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

/ Completed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.

100 项与 Valiltramiprosate 相关的临床结果

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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）

2026-02-01·CNS DRUGS

Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer’s Disease: Synthesis of Evidence from Observational and Interventional Trials

Review

作者: Porsteinsson, Anton ; Dickson, Sam ; Hey, John A ; Tosun, Duygu ; Yu, Jeremy ; Albayrak, Adem ; Kesslak, J Patrick ; Petrella, Jeffrey ; Flint, Susan ; Bracoud, Luc ; Durrant, Abe ; Ritchie, Craig ; Doraiswamy, P Murali ; McLaine, Rosalind ; McSweeney, Emer ; Schaefer, Jean F ; Tolar, Martin ; Abushakra, Susan ; Sabbagh, Marwan ; Gauthier, Serge ; Bray, Margaret ; Barakos, Jerome ; Barkhof, Frederik ; Liang, Earvin ; Hendrix, Suzanne ; Boada, Merce ; Watson, David ; Cohen, Sharon ; Power, Aidan

Amyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer's disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV-cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months' duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV-cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N ~10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18-24 months (r = -0.40 to -0.44, p < 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm³ or ≥ 10% of atrophy in the placebo arm over 18 months. Our findings demonstrate that hippocampal atrophy is an early indicator of cognitive decline in AD, linked to amyloid and tau-related neurodegeneration. HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD.

2026-01-01·INTERNAL MEDICINE

Therapeutic Potential of Oral ALZ-801 in Patients with Alzheimer's Disease

Article

作者: Noguchi-Shinohara, Moeko ; Ono, Kenjiro ; Muramatsu, Daiki

Alzheimer's disease (AD), the most common cause of dementia, is characterized by amyloid-β (Aβ) plaques in the brain. ALZ-801, a prodrug of tramiprosate, was developed as an oral disease-modifying therapy for patients with AD. Tramiprosate and ALZ-801 inhibit Aβ aggregation and reduce Aβ-induced cytotoxicity. Although the prespecified endpoints were not met in two Phase 3 trials involving tramiprosate, post hoc analyses indicated benefits in apolipoprotein E ε4 homozygotes. Furthermore, no cases of amyloid-related imaging abnormalities-edema/effusion were detected. In the APOLLOE4 Phase 3 study of ALZ-801 in apolipoprotein E ε4 homozygous patients with early AD, the primary endpoint was not achieved; however, the mild cognitive impairment subgroup demonstrated nominal efficacy. ALZ-801 has not been associated with amyloid-related imaging abnormalities, a major safety concern of anti-Aβ antibodies, and may represent a safe oral alternative to anti-Aβ antibody therapies.

2025-12-01·Alzheimers & Dementia

Quantitative Systems Pharmacology Analysis of Hippocampal Volume Trajectory by APOE Genotype and Neuroprotective Effects of Valiltramiprosate/ALZ‐801 in Early AD

Article

作者: Hey, John A. ; Yu, Jeremy ; Power, Aidan ; Schaefer, Jean ; Abushakra, Susan ; Tolar, Martin ; Short, Shaina M ; Geerts, Hugo

Abstract:

Background:

Valiltramiprosate is an oral, small‐molecule inhibitor of β‐amyloid oligomer formation in late‐stage development as a disease‐modifying therapy for AD. We provide a quantitative systems pharmacology analysis of the natural AD trajectory of hippocampal volume changes by APOE genotype and the neuroprotective effect of valiltramiprosate in Early AD.

Method:

A novel QSP model for natural AD trajectory of hippocampal volume was developed, integrating factors of age, non‐amyloid pathology, amyloid oligomers, protofibrils and plaques, ARIA‐E, clearance and microglia activation. The model applied longitudinal observational and interventional data from the lecanemab CLARITY and donanemab TRAILBLAZER clinical trials. Impact of APOE genotype was applied based on its differential Aβ synthesis and clearance. The analysis of valiltramiprosate effect was based on mechanism of action on inhibition of Aβ oligomer formation and an effect as an APOE4 structural corrector.

Result:

The QSP trajectory model of hippocampal volume in AD exhibited pronounced genotype differences in disease progression, with APOE4/4 >> APOE3/4 > APOE3/3. APOE4/4 AD subjects exhibit a greater degree of disease acceleration in Aβ pathology and hippocampal atrophy compared to APOE3/4 and APOE3/3, including an earlier onset (∼4‐year leftward shift) and more rapid decline consistent with an earlier manifestation of pathologies prior to clinical decline. QSP analysis of valiltramiprosate pharmacology demonstrates a substantial reduction of neurotoxic oligomers and protofibrils, leading to a reduction of hippocampal atrophy that is exposure, age and disease‐stage dependent. Due to its anti‐aggregation MOA upstream in the amyloid cascade, there is minimal effect on plaque deposition and thereby no ARIA liability, consistent with the safety results from APOLLOE4 Phase 3 study evaluating valiltramiprosate.

Conclusion:

QSP analysis supports the hypothesis that acceleration of Aβ aggregation is the initial step in Early AD triggering an increase in toxic oligomers that drives AD neurodegeneration, measured by hippocampal atrophy, followed by subsequent rapid cognitive decline. Valiltramiprosate intervention in Early AD produces an exposure, age and stage of disease‐dependent reduction in hippocampal atrophy in all APOE genotypes, with the magnitude of benefit greatest at early symptomatic disease stage. The neuroprotective effect is driven by an exposure‐related reduction of Aβ oligomers and protofibrils that blunts the pathological amyloid cascade in AD.

