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 ; Ritchie, Craig ; Durrant, Abe ; Doraiswamy, P Murali ; McLaine, Rosalind ; McSweeney, Emer ; Schaefer, Jean F ; Tolar, Martin ; Sabbagh, Marwan ; Abushakra, Susan ; 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

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

Article

作者: Tolar, Martin ; Doraiswamy, P. Murali ; Abushakra, Susan ; Tosun, Duygu ; Rosenthal, Arthur ; Kesslak, Patrick ; Ingalhalikar, Madhura ; Albayrak, Adem ; Liang, Earvin ; Sabbagh, Marwan N. ; Watson, David ; Porsteinsson, Anton P. ; Flint, Susan ; Conklin, Chris ; Cohen, Sharon ; Hey, John A. ; MacSweeney, Emer ; Power, Aidan

Abstract:

Background:

Valiltramiprosate/ALZ‐801, an oral inhibitor of amyloid oligomer formation, was evaluated in a Phase 3 trial in APOE4/4 subjects with Early AD. While the study did not meet its primary clinical endpoint, volumetric MRI (vMRI) showed significant brain atrophy slowing. The pre‐specified MCI subgroup showed positive effects on both clinical and vMRI outcomes. Amyloid oligomers are hypothesized to cause synaptic dysfunction and axonal damage, leading to microstructural changes and volume loss. The effects of valiltramiprosate on microstructural tissue changes in grey/white matter (GM, WM) were investigated using mean water diffusivity (MD) on diffusion MRI (dMRI‐MD).

Method:

This study enrolled 325 APOE4/4 homozygotes (162 placebo, 163 valiltramirposate) stratified by MCI/Mild AD. The ADAS‐Cog13/CDR‐SB were primary/key secondary outcomes; hippocampal volume and cortical thickness (HV, CT) were main/secondary vMRI outcomes, respectively. dMRI from 1.5/3 Tesla scanners were centrally analyzed by Clario Inc. (lower MD indicates tissue preservation). MMRM was primary analysis; Pearson’s correlations were conducted.

Result:

The clinical/vMRI datasets included 320/290 subjects respectively; dMRI included 206 subjects (84 MCI, 122 Mild AD). In the overall population, valiltramiprosate effects on MD compared to placebo showed positive trends ( p <0.1) on cingulate/occipital cortex and caudate/striatum, and significant WM effects (corpus callosum genu [GCC] p <0.001; fornix p =0.007). Mild AD showed positive trends on occipital cortex and significant WM effects (GCC p =0.005; fornix p =0.019). MCI showed significant effects in cingulate ( p =0.031) and WM (GCC/whole CC: p =0.003/0.013) and fornix ( p =0.032). In MCI active arm, dMRI effects correlated significantly with clinical and volumetric effects. Frontal cortex MD correlated significantly with ADAS‐Cog13/CDR‐SB ( p < 0.05) and HV and CT (both p =0.002). WM‐GCC diffusivity correlations to HV ( p =0.03) and CT were significant ( p =0.006).

Conclusion:

Consistent with valiltramiprosate’s effects on brain volumes, its effects on microstructural integrity were most prominent in the MCI subgroup that showed lower diffusivity in the cingulate cortex and major hippocampal outflow tracts. This microstructural preservation correlated significantly with preservation of HV/CT and with clinical benefits. These findings support valiltramiprosate’s proposed mechanism: inhibiting oligomer formation may directly protect synapses/axons from damage, thus slowing neurodegeneration at a microstructural level and contributing to macrostructural preservation of brain volumes and clinical benefit.

