Long-Term Real-World Comparative Effectiveness of Donanemab Plus Usual Care Versus Usual Care Alone in US Patients With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-REAL US)

The main purpose of this study is to evaluate the long-term effectiveness of donanemab plus usual care versus usual care alone in participants with early symptomatic AD. The study will employ a prospective, observational cohort design with participant management resembling real-world practice to the greatest extent possible via prospective assessments and linkage to historical and prospective electronic health records. The study will last about 273 weeks and may include up to 28 visits.

开始日期2024-10-07

申办/合作机构

Eli Lilly & Co.

NCT06406348 / Recruiting临床1期

A Randomized, Double-Blind, Placebo-Controlled, Phase 1, Single Ascending Dose Trial to Assess the Safety, Tolerability and Pharmacokinetic Effects of ALIA-1758 in Healthy Participants

This is a Phase 1, first in human (FIH), double-blind, placebo-controlled, single ascending dose (SAD) trial to assess the safety, tolerability, and pharmacokinetics (PK) of intravenously (IV) or subcutaneously (SC) injected ALIA-1758 in healthy male and female participants.

开始日期2024-05-09

申办/合作机构

Aliada Therapeutics, Inc.初创企业

NCT05738486 / Active, not recruiting临床3期

Investigating the Effect of Different Donanemab Dosing Regimens on ARIA-E and Amyloid Lowering in Adults With Early Symptomatic Alzheimer's Disease

This study will investigate different donanemab dosing regimens and their effect on the frequency and severity of ARIA-E in adults with early symptomatic Alzheimer's disease (AD) and explore participant characteristics that might predict risk of ARIA.

开始日期2023-02-28

申办/合作机构

Eli Lilly & Co.

100 项与 pGlu3Aβ 相关的临床结果

登录后查看更多信息

100 项与 pGlu3Aβ 相关的转化医学

登录后查看更多信息

0 项与 pGlu3Aβ 相关的专利（医药）

登录后查看更多信息

项与 pGlu3Aβ 相关的文献（医药）

2024-08-01·Glia

Astrocytic uptake of posttranslationally modified amyloid‐β leads to endolysosomal system disruption and induction of pro‐inflammatory signaling

Article

作者: Lohr, Christian ; Schweizer, Michaela ; Schlößer, Annika ; Wirth, Sarah ; Woo, Marcel S. ; Beiersdorfer, Antonia ; Friese, Manuel A. ; Grochowska, Katarzyna M.

AbstractThe disruption of astrocytic catabolic processes contributes to the impairment of amyloid‐β (Aβ) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late‐onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Aβ have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N‐terminally pyroglutamylated Aβ3(pE)‐42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro‐inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aβ3(pE)‐42, but not Aβ1‐42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome‐dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). Treatment with a lysosomal protease inhibitor, E‐64, rescues GFAP upregulation, NF‐κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro‐inflammatory signaling and related synapse loss. Collectively, our data suggest that Aβ3(pE)‐42‐induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro‐inflammatory signaling and synapse loss, hallmarks of AD‐pathology.

2024-07-01·Proteins: Structure, Function, and Bioinformatics

Pyroglutamylation modulates electronic properties and the conformational ensemble of the amyloid β‐peptide

Article

作者: Davidson, Darcy S ; Lemkul, Justin A

AbstractAlzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid‐β (Aβ) plaques. The underlying cause of AD is unknown, however, post‐translational modifications (PTMs) of Aβ have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in Aβ, Glu3 and Glu11. This modification of Aβ involves the truncation and charge‐neutralization of N‐terminal glutamate, causing Aβ to become more hydrophobic and prone to aggregation. The molecular mechanism by which the introduction of pyroglutamate (pE) promotes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and truncation of the N‐terminus plays on Aβ conformational sampling, we used the Drude polarizable force field (FF) to perform molecular dynamics simulations on AβpE3–42 and AβpE11–42 and comparing their properties to previous simulations of Aβ1–42. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore providing novel insights into the role that charge plays in protein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamylation on Aβ. We found that AβpE3–42 and AβpE11–42 alter the permanent and induced dipoles of the peptide. Specifically, we found that AβpE3–42 and AβpE11–42 have modification‐specific backbone and sidechain polarization response and perturbed solvation properties that shift the Aβ conformational ensemble.