项与 Valiltramiprosate 相关的新闻（医药）

2026-02-03

·药物宇宙

AD 药物发现：从Aβ到 Tau

—Aβ？ Tau？阿尔茨海默病治疗正经历从靶向Aβ到聚焦Tau的关键转变。尽管抗Aβ疗法在清除病理蛋白和延缓认知衰退方面已取得重要突破，但其对Tau病理的影响仍有限。随着研究发现Tau在疾病后期可独立驱动神经退行，直接靶向Tau已成为治疗策略的新焦点。背景阿尔兹海默症，作为最常见的一种慢性获得性进行性智能障碍综合征(痴呆)及Tau病，现如今有着巨大的临床需求。全球约有3,200万例AD患者，这一数字预计到2050年将增长到1.53亿，给公共健康和社会经济带来巨大挑战。AD脑内同时存在Aβ病理（A）、Tau病理（T）和神经退行（N）三种病变，这成为AD的主要病理标志，并构成临床-生物学的诊断框架（ATN框架）。在AD病程中，Aβ聚集通常被视为病理进程的发起者，而Tau蛋白的聚集与执行病理过程密切相关，并与临床症状的进展高度相关。此外，除了AD之外，多种原发性Tau病也由持续的Tau聚集引起，如进行性核上性麻痹（PSP）和额颞叶痴呆（CBD），这些疾病在Tau病理上具有主要特征，并缺乏有效治疗。家族性Tau病，尤其是MAPT基因突变导致的Tau变异，也充分证明Tau功能紊乱本身足以驱动神经退行过程，将Tau确立为直接病因。这些认识说明，尽管Aβ可能引发AD病程，Tau却真正决定神经元的损伤和认知衰退，因此两者都是合理且重要的治疗靶点。 Figure 1 Evolutions in AD therapy—From Aβ to tau therapy DOI: 10.1016/j.cell.2025.11.033 AD的特征是Aβ聚集成细胞外Aβ斑块，随后过度磷酸化的tau（T）聚集成神经元内神经元缠结，Aβ被认为是疾病过程的启动者，tau被认为是疾病过程的执行者，tau聚集与症状进展密切相关。如今，阿尔茨海默病（AD）治疗研究正经历显著的转变和加速发展。近期针对Tau蛋白的靶向策略已经显示出潜在的疾病修饰性效果：脑脊液和PET影像显示Tau在治疗患者中的沉积速度减缓，并伴有早期认知获益的迹象。 AD治疗的演进——从Aβ到Tau疗法针对Aβ的治疗策略经历了漫长而曲折的发展历程，最终实现了重要突破。多年的早期抗Aβ策略未能取得明显成功，一度让人怀疑淀粉样蛋白级联假说。然而，这一优化探索过程并未停滞，反而积累了大量经验。从1999年起，研究者在动物模型和最初的免疫化试验中就证明了抗Aβ能够清除淀粉样病变并减缓疾病进程，但在人体试验中，仅表现出生物学层面的改善（如斑块减少或神经损伤标志物下降），而未马上转化为明显的临床效益。此外，早期主动免疫实验还引发了脑炎等严重副作用，使人们转而开发安全性更高的被动免疫策略。后来，即使是成功上市的抗Aβ抗体也会导致一部分患者出现ARIA（淀粉样相关成像异常），需要通过严格筛选和监测来降低风险。这些经验表明，在AD治疗中，安全性和疗效之间需要精细平衡：在确保最大限度清除病理蛋白的同时，必须避免或减轻免疫介导的不良反应。长期来看，抗Aβ试验形成了一个成熟的框架，极大地推动了AD疗法的快速发展。这包括：（1）针对抗体靶点（表位/结构）和功能特性的反复优化，使生物学停滞和临床改善得以同步验证；（2）改进患者筛选，基于Aβ和Tau等生物标志物明确疾病分期和最优干预时机；（3）使用灵敏的生物标志物（PET、脑脊液、血液指标）来评估治疗效果，制定阈值和剂量以确保病理足够抑制；（4）结合生物学读出调整疗法剂量和用药间隔，从而在安全与效果之间取得平衡。以这些经验为基础的优化策略直接促成了Lecanemab和Donanemab的成功上市。 Figure 2 Lessons from anti-Aβ clinical trials: Roadmap for accelerated trial optimization from preclinical to biological and clinical halting for regulatory agency therapy approval DOI: 10.1016/j.cell.2025.11.033 AD疗法研究的转折点之一是近期的FDA批准事件：抗Aβ单抗Lecanemab和Donanemab的获批则标志着几十年AD免疫疗法探索的积累终于结出了硕果。它们可以剂量依赖地几乎完全清除脑内Aβ斑块，同时显著减缓认知衰退。在大规模III期临床试验中，Lecanemab对早期AD患者的认知下降速度减缓了约27%，并在2023年6月获得FDA加速批准。Donanemab在另一项III期试验中整体减缓认知进展29%，对低Tau水平患者的作用更强（提高至40%）。这些结果表明，精准设计的抗Aβ免疫疗法在生物学上有效降低了Aβ病理，对认知具有明显益处——尽管治疗尚未完全阻断病程，但这标志着“疾病修饰性”疗法的可行性。这也启示了AD治疗的一个重要教训：通过不断迭代改进靶向策略（例如选择不同的Aβ表位和抗体亲和力），并结合适当的用药时机和患者筛选，最终可以显著提高疗效，为类似的Tau靶向疗法指明了优化路径。这些疗法证明了清除Aβ能够部分减缓临床症状的发展，奠定了疾病修饰性治疗的概念基础。 Table 1 Aβ蛋白相关抗体 Aβ蛋白相关抗体 Lecanemab：一种经过人源化改造的小鼠抗体mAb158。它属于免疫球蛋白G1类单抗，能够优先攻击可溶性的Aβ原纤维，同时对不溶性Aβ纤维也具有作用效果。