106

项与 Valiltramiprosate 相关的新闻（医药）

2026-04-07

·BioSpace

Alzheon Advances Industry-Leading Portfolio of Oral Anti-Amyloid Aggregation Inhibitors with First Subject Dosed in Phase 1 of ALZ-507, Highlighting Potential for Once-Daily Administration, Improved Safety and Efficacy, and APOE4 Corrector Mechanism

ALZ-507 Designed as Well-Differentiated Oral Candidate Targeting Soluble Amyloid Oligomer Pathology, with Additional Mechanism of Action as APOE4 Corrector ALZ-507 IND Program Demonstrated Favorable Nonclinical Safety and Pharmacokinetic Pro Supports Once-Daily Dosing ALZ-507 Broadens Alzheon’s Proprietary Precision Medicine Therapeutic Pipeline Targeting Disease Modification in Alzheimer’s Disease 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 the dosing of the first cohort of human volunteer subjects in a Phase 1 single and multiple ascending dose clinical trial of ALZ-507, a novel investigational oral drug candidate for the treatment of Alzheimer’s disease. Martin Tolar, MD, PhD, Founder, President, and CEO of Alzheon, commented: “Dosing the first subject with ALZ-507 marks years of scientific progress at Alzheon as we deepen our understanding of Alzheimer’s disease biology. This well-differentiated next-generation Alzheimer’s drug candidate also functions as an APOE4 corrector, strengthening its anti-oligomer properties. ALZ-507 is a major step forward for Alzheon’s precision medicine platform aimed at the prevention of formation of neurotoxic soluble amyloid oligomers. With Alzheimer’s disease still representing a critical global unmet medical need, we are committed to work toward bringing to patients novel, safe, and accessible therapies that have the potential to slow disease progression.” ALZ-507 is an orally administered small molecule developed to target upstream amyloid aggregation and inhibit the formation of neurotoxic soluble amyloid oligomers, which are recognized as a key trigger and driver of Alzheimer’s disease pathology. Additionally, ALZ-507 features an APOE4 corrector mechanism of action, potentially augmenting its primary anti-oligomer pharmacological effects. Designed as a next-generation oral treatment for Alzheimer's disease, ALZ-507 may offer the advantages of once-daily dosing and improved gastrointestinal tolerability. The Phase 1 study, employing an oral capsule formulation, will assess the safety, tolerability, and pharmacokinetics in healthy volunteer participants. “The initiation of the ALZ-507 Phase 1 study with our novel oral product candidate demonstrates the capability of our development platform and our methodical approach to progressing high-quality, disease-modifying oral therapies with optimized pharmaceutical properties,” stated John Hey, PhD, Chief Scientific Officer at Alzheon. “Building on our experience with upstream inhibition of amyloid aggregation, ALZ-507 further expands our portfolio of oral treatments designed to target the main causes of neurodegeneration. Preclinical studies have shown evidence of a positive safety and pharmacokinetic profile, as well as an enhanced efficacy profile, making ALZ-507 a valuable addition to Alzheon’s portfolio of potential disease-modifying treatments for Alzheimer's disease.” The Phase 1 clinical trial will assess the safety, tolerability, and pharmacokinetics of both single and multiple ascending doses of ALZ-507. Findings from this investigation are anticipated to guide dose selection and inform formulation strategy for subsequent Phase 2 studies involving patients diagnosed with Alzheimer’s disease (AD), Down syndrome–associated AD, and cerebral amyloid angiopathy (CAA). 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. 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) A long-term extension of the trial, APOLLOE4-LTE, evaluated 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 ended in January 2026 ( 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. Its well-differentiated follow-on candidate, ALZ-507, is a once daily oral therapy designed to inhibit the formation of amyloid oligomers while also correcting the high risk APOE4 gene. 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, CNS Drugs 2026; 40, 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3期临床2期临床1期临床结果快速通道

