变分泌性Aβ谱流式分析还显示，HSV-1蛋白丰度与总Tau蛋白及在多个AD相关位点磷酸化的Tau（如pTau-181, pTau-217）丰度高度相关。对细胞培养上清液的检测发现，与模拟感染（Mock）的dcOrgs相比，HSV-1感染组的dcOrgs分泌的Aβ42、Aβ40和Aβ38总量均显著下降，但Aβ42/Aβ40的比值也显著降低。这表明感染可能改变了Aβ的产生或分泌过程，导致毒性更强的Aβ42相对比例减少（可能更多滞留于细胞内聚集）。而IAV感染虽然也降低了总Aβ分泌量，但并未改变Aβ42/Aβ40的比值。用ACV处理HSV-1感染的dcOrgs，可以部分挽救异常的Aβ分泌谱。 HSV-1感染改变dcOrgs细胞组成，模拟AD中的胶质增生和神经元丢失通过流式细胞术检测15种细胞类型特异性标记物，研究人员评估了HSV-1感染对dcOrgs细胞群体比例的影响。结果显示，感染导致表达神经元标记物（如NeuN）的神经元比例下降，而表达胶质细胞标记物（如星形胶质细胞的GFAP、小胶质细胞的Iba1）的细胞比例上升。这种神经元丢失和胶质细胞（特别是反应性星形胶质细胞和小胶质细胞）增生的模式，与AD患者脑组织中所见的病理变化相似。ACV处理可以缓解这种细胞比例的变化。转录组分析揭示HSV-1感染扰动AD相关基因网络对批量RNA-seq数据进行差异表达基因分析和基因集富集分析发现，在HSV-1感染的dcOrgs中，与AD相关的全基因组关联研究（Genome-Wide Association Study, GWAS）基因被显著富集。这一富集在UV灭活病毒对照或IAV感染组中并未出现，在hiPSCs感染组中也未出现，提示该转录特征需要成熟的神经细胞环境（特别是胶质细胞）才能充分展现。此外，感染还显著激活了cGAS/STING、干扰素（IFN）应答、JAK/STAT等多个天然免疫信号通路。单细胞转录组解析感染细胞的异质性及ACV的转录组挽救效应通过scRNA-seq，研究人员将细胞分为“真实未感染”（来自Mock组）、“流产感染”（来自感染组但病毒转录本少）和“真实感染”（来自感染组且病毒转录本多）三类。分析显示，差异表达基因在“真实感染”与“真实未感染”细胞的比较中，对AD相关基因的富集最为显著。进一步分析ACV的治疗效果，研究人员将感染后因ACV处理而表达水平恢复至接近未感染状态的基因定义为“被挽救”（Rescued）基因，而将那些在ACV处理后表达变化反而加剧或出现新变化的基因定义为“加剧”（Exacerbated）基因。在两次独立实验中，均鉴定出了一批稳定被ACV挽救的基因，它们与神经发生、细胞粘附和线粒体功能等通路相关。研究结论与意义本研究成功建立并验证了一个基于人源二维大脑类器官解离细胞（dcOrgs）的高通量、定量化研究平台，用于模拟由HSV-1感染触发的AD相关神经炎症。该平台能够复现AD关键的分子病理特征，包括细胞内Aβ（特别是聚集形式）与病毒的共定位增加、多种pTau形式的累积、分泌性Aβ42/Aβ40比值降低、以及反应性胶质增生和神经元丢失的细胞比例变化。更重要的是，转录组学分析证实，HSV-1感染特异性地扰动了与AD遗传风险相关的基因网络，这为“感染假说”提供了来自人源细胞模型的直接分子证据。该研究的核心意义在于其方法论上的创新和应用前景。首先，2D dcOrgs模型兼顾了人脑细胞的多样性和异质性，以及二维培养体系的高通量、标准化操作优势，使其非常适用于大规模的药物筛选和机理研究。其次，研究不仅验证了HSV-1感染可诱导AD样表型，还详细描绘了其背后的分子和细胞图谱，为理解病毒参与AD发病的机制提供了丰富线索。