Long-term Extension of a Phase 3, Multicenter, Randomized, Double-Blind, Placebo- Controlled Study of the Efficacy, Safety, and Biomarker Effects of ALZ-801 in Subjects With Early Alzheimer's Disease and APOE4/4 Genotype

This study is being conducted to evaluate the long-term safety and efficacy of ALZ-801 in Early Alzheimer's disease (AD) subjects with the APOE4/4 genotype. This is an open-label trial of treatment with ALZ-801.

开始日期2024-04-02

申办/合作机构

Alzheon, Inc.

NCT04770220

/ Completed临床3期

A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy, Safety and Biomarker Effects of ALZ-801 in Subjects With Early Alzheimer's Disease and APOE4/4 Genotype

This study is being conducted to evaluate the safety and efficacy of ALZ-801 in Early Alzheimer's disease (AD) subjects with the APOE4/4 genotype. This is a double-blind, randomized trial with one dose of ALZ-801 compared to placebo.

开始日期2021-05-19

申办/合作机构

Alzheon, Inc.

[+1]

NCT04693520

/ Active, not recruiting临床2期

A Phase 2, Single-arm Study of the Biomarker Effects of ALZ-801 in Subjects With Early Alzheimer's Disease Who Are Carriers of the ε4 Variant of the Apolipoprotein E Gene (APOE4/4 or APOE3/4)

The study will investigate the effects of oral ALZ-801, in subjects with Early AD who have the APOE4/4 or APOE3/4 genotype, on the biomarkers of core AD pathology. The objectives of this study include determining the efficacy and safety/tolerability of ALZ-801. In addition, the study will evaluate the extended PK profile over 8 hours in 16 subjects after 65 weeks of treatment.

开始日期2020-09-30

申办/合作机构

Alzheon, Inc.

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100 项与 Valiltramiprosate 相关的转化医学

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100 项与 Valiltramiprosate 相关的专利（医药）

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项与 Valiltramiprosate 相关的文献（医药）

2024-11-01·Pharmaceutical Patent Analyst

Sulfopropanoic acid derivatives for treating neurodegenerative disorders: a patent spotlight

Review

作者: Al-Horani, Rami A

The patent introduces a class of agents that target amyloid aggregation, and subsequently, reduce amyloid β-oligomer neurotoxicity. The class encompasses sulfopropanoic acid derivatives and is represented by tramiprosate and its prodrug ALZ-801 (valiltramiprosate). Clinical trials showed that ALZ-801 oral tablet is well tolerated and showed superior pharmacokinetic properties in healthy volunteers and Alzheimer's disease (AD) patients. Results from phase II & III trials of ALZ-801 in early AD have provided evidence of efficacy and to adjudicate the role of amyloid β-oligomers in AD pathogenesis. The confirmatory APOLLOE4 phase III trial of ALZ-801 in APOE4/4 homozygotes with early AD has been initiated. If ALZ-801 is approved, it will be among the first oral disease-modifying drugs for AD.

2024-07-01·Alzheimers & Dementia-Translational Research & Clinical Interventions

APOLLOE4 Phase 3 study of oral ALZ‐801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics

Article

作者: Abushakra, Susan ; Porsteinsson, Anton P. ; Tolar, Martin ; Watson, David ; Liang, Earvin ; Sabbagh, Marwan ; McLaine, Rosalind ; Power, Aidan ; Kesslak, J. Patrick ; Boada, Merce ; Hey, John A. ; MacSweeney, Emer ; Flint, Susan

Abstract:

INTRODUCTION:

The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD.

METHODS:

This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes.

RESULTS:

The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024.

DISCUSSION:

APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population.

Highlights:

The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ‐801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

2024-07-01·DRUGS

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model

Article

作者: Schaefer, Jean F ; Power, Aidan ; Abushakra, Susan ; Kesslak, Patrick ; Hey, John A ; Tolar, Martin ; Yu, Jeremy Y

INTRODUCTION:

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD.

METHODS:

The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aβ₄₂/Aβ₄₀) and tau pathology (p-tau₁₈₁) were enrolled, with serial CSF and plasma levels of Aβ₄₂ and Aβ₄₀ measured over 104 weeks. Longitudinal changes of CSF Aβ₄₂, plasma Aβ₄₂/Aβ₄₀ ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex.

RESULTS:

A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aβ₄₂ level and plasma Aβ₄₂/Aβ₄₀ ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26).

CONCLUSIONS:

In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD.

TRIAL REGISTRY:

https://clinicaltrials.gov/study/NCT04693520.