2024-04-01·Journal of Inorganic Biochemistry

Investigating Cu(I) binding to model peptides of N-terminal Aβ isoforms

Article

作者: Haas, Kathryn L ; Pushie, M Jake ; Strausbaugh Hjelmstad, Abigail ; Ruth, Kaylee ; Kuter, Kristin ; Escobedo, Maria

Amyloid beta (Aβ) peptides and copper (Cu) ions are each involved in critical biological processes including antimicrobial activity, regulation of synaptic function, angiogenesis, and others. Aβ binds to Cu and may play a role in Cu trafficking. Aβ peptides exist in isoforms that vary at their C-and N-termini; variation at the N-terminal sequence affects Cu binding affinity, structure, and redox activity by providing different sets of coordinating groups to the metal ion. Several N-terminal isoforms have been detected in human brain tissues including Aβ_1-40/42, Aβ_3-42, pEAβ_3-42, Aβ_4-42, Aβ_11-40 and pEAβ_11-40 (where pE denotes an N-terminal pyroglutamic acid). Several previous works have individually investigated the affinity and structure of Cu(I) bound to some of these isoforms' metal binding domains. However, the disparately reported values are apparent constants collected under different sets of conditions, and thus an integrated comparison cannot be made. The work presented here provides the Cu(I) coordination structure and binding affinities of these six biologically relevant Aβ isoforms determined in parallel using model peptides of the Aβ metal binding domains (Aβ_1-16, Aβ_3-16, pEAβ_3-16, Aβ_4-16, Aβ_11-16 and pEAβ_11-16). The binding affinities of Cu(I)-Aβ complexes were measured using solution competition with ferrozine (Fz) and bicinchoninic acid (BCA), two colorimetric Cu(I) indicators in common use. The Cu(I) coordination structures were characterized by X-ray absorption spectroscopy. The data presented here facilitate comparison of the isoforms' Cu-binding interactions and contribute to our understanding of the role of Aβ peptides as copper chelators in healthy and diseased brains.

项与 pGlu3Aβ 相关的新闻（医药）

2024-10-30

·药明康德

穿越血脑屏障！艾伯维14亿美元囊获潜在“best-in-class”疗法

艾伯维（AbbVie）与Aliada Therapeutics宣布达成最终协议，艾伯维将以约14亿美元款项收购Aliada，并获得其主要项目阿尔茨海默病（AD）疗法ALIA-1758，目前该疗法正在1期试验当中受检视。此收购预计将在2024年第四季度完成。 Aliada是一家致力于利用新型血脑屏障（BBB）穿越技术开发治疗中枢神经系统（CNS）疾病创新疗法的生物技术公司。该公司专有的Modular Delivery（MODEL）平台专为高精度CNS药物递送而设计，其新型BBB穿越技术通过优化设计靶向转铁蛋白（TfR）和CD98受体的接合器，将各种生物载荷（如治疗性抗体和基因药物siRNA）递送至大脑。这些受体在脑部内皮细胞中高度表达。 ALIA-1758是一款采用该公司的创新递送技术，通过TfR将靶向焦谷氨酸化淀粉样蛋白（3pE-Aβ）抗体运输穿越BBB的在研AD疗法，该疗法旨在实现降解和清除淀粉样蛋白斑块，这是AD的病理特征。目前，该疗法正处于1期临床试验阶段，以评估其在健康受试者中的安全性和耐受性。艾伯维执行副总裁、研发主管兼首席科学官Roopal Thakkar博士表示：“此次收购使我们能够立即推进ALIA-1758的开发，这是一种潜在’best-in-class’的阿尔茨海默病疗法。此外，Aliada的新型BBB穿越技术将增强我们的研发能力，加速针对神经系统疾病及其他需要增强CNS药物递送疾病的下一代疗法开发。” 参考资料： [1] AbbVie to Acquire Aliada Therapeutics, Strengthening Focus in Alzheimer's Disease and Neuroscience Pipeline. Retrieved October 28, 2024 from https://news.abbvie.com/2024-10-28-AbbVie-to-Acquire-Aliada-Therapeutics,-Strengthening-Focus-in-Alzheimers-Disease-and-Neuroscience-Pipeline _gl=1*arq1y5*_ga*MTMyOTk2NTA1My4xNzMwMTUxNTkz*_ga_5LEXD56YGK*MTczMDE1MTU5My4xLjAuMTczMDE1MTU5My4wLjAuMA..*_fplc*JTJCV3RpTWwlMkJld1pQaE9TQ0dvRWw4bjdvVXVHVWFOdzIwcHR3VEg1ZXF1a0FDNTVrZlBBWSUyRmpRaXlwWkJCVDklMkJFSG51N20zYzhzVm1VUElGd3oweUhkcjFHVUU4MVQ5bmhIMmdXJTJCekglMkZIVk1RNTJUSiUyQjglMkIzNlQ3T0hsMVpPZyUzRCUzRA.. 内容来源于网络，如有侵权，请联系删除。

