Biomarker Data Across Studies Support Disease-Targeted Effects of Valiltramiprosate

Newly reported biomarker analyses from previously completed phase 2 (NCT04693520) and phase 3 (NCT04770220) studies showed that treatment with investigational valiltramiprosate (Alzheon), an oral brain-penetrant amyloid-oligomer inhibitor, led to consistent effects on Alzheimer disease (AD)-related biomarkers like phosphorylated tau 217 (p-tau) among others. Alzheon is expected to begin another phase 3 study in 2026 to further test the promise of valiltramiprosate as a treatment for early-stage AD.¹

The first trial, a phase 2 study completed in late 2024, originally enrolled 84 patients with early-stage AD who had at least 1 copy of the apolipoprotein e4 allele (APOE4 carrier), while the phase 3 study, dubbed APOLLOE4, included 325 patients with who were APOE4/4 homozygous. Across the phase 2 and phase 3 studies, 94% to 97% of participants met AD positivity criteria, indicating strong enrichment for amyloid-driven disease across both studies.

In the newly released biomarker results, the greatest effects were seen in those in the mild cognitive impairment (MCI) stage, similar to the original data released in early 2025. Among those with MCI, investigators recorded a 17% increase in p-tau217 among placebo-treated participants over the 78-week treatment period whereas those on valiltramiprosate demonstrated approximate decreases of 36%. More notably, decreases in p-tau217 within this subgroup translated to benefits on a number of clinical outcomes, including ADAS-Cog scale (r = 0.28; P = .039), Clinical Dementia Rating-Sum of Boxes (r = 0.38; P = .005), as well as protection of hippocampal volume (r = 0.35; P = .013).

“Valiltramiprosate has emerged as the only late-stage oral treatment with a potential to materially change the Alzheimer 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,” Martin Tolar, founder, president, and chief executive officer at Alzheon, said in a statement.¹

Tolar added, “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.”

In the original data release of APOLLOE4, presented at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Disease, valiltramiprosate did not meet its primary end point of change in ADAS-Cog13, but did show prominent benefits in the prespecified MCI population.² Within this group, there was a nominally significant 52% benefit on ADAS-Cog13 and a 102% improvement in CDR-SB. For comparison, in the full analysis set comprising both MCI and mild AD, treatment with the agent led to an 11% slowing in ADAS-Cog13 (P = .607), 23% slowing on CDR-SB, 29% slowing on Disability Assessment for Dementia, and 17% slowing on Mini-Mental State Exam (P = .454).

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In the latest pooled data release, baseline plasma p-tau217 levels showed strong correlations with both clinical and neuroimaging outcomes across the phase 3 study, supporting the link between valiltramiprosate benefit and treatment at the appropriate disease stage. In the phase 3 MCI cohort treated with valiltramiprosate, baseline p-tau217 was significantly associated 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); similar significant correlations were also observed in the overall phase 3 population, including both active and placebo groups.¹

“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,” John Hey, MD, PhD, chief scientific officer at Alzheon, said in a statement.¹ “The consistent demonstration of Alzheimer positivity, early and sustained reductions in p-tau217, and strong correlations with cognitive, functional, and imaging outcomes highlight the importance of p-tau217 as a marker for disease progression and treatment efficacy, particularly in patients at earlier stages of Alzheimer disease.”

The previously completed phase 2 study comprised mostly those with MCI (70%), using change in plasma p-tau181 as the primary outcome. Among 70 patients who completed the 104-week treatment period, findings revealed a 31%-43% decrease in plasma p-tau181 over weeks 52-104 and a 4% decrease in amyloid-ß42 levels. In addition, cognitive stabilization, maintained in 50% and 33% of patients with MCI and mild AD, respectively, correlated with decreased hippocampal atrophy (Spearman’s r = 0.38-0.43; P <.002) and cortical thinning (r = 0.35-0.58; P ≤.004).³

REFERENCES
1. 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. News release. Alzheon. February 3, 2026. Accessed February 3, 2026. https://www.businesswire.com/news/home/20260203941149/en/Alzheon-Reports-Plasma-Biomarker-Results-from-Phase-3-and-2-Studies-of-ValiltramiprosateALZ-801-Validating-Its-First-in-Class-Mechanism-of-Action-and-Underscoring-Benefits-in-Cognition-Function-and-Brain-Volume-Protection-in-Alzheimers-Patients
2. Inhibition of beta amyloid oligomer neurotoxicity with oral valiltramiprosate/ALZ-801 in APOE e4/e4 homozygotes with early Alzheimer disease. Presented at: 2025 AD/PD Annual Meeting.
3. Kesslak JP, Hey JA, Abushakra S, et al. Positive disease modifying effects of oral ALZ-801 on plasma biomarkers, volumetric MRI and cognition at 104 weeks: results of a phase 2 study of APOE4 carriers with early Alzheimer’s disease. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract ES1-001