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

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with few treatment options, especially for APOE4/4 homozygotes who carry high genetic risk. Valiltramiprosate/ALZ-801 is an oral small-molecule inhibitor of amyloid-beta oligomer formation in late-stage development as a disease-modifying therapy for AD. A recent Phase 3 trial did not meet its primary clinical endpoint in the overall population, but demonstrated significant benefits in cognition, function, and brain volumetric MRI (vMRI) in the prespecified subgroup with mild cognitive impairment (MCI). Here, we report plasma p-tau217, p-tau217/Aβ42, and neurofilament light chain (NfL) results from the Phase 3 trial, along with 4-year fluid biomarker data from the Phase 2 study in APOE4 carriers with early AD. METHODS: The 78-week, APOLLOE4 Phase 3 trial randomized APOE4/4 homozygotes to placebo (n = 162) or valiltramiprosate 265 mg BID (n = 163). The Phase 2 trial was an open-label biomarker study in APOE4 carriers with early AD who received valiltramiprosate 265 mg BID (N = 84) for 104 weeks, followed by a 2-year extension on the same regimen. Plasma p-tau217 and p-tau217/Aβ42 were measured every 6 months in both trials using FDA-approved Fujirebio Lumipulse G assay. Plasma NfL was measured in the Phase 3 trial using the Simoa assay. Associations between plasma biomarkers and clinical or vMRI outcomes were assessed using Spearman's correlation. Data are reported separately by study. RESULTS: Baseline plasma p-tau217/Aβ42 confirmed amyloid positivity in 94% of 294 Phase 3 APOE4/4 subjects, including 91% of those with MCI, as well as in 97% of 80 Phase 2 subjects. In the overall Phase 3 population, valiltramiprosate significantly reduced plasma p-tau217 compared with placebo at weeks 26, 52, and 78 (all p < 0.025, observed values). A similar effect was seen in the Phase 3 MCI subgroup (p < 0.05 at weeks 52 and 78), whereas the Mild AD subgroup showed only a numerical trend. In observed case analyses of MCI subjects, plasma p-tau217 decreased by 36% from baseline with valiltramiprosate and increased by 17% with placebo. In the same subgroup, the p-tau217/Aβ42 ratio decreased by 40% with valiltramiprosate and increased by 7% with placebo. Among Phase 3 MCI subjects, week 78 reductions in p-tau217 correlated significantly with improvements in ADAS-Cog13 (r = 0.276, p = 0.039), CDR-SB (r = 0.377, p = 0.005), hippocampal volume (r = - 0.353, p = 0.013), cortical thickness (r = - 0.337, p = 0.018), and whole brain volume (r = - 0.312, p = 0.029). Plasma NfL was also significantly lower with valiltramiprosate than placebo at week 78 in MCI subjects (p = 0.032). NfL stability over 78 weeks correlated significantly with improvements in ADAS-Cog13 (r = 0.29, p = 0.03) and hippocampal volume (r = - 0.282, p = 0.047), and with reductions in p-tau217 (r = 0.42, p = 0.001). In Phase 2 APOE4 carriers, valiltramiprosate-induced reductions in plasma p-tau217 were sustained over 4 years and remained significantly lower in both MCI APOE4 carriers and heterozygotes than in the Phase 3 APOE4/4 MCI placebo group at weeks 26, 52, and 78 (all p < 0.001). CONCLUSIONS: Valiltramiprosate 265 mg BID produced early and sustained reductions in plasma p-tau217 and p-tau217/Aβ42 in APOE4 homozygotes and carriers with MCI. In Phase 3 MCI subjects, drug effects on both p-tau217 and NfL correlated significantly with clinical and vMRI benefits, and the two biomarkers were also significantly correlated with each other. These findings suggest that valiltramiprosate engages its central target, thereby reducing Aβ aggregation, tau hyperphosphorylation, and downstream neurodegeneration. The consistent associations of plasma p-tau217 and NfL changes with positive clinical and vMRI outcomes in MCI indicate that the pharmacodynamic biomarker response reflects broader disease-modifying biological effects and are consistent with valiltramiprosate's mode of action. Together with the previously reported favorable safety and absence of increased ARIA-E risk, these biomarker findings and their clinical correlations support the promising benefit-risk profile of valiltramiprosate in APOE4/4 MCI patients. CLINICAL TRIAL REGISTRY: NCT04770220 and NCT04693520.