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, Journal Year: 2024, Volume and Issue: 84(7), P. 811 - 823

Published: June 20, 2024

ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in phase 2 trial APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid imaging biomarkers cognitive assessments.

Language: Английский

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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, Journal Year: 2024, Volume and Issue: 84(7), P. 825 - 839

Published: June 20, 2024

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 quantitative systems pharmacology (QSP) analysis amyloid fluid biomarkers cognitive results from 2-year ALZ-801 Phase 2 trial APOE4 carriers with AD.

Language: Английский

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dyphAI dynamic pharmacophore modeling with AI: a tool for efficient screening of new acetylcholinesterase inhibitors

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 4, 2025

Therapeutic strategies for Alzheimer’s disease (AD) often involve inhibiting acetylcholinesterase (AChE), underscoring the need novel inhibitors with high selectivity and minimal side effects. A detailed analysis of protein-ligand pharmacophore dynamics can facilitate this. In this study, we developed employed dyphAI , an innovative approach integrating machine learning models, ligand-based complex-based models into a model ensemble. This ensemble captures key interactions, including π-cation interactions Trp-86 several π-π residues Tyr-341, Tyr-337, Tyr-124, Tyr-72. The protocol identified 18 molecules from ZINC database binding energy values ranging −62 to −115 kJ/mol, suggesting their strong potential as AChE inhibitors. To further validate predictions, nine were acquired tested inhibitory activity against human AChE. Experimental results revealed that molecules, 4 (P-1894047), its complex multi-ring structure numerous hydrogen bond acceptors, 7 (P-2652815), characterized by flexible, polar framework ten donors exhibited IC₅₀ lower than or equal control (galantamine), indicating potent activity. Similarly, 5 (P-1205609), 6 (P-1206762), 8 (P-2026435), 9 (P-533735) also demonstrated inhibition. contrast, molecule 3 (P-617769798) showed higher IC 50 value, 1 (P-14421887) 2 (P-25746649) yielded inconsistent results, likely due solubility issues in experimental setup. These findings underscore value computational predictions validation, enhancing reliability virtual screening discovery enzyme

Language: Английский

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Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer’s Disease

Clinical Pharmacokinetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Language: Английский

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Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer’s Disease: A Narrative Review

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 229 - 229

Published: Feb. 6, 2025

The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer’s disease (AD) is a complex area study. Aging primary risk factor for AD, it associated with decline in function. This dysfunction believed to contribute neurodegenerative processes observed AD. Neurodegeneration AD characterized by progressive loss synapses neurons, particularly regions brain involved memory cognition. It hypothesized that plays pivotal role disrupting cellular energy metabolism increasing production reactive oxygen species (ROS), which can damage components exacerbate neuronal loss. Despite extensive research, precise molecular pathways linking pathology are not fully understood. Various hypotheses have been proposed, including cascade hypothesis, suggests an early event pathogenesis triggers events leading neurodegeneration. With this narrative review, we aim summarize some specific issues literature on mitochondria their involvement onset, focus development therapeutical strategies targeting environment potential application treatment itself.

Language: Английский

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ALZ‐801 prevents amyloid β‐protein assembly and reduces cytotoxicity: A preclinical experimental study

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(3)

Published: Feb. 8, 2025

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in brain. Numerous new agents are currently undergoing clinical trials as disease-modifying therapies (DMTs) targeting Aβ. ALZ-801 a promising candidate DMT for AD, with phase 3 trial of ongoing specifically apolipoprotein E (APOE) ε4 homozygous patients early-stage AD. This study aimed to examine effects on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays two imaging modalities-transmission electron microscopy (TEM) high-speed atomic force (HS-AFM)-were used evaluate ALZ-801's assembly. To assess effect Aβ42-induced cytotoxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) lactate dehydrogenase (LDH) were performed. ThT revealed increased lag time decreased fluorescence presence ALZ-801, confirming inhibition Aβ42 fibril formation, confirmed TEM. Real-time observation using HS-AFM that inhibited formation from low-molecular-weight (LMW)-Aβ42 seeds. also globular aggregates LMW-Aβ42 significantly larger few fibrils noted. MTT LDH indicated prevented LMW-Aβ42-induced cytotoxicity but did not reduce induced high-molecular-weight-Aβ42. can inhibit aggregation preventing both nucleus elongation, while promoting large oligomer cytotoxicity. These findings underscore potential an effective APOE

Language: Английский

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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, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

Language: Английский

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A review: From old drugs to new solutions: The role of repositioning in alzheimer’s disease treatment

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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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 Translational Research & Clinical Interventions, Journal Year: 2024, Volume and Issue: 10(3)

Published: July 1, 2024

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 beta oligomer inhibitor is being evaluated homozygotes with AD. METHODS This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. powered detect 2.0 2.5 drug–placebo difference on Disease Assessment Scale 13‐item Cognitive subscale primary outcome 150 subjects/arm. key secondary outcomes Rating–Sum Boxes Instrumental Activities Daily Living; volumetric magnetic resonance fluid biomarkers additional outcomes. RESULTS APOLLOE4 trial 325 subjects mean age 69 years, 51% female, MMSE 25.6, 65% mild cognitive impairment. Topline results expected 2024. DISCUSSION first disease‐modification AD focused Oral has potential be effective safe anti‐amyloid treatment high‐risk population. Highlights 3, designed evaluate efficacy safety genotype. population N = 325) females, majority impairment subjects, similar stage lecanemab (Clarity AD). subscale, two functional measures (Clinical Boxes, Amsterdam‐Instrumental Living), hippocampal volume unique allowing large number microhemorrhages siderosis at baseline imaging, lesions indicate concomitant cerebral angiopathy (CAA). At baseline, 32% had least 1 microhemorrhage, 24% 4, 8% > 4 microhemorrhages; 10% lesion; more males than females having (63% vs. 37%) (68% 32%). Study will become available second half 2024 and, if positive, may drug demonstrate favorable benefit/risk profile subjects.

Language: Английский

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Effects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: Nov. 25, 2024

Sarcopenia and AD are both classic degenerative diseases, there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying biology commonality have not yet been thoroughly investigated. APP a membrane protein that expressed in tissues only nervous system but also NMJ muscle. Deposition its proteolytic cleavage product, Aβ, has described as central component pathogenesis. Recent studies shown excessive accumulation aberrant expression muscle lead to pathological lesions, pathogenic mechanism by which products act skeletal less well understood. By summarizing analyzing literature concerning role, pathogenicity muscles, we aimed explore intrinsic myocerebral comorbidities provide new perspectives theoretical foundations for prevention treatment sarcopenia comorbidities.

Language: Английский

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