On March 21, at the AD/PD 2026 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, during a symposium on “Advances in AD Treatment”, Alzheon presented new biomarker data for its oral anti-amyloid therapy valiltramiprosate from its Phase III APOLLOE4 (NCT04770220) trial and its Phase II Biomarker long-term extension (LTE) study (NCT04693520). At the 2025 AD/PD conference, Alzheon announced that the Phase III APOLLOE4 failed to meet its primary endpoint for early Alzheimer’s disease – mild cognitive impairment (MCI) and mild Alzheimer’s – in patients homozygous for the APOE4 gene. However, when evaluating just the prespecified MCI patient population, which accounted for 39% of the overall trial population, treatment with valiltramiprosate was found to be significantly effective over 78 weeks.
The biomarker data presented at AD/PD 2026 from the Phase III APOLLOE4 trial showed that in the MCI subgroup, treatment with valiltramiprosate resulted in a significant reduction in plasma p-tau217—a biomarker of amyloid pathology. Furthermore, this reduction in plasma p-tau217 was sustained at week 78, representing a 36% decrease from baseline in the valiltramiprosate group compared with a 17% increase in plasma p-tau217 levels in patients in the placebo group. There were also significant subject-level correlations between p-tau217 reduction and clinical benefit, as measured by Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating – Sum of Boxes (CDR-SB), as well as significant correlations between p-tau217 reduction and slowing of hippocampal volume (HV) atrophy.
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In line with the APOLLOE4 Phase III results, the Phase II LTE trial showed that in MCI APOE4 carriers, treatment with valiltramiprosate resulted in a 32% decrease in plasma p-tau at week 78 (two years) compared with baseline. This reduction in p-tau217 was sustained at four years of treatment with valiltramiprosate and correlated with clinical stability and the preservation of hippocampal brain volume.
Based on the consistent positive correlations in biomarkers and clinical outcome, Alzheon is now planning to run a confirmatory trial for valiltramiprosate in patients with MCI who are homozygous for the APOE4 gene. Alzheimer’s patients who are APOE4 homozygous typically have an earlier onset of disease that is also more likely to progress quickly, resulting in more rapid clinical decline, and they have a higher risk of developing amyloid-related imaging abnormalities (ARIAs). In some geographies, such as Europe, this means that they are not eligible for the approved anti-amyloid monoclonal antibodies. Therefore, if valiltramiprosate were to be approved, it would help meet a large unmet need for safe and effective treatments for the APOE4-homozygous subset of MCI patients, as no symptomatic ARIA has been observed in the Phase III study or Phase II LTE.
Additionally, it is widely acknowledged that the earlier Alzheimer’s is treated, the better the outcomes are. This, combined with valiltramiprosate’s favourable safety profile, mechanism of action (which acts upstream in the amyloid cascade), and oral administration, makes the drug an attractive candidate for preclinical Alzheimer’s. If the drug receives approval after the confirmatory trial in MCI, Alzheon will likely investigate valiltramiprosate as a preventive therapy in the preclinical Alzheimer’s population.