项与 Valiltramiprosate 相关的新闻（医药）

2025-08-15

·医药速览

Nat. Rev. Drug. Disc.(IF 101.8) ）| 挑战“不可成药”靶点--无序蛋白

在人体的复杂生理机制中，存在一类特殊的蛋白质，它们因缺乏稳定的三维结构，长期以来被认为难以被传统小分子药物靶向，因而被冠以“不可成药”的标签。然而，这一局面正在悄然改变。随着实验技术的精进、计算方法的革新以及筛选平台的不断完善，越来越多的科研团队和企业开始向这些曾经被认为难以攻克的靶点发起挑战。文章标题近期，Nature Reviews Drug Discovery期刊上发表了一篇名为“Targeting protein disorder: the next hurdle in drug discovery”的综述文章，系统地梳理了这一领域的研究进展，并指出：“尽管这些无序蛋白看似难以靶向，但并非全无可能。未来几年，我们或许能真正看到靶向无序蛋白的小分子药物进入临床，为这些曾经被认为‘不可成药’的靶点带来新的希望。” 不可成药靶点的挑战在现代药物研发中，一直奉行着“结构决定功能”的原则。科学家们通常通过解析蛋白质的高分辨率结构，寻找其结合口袋，进而设计出能够精准干预的小分子药物。然而，随着研究的不断深入，人们逐渐发现，人体中有一类关键蛋白并不遵循这一规律——它们没有固定的三维结构，形态灵活多变，传统药物难以结合。因此，这些蛋白被贴上了“不可成药”的标签。这类蛋白被称为“内在无序蛋白”（IDPs），或含有“内在无序区域”（IDRs）。它们广泛存在于调控类蛋白中，如转录因子和信号分子，并在多种重大疾病中发挥着重要作用。例如，在癌症中，MYC和雄激素受体（AR）扮演着关键角色；在阿尔茨海默病中，tau蛋白和Aβ蛋白是主要的病理因素；而在肌萎缩侧索硬化症（ALS）等神经退行性疾病中，TDP-43和α-synuclein蛋白也起着核心作用。尽管这些蛋白在疾病的发病机制中至关重要，但由于缺乏稳定的结构，它们长期难以被传统小分子药物靶向。更具挑战性的是，许多无序蛋白并不是静态存在的，而是呈现出高度动态的构象变化。它们可以与其他蛋白结合、被修饰，甚至发生聚集，参与调控基因转录、信号传导，甚至病理性蛋白沉积。正是这种高度动态的特性，使得它们难以被“锁定”或精准靶向，成为药物研发中极具难度的一类靶点。干预策略的探索然而，尽管靶向无序蛋白面临诸多挑战，但研究者们并未因此却步。相反，越来越多的团队正积极探索多种策略，从不同角度切入，试图干预这些结构灵活的蛋白在疾病中的病理功能。其中一类策略是间接干预，即不与无序区域本身结合，而是从蛋白的表达调控、翻译过程或修饰机制等环节入手，打断其功能链条。例如，MYC是一种广泛参与多种癌症发展的转录因子，其结构高度无序，传统药物难以直接作用。研究人员发现，其表达受转录调控因子BRD4的影响，因此开发出BRD4抑制剂JQ1，通过调控网络上游环节来降低MYC的活性。这种间接方式虽然未直接靶向MYC本身，但在一定程度上仍能抑制肿瘤的进展。类似的机制也出现在神经退行性疾病中。以阿尔茨海默病为例，tau蛋白的过度磷酸化会促使其异常聚集，这是疾病发展的关键一步。因此，研究者尝试靶向CDK5激酶，通过调节修饰过程来间接干预tau的致病行为。此外，间接干预还可以通过阻断无序蛋白的蛋白–蛋白相互作用来实现。许多无序蛋白依赖与其他蛋白的结合发挥功能，而这种结合往往发生在有序蛋白的一端。例如，p53蛋白的活性受到MDM2的调控，后者通过结合p53的无序区域促进其降解。研究人员通过开发MDM2抑制剂，成功恢复了p53的功能，这一策略已进入临床应用。同样，来自MYC蛋白的Omomyc肽段也被设计为与其结合伙伴MAX竞争，从而破坏MYC–MAX复合物，间接抑制MYC的致癌活性。还有一些策略则是通过调控无序蛋白的细胞定位来实现功能抑制。某些蛋白的功能依赖其准确的亚细胞分布，而异常定位常常与疾病相关。例如，未磷酸化的AR通常被运出细胞核并降解，但在癌症中，CDK9介导的磷酸化会阻止这一过程，导致AR异常积聚。抑制CDK9可改变AR的定位，从而削弱其致病作用。小分子直击无序蛋白尽管间接干预策略在某些情况下已取得积极进展，但在许多疾病中，无序区域本身往往是病理机制的核心。简单地去除整条致病蛋白，可能引发严重的副作用或破坏正常生理功能。因此，如何在保留关键功能的同时，精准靶向无序区域，成为攻克这一类“难以成药”蛋白的重要方向。近年来，随着分子模拟、结构筛选、表面等离子共振（SPR）、核磁共振（NMR）等技术的不断进步，科研人员已识别出一批能够直接结合内在无序蛋白的小分子候选药物，哪怕这些结合位点并不具备传统意义上的稳定结构。以MYC为例，这是一种在多种癌症中高度激活的无序转录因子。研究人员利用分子动力学模拟和NMR实验，发现小分子PKUMDL-YC-1205能够结合MYC的无序区域，并干扰其构象变化，从而发挥功能抑制作用。在另一项研究中，针对全无序蛋白NUPR1（与胰腺癌高度相关），研究人员通过热转移分析和建模筛选出老药trifluoperazine具有结合活性，并优化得到新分子ZZW-115，显著抑制了癌细胞的迁移和增殖。经典靶点AR的研究也取得了突破。传统药物多聚焦于其配体结合区（LBD），但在晚期前列腺癌中，LBD常被剪切缺失，导致治疗失效。