2026-03-27

·BioSpace

Eisai, Alzheon Drill Down on Promising Results in High-Risk Alzheimer’s Subset

iStock, Nomadsoul1 At the AD/PD annual meeting, Eisai presented real-world data suggesting Leqembi’s long-term safety and efficacy in people homozygous for APOE4 , who were identified in trials as being at higher risk of brain bleeds while on the treatment. Alzheon, meanwhile, added further detail to trial results of its candidate in patients with the same genetic profile. Carrying two copies of the gene variant APOE ɛ4 has long been linked to an increased risk of developing Alzheimer’s disease. Cruelly, the same genetic pro associated with brain bleed events known as ARIA-H and ARIA-E in trials of Biogen and Eisai’s Leqembi, and some regulators, including the European Medicines Agency, have carved out APOE ɛ4 homozygotes as ineligible for the groundbreaking anti-amyloid therapy. Armed with real-world data, Eisai made a case earlier this month at the AD/PD annual meeting in Copenhagen that most of these treatment-associated bleeds in people with two copies of APOE4 (defined as homozygous) were not as common as in earlier trial data, and that the risk dropped off after six months of treatment. Moreover, most people did not experience disease progression over the course of the study. Meanwhile, Alzheon, which rolled out topline results at the same meeting last year showing that its candidate, valiltramiprosate, missed its primary endpoint in a Phase 3 trial that enrolled people homozygous for APOE4 , was back this year with more details on that study as well as a new data from a Phase 2 trial. Alzheon presented biomarker and brain imaging data to bolster positive results on a cognitive assessment for patients who enrolled in the study with mild cognitive impairment (MCI) rather than later in the course of the disease. “The conference had a significant focus on biomarkers, and there [have] been such tremendous advances that these biomarkers are really allowing us to understand the underlying biology of the patients that we’re trying to treat with therapies,” Aaron Burstein, head of search and evaluation at the Alzheimer’s Drug Discovery Foundation, told BioSpace . Eisai’s data was “very encouraging” and “provides additional support for the potential use of these agents in the APOE4 carrier status as was approved by FDA,” he said. As for Alzheon’s results, Burstein said the biomarker data “provided support that the hypothesized clinical benefits they were seeing were associated with measures consistent with actually having effects on the underlying biological processes.” Genes and Brain Bleeds Approved by the FDA in July 2023, Leqembi carries a black-box warning noting that APOE4 homozygotes have a higher risk of amyloid-related imaging abnormalities (ARIA) when treated with this class of medication and recommending that providers genetically test patients before prescribing it. “Consider the benefit for the treatment of Alzheimer’s disease and risk of ARIA when deciding to treat with LEQEMBI.,” the warning states. An analysis of the Phase 3 trial results found that people homozygous for APOE4 had a 45% chance of developing ARIA-E when taking Leqembi, compared with 13% for noncarriers and 19% for patients heterozygous for the variant. This is thought to be because APOE4 is associated with a greater buildup of amyloid proteins near the blood vessel walls, and when that buildup is removed, “sometimes there’s this leakage that occurs,” explained Lynn Kramer, Eisai’s chief clinical officer. In the real-world analysis, which included the records of 207 patients at sites across the U.S., the increased risk was less stark than in the trial: 21.2% of APOE4 homozygotes developed ARIA, versus 13.7% of noncarriers. All but one of the cases in each group were asymptomatic. On the benefits side of the equation, 76% of people with two copies of APOE4 were at the same or an improved disease stage at the final follow-up compared to when they began treatment. On average, patients were followed for 491 days. Kramer noted that relative to the pivotal trial, homozygous patients in the real-world analysis were, on average, enrolled at a later disease stage. “Our thinking is they should be treated earlier like everybody else if you want to get maximum benefit,” he told BioSpace . “But I think this type of information makes physicians maybe more comfortable in understanding the risks so that they start treating the patients a little sooner.” In addition, he said, the company intends to continue collecting real-world data in hopes of eventually getting labels changed in countries that don’t include APOE4 -homozygous patients in their drug authorizations. In an extension of Leqembi’s Phase 3 trial, Eisai has seen the difference in disease stage between treated people and matched external controls widen over time, Kramer added. And “after the first six months or so, these ARIA events just occur at the same frequency as they would in the [external control] group. . . . So the risk is really at the beginning. . . . That’s why the benefit improvement is important.” Toward a Precision Approach The fact that Alzheon focused on APOE4 carriers in its own trials is no accident. Under its original sponsor, NeuroChem, tramiprosate did not have statistically significant effects in patients with Alzheimer’s in a clinical trial and was put on ice. But posthoc analysis indicated the modified amino acid had benefited participants homozygous for APOE4 , said John Hey, chief scientific officer at Alzheon. The startup licensed the drug from NeuroChem and is developing a prodrug version, valiltramiprosate, specifically in that population. Apart from the drug’s biological effects, an additional reason for focusing on APOE4 homozygotes first, Hey said, is their higher unmet need due to restrictions and warnings around Leqembi’s use. Among the new results presented at AD/PD, Burstein singled out those showing a sustained reduction in levels of p-tau-217, a biomarker associated with amyloid pathology, as particularly interesting. Patients with MCI in the Phase 2 study have shown a drop in levels of the biomarker compared with baseline that has lasted through four years of follow-up, according to Hey’s presentation. That reduction correlated with clinical measures. Speaking with BioSpace , Hey highlighted the safety results of the Phase 3 study, which found no difference in ARIA-E rates for the drug versus placebo. For ARIA-H, rates were actually lower in the treatment group. Valiltramiprosate acts to block the formation of toxic aggregates in the brain, and “if you prevent that neurotoxic wave in the neurodegeneration and the sequelae of events that lead to the inflammatory milieu that leads to ARIA . . . you get a benefit on neurovascular outcomes,” Hey suggested. The next steps for Alzheon, he said, will be to conduct confirmatory studies in APOE4 homozygous and heterozygous patients with MCI. Ultimately, he sees the drug being used for patients when they first begin to show symptoms—or even before—in order to glean maximum benefit from treatment. “I think as we see the advent of the fluid biomarkers, those will be used increasingly for diagnostic and for precision treatment to give some tools for the physician on how to treat these subjects,” Hey said.