Lecanemab专门针对Aβ原纤维这一靶点，这一特点使其区别于其他抗淀粉样蛋白单抗。Aβ原纤维是一种大型、可溶性的Aβ聚集体，它们通过破坏与记忆功能相关的电生理机制而表现出神经毒性。Aβ原纤维的形成是由“北极APP突变”所促成的。研究表明，这种突变会导致早发性阿尔茨海默病，这说明Aβ原纤维在阿尔茨海默病的发病机制中起着关键作用。此外，中等大小的Aβ寡聚体和原纤维被认为是最具神经毒性的形式，因此针对Aβ原纤维进行治疗可能是一种有效的治疗策略。在明确了导致早发性阿尔茨海默病的“北极APP突变”相关机制后，Lecanemab被设计用来专门攻击这些大型、可溶性的Aβ原纤维（其体积比Aβ单体大1000多倍），同时它也能与构成脑淀粉样斑块的主要成分——不溶性Aβ纤维发生相互作用。在所有第二代单克隆抗体中，Lecanemab在清除Aβ原纤维方面效果最为显著，尤其是可溶性原纤维和寡聚体。与Aducanumab相比Lecanemab对小尺寸原纤维的结合亲和力高出100倍，对大尺寸原纤维的结合亲和力则高出25倍，而对单体的结合亲和力较低。 Donanemab：一种针对Aβ的IgG1单克隆抗体，其临床前研究表明其可有效减少Aβ沉积水平。在TRAILBLAZER-ALZ 的2期试验中，Donanemab达到了主要临床终点（通过iADRS评分评估）。基于上述结果，启动了Donanemab的另一项全球3期临床试验，即TRAILBLAZER-ALZ2，该试验在更大规模的早期症状性AD（包括MCI和轻度痴呆）人群中进行，通过脑内Tau沉积水平将受试者分为低和中度Tau病理人群以及高Tau病理人群。参与者MMSE评分为20 至28分。主要疗效指标是从基线到76周的iADRS评分的变化。低中Tau病理人群中约80%达到Aβ沉积清除，整体人群中约76%达到Aβ清除。结构MRI显示Donanemab组的脑容积减少大于安慰剂组，这可能与Aβ的清除相关。经过Donanemab 76周干预后，以iADRS评分的变化为标准衡量，低中Tau病理人群和整体人群中分别减缓了35.1%和22.3%的认知衰退。与安慰剂相比，Donanemab治疗在18个月的试验期间降低了约38%的疾病进展风险。换算成时间，Donanemab 在iADRS和CDR-SB评分方面分别延缓了4.36个月和7.53个月的认知衰退。在高Tau 病理人群中，Donanemab治疗组人群未达到主要研究终点，表明在临床前阶段治疗AD可能会产生更大的临床获益。2024年7月2日，FDA批准了Donanemab 用于早期症状性AD患者的临床使用。作用于Aβ蛋白的小分子药物（1）BACE1抑制剂：BACE1是一种位于高尔基体膜上的天冬氨酸蛋白酶，负责切割APP生成sAPPβ和C99片段，后者再经γ-分泌酶切割生成Aβ。BACE1抑制剂通过占据其活性位点，阻止APP的β-位点切割，从而从源头上减少Aβ的生成。 GRL-823：含有一个异羟肟酸基团和一个苯并噻唑环，具有较强的氢键供体和疏水相互作用位点。与BACE1活性位点的两个天冬氨酸残基（Asp32和Asp228）形成氢键，模拟底物过渡态。IC₅₀ = 1.0 nM，在Tg2576小鼠中显著降低脑内Aβ40水平。 Verubecestat （MK-8931）：含有一个氨基吡啶和一个苯并噻吩环，具有良好的脑穿透性和代谢稳定性。高选择性抑制BACE1，对其它天冬氨酸蛋白酶（如胃蛋白酶、组织蛋白酶D）抑制作用较弱。在健康志愿者中单次给药可降低CSF中Aβ达90%以上，III期试验因认知恶化终止。 Umibecestat （CNP-520）：结构中含有苯并咪唑和嘧啶环，增强与BACE1活性口袋的疏水相互作用。强效抑制BACE1，同时具有一定的脑穿透性，降低脑内Aβ42和sAPPβ水平。在II/III期试验中因认知功能加速下降而提前终止。 LY2886721：含有一个磺酰胺和一个苯并噁唑环，提高代谢稳定性。第二代口服BACE1抑制剂，减少肝脏毒性风险，但仍有肝酶升高问题。在II期试验中因肝毒性停止开发。 Figure 3 Structures of the beta-site APP cleaving enzyme 1 (BACE1) inhibitors in study. DOI: 10.3389/fnagi.2022.1019412 （2）γ-分泌酶抑制剂（GSIs）与调节剂（GSMs）：γ-分泌酶是一个跨膜蛋白酶复合物（含Presenilin、Nicastrin等亚基），负责切割C99生成Aβ。GSIs直接抑制其酶活性，而GSMs则改变其切割偏好，减少Aβ42（更易聚集）的生成，增加较短的Aβ38（不易聚集）。 Semagacstat （LY-450139）：含有一个苯磺酰基和一个叔丁基，增强脂溶性。抑制γ-分泌酶对APP和Notch等多种底物的切割，导致Notch信号通路抑制，引起胃肠道和免疫系统毒性。在III期试验中因严重副作用（腹泻、感染、皮肤癌风险）终止。 Avagacstat （BMS-708163）：含有一个苯并噻吩和一个咪唑环，增强选择性。设计为“Notch-sparing” GSI，对APP的选择性高于Notch（约15倍）。在II期试验中虽安全性改善，但未显著改善认知功能。 CHF5074（GSM）：含有一个二苯甲酮核心和一个羧酸基团。作为γ-分泌酶调节剂，不抑制Notch切割，而是减少Aβ42生成，增加Aβ38。在轻度AD患者中耐受性良好，II期试验显示可降低CSF中Aβ42。 