科学家通过筛选海洋海绵提取物，发现EPI-001可作用于AR的无序N端结构域，并有效抑制其功能。其优化版本EPI-7386目前已进入2期临床试验，成为靶向无序区域的代表性成果之一。在神经退行性疾病领域，针对聚集型无序蛋白的研究也在不断推进。多项研究表明，一些小分子不仅能直接结合这些蛋白，还能有效阻断其病理性聚集过程。例如，ROCK抑制剂fasudil可结合α-synuclein，改善帕金森病模型中的运动功能；而针对Aβ蛋白的小分子ALZ-801则通过稳定其构象、抑制聚集，目前已完成3期临床试验，为阿尔茨海默病治疗带来新的希望。精准狙击无序蛋白新方法为了找到能够精准作用于内在无序蛋白的药物，科学家们除了继续通过传统的小分子化合物筛选，还在不断探索更灵活的新方法。例如，一种备受关注的策略是片段筛选（fragment-based screening）。与传统小分子相比，化学“片段”结构更小、形态更灵活，虽然初期活性不强，但能覆盖更广泛的化学空间。一旦发现这些片段能与蛋白某个区域发生结合，研究者就可以通过拼接、延伸等手段逐步构建出具有活性的完整分子。目前，该策略已被应用于α-synuclein、Aβ和tau等多个无序蛋白的初筛研究中。共价抑制剂也是另一类极具潜力的候选手段。这类分子通过与目标蛋白形成稳定的共价键，从而增强结合强度并延长作用时间。尽管可能存在一定脱靶风险，但已有多个成功案例，如靶向MYC、tau蛋白和AR的共价小分子，皆显示出良好的前景。针对难以通过传统手段抑制的无序蛋白，近年来兴起的一项策略是诱导其降解。这类技术通过设计双功能分子将目标蛋白引导至细胞的降解系统，让其被直接清除。其中最具代表性的是蛋白降解靶向嵌合体（PROTAC®）技术，它通过桥接靶蛋白和泛素E3连接酶，触发靶标的泛素化及蛋白酶体介导的降解。已有研究用该策略成功作用于AR和tau蛋白。此外，针对不同降解路径，研究人员还开发了能作用于溶酶体（LysoTAC）和自噬通路（AutoTAC）的降解分子，进一步拓展了蛋白降解在无序蛋白干预中的适用范围。除了靶向蛋白本身，部分研究还将干预的焦点上移至基因表达层面。例如，使用反义寡核苷酸（ASO）直接阻断无序蛋白的mRNA表达，或利用适配体（aptamers）来防止聚集型蛋白（如Aβ和α-synuclein）形成毒性聚集体，这些都为干预策略提供了新的维度。值得关注的是，大分子生物制品药物也正在逐步加入靶向无序蛋白的阵营。以阿尔茨海默病为例，FDA已批准的抗体药物lecanemab和aducanumab，可结合Aβ蛋白，阻止其形成致病聚集体，并已在临床中展现出实际疗效。此外，肽类药物也在这个领域扮演着越来越重要的角色。一些环状或稳定构型的肽段可以精准锁定无序蛋白的关键结合界面。更进一步，这些肽分子还能作为先导结构，为后续开发类似功能的小分子药物提供模板与方向。这些研究成果表明，直接靶向无序蛋白不仅在技术上具有可行性，而且在多种重大疾病中展现出良好的转化前景。随着更多机制被揭示、更多先导化合物被优化，未来有望看到更多新型靶向药物进入临床，为那些长期缺乏有效治疗手段的“不可成药”无序蛋白靶点带来真正的突破。未来展望：突破“不可成药”的边界随着技术的不断进步和研究的深入，靶向无序蛋白的药物研发正在逐步打破传统药物设计的局限。科学家们不再局限于传统的“锁钥模型”，而是通过多维度的策略，探索无序蛋白的动态特性，寻找新的治疗机会。这些努力不仅为癌症、神经退行性疾病等难治性疾病带来了新的希望，也为整个药物研发领域开辟了新的方向。未来，随着人工智能、机器学习等新兴技术的引入，药物研发的效率和精准度将进一步提升。这些技术能够帮助科学家更好地理解无序蛋白的动态构象变化，预测其与药物的相互作用，从而加速新型药物的发现和优化。同时，多学科的交叉合作也将为这一领域注入新的活力，从基础研究到临床应用的转化将更加高效。结语无序蛋白的靶向药物研发，是现代医学和药物科学中最具挑战性的前沿领域之一。从间接干预到直接靶向，从传统小分子到新兴生物制品，科学家们正在不断探索和创新。尽管道路充满挑战，但每一步的突破都为人类健康带来了新的曙光。未来，随着更多靶向无序蛋白的药物进入临床，我们有望见证这一领域从“不可成药”到“可成药”的历史性转变，为全球患者带来新的治疗选择和希望。欢迎感兴趣的朋友进群讨论，群二维码如下：推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。原创内容未经授权，禁止转载至其他平台。有问题可发邮件至yong_wang@pku.edu.cn获取更多信息。 ©2021 医药速览保留所有权利往期链接 “小小疫苗”养成记 | 医药公司管线盘点人人学懂免疫学| 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普|医药前沿笔记 PROTAC技术| 抗体药物| 抗体药物偶联-ADC 核酸疫苗 | CAR技术| 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群请扫描上方二维码，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送 ①点击标题下方“医药速览” ②至右上角“...” ③点击“设为星标

