A Randomised, Double-Blind, Placebo Controlled, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEDI1814 in Subjects With Mild to Moderate Alzheimer's Disease.

The purpose of this study is to assess the safety, drug levels and effects on the body of 1 or 3 injections of MEDI1814, in people with mild to moderate Alzhiemer's Disease or healthy elderly people.

开始日期2014-02-04

申办/合作机构

AstraZeneca PLC

100 项与 MEDI-1814 相关的临床结果

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100 项与 MEDI-1814 相关的转化医学

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100 项与 MEDI-1814 相关的专利（医药）

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项与 MEDI-1814 相关的文献（医药）

2025-01-01·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

sTREM2 in discordant CSF Aβ₄₂ and p‐tau181

Article

作者: Jain, Ishika ; Men, Lu ; Glittenberg, Matthew ; An, Binchong ; Li, Ling ; Li, Danni ; Zhang, Lin ; Mantyh, William G.

Abstract:

INTRODUCTION:

Little is known about the factors underpinning discordant cerebrospinal fluid (CSF) amyloid beta (Aβ)42 versus p‐tau181/Aβ42 or CSF Aβ42 versus Aβ positron emission tomography (PET).

METHODS:

We stratified 570 non‐demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants by Aβ PET and further by CSF Aβ42 or p‐tau181/Aβ42. We used analysis of covariance testing adjusting for covariates, followed by Tukey post hoc pairwise comparisons, to compare CSF soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) across four participant groups: CSF+ Aβ42 with CSF− p‐tau/Aβ42, CSF− Aβ42 with CSF+ p‐tau/Aβ42, and concordant CSFAβ42/CSFp‐tau/Aβ42. We also compared sTREM2 across discordant and concordant CSFAβ42/PET.

RESULTS:

Regardless of Aβ PET status, CSF+Aβ42 with CSF−p‐tau/Aβ42 had lower sTREM2 than CSF−Aβ42 with CSF+p‐tau/Aβ42. CSF sTREM2 was similarly also associated with discordant CSF Aβ42 /PET.

DISCUSSION:

Our study suggests the potential roles of sTREM2 in discordant CSF Aβ42 and p‐tau181/Aβ42 and discordant CSFAβ42/PET. Low‐ and high‐CSF sTREM2 may affect the accuracy of p‐tau181/Aβ42 during the clinical work‐up of AD.

Highlights:

17% of non‐demented older adults had discordant CSF Aβ42 versus p‐tau181/Aβ42.sTREM2 differed between discordant cases of CSF Aβ42 versus p‐tau181/Aβ42.20% of non‐demented older adults had discordant CSF Aβ42 versus Aβ PET.sTREM2 also differed between discordant cases of CSF Aβ42 versus Aβ PET.p‐tau181/Aβ42 may miss 6.7% of PET+ non‐demented older adults with low sTREM2.

2024-11-01·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

An optimized UPLC-MS/MS method for human plasma amyloid-β 42 and 40 measurement and application in Alzheimer's disease diagnosis

Article

作者: Zhuang, Junhua ; Jin, Xing ; Zhang, Qiaoxuan ; Huang, Xianzhang ; Zhan, Min ; Han, Liqiao ; Bai, Kai

Critical events in Alzheimer's disease (AD) involve an imbalance between the production and clearance of amyloid-β (Aβ) peptides from the brain. The ratio of Aβ42 to Aβ40 in plasma was useful for evaluating AD, but quantification is limited by factors including preanalytical analyte loss and insufficient sensitivity. The availability of a targeted UPLC-MS/MS method with adequate analytical sensitivity and accurate values traceable to the SI units is essential for implementing a strategy for assay standardization. A targeted UPLC-MS/MS method for plasma Aβ42 and Aβ40 quantification was developed based on selected characteristic peptides spiked by ¹⁵N-labeled Aβ. The calibrator was assigned using an amino acid analysis reference method trace to SI units. UPLC-MS/MS conditions and sample preparation procedures were assessed. 59 plasma samples comparison were used to evaluate immunoassays. Additionally, two clinical cohorts were selected for diagnostic performance evaluation. The LOQ of Aβ42 and Aβ40 is 10 pg mL^-1 and 20 pg mL^-1, respectively. The linear range was 10-500 pg mL^-1 for Aβ42 and 20-1000 pg mL^-1 for Aβ40, recoveries between 95.3 % and 108.2 % for Aβ42, 93.2 % and 104.1 % for Aβ40, imprecisions were <7 %. The accuracy of method was validated by analysis of a certified reference material. Clinical cohorts for diagnostic performance evaluation shown that the area under the curve (AUC) for plasma Aβ42 and Aβ42/Aβ40 to differentiate between AD and CN were 0.767 and 0.799, respectively. A robust UPLC-MS/MS method was developed and demonstrated that suitable for a wide range of plasma Aβ42 and Aβ40. Applied to the investigation of clinically discrepant results, this method can act as an arbiter of the concentration of plasma Aβ42 and Aβ40 present.

