Alzheon Reports Biomarker Findings Supporting Potential Disease-Modifying Effects of Valiltramiprosate in Early Alzheimer’s Disease
Alzheon, Inc., a clinical-stage biopharmaceutical company focused on developing investigational therapies and diagnostic assays for Alzheimer’s disease (AD) and other neurodegenerative disorders, has announced the peer-reviewed publication of new biomarker analyses evaluating its investigational oral therapy valiltramiprosate, also known as ALZ-801. The findings have been published in Drugs in an article titled “Plasma Biomarker Effects of Oral Valiltramiprosate/ALZ-801 in Early Alzheimer’s Disease from Phase 3 and Phase 2 Trials: Analysis of Core Biomarkers and Correlations with Clinical and Neuroimaging Outcomes.”
The publication brings together blood-based biomarker data from the Phase 3 APOLLOE4 trial and four-year fluid biomarker findings from a Phase 2, single-arm, open-label study. According to Alzheon, the results provide evidence of biological activity associated with valiltramiprosate and support further investigation of the therapy as a potential disease-modifying treatment for individuals with early Alzheimer’s disease who carry the APOE4 genetic variant.
The analysis particularly examined plasma phosphorylated tau 217 (p-tau217), the plasma p-tau217/amyloid-beta 42 (Aβ42) ratio, and neurofilament light chain (NfL). These biomarkers are increasingly being investigated as minimally invasive indicators of Alzheimer’s-related pathology and neurodegeneration. The company reported that reductions in p-tau217 and the p-tau217/Aβ42 ratio were observed following treatment and were associated with clinical and neuroimaging measures.
Valiltramiprosate Targets an Early Stage of the Amyloid Cascade
Valiltramiprosate is an investigational oral small-molecule therapy designed to intervene early in the amyloid pathway associated with Alzheimer’s disease. The drug is intended to inhibit the formation of neurotoxic soluble amyloid oligomers, which are considered precursors to the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease.
By targeting soluble amyloid oligomers before they aggregate and contribute to plaque deposition, valiltramiprosate is designed to act upstream in the disease process. The therapeutic strategy is intended to potentially reduce downstream pathological processes, including tau hyperphosphorylation and neurodegeneration.
The newly published analysis was designed to determine whether these biological effects could be detected using blood-based biomarkers and whether changes in biomarkers were associated with clinical outcomes and changes in brain structure.
Data from the Phase 3 APOLLOE4 study focused on individuals who were homozygous for APOE4, meaning they carry two copies of the APOE4 allele. The analysis also incorporated biomarker findings from a Phase 2 study involving both APOE4 homozygotes and heterozygotes.
According to Alzheon, the combined findings provide evidence that the biological effects associated with valiltramiprosate can be detected through blood testing and may align with changes in cognition, functional status, and brain volume.
Phase 3 APOLLOE4 Trial Demonstrates Reductions in Plasma p-tau217
In the overall Phase 3 population, baseline plasma p-tau217 levels were comparable between participants receiving valiltramiprosate and those receiving placebo. Following treatment, however, plasma p-tau217 levels were significantly lower among patients treated with valiltramiprosate at Weeks 26, 52, and 78, with all reported p-values below 0.025.
The findings were particularly notable in the pre-specified subgroup of patients with mild cognitive impairment (MCI). In this group, p-tau217 levels were significantly reduced at Weeks 52 and 78, with p-values below 0.05. The subgroup of patients with mild Alzheimer’s disease also showed a numerical trend toward lower p-tau217 levels, although the effect was less pronounced.
The company said the findings are relevant because plasma p-tau217 is increasingly recognized as a biomarker associated with Alzheimer’s pathology, particularly processes involving abnormal tau phosphorylation.
The study also evaluated relationships between baseline p-tau217 levels and measures of disease severity among Phase 3 participants with MCI. Baseline p-tau217 was significantly correlated with several clinical and neuroimaging measures.
For example, baseline p-tau217 correlated positively with the Clinical Dementia Rating-Sum of Boxes (CDR-SB), with a correlation coefficient of 0.403 and a p-value of 0.002. Higher plasma p-tau217 was also associated with smaller hippocampal volume, reflected by a correlation coefficient of -0.393 and a p-value of 0.002.
A stronger inverse correlation was observed between p-tau217 and cortical thickness, with a correlation coefficient of -0.601 and a p-value below 0.0001. These findings suggest an association between higher circulating p-tau217 levels and greater measures of disease-related brain changes.
Biomarker Changes Associated With Cognitive and Brain Outcomes
The analysis also examined whether reductions in plasma p-tau217 during treatment were associated with clinical and neuroimaging outcomes.
Among participants receiving valiltramiprosate, reductions in p-tau217 at Week 78 were significantly correlated with less cognitive decline as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, 13-item version (ADAS-Cog13). The reported correlation coefficient was 0.276, with a p-value of 0.039.
Reductions in p-tau217 were also correlated with less worsening in CDR-SB, with a correlation coefficient of 0.377 and a p-value of 0.005. In addition, p-tau217 reductions were associated with less hippocampal atrophy, with a correlation coefficient of -0.353 and a p-value of 0.013.
These relationships are important because they connect a biological marker measured in blood with clinical and structural measures of Alzheimer’s disease progression. While biomarker associations do not independently establish clinical efficacy or disease modification, they may provide additional evidence about the biological activity of an investigational treatment.