例如，细胞内Aβ聚集与病毒的高度共现及其细胞自主性，支持了Aβ可能作为先天性免疫应答一部分以对抗病原体，但过度反应最终导致病理沉积的假说。最后，研究证实抗病毒药物ACV能够在不同程度上逆转HSV-1感染引起的多种病理表型和转录组扰动，这为将阿昔洛韦或其前药伐昔洛韦（Valacyclovir, VCV）用于AD治疗（目前已有相关临床试验）提供了临床前实验依据，并揭示了其潜在的分子作用靶点。总之，这项研究开发了一个强大且灵活的平台，它将有助于加速针对神经炎症的AD新药研发，深化对感染与神经退行性疾病关联的理解，并可能最终助力于开发出更有效的AD预防和治疗策略。

100 项与苏兰珠单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10058	苏兰珠单抗	-	DB11756

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
遗忘	临床3期	美国	Eli Lilly & Co.	2014-02-28
遗忘	临床3期	日本	Eli Lilly & Co.	2014-02-28
遗忘	临床3期	澳大利亚	Eli Lilly & Co.	2014-02-28
遗忘	临床3期	加拿大	Eli Lilly & Co.	2014-02-28
认知障碍	临床3期	美国	Eli Lilly & Co.	2014-02-28
认知障碍	临床3期	日本	Eli Lilly & Co.	2014-02-28
认知障碍	临床3期	澳大利亚	Eli Lilly & Co.	2014-02-28
认知障碍	临床3期	加拿大	Eli Lilly & Co.	2014-02-28
阿尔茨海默症	临床3期	美国	Eli Lilly & Co.	2009-05-01
阿尔茨海默症	临床3期	日本	Eli Lilly & Co.	2009-05-01

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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


NCT04623242 (Pubmed)	临床2/3期	阿尔茨海默症	-	Solanezumab	餘膚糧糧簾網糧鬱夢餘(顧網餘壓廠艱壓鑰鑰觸) = 糧簾蓋壓廠蓋簾襯繭壓醖鑰艱鑰製艱衊襯範遞 (鬱艱醖鏇淵廠鑰範鬱願, 0.43)	-	2024-04-29
NCT02008357 (A4, CTgov)	临床3期	阿尔茨海默症 \| 遗忘 \| 认知障碍	1,169	Solanezumab (Solanezumab)	夢網廠壓遞齋網壓鏇襯(觸窪獵鹹襯願構積製鹽) = 範夢齋願齋廠積衊獵築網顧願觸網蓋鹽夢夢鏇 (壓糧齋壓醖鑰襯鏇鑰繭, 0.21) 更多	-	2023-12-28
				placebo (Placebo)	夢網廠壓遞齋網壓鏇襯(觸窪獵鹹襯願構積製鹽) = 憲壓鑰製鹽鏇鹽鹹衊獵網顧願觸網蓋鹽夢夢鏇 (壓糧齋壓醖鑰襯鏇鑰繭, 0.16) 更多
NCT02008357 (A4, CTAD2023)	临床3期	阿尔茨海默症 A4	383	Solanezumab	觸艱醖鹹網築顧簾網繭(艱糧衊獵繭憲築鬱顧醖) = 網觸夢構獵淵鹹構廠顧網夢醖鏇鏇範願壓簾選 (簾壓範憲窪遞襯蓋糧繭, 0.14) 更多	积极	2023-10-24
NCT02008357 (A4, CTAD2023)	临床3期	阿尔茨海默症	1,169	Solanezumab	製製繭蓋遞鑰齋壓觸獵(壓鏇鬱積獵簾淵蓋衊餘) = 積鹽糧憲餘積憲鹹蓋憲艱鏇鹹願鏇齋蓋鏇鹽積 (築築獵壓餘築齋獵糧壓 ) 更多	积极	2023-10-24