临床结果临床3期临床2期上市批准

2026-03-16

·温老李Eason

神经内科·阿尔茨海默病｜2026-03-16

阿尔茨海默病前沿速递｜2026-03-6 🧠 每日精选神经内科阿尔茨海默病领域最新研究动态，助您把握前沿进展 📖 本期目录 CAR-星形胶质细胞疗法：单次注射清除AD淀粉样斑块 - Science (IF=44.7)AI揭示AD基因"沉默子"破坏机制 - Science Advances (IF=13.6)AD制药行业管线全景分析 - npj Drug Discovery血液"分子时钟"可预测AD症状出现时间 - Nature (IF=50.5)肠道菌群失调与AD神经影像学证据综述 - J Neural Transm (IF=4.5) 🔬 01 CAR-星形胶质细胞疗法：单次注射清除AD淀粉样斑块期刊： Science (IF=44.7) 发表日期： 2026年3月5日 📌 研究亮点华盛顿大学医学院研究团队开创性地将CAR技术应用于星形胶质细胞，开发出一次性基因疗法。在阿尔茨海默病小鼠模型中，预防性治疗组小鼠6月龄时大脑中未检测到斑块形成；治疗组（已存在斑块的小鼠）淀粉样斑块降低约50%。仅需单次注射，效果持久，无需像现有抗体药物（Lecanemab、Donanemab）那样频繁输注。 💡 为何值得关注这是继CAR-T治疗肿瘤后的又一颠覆性应用。相比需要每2-4周静脉输注的抗体药物，单次注射疗法若成功转化，将彻底改变AD治疗模式和患者依从性。研究由AD领域权威David Holtzman和Marco Colonna教授团队完成，Science正刊发表，学术与临床价值极高。 📚 参考文献 Chen Y, et al. Targeting amyloid-β pathology by chimeric antigen receptor astrocytes. Science. 2026 Mar 5. DOI: 10.1126/science.ads3972 期刊IF(2025): 44.7 | 中科院综合性期刊1区 🧬 02 AI揭示AD基因"沉默子"破坏机制期刊： Science Advances (IF=13.6) 发表日期： 2026年2月13日 PMID： 41671378 📌 研究亮点美国国立卫生研究院（NIH）研究团队开发深度学习模型TREDNet，首次系统揭示阿尔茨海默病约90%非编码区风险变异的作用机制。研究发现，SL（沉默子主导）位点变异破坏基因抑制功能，导致小胶质细胞炎症基因（如TREM2、MS4A6A、HLA-D）过度表达，这正是AD脑中炎症基因上调的根本原因。 💡 为何值得关注这项研究填补了AD遗传学领域的重大空白——90%的AD遗传风险来自非编码区，但此前机制不明。TREDNet模型提供了"从变异到功能"的解析框架，为精准医学分层和靶点发现开辟新路径。研究揭示的"沉默子破坏-炎症基因激活"机制，为抗炎治疗提供了遗传学依据。 📚 参考文献 Huang D, Ovcharenko I. Silencer variants are key drivers of gene up-regulation in Alzheimer's disease. Sci Adv. 2026 Feb 13;12(7):eadz3323. DOI: 10.1126/sciadv.adz3323 期刊IF(2025): 13.6 | PMID: 41671378 | 中科院综合性期刊1区 💊 03 AD制药行业管线全景分析期刊： npj Drug Discovery 发表日期： 2026年3月2日 📌 研究亮点这篇来自Nature子刊的系统性综述显示，AD药物研发已进入突破阶段。截至2025年8月，全球共有213种AD相关药物处于临床开发阶段（193种治疗药物+20种诊断药物）。已上市药物10种（含Lecanemab、Donanemab等），诊断药物5种。研发靶点从单一Aβ扩展至Tau、炎症/免疫通路等多元化方向。 💡 为何值得关注这是目前最全面的AD药物管线全景图，为临床医生了解治疗前景提供了权威参考。特别值得注意的是，新一代口服药物（Blarcamesine、ALZ-801）和非侵入性疗法（脑刺激、40Hz光声刺激）正在崛起，治疗格局日趋多元化。 