Figure 4 Structures of γ-secretase inhibitors and modulators. DOI: 10.3389/fnagi.2022.1019412 Aβ聚集抑制剂Aβ单体可聚集成寡聚体（毒性最强）→原纤维→淀粉样斑块。这类药物通过结合Aβ单体或寡聚体，阻止其进一步聚集，或促进其解聚。 Tramiprosate（及其前药ALZ-801）：Tramiprosate为3-氨基丙磺酸；ALZ-801为其缬氨酸前药，提高口服生物利用度。Tramiprosate结合可溶性Aβ，稳定其构象，抑制寡聚体形成；ALZ-801在体内水解为Tramiprosate和3-SPA（内源性代谢物），后者也有抗聚集活性。Tramiprosate在III期试验中未能改善认知；ALZ-801在II/III期试验中显示更好的耐受性和脑穿透性。 Scyllo-inositol：肌醇的立体异构体，与内源性肌醇结构相似。直接结合Aβ寡聚体，阻止其与神经元膜相互作用，减少突触毒性。在II期试验中安全性良好，但疗效有限。 EGCG：属于儿茶素类多酚，含多个酚羟基和一个酰基。通过氢键和疏水作用结合未折叠的Aβ肽，促进其形成非毒性寡聚体；同时具有抗氧化、抗炎作用。在动物模型中显著减少Aβ斑块和认知改善，临床研究仍在早期。 Figure 5 Structures of molecules in preventing amyloid beta (Aβ) aggregation. DOI: 10.3389/fnagi.2022.1019412 尽管抗Aβ治疗可以在绝大多数患者身上消除脑内Aβ病变，但其对Tau病理的影响并不完全。即便Aβ蛋白被近乎清除，研究发现Tau病理的相关生物标志物（例如脑脊液或血浆中的Tau，以及Tau PET信号）往往只能得到部分改善。这可能的解释是，Tau蛋白的致病过程在后期可能已经不再依赖Aβ触发剂，Tau的病理聚集具有自身传播的特点，就像在原发性Tau病中看到的那样。因此，仅仅清除Aβ这一“诱发因素”并不足以完全阻断Tau在大脑中的扩散和累积。这突出说明在疾病的后期阶段，Tau独立于Aβ成为了主要的驱动因子，需要通过直接抑制Tau来进一步减缓或阻止疾病进展。尽管目前还未能完全证明Tau靶向疗法在AD中的最终疗效，但Tau是Tau病变（包括AD）的核心因子，有充分理由进行深入研究。支持Tau为关键治疗靶点的论据包括：Tau基因突变可以单独引发神经退行；Tau蛋白在神经元间的时空聚集与疾病进展密切相关；而且Tau蛋白的截断和聚集产物本身具有传播能力，可以引发连锁反应。因此，除了继续优化Aβ疗法外，研究者们急需开发和测试针对Tau的干预手段，以期在AD治疗上获得更加完整的病理抑制效果。 Figure 6 Hyperphosphorylated Tau protein detaches from microtubules, assembles into oligomeric structures, and eventually aggregates into neurofibrillary tangles. DOI: 10.12360/CPB202507039 Tau治疗策略进展：ASO、抗体免疫疗法等证据剖析鉴于Tau蛋白在AD及其他Tau病理中的关键作用，研究者已经开发出多种阻断Tau病理进展的治疗策略。在临床和临床前研究中，包括使用反义寡核苷酸（ASO）或小干扰RNA（siRNA）下调Tau表达，调节Tau的翻译后修饰（如磷酸化、乙酰化、糖基化或截断），主动或被动Tau疫苗，以及利用分子诱饵（PROTAC）促进Tau降解，阻断Tau聚集的小分子，以及O-GlcNAcase抑制剂等途径。这些策略的目标都是削弱Tau蛋白的病理作用或增强其清除。 Table 2 Tau蛋白相关抗体抗Tau单克隆抗体 BIIB080：一种针对MAPT蛋白的反义寡核苷酸，它能够选择性地抑制MAPT信使RNA的表达，从而减少tau蛋白的合成。在临床前研究中，通过对转基因小鼠进行反义寡核苷酸干预来降低MAPT mRNA的水平，结果发现tau蛋白的含量随之下降，原有的tau蛋白相关病理变化也得到了改善。在临床研究中，一项针对轻度阿尔茨海默病患者的1b期试验完成了剂量递增阶段的测试，该试验的主要目的是评估BIIB080的安全性和耐受性。正如先前发表的研究结果所示，BIIB080通常具有较好的耐受性；出现的不良事件大多属于轻度或中度，其中最常见的症状包括头痛、背痛以及腰椎穿刺后综合征。研究还对相关的生物标志物进行了检测。在剂量递增阶段，BIIB080能够导致脑脊液中的tau蛋白及磷酸化tau 181蛋白水平呈剂量依赖性下降。在一项1b期研究中，轻度AD患者接受不同剂量的BIIB080治疗，结果显示该药物能剂量依赖性地降低脑脊液中的总Tau和磷酸Tau水平，同时在Tau PET影像中观察到Tau沉积增长的减缓。随着治疗时间延长（到2年），参与者的Tau PET信号明显稳定或减弱，与对照组相比有统计学上的趋势差异。更重要的是，这些生物学信号改善伴随着认知功能评分的改善趋势。目前，BIIB080已获得FDA快速通道资格，被认为是Tau疗法领域的一个重要里程碑。这一初步成果表明，通过靶向TaumRNA，ASO疗法在体内确实可以减轻Tau病理，类似于抗Aβ疗法对于Aβ的影响，为Tau免疫疗法的临床转化提供了坚实的支持。 Bepranemab：除了ASO策略外，被动免疫（抗体）疗法也在不断发展。第二代抗Tau抗体在初步研究中表现出令人鼓舞的结果：例如，抗体bepranemab在一项大型II期AD临床试验中显著减缓了Tau PET信号增加（与安慰剂组相比降低33%–58%）和认知衰退速度（ADAS-Cog14评分下降21%–25%）。