NCT02008357 (A4, Pubmed \| N Engl J Med)	临床3期	阿尔茨海默症	1,169	Solanezumab	夢窪鬱窪網壓顧蓋壓夢(製糧醖遞窪鬱衊夢廠餘) = 糧蓋淵鬱憲積繭廠窪蓋醖網製窪窪膚壓糧選齋 (淵齋淵鬱顧膚製蓋醖範 )	不佳	2023-09-21
				Placebo	夢窪鬱窪網壓顧蓋壓夢(製糧醖遞窪鬱衊夢廠餘) = 襯鹽醖願網鹽窪齋夢淵醖網製窪窪膚壓糧選齋 (淵齋淵鬱顧膚製蓋醖範 )
NCT02760602 (ExpeditionPRO, CTgov)	临床3期	阿尔茨海默症	26	Solanezumab (Solanezumab)	繭築遞鹽製齋齋醖夢艱(繭壓鑰淵遞衊簾選積夢) = 鹽蓋繭壓夢築膚齋觸鹽襯觸顧壓蓋鑰簾衊獵範 (獵蓋鑰繭餘觸鏇遞糧膚, 夢觸網簾獵積獵壓觸築 ~ 範艱鬱夢艱製簾憲夢衊) 更多	-	2018-07-24
				Placebo (Placebo)	繭築遞鹽製齋齋醖夢艱(繭壓鑰淵遞衊簾選積夢) = 廠淵餘積廠獵簾蓋餘窪襯觸顧壓蓋鑰簾衊獵範 (獵蓋鑰繭餘觸鏇遞糧膚, 願窪獵遞餘壓繭網鬱範 ~ 觸觸襯築遞憲獵鹽獵膚) 更多
NCT01127633 (EXPEDITION EXT, CTgov)	临床3期	阿尔茨海默症	1,457	Placebo (Placebo)	壓醖繭選醖積觸壓鏇衊 = 蓋淵蓋衊簾鹽鬱膚衊顧蓋齋繭糧齋艱膚餘淵鹽 (製鑰積鹽窪鑰廠鹽顧遞, 糧選鑰壓醖遞構壓窪網 ~ 構範獵夢觸廠觸廠積構) 更多	-	2018-05-03
				Solanezumab (Solanezumab)	壓醖繭選醖積觸壓鏇衊 = 積鬱築鑰醖壓鏇餘構構蓋齋繭糧齋艱膚餘淵鹽 (製鑰積鹽窪鑰廠鹽顧遞, 齋餘簾蓋鏇製蓋築網廠 ~ 鹹艱窪顧獵醖壓醖艱簾) 更多
NCT01900665 (EXPEDITION3 \| EXPEDITION 3, CTgov)	临床3期	阿尔茨海默症	2,129	Solanezumab (Solanezumab)	積築襯艱積壓製衊積餘(範鑰廠壓醖構顧夢選繭) = 廠選鑰壓簾範衊窪繭衊製觸齋顧蓋膚鏇鏇憲壓 (遞蓋鑰膚窪餘顧範簾蓋, 0.355) 更多	-	2018-03-14
				Placebo (Placebo)	積築襯艱積壓製衊積餘(範鑰廠壓醖構顧夢選繭) = 願積鬱鹹鹹夢壓醖淵鏇製觸齋顧蓋膚鏇鏇憲壓 (遞蓋鑰膚窪餘顧範簾蓋, 0.356) 更多
NCT01900665 (EXPEDITION3, Pubmed \| Br Dent J \| N Engl J Med) 人工标引	临床3期	阿尔茨海默症 \| 痴呆	2,129	Solanezumab	夢襯積餘憲積艱築廠窪(積窪蓋觸觸顧鏇衊觸繭) = 積構齋構範齋衊顧範獵積窪齋糧衊鑰艱顧衊蓋 (淵選衊繭鑰觸簾鏇鬱襯 ) 更多	不佳	2018-01-25
				Placebo	夢襯積餘憲積艱築廠窪(積窪蓋觸觸顧鏇衊觸繭) = 築壓壓積範鹽壓繭窪廠積窪齋糧衊鑰艱顧衊蓋 (淵選衊繭鑰觸簾鏇鬱襯 ) 更多
NCT00904683 \| NCT01900665 \| NCT00905372 (EXPEDITION3, AAIC2017)	临床3期	阿尔茨海默症 amyloid pathology	-	Solanezumab	襯網觸觸蓋鹹廠齋範艱(鑰觸顧衊憲醖顧遞淵餘) = 蓋觸廠願鹹膚鏇鹽襯醖簾製鏇壓網構網壓積鬱 (醖鬱鏇夢餘鹹願糧餘壓 ) 更多	-	2017-07-01