2025-07-15

·Business Wire

Alzheon to Present Insights into Oral Valiltramiprosate/ALZ-801 Mode of Action and Clinical Efficacy at Dedicated Symposium at Alzheimer’s Association International Conference in Toronto on July 30 th , 2025

FRAMINGHAM, Mass.--(BUSINESS WIRE)--Alzheon, Inc., a clinical-stage biopharmaceutical company developing a broad portfolio of investigational therapies and diagnostic assays for patients with Alzheimer’s disease (AD) and other neurodegenerative disorders, today announced it will present new data on its lead investigational product, valiltramiprosate, highlighting the differentiated mode of action that acts upstream in the amyloid pathway, blocking formation of neurotoxic amyloid oligomers that drive disease progression. Valiltramiprosate showed positive clinical and volumetric MRI effects in patients with Mild Cognitive Impairment (MCI) who carry one or two copies of the ε4 allele of the apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively). The first of-its-kind data will be presented in a symposium during the Alzheimer’s Association International Conference (AAIC) in Toronto, Canada. Valiltramiprosate represents a promising advancement in targeting the early highly toxic forms of beta amyloid that drive Alzheimer’s disease onset and progression. “Valiltramiprosate represents a promising advancement in targeting the early highly toxic forms of beta amyloid that drive Alzheimer’s disease onset and progression,” said Sam Gandy, M.D., Ph.D., Professor of Neurology and Psychiatry at Icahn School of Medicine at Mount Sinai. “By focusing on oligomer formation upstream, this oral therapy has the potential to change the treatment paradigm for patients at risk for Alzheimer’s and those with early symptomatic disease, particularly the high-risk APOE4 carriers.” Valiltramiprosate is an investigational oral AD treatment in Phase 3 clinical development with an upstream mechanism of action from anti-amyloid antibodies that prevents formation of neurotoxic amyloid oligomers. A prodrug of tramiprosate with optimized pharmacokinetics and brain penetration, valiltramiprosate was designed to prevent amyloid aggregation at the initial stage of the amyloid cascade. Soluble amyloid oligomers play a central role in the pathogenesis and progression of Alzheimer’s disease. “Results from the APOLLOE4 Phase 3 trial evaluating valiltramiprosate showed promising clinical and volumetric MRI effects in Alzheimer’s patients with the APOE4/4 genotype at the earliest symptomatic stage of disease. With a mechanism of action directly blocking the formation of neurotoxic beta amyloid oligomers, valiltramiprosate addresses the upstream pathology of Alzheimer’s disease and offers a potential safe, effective, and accessible oral treatment,” said John Hey, PhD, Chief Scientific Officer of Alzheon. “These findings reinforce our understanding of how valiltramiprosate works at the molecular level and provide a mechanistic foundation for the positive clinical, fluid biomarker and imaging outcomes observed in our Phase 2 and Phase 3 studies in APOE4 carriers and homozygotes, respectively, with early symptomatic AD.” Preclinical and clinical studies demonstrate that valiltramiprosate interacts with monomeric beta amyloid and prevents the formation of soluble oligomers that drive synaptic toxicity and neuronal loss. Quantitative systems pharmacology (QSP) analysis further supports the clinical relevance of this mechanism of action by linking reductions in formation of toxic amyloid oligomers to preservation of hippocampal volume, attenuation of neurodegeneration in all brain regions, and slowing of disease progression. These effects are most pronounced in the high risk APOE4/4 population, which has a high burden of neurotoxic amyloid oligomers. These clinical and biomarker results support Alzheon’s precision medicine approach of focusing on high-risk APOE4 carriers with Alzheimer’s disease, and provide the scientific rationale for targeting beta amyloid oligomers upstream in the disease process and at the early symptomatic stages of AD. Details of Symposium at AAIC 2025 The symposium will be held in the afternoon on July 30th and will be available to all conference attendees, both in person at the Westin Harbor Castle in Toronto and virtually via the following link: https://aaic.alz.org/program/schedule.asp#a06 Title: Inhibition of Beta Amyloid Oligomer Neurotoxicity with Oral Valiltramiprosate Date and Time: Wednesday, July 30, 12:30 