尽管该试验的主要终点（CDR-SB）在整体人群中未达显著性，但二级终点数据显示Tau病理和认知得到了一定程度的改善。另一种第二代抗体E2814也在预临床AD患者中显示出积极信号：它在少数Dominantly Inherited AD（家族性AD）患者中联合用药显著降低了CSF中MTBR区域的Tau片段和p-tau水平。其他第二代抗体（如etalanatug、posdinemab、BMS-986446等）目前也正在临床试验中，其结果预计将于2025年底前陆续公布。作用于Tau蛋白的小分子药物（1）Tau聚集抑制剂：Tau蛋白异常磷酸化后从微管上解离，聚集成寡聚体→神经纤维缠结（NFTs）。这类药物直接结合Tau蛋白，阻止其异常聚集或促进其降解。 LMTX (TRx0237)：亚甲基蓝的还原形式，为一种吩噻嗪衍生物，水溶性较好。结合Tau蛋白的疏水区域，抑制其自我聚集；同时具有线粒体保护和抗氧化作用。在III期试验中作为单药使用时显示出一定的认知改善趋势，但总体疗效有限。（2）GSK-3β抑制剂：GSK-3β是一种丝氨酸/苏氨酸激酶，过度激活会导致Tau蛋白多个位点的异常磷酸化，促进其聚集。抑制GSK-3β可减少Tau磷酸化，维持微管稳定性。 Tideglusib （NP-031112）：含有一个噻唑烷二酮环和一个苯磺酰基，为非ATP竞争性抑制剂。通过共价修饰GSK-3β的Cys199残基，不可逆地抑制其活性，减少Tau磷酸化。在IIa期试验中安全性良好，但IIb期未能达到主要终点（认知改善）。 Figure 6 Structures of tau aggregation inhibitors. DOI: 10.3389/fnagi.2022.1019412 Figure 7 Therapeutic strategies targeting Tau DOI: 10.12360/CPB202507039 目前靶向Tau的小分子药物研发仍面临诸多挑战，包括靶点选择性、血脑屏障穿透、疾病阶段适应性等。多数药物尚处于临床前研究，进入临床的也大多未能显著改善症状。未来可能的发展方向包括：开发更具选择性的调控策略，如DEPTAC技术；结合人工智能进行分子设计与患者分层；探索Tau与Aβ、神经炎症等多靶点协同治疗；加强临床前模型与人体病理的相关性验证。总体而言，Tau靶向治疗仍是一个活跃且充满挑战的研究领域，需要多学科交叉与持续探索。思考与展望随着抗Aβ免疫疗法的临床应用成为现实，研究者可以探索将抗Aβ和抗Tau策略相结合的治疗方案。这种组合疗法的理念是同时作用于AD发病过程的两个不同阶段：Aβ的聚集被认为触发了疾病，而Tau聚集则执行并推进了疾病进展。因此，联合使用抗Aβ和抗Tau疗法有望对病理过程的始动与执行阶段进行双重抑制。当前已有几项组合用药的临床试验正在进行中，例如在Presymptomatic AD患者中联合使用E2814和Lecanemab，这些研究预期于2027–2028年公布结果。此外，在早期MCI患者中也启动了E2814与Lecanemab的联合试验。根据AD病理在脑内不同区域和时间上的分布特点，采用组合疗法可在多个层面上同时干预病程，这一理念为治疗提供了新的思路。虽然理论上两者联用具有优势，但临床实践中需要审慎处理多种因素。首先，为了评估哪部分疗效归于哪种药物，试验设计可能需要设计交叉对照组或先后给药阶段等。其次，既然抗Aβ疗法的副作用如ARIA是已知风险，联合用药可能放大这些风险，需要额外的安全监控和风险评估。参考资料： 1. Courade JP, Zetterberg H, Höglinger GU, Dewachter I. The evolving landscape of Alzheimer's disease therapy: From Aβ to tau. Cell. 2025;188(26):7337-7354. 2. Vitek GE, Decourt B, Sabbagh MN. Lecanemab (BAN2401): an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease. Expert Opin Investig Drugs. 2023;32(2):89-94. 3. Demattos RB, Lu J, Tang Y, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer's disease mice. Neuron. 2012;76(5):908-920. 4. Edwards AL, Collins JA, Junge C, et al. Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2023;80(12):1344-1352. 5. Yao W, Yang H, Yang J. Small-molecule drugs development for Alzheimer's disease. Front Aging Neurosci. 2022;14:1019412. 往期回顾：转录因子：药物设计难题？蛋白激酶：抑制剂与激动剂药物设计与优化：基于结构的分子生成 RIPTAC：更好的多特异性药物？蛋白互作抑制剂：Ziftomenib的13年研发之路排版/整理：舒黄亮/杨俊杰