引进/卖出siRNA并购

2024-10-29

·艾伯维abbvie

艾伯维收购Aliada Therapeutics，深化阿尔茨海默病及神经科学研发布局

2024年10月28日，艾伯维与Aliada Therapeutics宣布达成最终协议：艾伯维将收购Aliada，一家致力于利用创新血脑屏障（BBB）穿透技术研发针对难治性中枢神经系统（CNS）疾病新型疗法的生物技术公司。利用这一递送技术，Aliada研发的在研药物ALIA-1758，是一种抗焦谷氨酸化β淀粉样蛋白（3pE-Aβ）抗体，该药物目前正积极开发用于治疗阿尔茨海默病。 Roopal Thakkar博士艾伯维研发执行副总裁兼首席科学官神经科学一直是艾伯维的重点发展领域，我们致力于推动该领域的创新，以应对阿尔茨海默病等严重神经系统疾病患者的迫切医疗需求。此次收购使我们能够迅速推进ALIA-1758的研发工作，该药物有望成为阿尔茨海默病治疗领域的佼佼者。此外，Aliada创新的血脑屏障（BBB）穿透技术将显著提升我们的研发能力，加速我们研发针对神经系统疾病及其他需通过改进药物递送至中枢神经系统来治疗疾病的新一代疗法。 Michael Ryan博士 Aliada Therapeutics首席医学官我们很高兴地宣布艾伯维成功收购Aliada，并对艾伯维公司致力于为阿尔茨海默病患者提供ALIA-1758这一创新疗法感到振奋。Aliada自主研发的MODEL™平台推动了ALIA-1758的研发进程，这是抗淀粉样蛋白抗体疗法在脑部递送方面取得的重要进展。许多颇具前景的中枢神经系统（CNS）靶向疗法因无法穿透血脑屏障而止步于后期试验。但我们的MODEL™平台直击这一挑战，实现了靶向药物的有效递送，并有望彻底转变神经系统疾病的治疗方式。根据协议条款，艾伯维将以14亿美元现金收购Aliada所有流通股权，此金额需根据常规调整因素确定。此次交易预计将于2024年第四季度完成，但还需获得监管机构批准，并满足交易惯例中的其他成交条件。 Aliada利用其模块化递送（MODEL™）平台推进候选药物研发进程。该平台专为实现高精度中枢神经系统（CNS）药物递送而设计。这一新型血脑屏障（BBB）穿透技术，精准靶向在脑内皮细胞中高度表达的转铁蛋白（TfR）和CD98受体（CD98）。通过研发高度优化的TfR或CD98结合剂，该平台能够将多种生物载荷递送至大脑，包括治疗性抗体和基因药物，如siRNA。 ALIA-1758通过转铁蛋白受体（TfR）的介导，助力3pE-Aβ抗体穿透血脑屏障（BBB），实现β淀粉样蛋白斑块的降解与清除，这一病理特征是阿尔茨海默病的重要标志。这一创新性的候选药物正处于1期临床阶段，旨在评估其在健康受试者中的安全性与耐受性（NCT06406348）。上下滑动查看更多信息关于艾伯维艾伯维的使命是发现和提供创新药物，解决复杂且棘手的疾病难题和未来的医学挑战。我们不懈努力，凭借在多个关键治疗领域的科研创新为人们的生活带来深远影响，包括免疫学、肿瘤学、神经科学、眼科学、病毒学、胃肠病学，以及艾尔建美学产品组合中的产品和服务。更多关于艾伯维的信息，请访问www.abbvie.com。艾伯维在中国的总部位于上海，专注于在免疫学、肿瘤学、病毒学、眼科学、麻醉学、神经科学和美学等领域为人们发展和提供创新的医疗方案。如欲了解更多关于艾伯维在中国的信息，请浏览艾伯维中文官网www.abbvie.com.cn。