p.m. local Toronto time (ET) Location: Westin Harbor Castle, Frontenac Ballroom Symposium Chair & Moderator: Sharon Cohen, M.D., FRCPC, Medical Director, Toronto Memory Program, Toronto, ON, Canada Presenters: Samuel Gandy, M.D., Ph.D., Professor of Neurology and Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Kenjiro Ono, M.D., Ph.D., Department of Neuropathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Huge Geerts, M.D., Ph.D., Head of Neuroscience Modeling, Quantitative Systems Pharmacology, Certara, Berwyn, PA, USA John Hey, Ph.D., Chief Scientific Officer, Alzheon, Inc. Framingham, MA, USA In addition, Alzheon scientists will be provide clinical and imaging analyses from the APOLLOE4 Phase 3 study of valiltramiprosate in APOE4/4 homozygotes in eight poster presentations at the conference: Poster: “Quantitative Systems Pharmacology Analysis of Hippocampal Volume Trajectory by APOE Genotype and Neuroprotective Effects of Valiltramiprosate/ALZ-801 in Early AD” Poster: “Efficacy and Safety of Oral Valiltramiprosate in APOE4/4 Homozygotes with Early AD: Topline Results from the APOLLOE4 Phase 3 Trial” Poster: “Safety and ARIA Results of the Oral Anti-Amyloid Agent Valiltramiprosate from the Phase 3 APOLLOE4 Trial in APOE4/4 Homozygotes with Early AD” Poster: “Correlations of Valiltramiprosate Effects on Hippocampal Volume and Cortical Thickness with Clinical Outcomes in the Pre-Specified MCI Group: Subgroup Analysis from the 78-Week APOLLOE4 Phase 3 Trial in APOE4/4 Homozygotes” Poster: “Valiltramiprosate Effects on Microstructural Integrity of Grey and White Matter in APOE4/4 Homozygotes with Early AD and their Correlations to Clinical Outcomes: MRI Mean Diffusivity Results from the 78-Week APOLLOE4 Phase 3 Trial” Poster: “Quantitative Systems Pharmacology Analysis of Oral Valiltramiprosate/ALZ-801 Predicts Slowing of Alzheimer’s Disease Progression by Anti-Amyloid Oligomer and APOE4 Structural Corrector Modes of Action” Poster: “Valiltramiprosate/ALZ-801 Prevents Hippocampal Atrophy and Clinical Decline in a Stage 2 AD Subpopulation in APOLLOE4 Phase 3 Study” About ALZ-801 Valiltramiprosate/ALZ-801 is a potential first-in-class, investigational oral agent in Phase 3 development as a potentially disease-modifying treatment for AD.1-5,7,10 Valiltramiprosate is designed to block the formation of neurotoxic soluble beta amyloid oligomers implicated in cognitive decline in Alzheimer’s patients.1-5,7,12 In mechanism of action studies, ALZ-801 has fully inhibited the formation of neurotoxic soluble beta amyloid oligomers at the Phase 3 clinical trial dose.1,7,10,12 Valiltramiprosate acts through a novel enveloping molecular mechanism of action to block formation of neurotoxic soluble amyloid oligomers in the human brain12 associated with the onset and progression of cognitive decline in AD patients.1,2,5,7,8 Valiltramiprosate received Fast Track designation from the U.S. Food and Drug Administration in 2017 for Alzheimer’s disease. In clinical trials, valiltramiprosate has shown potential for robust clinical efficacy and favorable safety results with no increased risk of brain vasogenic edema.3-8,11,13 The initial Phase 3 program for valiltramiprosate is focusing on Early AD patients with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), with potential future program expansion to AD treatment and prevention in patients carrying one copy of the APOE4 gene and noncarriers.1–8 Valiltramiprosate APOLLOE4 Phase 3 Trial An Efficacy and Safety Study of Valiltramiprosate in APOE4/4 Early Alzheimer's Disease Subjects (NCT04770220): This trial was designed to evaluate the efficacy, safety, biomarker and imaging effects of 265 mg twice daily oral dose of valiltramiprosate in Early AD subjects with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), who constitute approximately 15% of Alzheimer's patients. This double-blind, randomized trial compared oral valiltramiprosate to placebo treatment over 78 weeks. The APOLLOE4 trial was supported by a grant from the National Institute on Aging to Alzheon, with Susan Abushakra as the principal investigator. Valiltramiprosate APOLLOE4 Long Term Extension Trial (LTE) An ongoing long-term extension of the trial, APOLLOE4-LTE evaluates valiltramiprosate in subjects who complete the core APOLLOE4 study for an additional 104 weeks of treatment for a total of 182 weeks or 3.5 years over the core and LTE study. This LTE study is currently ongoing in the US, UK and Canada (NCT06304883). Valiltramiprosate