临床结果抗体药物偶联物细胞疗法

2026-02-03

·BioSpace

Alzheon Reports Plasma Biomarker Results from Phase 3 and 2 Studies of Valiltramiprosate/ALZ-801, Validating Its First-in-Class Mechanism of Action and Underscoring Benefits in Cognition, Function, and Brain Volume Protection in Alzheimer’s Patients

Early and Consistent Decreases in P-tau 217 Plasma Levels Were Associated with Improvements in Cognition, Function, and Brain Atrophy Measures MCI Subjects Receiving Valiltramiprosate Showed Significant Correlations Between Decreases in Plasma P-tau 217 and Improvements on ADAS-Cog (r = 0.28, p = 0.039), CDR-SB (r = 0.38, p = 0.005), and Hippocampal Volume (r = 0.35, p = 0.013) High Rates of Alzheimer’s Disease Positivity Were Confirmed Across Phase 3 and 2 Trials Using FDA-Approved P-tau 217 /Aβ1-42 Biomarker Threshold Results Validate Upstream Molecular Mechanism of Inhibiting Formation of Neurotoxic Soluble Amyloid Oligomers – A Key Driver of Alzheimer’s Pathology Valiltramiprosate Has Potential to Become the First Oral Agent to Slow Alzheimer’s Pathology in Patients FRAMINGHAM, Mass.--(BUSINESS WIRE)-- #ALZ801 -- 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 plasma biomarker analyses from its APOLLOE4 Phase 3 and Phase 2 clinical studies of valiltramiprosate/ALZ-801. New results offer robust evidence supporting the biological activity of valiltramiprosate’s, its novel mechanism of action, and effects in therapeutic studies, while validating the Alzheimer’s disease pathology in trial participants through FDA-approved plasma biomarker thresholds. “Valiltramiprosate has emerged as the only late-stage oral treatment with a potential to materially change the Alzheimer’s therapeutic landscape in the near future, and this data completes the picture showing how valiltramiprosate’s action leads to positive effects on cognition, daily function, and brain protection against atrophy,” said Martin Tolar, Founder, President, and CEO of Alzheon. “In 2026, we will move forward with our plans for the next Phase 3 study based on analyses from the APOLLOE4 Phase 3 trial and its long-term extension. These efforts put us in a strong position as we focus on expanding the valiltramiprosate platform, developing new candidates, and investigating additional target groups.” Alzheon will continue to use these biomarker insights to advance the valiltramiprosate platform, improve patient selection, and guide clinical development for genetically defined and high-risk Alzheimer’s disease groups. “These findings underscore the usefulness of plasma biomarkers in connecting Alzheimer’s disease pathology with clinically relevant outcomes,” stated Robert Rissman, PhD, Professor of Physiology and Neurosciences at the University of Southern California. “The robust associations between decreases in plasma p-tau 217 , benefits on cognition and function, and protection from brain atrophy, offer valuable insights into disease mechanisms and further justify the advancement of valiltramiprosate as a potential disease-modifying therapy.” Across both studies, the majority of participants satisfied criteria for AD positivity in accordance with the recently FDA-approved plasma p-tau 217 /Aβ1-42 ratio. In the Phase 3 APOLLOE4 trial involving APOE4/4 homozygotes, 94% of enrolled subjects were confirmed as AD positive, and in the Phase 2 trial targeting APOE4 carriers that utilized CSF biomarkers as inclusion criteria, 97% of homozygote and 96% of heterozygote patients met the AD positivity threshold. These results demonstrate substantial enrichment for amyloid-driven disease across both clinical trials. Biomarker analyses of Phase 3 and 2 studies examining the effects of valiltramiprosate revealed consistent and early decreases in plasma p-tau 217 , which is a biomarker linked to beta amyloid and early tau pathology. In the Phase 3 trial, participants who received valiltramiprosate for 78 weeks showed reductions in p-tau 217 starting at 26 weeks that continued throughout the treatment period, with even greater benefits seen in patients at the Mild Cognitive Impairment (MCI) stage. For those with MCI in the placebo group, p-tau 217 increased by about 17% from baseline over 78 weeks, while those given valiltramiprosate experienced a decrease in p-tau 217 of approximately 36%, translating to a 53% difference vs. placebo. Among the MCI group receiving valiltramiprosate, there were significant and meaningful relationships between decreases in plasma p-tau 217 and benefits on clinical outcomes ADAS-Cog (r = 0.28, p = 0.039), CDR-SB (r = 0.38, p = 0.005), as well as protection of hippocampal volume (r = 0.35, p = 0.013). Baseline plasma p-tau 217 levels were strongly correlated with both clinical and neuroimaging outcomes throughout the Phase 3 study, providing further biological support for the discovery that valiltramiprosate benefits are tied to treatment at the appropriate disease stage. Within the Phase 3 MCI cohort, baseline p-tau 217 demonstrated significant and consistent associations in valiltramiprosate–treated participants with ADAS-Cog at baseline (r = 0.31, p = 0.019), CDR-SB (r = 0.40, p = 0.002), hippocampal volume (r = -0.532, p <0.0001), and cortical thickness (r = -0.60, p <0.0001). Notably, significant correlations were also identified in the overall Phase 3 population, including both active and placebo arms. "Our new biomarker results offer robust biological validation for valiltramiprosate's upstream molecular mechanism, designed to inhibit formation of neurotoxic soluble amyloid oligomers, which are considered pivotal drivers of Alzheimer’s disease pathology,” said John Hey, Chief Scientific Officer of Alzheon, Inc. “The consistent demonstration of Alzheimer’s positivity, early and sustained reductions in p-tau 217 , and strong correlations with cognitive, functional, and imaging outcomes highlight the importance of p-tau 217 as a marker for disease progression and treatment efficacy, particularly in patients at earlier stages of Alzheimer’s disease." About ALZ-801 Valiltramiprosate/ALZ-801 is an investigational oral agent currently in Phase 3 development as a potential first-in-class, disease-modifying treatment for Alzheimer’s disease. 3-7,9,12 Valiltramiprosate is designed to inhibit the formation of neurotoxic soluble beta amyloid oligomers that contribute to cognitive decline in individuals with AD. 4-8,10,15 Preclinical mechanism-of-action studies have demonstrated that ALZ-801 can completely block the formation of these neurotoxic oligomers at the dosage used in Phase 3 clinical trials. 3,9,12,14 Valiltramiprosate employs an enveloping molecular mechanism of action intended to prevent the aggregation of soluble amyloid oligomers in the human brain, 14 which are associated with the onset and progression of cognitive impairment in AD patients. 3,4,7,9,10 In recognition of its therapeutic promise, valiltramiprosate received Fast Track designation from the U.S. Food and Drug Administration in 2017 for the treatment of Alzheimer’s disease. Clinical trial data indicate that valiltramiprosate exhibits strong clinical efficacy at the MCI stage, and a favorable safety profile, with no observed increase in the risk of brain vasogenic edema. 5-1-10,13,15 The initial Phase 3 program for valiltramiprosate targets Early AD patients who are homozygous for the apolipoprotein ε4 allele (APOE4/4), with plans to expand future research to include AD treatment and prevention in individuals carrying one copy of the APOE4 gene. 3–10 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 (Phase 3 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 was the change from baseline in plasma p-tau 181 . The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic pro valiltramiprosate over 104 weeks of treatment. A completed long-term extension of the trial evaluated the same dose of valiltramiprosate for an additional 104 weeks of treatment for a total of 208 weeks. 3,7,8 About Alzheon Alzheon, Inc. is a clinical-stage biopharmaceutical company dedicated to advancing a diverse portfolio of product candidates and diagnostic assays for individuals affected by Alzheimer’s disease and other neurodegenerative disorders. The company is focused on innovating therapeutic solutions that directly target the underlying pathology of neurodegeneration. Its lead Alzheimer's clinical candidate, valiltramiprosate/ALZ-801 , is a first-in-class oral agent currently in Phase 3 clinical development as a potentially disease-modifying treatment for Alzheimer’s disease. Valiltramiprosate is an orally administered small molecule shown in preclinical studies to completely inhibit the formation of neurotoxic soluble amyloid oligomers. Leveraging clinical expertise and a robust technology platform, Alzheon pursues drug discovery and development using a precision medicine approach that incorporates individual genetic and biomarker pro aiming to advance therapies with meaningful benefits for patients. Alzheon Scientific Publications 1 Abushakra S, et al: Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer’s Disease: Synthesis of Evidence from Observational and Interventional Trials, Drugs 2026;40(2):199-214. 2 Abushakra S, et al: Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer’s Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial , Drugs 2025; 85, 1455-1472. 3 Pearson 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; 55, 206-215. 4 Hey 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; 64, 407-424. 5 Aye 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. 6 Abushakra S, et al: APOLLOE4 Phase 3 Study of Oral ALZ-801/Valiltramiprosate in APOE ε 4/ ε 4 Homozygotes with Early Alzheimer’s Disease: Trial Design and Baseline Characteristics, Alzheimer’s & Dementia 2024; 10(3): e12498. 7 Tolar 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. 8 Hey 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. 9 Hey 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. 10 Tolar 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. 11 Abushakra 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. 12 Tolar 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. 13 Tolar M, et al: The Path Forward in Alzheimer’s Disease Therapeutics: Reevaluating the Amyloid Cascade Hypothesis , Alzheimer’s & Dementia 2020; 16(11):1553-1560. 14 Hey 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. 15 Hey 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. 16 Abushakra 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. 17 Kocis P, et al: Elucidating the A β 42 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. 18 Abushakra 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. Contacts Media Contact Yasemin Khakian, Alzheon, Inc. 508.808.2301 yasemin.khakian@alzheon.com Investor Contact Erwan de Naurois, Alzheon, Inc. 802.735.8789 erwan.denaurois@alzheon.com