📚 参考文献 Cheng H, Kang L, Xu Y, Tanzi RE, Zhang C, Wang C. Innovation breakthrough in the Alzheimer's disease pharmaceutical industry. npj Drug Discov. 2026 Mar 2. DOI: 10.1038/s44386-026-00044-7 期刊IF: Nature Partner Journal 新刊 ⏰ 04 血液"分子时钟"可预测AD症状出现时间期刊： Nature (IF=50.5) 发表日期： 2026年2月19日 📌 研究亮点基于血液生物标志物的新型"阿尔茨海默病时钟"不仅能预测某人是否会患病，还能估算症状何时出现。该研究为在记忆问题出现前及早干预开辟了全新可能，相关方法已发表于Nature Medicine等期刊。 💡 为何值得关注这是AD早期诊断领域的重大突破。此前，血液标志物（如p-tau217）主要用于判断"是否患病"，而本研究进一步实现了"何时发病"的时间预测。这对于AHEAD等预防性临床试验的设计和患者管理具有重要价值。 📚 参考文献 Ledford H. Blood test holds promise for predicting when Alzheimer's symptoms will start. Nature. 2026 Feb 19. DOI: 10.1038/d41586-026-00531-x 期刊IF(2025): 50.5 | 中科院综合性期刊1区 🦠 05 肠道菌群失调与AD神经影像学证据综述期刊： Journal of Neural Transmission (IF=4.5) 发表日期： 2026年3月14日 📌 研究亮点这篇发表于2026年3月14日的综述系统总结了肠道菌群失调通过脑-肠轴影响AD的神经影像学证据。PET研究显示菌群失调与神经炎症、Aβ斑块和tau蛋白缠结增加相关；MRI证实与海马萎缩、白质完整性丧失有关。部分研究表明益生菌干预可能改善认知功能。 💡 为何值得关注脑-肠轴是近年来AD研究的热点方向，但此前缺乏系统的神经影像学证据汇总。本综述整合了PET和MRI的多模态影像数据，为"肠道干预-脑部改善"提供了可视化证据链。对于临床医生理解AD的系统性病理机制具有参考价值。 📚 参考文献 Ghaeini Hesarooeyeh Z, Khalili E, Michel TM, Seyedi Vafaee M. The pathogenic role of gut microbiota dysbiosis in Alzheimer's disease: a narrative review of neuroimaging evidence. J Neural Transm. 2026 Mar 14. DOI: 10.1007/s00702-026-03126-y 期刊IF(2025): 4.5 | 中科院医学3区 📊 本日动态总结序号主题期刊 IF值 PMID 1 CAR-星形胶质细胞单次注射疗法 Science 44.7 - 2 基因沉默子破坏AI解析 Science Advances 13.6 41671378 3 AD制药管线全景分析 npj Drug Discovery 新刊 - 4 血液分子时钟预测AD发病时间 Nature 50.5 - 5 肠道菌群-AD神经影像学综述 J Neural Transm 4.5 - 📝 编辑手记本期五篇文献涵盖从基础机制到临床转化的全链条进展。Science正刊报道的CAR-星形胶质细胞疗法是继CAR-T之后的又一颠覆性创新，单次注射清除斑块的模式若能临床转化，将彻底改变AD治疗格局。Science Advances的AI深度学习模型首次解析了90%非编码区遗传风险的机制，填补了AD遗传学重大空白。Nature报道的血液分子时钟实现了从"是否患病"到"何时发病"的预测跨越，为预防性干预提供了时间窗口。每天20点，准时推送，不见不散。 🔔 关注我们获取每日神经内科前沿动态本速递由 WorkBuddy 自动抓取整理仅供学术参考，不作为临床诊疗依据