2024-11-01·Neurologia

The CORCOBIA study: Cut-off points of Alzheimer’s disease CSF biomarkers in a clinical cohort

Article

作者: Abellán-Vidal, M T ; Pont-Sunyer, M C ; Roquer, J ; López-Villegas, D ; Manero-Borràs, R M ; Puente-Périz, V ; Suárez-Calvet, M ; Martínez-Casamitjana, M I ; Puig-Pijoan, A ; Boltes Alandí, A ; Cascales Lahoz, D ; Grau-Rivera, O ; Navalpotro-Gómez, I ; Padrós Fluvià, A ; Carrillo-Molina, S ; Sánchez-Benavides, G ; Fernández-Lebrero, A ; Hernández-Sánchez, J J ; Ortiz-Gil, J ; García-Escobar, G ; Peña-Casanova, J

INTRODUCTION:

The analysis of the core biomarkers of Alzheimer's Disease (AD) in the cerebrospinal fluid (CSF) is recommended in the clinical units where it is available. Because of the absence of universal validated values, the determination of specific cut-off points for each center and its population is recommended. The main objective of the CORCOBIA study was to determine the cut-off points of core AD CSF biomarkers for several centers (Parc de Salut Mar, Barcelona and Hospital General de Granollers), which work with the same reference laboratory (Laboratori de Referència de Catalunya).

METHODS:

Prospective study including cognitively unimpaired individuals (CU, n = 42), subjects with amnestic mild cognitive impairment (aMCI, n = 35) and patients with dementia due to Alzheimer's Disease (AD, n = 48), in whom clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture to analyse amyloid beta peptides (Aβ42, Aβ40), total tau (tTau) and phosphorylated Tau (pTau181) using the Lumipulse G600II (Fujirebio) was performed. The values of sensitivity (SE), specificity (SP), predictive values and area under the curve (AUC) were calculated, determining the cut-off point according to the Youden index by comparing the CU and AD groups.

RESULTS:

The resulting cut-offs and their AUC were the following: Aβ42 750 pg/mL (AUC 0.809); Aβ42/Aβ40 0.062 (AUC 0.78); pTau181 69.85 pg/mL (AUC 0.81); tTau 522.0 pg/mL (AUC 0.79); Aβ42/tTau 1.76 (AUC 0.86); Aβ42/pTau181 10.25 (AUC 0.86).

CONCLUSIONS:

The determination of cut-off points of core AD CSF biomarkers for the participating centers allows a better diagnostic accuracy. The ratio CSF Aβ42/pTau181 shows the highest AUC and better balance between sensitivity and specificity.

项与 MEDI-1814 相关的新闻（医药）

2025-05-03

·思齐俱乐部

AZ终止三款神经科学药物研发，全力押注减肥和免疫学...