临床2期临床结果临床3期快速通道

2026-01-31

·今日头条

润佳医药RP902进入临床三期：国产首款口服Aβ抑制

关键词：阿尔茨海默病、RP902、口服小分子药物、β淀粉样蛋白、神经毒性寡聚体 Keywords: Alzheimer's Disease, RP902, oral small molecule drug, Amyloid-β, neurotoxic oligomers 新闻发生时间： 2022年12月28日（临床试验获批）；2025年（进入临床三期）润佳（苏州）医药科技有限公司自主研发的1类化药RP902片在阿尔茨海默病（AD）治疗领域取得重要进展[1]。该药物于2022年12月28日获得中国国家药品监督管理局（NMPA）临床试验批准通知书，成为我国首个进入临床试验的小分子Aβ抑制剂[2]。根据最新数据，RP902目前已推进至临床三期阶段，为中国约1000万AD患者带来了全新的口服治疗选择。 RP902是一款采用氘代技术的稳定同位素取代小分子创新药，其核心机制是通过靶向β淀粉样蛋白（Aβ），显著抑制大脑中与AD患者认知功能下降直接相关的神经毒性可溶性淀粉样蛋白寡聚体的形成[3]。与目前市场上主要依赖静脉注射的单克隆抗体药物不同，RP902以口服给药的便捷方式在淀粉样蛋白级联反应的上游发挥作用，能够有效保护脑血管及血脑屏障。临床前药效学研究数据显示，RP902在APP/PS1转基因AD模型小鼠中表现出显著疗效，能够改善形象识别记忆、空间记忆和长期记忆障碍，同时改善模型小鼠海马及大脑皮层神经细胞及树突损伤、提高突触可塑性，并降低模型小鼠海马及大脑皮层可溶性和不溶性Aβ1-40/1-42水平[4]。在研发进程方面，润佳医药于2022年3月完成1a期临床试验，并于2022年12月注册了1b期临床试验[5]。进入临床三期后，RP902的研发进展引起业界广泛关注。与国际同类药物ALZ-801相比，RP902在作用机制上具有相似性，但作为国产创新药，其研发突破为中国AD治疗领域填补了小分子口服药物的空白。目前，我国AD治疗市场仍以胆碱酯酶抑制剂等传统药物为主，这些药物普遍只能短期控制症状，难以针对病因机制延缓疾病进程。随着礼来、卫材等跨国药企的单抗类药物陆续获批，以及RP902等国产创新药的临床推进，中国AD患者正迎来更多元化的治疗选择。相关内容： 2022年12月28日，润佳（苏州）医药科技有限公司宣布其自主研发的RP902片临床试验申请获得NMPA批准，该药物作为针对Aβ的小分子口服药，拟用于阿尔茨海默病的治疗[1]。此后，RP902顺利完成早期临床试验，并持续推进至临床三期阶段。 2025年1月，业界分析报告《从ALZ-801到RP902：口服Aβ抑制剂如何重塑阿尔茨海默病治疗格局》指出，RP902在临床前研究中表现出改善多种记忆认知障碍、减少脑内Aβ沉积、保护神经元及突触结构的明确效果，临床进展稳健[6]。相关介绍：润佳（苏州）医药科技有限公司是润佳（上海）医药科技股份有限公司的全资子公司，专注于退行性疾病治疗领域的创新药物研发。公司集团至今已转化新药研发管线20余项，重点关注退行性疾病、小核酸药物和感染领域，多个药物管线处于关键性临床试验阶段[7]。参考文献 [1] 润佳医药RP902（靶向Aβ）临床试验申请获得中国NMPA批准. http://www.risen-pharma.com/news_info/id-18.html [2] 12款阿尔茨海默病在研新药正在中国开展临床！来自礼来、强生. https://www.phirda.com/artilce_36376.html?module=trackingCodeGenerator [3] 阿尔茨海默病"突围"：口服Aβ抑制剂，下一个潜力破局者. https://www.163.com/dy/article/JVU55NH30534Q32Z.html [4] 临床开发 - 润佳医药. http://www.risen-pharma.com/clinical.html [5] 百健/卫材第二款新药获批礼来(LLY.US)新药被拒AD药物. https://finance.sina.cn/hkstock/ggyw/2023-02-12/detail-imyfmats5720334.d.html [6] 从ALZ-801到RP902：口服Aβ抑制剂如何重塑阿尔茨海默病治疗格局. https://news.qq.com/rain/a/20260112A068NR00 [7] 关于润佳 - 润佳医药. http://www.risen-pharma.com/about.html 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