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)	夢築夢夢鏇膚網築齋選(窪膚醖選選齋構衊顧淵) = 繭襯製壓鹽鬱鑰製鹽夢網蓋蓋積鏇網膚繭積鹽 (窪蓋淵廠壓夢蓋獵窪獵, 0.69) 更多	-	2025-11-10
				Placebo Comparator: Placebo+Experimental: ALZ-801 (ALZ-801)	夢築夢夢鏇膚網築齋選(窪膚醖選選齋構衊顧淵) = 壓膚構廠構襯蓋網壓醖網蓋蓋積鏇網膚繭積鹽 (窪蓋淵廠壓夢蓋獵窪獵, 0.69) 更多
NCT04770220 (APOLLOE4, Pubmed \| Drugs)	临床3期	阿尔茨海默症	325	Valiltramiprosate	鹹鑰遞繭襯窪積憲艱衊(鹹築簾繭窪醖鹹鹹憲獵): 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	糧鹽廠鏇鹽顧繭選鹽網(遞鹽構顧廠顧鬱鹽鬱簾): 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	壓顧願夢觸衊網願築夢(艱壓築鹹鑰艱鬱蓋積遞) = 襯構選夢廠鑰範艱簾醖襯齋積繭繭選選夢積觸 (襯夢鹹齋醖壓鬱願鑰願 )	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	衊簾壓願範廠艱築構糧(簾壓繭鹽願憲鹽遞壓醖) = 製艱製廠範範糧醖壓網遞網醖餘顧簾積壓顧艱 (鹽積糧鹽衊窪觸鏇遞繭 )	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	獵蓋淵鏇襯築夢醖鬱獵(廠繭壓簾範鏇醖窪夢選) = 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. 願憲觸膚鹽積鑰顧獵積 (襯網遞壓艱選積獵憲醖 )	积极	2024-06-25
NCT04770220 (APOLLOE4, CTAD2023)	临床3期	阿尔茨海默症 APOE4/4	325	ALZ-801	構繭蓋醖範鬱網衊顧積(窪願鏇簾獵鬱淵壓範製) = 顧鹹醖鹽膚願壓淵鬱壓憲蓋製淵襯夢夢艱鑰簾 (蓋積鹽鑰膚蓋窪襯糧製 ) 更多	积极	2023-10-24
				ALZ-801 (CAA subgroup)	構繭蓋醖範鬱網衊顧積(窪願鏇簾獵鬱淵壓範製) = 簾獵衊淵築艱構窪積鹽憲蓋製淵襯夢夢艱鑰簾 (蓋積鹽鑰膚蓋窪襯糧製 ) 更多
CTAD2023	临床2期	阿尔茨海默症 p-tau181 \| Aβ42 \| Aβ40	84	ALZ-801 265 mg BID	蓋鬱鑰襯築遞願築糧構(蓋繭襯獵鬱鏇醖範構鏇) = no ARIA-E to date 壓顧繭鹽獵醖憲齋鬱願 (艱獵鏇餘膚壓襯糧齋選 ) 更多	积极	2023-10-24
NCT04693520 (Corporate Publications) 人工标引	临床2期	阿尔茨海默症	75	Valiltramiprosate	衊網製簾廠壓齋醖鬱窪(壓齋衊鏇糧鏇觸鏇鹹艱) = 餘壓廠築憲範觸醖築醖願糧鏇衊壓齋繭網積獵 (鹽艱醖繭鏇壓鹽範衊鏇 ) 更多	积极	2022-09-20