Phase 2 Biomarker Trial Biomarker Effects of Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease (NCT04693520): This trial was designed to evaluate the effects of 265 mg twice daily oral dose of valiltramiprosate on biomarkers of AD pathology in subjects with Early AD, who have either the APOE4/4 or APOE3/4 genotype and constitute 65-70% of Alzheimer's patients. The primary outcome is the change from baseline in plasma p-tau181. The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic profile of valiltramiprosate over 104 weeks of treatment. An ongoing long-term extension of the trial evaluates the same dose of valiltramiprosate for an additional 104 weeks of treatment for a total of 208 weeks1,5,6. About Alzheon Alzheon, Inc. is a clinical-stage biopharmaceutical company developing a broad portfolio of product candidates and diagnostic assays for patients suffering from Alzheimer’s disease and other neurodegenerative disorders. We are committed to developing innovative medicines by directly addressing the underlying pathology of neurodegeneration. Our lead Alzheimer’s clinical candidate, valiltramiprosate/ALZ-801, is a first-in-class oral agent in Phase 3 development as a potentially disease-modifying treatment for AD. Valiltramiprosate is an oral small molecule that has been observed to fully block the formation of neurotoxic soluble amyloid oligomers in preclinical tests. Our clinical expertise and technology platform are focused on developing drug candidates and diagnostic assays using a precision medicine approach based on individual genetic and biomarker information to advance therapies with the greatest impact for patients. Alzheon Scientific Publications 1Pearson D, et al: Polymorph Analysis of ALZ-801 (Valiltramiprosate), a Valine-Conjugated Oral Prodrug of Tramiprosate in Late-Stage Clinical Development for Alzheimer’s Disease, Journal of Chemical Crystallography 2025. 2Hey JA, et al: Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a Two-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer’s Disease, Clinical Pharmacokinetics 2025. 3Aye S, et al: Point of View: Challenges in Implementation of New Immunotherapies for Alzheimer's Disease, The Journal of Prevention of Alzheimer’s Disease 2025;12(1):100022. 4Abushakra S, et al: APOLLOE4 Phase 3 Study of Oral ALZ-801/Valiltramiprosate in APOE ε4/ε4 Homozygotes with Early Alzheimer’s Disease: Trial Design and Baseline Characteristics, Alzheimer’s & Dementia 2024; 10(3): e12498. 5Tolar M, et al: The Single Toxin Origin of Alzheimer’s Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention, International Journal of Molecular Sciences 2024; 25(5), 2727. 6Hey JA, et al: Analysis of Cerebrospinal Fluid, Plasma β Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model, Drugs 2024; 84(7), 825-839. 7Hey JA, et al: Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single Arm, Open Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer’s Disease, Drugs 2024; 84(7), 811-823. 8Tolar M, et al: Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression, International Journal of Molecular Sciences 2021; 22(12), 6355. 9Abushakra S, et al: APOE ε4/ε4 Homozygotes with Early Alzheimer’s Disease Show Accelerated Hippocampal Atrophy and Cortical Thinning that Correlates with Cognitive Decline, Alzheimer’s & Dementia 2020; 6(1): e12117. 10Tolar M, et al: Aducanumab, Gantenerumab, BAN2401, and ALZ-801—the First Wave of Amyloid-Targeting Drugs for Alzheimer’s Disease with Potential for Near Term Approval, Alzheimer’s Research & Therapy 2020; 12(1): 95. 11Tolar M, et al: The Path Forward in Alzheimer’s Disease Therapeutics: Reevaluating the Amyloid Cascade Hypothesis, Alzheimer’s & Dementia 2020; 16(11):1553-1560. 12Hey JA, et al: Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain, CNS Drugs 2018; 32(9): 849-861. 13Hey JA, et al: Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease, Clinical Pharmacokinetics 2018; 57(3): 315-333. 14Abushakra S, et al: Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential, Journal of Prevention of Alzheimer’s Disease 2017; 4(3): 149-156. 15Kocis P, et al: Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer’s Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data, CNS Drugs 2017; 31(6): 495-509. 16Abushakra S, et al: Clinical Benefits of Tramiprosate in Alzheimer’s Disease Are Associated with Higher Number of APOE4 Alleles: The “APOE4 Gene-Dose Effect,” Journal of Prevention of Alzheimer’s Disease 2016; 3(4): 219-228.