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 (APOLLOE4, CTgov)	临床3期	阿尔茨海默症	325	Placebo Comparator: Placebo (Placebo)	鹹願鏇壓艱範壓獵範鏇(衊築構鑰襯觸衊鬱蓋遞) = 淵糧鏇選膚衊獵選獵醖艱廠網齋襯製廠積願願 (築壓襯廠淵簾構鬱鏇餘, 0.69) 更多	-	2025-11-10
				Placebo Comparator: Placebo+Experimental: ALZ-801 (ALZ-801)	鹹願鏇壓艱範壓獵範鏇(衊築構鑰襯觸衊鬱蓋遞) = 積鏇願顧築構淵夢醖襯艱廠網齋襯製廠積願願 (築壓襯廠淵簾構鬱鏇餘, 0.69) 更多
NCT04770220 (APOLLOE4, Pubmed \| Drugs)	临床3期	阿尔茨海默症	325	Valiltramiprosate	衊鹽鬱積餘觸獵選鏇艱(襯糧築鏇願醖鏇淵選餘): P-Value = 0.607 更多	积极	2025-11-01
				Placebo
NCT04770220 (Company_Website) 人工标引	临床3期	阿尔茨海默症 APOE4/4 homozygotes	325	valiltramiprosate	夢鬱鹽願積糧夢淵醖鏇(夢醖艱淵淵艱簾網願襯): Difference (LS Mean) = -0.504, P-Value = 0.607 未达到更多	不佳	2025-04-10
				Placebo
AAIC2024	临床2期	阿尔茨海默症 Aβ42 \| p-tau181	70	ALZ-801 265 mg BID	網繭襯衊鑰繭簾簾鑰襯(積觸窪餘觸糧鹹簾網顧) = 廠憲鏇鑰艱艱窪範鏇鬱鹽築淵鑰積選窪網願製 (淵淵廠衊鏇積選壓網窪 )	积极	2024-07-28
NCT04693520 (phase 2, Pubmed \| Drugs)	临床2期	阿尔茨海默症 plasma Aβ42	84	ALZ-801 265 mg tablet	窪構淵醖範簾蓋範艱鑰(積鑰願鏇憲範願鑰夢艱) = 顧遞窪鏇壓膚遞夢鑰鬱獵鏇遞膚選醖窪廠願廠 (鑰獵艱觸願淵簾淵選網 )	积极	2024-07-01
NCT04693520 (Biospace) 人工标引	临床2期	阿尔茨海默症	84	ALZ-801/Valiltramiprosate 265 mg	獵淵鑰顧壓簾觸衊艱積(夢繭膚餘遞觸繭簾繭獵) = 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. 糧憲醖遞繭鹽鹹簾艱糧 (窪獵窪鏇鑰夢衊觸鹽淵 )	积极	2024-06-25
CTAD2023	临床2期	阿尔茨海默症 p-tau181 \| Aβ42 \| Aβ40	84	ALZ-801 265 mg BID	壓齋憲觸範積鬱網製遞(餘觸夢簾襯構選糧淵觸) = no ARIA-E to date 齋願繭願範構構鹹窪鹹 (餘選餘壓鬱憲憲積壓膚 ) 更多	积极	2023-10-24
NCT04770220 (APOLLOE4, CTAD2023)	临床3期	阿尔茨海默症 APOE4/4	325	ALZ-801	簾淵選襯網築齋鬱獵衊(衊齋築蓋鹽鬱繭觸繭醖) = 夢鹽夢壓顧窪鏇鑰觸願膚選鑰鹽衊鬱願鹹願醖 (糧構鹹衊範鬱築選艱鏇 ) 更多	积极	2023-10-24
				ALZ-801 (CAA subgroup)	簾淵選襯網築齋鬱獵衊(衊齋築蓋鹽鬱繭觸繭醖) = 選憲廠鏇餘願網餘築鑰膚選鑰鹽衊鬱願鹹願醖 (糧構鹹衊範鬱築選艱鏇 ) 更多
NCT04693520 (Corporate Publications) 人工标引	临床2期	阿尔茨海默症	75	Valiltramiprosate	淵憲餘構鹹築淵膚衊顧(夢衊觸鬱餘襯繭壓簾鹹) = 艱憲觸蓋鹽築鹽網衊膚廠願顧鹽艱齋餘蓋製膚 (淵鹹顧憲淵鏇膚積鹽範 ) 更多	积极	2022-09-20