据外媒报道，阿斯利康在2025年第一季度做出了重大战略调整，正式退出神经科学领域，将资源重新分配到减肥、免疫学等更具潜力的领域。阿斯利康在第一季度终止了多个神经科学项目，包括与礼来合作开发的阿尔茨海默病药物MEDI1814、用于治疗偏头痛的MEDI0618以及针对骨关节炎疼痛和糖尿病神经痛的MEDI7352。三款药品相关信息如下：1.MEDI1814（阿尔茨海默病药物）基本信息：MEDI1814是一种抗淀粉样β42（Aβ42）单克隆抗体，由阿斯利康与礼来公司合作开发，主要用于治疗阿尔茨海默病。该药物的研发基于阿尔茨海默病患者大脑中淀粉样β斑块积累的病理特征，MEDI1814能够选择性地结合Aβ42，这种Aβ的特定形式与阿尔茨海默病的发生和发展密切相关。研发进展：MEDI1814在终止前处于1期临床试验阶段。在临床前研究和早期临床试验中，MEDI1814显示出剂量依赖性地降低Aβ42肽水平的潜力，有望延缓阿尔茨海默病的进展。终止原因：尽管MEDI1814在早期研究中显示出一定的潜力，但阿斯利康在战略调整中决定退出神经科学领域，将资源重新分配到其他更具潜力的治疗领域。此外，阿尔茨海默病药物研发的高难度和不确定性，以及市场上已有多种竞争药物，也可能是阿斯利康做出这一决策的因素之一。2.MEDI0618（偏头痛药物）基本信息：MEDI0618是一种PAR2（蛋白酶激活受体2）拮抗剂单克隆抗体，用于治疗偏头痛。PAR2在偏头痛的发病机制中被认为与神经炎症和疼痛信号传导有关，通过拮抗PAR2，MEDI0618旨在减轻偏头痛发作的频率和严重程度。研发进展：该药物在终止前处于2期临床试验阶段。近年来，偏头痛治疗领域竞争激烈，多种新型药物不断涌现，包括CGRP（降钙素基因相关肽）受体拮抗剂等，这些药物在偏头痛的预防和治疗方面取得了显著的临床效果。终止原因：阿斯利康终止MEDI0618的开发，一方面是由于公司整体战略调整，退出神经科学领域；另一方面，可能是因为在激烈的市场竞争中，MEDI0618的临床优势不够明显，难以在偏头痛治疗市场中占据主导地位。3.MEDI7352（骨关节炎疼痛和糖尿病神经痛药物）基本信息：MEDI7352是一种非阿片类NGF（神经生长因子）/TNF（肿瘤坏死因子）双特异性单克隆抗体，用于治疗骨关节炎疼痛和糖尿病神经痛。NGF和TNF在疼痛信号传导中发挥重要作用，通过同时靶向这两个靶点，MEDI7352旨在提供更有效的镇痛效果，同时避免阿片类药物的成瘾性和副作用。研发进展：MEDI7352在终止前处于2期临床试验阶段。在疼痛管理领域，尤其是对于慢性疼痛的治疗，开发非阿片类药物一直是研究的重点方向，以应对阿片类药物滥用的全球性问题。终止原因：与前两款药物类似，MEDI7352的终止也是阿斯利康战略调整的结果。此外，双特异性抗体药物的研发难度较大，需要在两个靶点的协同作用、药物的安全性和有效性之间找到平衡，这可能是阿斯利康在评估后决定终止该项目的另一个原因。其中，和礼来合作近十年开发的治疗阿尔茨海默病的药物MEDI1814，已被礼来收回研发权。这几款药均来自2007年阿斯利康收购的MedImmune公司，过去该公司已有多款实验性药物被清理。公司首席执行官Pascal Soriot表示：“中枢神经系统领域的研发更适合那些专注于此的公司来管理。”阿斯利康生物制药研发执行副总裁Sharon Barr也指出，公司已经关闭了神经科学项目，并为其中一些项目找到了合作伙伴。这一举措虽然导致极少数职位面临裁员风险，但阿斯利康的这一决定显然是出于战略考虑。公司希望通过退出神经科学领域，将有限的资源集中到更有潜力和更高价值的项目上。阿斯利康明确表示，未来将优先发展体重管理、血脂异常、呼吸系统疾病和免疫学领域。这些领域被认为是公司未来增长的关键驱动力。例如，阿斯利康在免疫学领域的布局已经初见成效，其多种免疫学药物在市场上表现强劲。此外，随着全球肥胖率的不断上升，减肥药物市场也呈现出巨大的潜力。阿斯利康的这一战略调整并非偶然。近年来，医药行业竞争日益激烈，尤其是在神经科学领域，研发难度大、市场竞争激烈，且研发成本高昂。相比之下，减肥和免疫学领域不仅市场潜力巨大，而且阿斯利康在这些领域已经具备了一定的技术积累和市场基础。2025年第一季度，AZ财务表现依然强劲。公司实现收入135.8亿美元，同比增长10%。尽管这一数字略低于分析师预期的136.8亿美元，但从每股收益来看，阿斯利康表现优于预期，实现了1.88美元的收益，而市场共识为1.10美元。癌症仍然是阿斯利康最强劲的业务领域，其各种产品总共实现了超过56亿美元的销售额。其中，2型糖尿病治疗药物Farxiga表现突出，同比增长15%，在第一季度实现了超过20亿美元的销售额。此外，激酶抑制剂Tagrisso、PD-1阻断剂Imfinzi等药物也表现强劲。展望未来，阿斯利康预计其全年总收入将实现高个位数百分比的增长，而核心每股收益将实现低两位数百分比的增长。公司首席财务官Aradhana Sarin表示，阿斯利康将继续评估其产品组合的发展，并根据市场需求和技术进展灵活调整投资方向。参考资料：[1] BioSpace、Fierce Biotech来源：一度医药作者：RR点击阅读原文了解更多