临床2期临床结果临床3期快速通道

2025-06-19

·CPHI制药在线

绿谷971停产背后，阿尔茨海默病还有哪些新药可期？

关注并星标CPHI制药在线近日，中国首个批准用于治疗阿尔茨海默病（AD）的国产原研药甘露特钠胶囊（商品名：九期一®，代号：GV-971），被爆已停产。 GV-971由国内绿谷医药研发，于2019年11月获NMPA有条件批准，用于治疗轻至中度阿尔茨海默病，改善患者认知功能。GV-971作用机理为通过调节肠道菌群失衡，降低脑部神经炎症，延缓AD的病程进展，是全球首个靶向脑肠轴的AD新药。不过自上市以来，围绕GV-971的疗效、安全性和科学性的争议不断。对于此次停产，公司给出的原因是GV-971的药品注册证到期，新的许可批件还未下发。 AD已获批上市药物众所周知，AD一直是新药研发黑洞。据1906年，一位名叫阿洛伊斯·阿尔茨海默的医生向世界报告了第一例AD患者以来，无数药企和科学家在AD药物研发中投入了大量时间和金钱，换来的却是一次次失败，折戟的临床药物超过300种，失败率高达99.6%，居所有药物研发失败率之首。在2021年之前，获FDA批准治疗AD的药物仅有6种，分别是他克林（Tacrine）、多奈哌齐（Donepezil）、卡巴拉汀（Revastigmine）、加兰他敏（Galantamine）、美金刚（Menantine）以及美金刚/多奈哌齐复方制剂。2021年之后，AD领域终于迎来新突破。 2021年，渤健的Aduhelm（aducanumab-avwa）上市，成为首个获FDA批准的靶向β淀粉样蛋白（Aβ）的疗法。目前，业界公认Aβ的生成和清除失衡是神经元变性和痴呆发生的始动因素，异常水平的β-淀粉样蛋白在大脑神经元之间形成的斑块具有神经毒性，导致神经元变性。 Aduhelm作为一种单克隆抗体，通过靶向Aβ，可有选择性地与AD患者大脑中的淀粉样蛋白沉积结合，再通过激活免疫系统，将大脑中的沉积蛋白清除。不过鉴于出现严重副作用，以及商业化问题，Aduhelm只短暂存在于AD的治疗江湖。尽管如此，Aduhelm还是为后续开发通过靶向Aβ来改善认知功能的AD免疫治疗药物，提供了有益的探索和开发经验。 2024年7月，礼来的AD新药Donanemab（多奈单抗）获FDA批准，用于治疗成人因AD引起的轻度认知功能障碍和阿尔茨海默病轻度痴呆。Donanemab是一种抗淀粉样蛋白单克隆抗体，可与 β 淀粉样蛋白亚型 N3pG 结合，促进 AD 患者大脑中淀粉样蛋白斑块的清除。 2025年1月，卫材/渤健的创新药物lecanemab（仑卡奈单抗）获FDA批准，用于早期AD患者的治疗（包括轻度认知障碍或轻度痴呆阶段）。lecanemab是一种抗Aβ药物，通过清除大脑中的Aβ蛋白斑块，逆转AD的病理进展。值得期待的新型在研药物目前，已获批上市药物主要集中于抗Aβ单抗，除此之外，针对AD的在研管线还有其他靶点聚焦。骨髓细胞表达触发受体2（TREM2） TREM2是免疫球蛋白超家族的一种免疫反应受体。生理状态下，TREM2的活性仅局限在特定的组织中，如大脑的小胶质细胞和外周的巨噬细胞。病理状态下， TREM2信号通路则成为感知并抑制组织损伤的免疫信号枢纽。研究证明，激活TREM2可以促进小胶质细胞向损伤部位的迁移，实现神经保护功能。因此，TREM2成为针对神经退行性疾病相关的潜力靶点。不过TREM2靶点在AD适应症的开发并不顺利，武田/Denali、艾伯维/Alector均折戟于此。近日，赛诺菲加入战局。其与Vigil Neuroscience达成协议，将以每股8美元的预付款购买Vigil的所有已发行股票，此次交易的企业价值为4.7亿美元，远高于Vigil目前约1.15亿美元的市值。赛诺菲之所以高溢价收购Vigil，就在于后者的靶向TREM2的口服小分子激动剂VG-3927。该药旨在增强小胶质细胞对Aβ和tau的保护性反应，同时不增加炎症反应。临床和临床前数据显示，VG-3927通过激活TREM2信号通路下游的小胶质细胞，进一步证实其具有神经保护作用。 T细胞免疫球蛋白和黏蛋白结构域蛋白3（TIM3） TIM-3是一种免疫检查点分子，参与免疫和炎症，也是备受瞩目的癌症免疫治疗靶点，当前主要适应症为肿瘤。近日，科学家在Nature发表最新研究，揭示了TIM-3 在小胶质细胞中的作用，并将其确定为AD治疗的一个有前途的靶点。目前尚无药企公开相关研发信息。 Aβ小分子抑制剂口服Aβ小分子抑制剂通过在淀粉样蛋白级联反应的上游起作用，抑制与AD发病机制有关的神经毒性Aβ寡聚体的形成，具有差异化的作用机制。近日，在该领域进展较快的Valiltramiprosate（ALZ-801）公布了治疗早期AD患者的关键性III期研究结果。ALZ-801由Alzheon开发，是一种潜在的FIC口服Aβ聚集抑制剂，旨在阻断与AD患者认知能力下降有关的神经毒性可溶性Aβ寡聚体的形成。在这项III期研究中，评估了ALZ-801治疗存在APOE4/4纯合子基因型（AD高发人群）的早期AD患者的有效性和安全性。结果显示，治疗第78周，在总人群中，该研究未达到主要终点（11%获益，p=0.607）。不过磁共振成像（MRI）扫描结果显示，总人群的脑萎缩减慢，表明ALZ-801具有潜在的神经保护作用，且血管源性脑水肿或微出血的风险未升高。目前，国内润佳医药研发的口服小分子Aβ抑制剂RP902进展最快，用于治疗携带APOE4基因的AD患者。在小分子Aβ抑制剂赛道，全球还有多家公司正在布局。阿尔茨海默病从发现至今已有100年的历史，在这漫长的研发历程中，无数药企的努力和资金打了水漂。如今AD的药物研发已迎来曙光，尽管依然面临很多挑战，但无数前赴后继的靶点和研究将为AD治疗打开新的大门。参考来源： 1.深蓝观《971断药背后，绿谷的“成功”和困境》 2.https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-025-08852-z 3.Becker RE, Greig NH. Increasing the success rate for Alzheimer's disease drug discovery and development. Expert Opin Drug Discov. 2012;7(4):367-370. doi:10.1517/17460441.2012.672409.END领取CPHI & PMEC China 2025展会门票来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