NfL Findings Provide Additional Evidence of Reduced Neurodegeneration
The publication also reported findings involving plasma neurofilament light chain, or NfL. NfL is a biomarker associated with neuronal injury and neurodegeneration and can be measured through blood testing.
In MCI participants in the Phase 3 study, plasma NfL was significantly lower in the valiltramiprosate group compared with placebo at Week 78. The reported p-value was 0.032.
NfL levels were also correlated with cognitive outcomes. The analysis reported a correlation coefficient of 0.29 between NfL values and cognitive improvement, with a p-value of 0.03. In addition, NfL was correlated with reductions in p-tau217, with a correlation coefficient of 0.42 and a p-value of 0.001.
According to Alzheon, plasma NfL remained relatively stable over the 78-week treatment period among participants receiving valiltramiprosate, while NfL increased progressively among patients receiving placebo. The company views this pattern as further evidence supporting the potential of valiltramiprosate to influence processes associated with neurodegeneration.
Potential Importance for APOE4 Carriers
A major focus of the development program is Alzheimer’s disease patients carrying the APOE4 genetic variant. APOE4 is the strongest common genetic risk factor for late-onset Alzheimer’s disease, and individuals carrying two copies of the variant, known as APOE4/4 homozygotes, have particularly high genetic risk.
Alzheon estimates that approximately 15% of people with Alzheimer’s disease are APOE4/4 homozygotes. This population also faces particular challenges with currently approved amyloid-targeting antibody therapies, including an increased risk of amyloid-related imaging abnormalities, or ARIA.
The company believes an oral therapy designed to target amyloid pathology upstream could potentially provide an alternative treatment approach for APOE4 carriers. The biomarker findings reported in the new publication are intended to strengthen the biological rationale for continued development in this population.
Long-Term Phase 2 Findings Add to the Evidence Base
In addition to the Phase 3 results, the publication includes four-year fluid biomarker data from a Phase 2 study. The study was single-arm and open-label and included APOE4 homozygotes and heterozygotes.
The longer-term data are important because Alzheimer’s disease is a chronic, progressive disorder, meaning that sustained biological effects may be relevant when evaluating potential disease-modifying therapies.
Alzheon said that the consistency and durability of biomarker effects observed in its Phase 2 and Phase 3 programs support further investigation of valiltramiprosate. The company is particularly interested in the continued reduction of p-tau217 and the relationship between biomarker changes and clinical and neuroimaging outcomes.
Expert Perspective on Blood-Based Biomarkers
Anton P. Porsteinsson, MD, Director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester School of Medicine and Dentistry, highlighted the potential importance of using accessible blood-based biomarkers to evaluate treatment effects in Alzheimer’s disease.
According to Porsteinsson, the consistency of the biomarker signal in patients with MCI was notable, particularly because reductions in plasma p-tau217 were associated with cognitive, functional, and brain-volume outcomes and remained evident over time.
Blood-based biomarkers could potentially become increasingly useful in Alzheimer’s research and clinical development because they are less invasive and generally easier to obtain than some traditional approaches to assessing disease pathology. They may help researchers determine whether an investigational therapy is engaging its intended biological target and monitor changes during treatment.
Company Plans Further Development of Valiltramiprosate
Martin Tolar, founder, president, and CEO of Alzheon, said the company’s findings position valiltramiprosate among late-stage Alzheimer’s disease treatments with the potential to influence future therapeutic approaches.
The company is now moving forward with plans for another Phase 3 study based on analyses from the APOLLOE4 Phase 3 trial and its long-term extension. At the same time, Alzheon plans to expand the broader valiltramiprosate platform, develop additional drug candidates, and investigate other patient populations.
John A. Hey, PhD, chief scientific officer of Alzheon and lead author of the publication, said the findings provide biological evidence consistent with the proposed mechanism of action of valiltramiprosate. He emphasized the reductions in plasma p-tau217, the relationship between biomarker changes and clinical and MRI outcomes, and the stability of NfL during treatment.
The company believes that the combined Phase 2 and Phase 3 findings support continued investigation of valiltramiprosate in APOE4 carriers with early Alzheimer’s disease, particularly those with MCI.
Overall, the newly published research adds to Alzheon’s growing body of clinical and biomarker data surrounding valiltramiprosate. The observed reductions in p-tau217 and NfL, together with reported correlations between biomarker changes and cognitive, functional, and brain-volume measures, provide additional biological evidence for the therapy’s continued clinical development. Further Phase 3 evaluation will be needed to determine whether these biomarker effects translate into meaningful and durable clinical benefits for people living with early 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.4-8,10,13 Valiltramiprosate is designed to inhibit the formation of neurotoxic soluble beta amyloid oligomers that contribute to cognitive decline in individuals with AD.5-9,11,16 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.4,10,13,15
Valiltramiprosate employs an enveloping molecular mechanism of action intended to prevent the aggregation of soluble amyloid oligomers in the human brain,15 which are associated with the onset and progression of cognitive impairment in AD patients.4,5,8,10,11 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.2-11,14,16 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.4–11
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-tau181. The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic profile of 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. 4,8,9
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 profiles, aiming to advance therapies with meaningful benefits for patients.