并购引进/卖出siRNA临床1期临床申请

2024-10-29

·医药魔方Pro

14亿美元！艾伯维最新收购，囊获潜在BIC阿尔茨海默病疗法

10 月 28 日，艾伯维与 Aliada Therapeutics宣布达成一项最终协议，根据该协议，艾伯维将以 14 亿美元现金收购 Aliada 的全部流通股权，这是一家旨在利用新型血脑屏障 (BBB) 穿越技术推进疗法，以应对具有挑战性的中枢神经系统 (CNS) 疾病的biotech。这项交易预计将于 2024 年第四季度完成。 Aliada利用这种递送技术的主要研究资产ALIA-1758是一种抗焦谷氨酸淀粉样蛋白β（3pE-Aβ）抗体，这种焦谷氨酸修饰的淀粉样蛋白β也叫pGlu3-Aβ、Aβ (p3-42)、N3pG。在新闻稿中，艾伯维表示ALIA-1758是一款针对阿尔茨海默病的潜在best-in-class疗法。 ALIA-1758利用TfR跨BBB转运3pE-Aβ抗体，以降解和消除β淀粉样蛋白斑块，这是阿尔茨海默病的病理标志。这项候选研究目前正在进行一期临床试验，以评估其在健康参与者中的安全性和耐受性（NCT06406348）。值得注意的是，就在3个月前，艾伯维被外媒披露正在终止开发其自研的Aβ单抗ABBV-916单药治疗阿尔茨海默病的适应症，并将考虑其它方案，包括联合疗法。ABBV-916与ALIA-1758同样靶向3pE-Aβ，而这也正是礼来在今年获批上市的阿尔兹海默病新药donanemab的靶点。 Aliada正在利用其模块化给药（MODEL）平台推进候选疗法，该平台专为高精度中枢神经系统给药而设计。这项新颖的BBB穿越技术以脑内皮细胞高度表达的转铁蛋白和CD98受体（TfR 和 CD98）为靶标。通过设计高度优化的TfR或CD98结合剂，该平台可将不同类型的生物载体送入大脑，包括治疗性抗体和 siRNA等基因药物。 “神经科学是我们的关键增长领域之一，我们致力于推动这一领域的创新，以满足阿尔茨海默病等严重衰弱性神经疾病患者尚未得到满足的关键需求。”艾伯维研发执行副总裁兼首席科学官 Roopal Thakkar 博士表示：“这次收购使我们立即能够推进 ALIA-1758 的发展，这是一种可能成为阿尔茨海默病最佳疾病修饰疗法的新药。此外，Aliada 的新型 BBB 穿透技术也增强了我们的研发能力，使我们能够加快开发治疗神经系统疾病和其他疾病的下一代疗法，在这些疾病中，加强向中枢神经系统输送治疗药物是有益的。” 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。

并购siRNA临床2期引进/卖出