临床2期临床1期

2025-04-30

·药时空

阿斯利康退出神经科学领域，优先发展减重和免疫学业务

2025年4月29日，阿斯利康（AstraZeneca）在发布2025年第一季度财报时宣布，将正式退出神经科学领域，转而优先发展减重、免疫学等核心治疗领域。一季度，阿斯利康终止了多个神经科学项目，包括与礼来（Eli Lilly）合作开发的阿尔茨海默病药物MEDI1814，以及针对偏头痛的II期单克隆抗体药物MEDI0618。这些项目的终止标志着阿斯利康正式关闭了其神经科学研发部门。阿斯利康表示，退出神经科学领域将使其能够将资源重新投入到更具价值的项目中，特别是在减重、免疫学和呼吸疾病等领域。近年来，减重药物市场迅速增长，阿斯利康希望通过加大投入，在这一领域取得突破。2024年5月，阿斯利康向SixPeaks Bio承诺提供8000万美元获得其主要一款靶向activin IIA和IIB受体双特异性抗体，旨在实现减重的同时保留肌肉质量。2023年11月，阿斯利康从诚益生物获得了小分子GLO-1R激动剂AZD5004（ECC5004）的全球开发和商业化权利。阿斯利康2025年第一季度收入达到136亿美元，同比增长10%，但略低于分析师预期的136.8亿美元。尽管如此，公司在每股收益方面表现超出预期，达到1.88美元，高于市场预期的1.10美元。肿瘤业务依然是阿斯利康的最强领域，第一季度相关产品销售额超过56亿美元。神经领域火热的交易👇近年来，神经领域的重磅交易不断，2022年，艾伯维以300亿美元收购了Neurocrine Biosciences，获得了治疗帕金森病、阿尔茨海默病和其他神经系统疾病的药物。2023年12月6日，艾伯维宣布以约87亿美元的现金收购Cerevel Therapeutics。获得其多种临床阶段和临床前候选药物，用于治疗精神分裂症、帕金森病和情绪障碍等疾病。2023年12月22日，百时美施贵宝（BMS）宣布以每股330美元的现金收购Karuna Therapeutics，总股本价值为140亿美元。Karuna的核心产品KarXT是一种口服M1/M4型毒蕈碱型乙酰胆碱受体激动剂，用于治疗精神分裂症和痴呆相关精神病性障碍。（已获批）结束语：近年来神经领域竞争已经十分充分，好的标的基本上已经名花有主。阿斯利康的这一战略调整反映了其在面对市场变化和资源限制时的灵活应对，同时也为公司在减重和免疫学领域的未来发展奠定了基础。识别微信二维码，可添加药时空小编请注明：姓名+研究方向！

财报并购免疫疗法

2025-04-29

·FierceBiotech

AstraZeneca culls a Lilly-partnered Alzheimer\'s drug alongside 2 other neuroscience meds in Q1 clear-out