上市批准免疫疗法临床2期申请上市临床结果

100 项与 Valiltramiprosate 相关的药物交易

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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
阿尔茨海默症	临床3期	美国	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	加拿大	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	捷克	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	法国	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	德国	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	冰岛	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	荷兰	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	西班牙	Alzheon, Inc.	2021-05-19
阿尔茨海默症	临床3期	英国	Alzheon, Inc.	2021-05-19
唐氏综合征	临床阶段不明	美国	Alzheon, Inc.	2022-06-11

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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


NCT04770220 (Company_Website) 人工标引	临床3期	阿尔茨海默症 APOE4/4 homozygotes	325	valiltramiprosate	夢醖觸醖憲醖醖齋鑰廠(醖蓋願簾願範膚壓窪餘): Difference (LS Mean) = -0.504, P-Value = 0.607 未达到更多	不佳	2025-04-10
NCT04770220 (Company_Website) 人工标引	临床3期	阿尔茨海默症 APOE4/4 homozygotes	325	Placebo		不佳	2025-04-10
NCT04693520 (Biospace) 人工标引	临床2期	阿尔茨海默症	84	ALZ-801/Valiltramiprosate 265 mg	壓夢願蓋鹽遞獵顧憲積(願壓願構範積憲簾廠築) = statistically significant and clinically relevant reduction in plasma biomarkers of neurodegeneration, preservation of brain volume, and positive cognitive effects in Early AD patients who are carriers of apolipoprotein ε4 allele (APOE4) following 24 months of treatment with investigational oral agent ALZ-801/valiltramiprosate. 築糧構鏇窪廠憲築衊觸 (網壓選衊願襯襯襯餘餘 )	积极	2024-06-25
NCT04693520 (phase 2, Pubmed)	临床2期	阿尔茨海默症 plasma Aβ42	84	ALZ-801 265 mg tablet	醖觸糧範鹽鏇繭膚構築(壓積築網鑰淵艱膚積淵) = 鹹衊願鬱鹹鬱壓餘淵衊製鹹廠鏇顧範簾壓壓獵 (襯膚夢鹽淵齋鹹夢範窪 )	积极	2024-06-20
NCT04693520 (Corporate Publications) 人工标引	临床2期	阿尔茨海默症	75	Valiltramiprosate	餘製鏇壓觸選顧窪夢簾(積築製膚遞製鏇蓋膚鑰) = 淵範鬱艱淵築齋鏇淵構餘範窪蓋鬱觸窪窪廠顧 (衊積積鑰鹽壓膚糧窪獵 ) 更多	积极	2022-09-20