On a call with members of the media Tuesday morning, AstraZeneca CEO Pascal Soriot focused heavily on the need for greater R&D innovation outside the U.S. \n AstraZeneca has axed three MedImmune legacy monoclonal antibody drugs from its neuroscience pipeline in a first-quarter clear-out.The Anglo-Swedish Big Pharma announced in its first-quarter presentation (PDF) Tuesday morning that it had stopped work on a phase 1 Alzheimer’s disease drug as well as two phase 2 therapies. One of the midstage candidates was being tested against migraines and the other was for osteoarthritis pain and painful diabetic neuropathy.The Alzheimer’s drug, MEDI1814, is an amyloid beta mAb that had been developed in collaboration with Eli Lilly in a pact dating back nearly a decade.Lilly, which markets its AD therapy Kisunla and teamed up with AZ on MEDI1814 back in 2016, has taken back the drug.AZ also axed two more clinically advanced prospects. The first, MEDI0618, works as a PAR2 antagonist mAb migraine drug. The market for migraine drugs, both as treatments and prophylactic options, has exploded over the past five years, with a host of meds from Pfizer/Biohaven, Eli Lilly, Amgen, Teva and more fighting for ground. The final midstage cull was for MEDI7352, a non-opioid NGF/TNF bispecific mAb targeting osteoarthritis pain and painful diabetic neuropathy.The decision for this neuro-focused clear-out was strategic, and AZ has formally terminated each of the projects. All three came from MedImmune, its $15.2 billion acquisition in 2007 that has seen multiple experimental drug clear-outs over the years.AZ generated $13.58 billion in revenue during the first quarter, a 10% increase at constant exchange rates from the first quarter in 2024. R&D spend, meanwhile, was up a hefty 16% at constant exchange rates to $3.08 billion and represented 23% of total sales.FDA layoffs, R&D boosts and a U.S. focus On a call with members of the media Tuesday morning, AZ’s chief Pascal Soriot said that despite the Trump administration-directed layoffs at the FDA, the Big Pharma has “so far not seen any delays in the processing of our applications [or] any delays to our meetings we regularly have with FDA staff.\" A big theme for Soriot was AZ\'s U.S. investment and focus, following a common trend for Big Pharmas working in the country amid pharmaceutical tariff threats from the U.S. government.He reiterated the multibillion-dollar investment AZ announced last November in manufacturing and R&D, saying that “we have even greater U.S. investment in manufacturing and R&D planned, leveraging our two large R&D sites\" in Gaithersburg, Maryland, and Cambridge, Massachusetts.Details on exactly what that R&D investment would like and specific dollar values were not given. AZ’s chief financial officer Aradhana Sarin said on the call that investments “will be driven by our portfolio” and that AZ will spend money where trials and trial sites are producing positive outcomes worthy of further investment. A spokesperson for AZ confirmed there were no immediate specifics on the R&D investment front as the company plans to review what is working over time and thus what will require deeper investment. One area will, however, be cell therapy, a field Soriot spotlighted during the call and where AZ recently acquired a Belgium cell therapy specialist.AZ also currently has seven cell therapy programs in the clinic, led by a BCMA and CD19 dual-targeting CAR-T for multiple myeloma.In response to questions about U.S. drug research innovation in general, Soriot said the country is “funding innovation in pharmaceuticals for the world” but that this was not fair. He said that Europe must take greater steps to invest more.Likening Europe’s recent decision to spend more of its gross domestic product on defense, he said Europe should take the same tack with pharmaceuticals spending, upping its percentage of GDP and/or healthcare budgets to pay more for R&D innovation.“Innovation has mostly been funded by the United States,” Soriot said on the call. “Europe now has to invest more. Just like Europe has decided to allocate a greater share of GDP to defense, a greater share of GDP has to be allocated to pharmaceutical innovation.”Soriot, when asked, did not give a specific percentage on what he thought that figure of GDP should be, but he noted the percentage of healthcare budgets spent on medicines was 13% to 15% in the U.S., while it was 10% to 11% in Europe and just 7% in the U.K., which has the NICE health technology assessment body to help temper drug prices.

$AstraZeneca culls a Lilly-partnered Alzheimer\'s drug alongside 2 other neuroscience meds in Q1 clear-out$

并购临床2期细胞疗法临床1期

100 项与 MEDI-1814 相关的药物交易

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