To evaluate effects of ALZ-801 on plasma and imaging biomarkers of AD pathology.
ALZ-801 (valiltramiprosate) is an oral small molecule inhibitor of amyloid oligomer formation. Fully enrolled Phase 2 study in APOE4 carriers is evaluating effects on plasma biomarkers, including hyperphosphorylated tau (p-tau181) and beta amyloid (Aβ42 and Aβ40). Plasma p-tau181 is elevated in AD and reduced by efficacious doses of lecanemab and aducanumab. APOLLOE4 Phase 3 trial is ongoing in Early AD patients with APOE4/4 genotype.
Phase 2 study enrolled subjects with MMSE ≥ 22 and CDR-G 0.5/1, and amyloid positive by CSF or PET scans who received ALZ-801 265 mg BID over 2 years (7 European sites). Biomarker analyses were conducted with Lumipulse (CSF) and Simoa (plasma) assays at Dr. Kaj Blennow’s laboratory. Hippocampal volume (HV) atrophy was assessed by Clario. Changes from baseline were analyzed in mITT population on observed data with paired t-tests and 2-sided p-values.
mITT population included 84 subjects with 75 completing 52 weeks. Mean age was 69 years, 51% female, MMSE 26.0, 70/30% MCI/Mild AD. Significant plasma p-tau181 reduction started at 13 weeks and reached -41% at 52 weeks (p=0.016), with significant reduction in plasma Aβ42 and Aβ40 at 52 weeks (-5%, p=0.002 & p=0.005). Hippocampal atrophy was reduced by 25% compared to matched ADNI controls. Composite cognitive Z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks. Common adverse events were mild nausea and COVID infection, with no drug-related serious events or ARIA-E.
ALZ-801 produced a significant reduction of plasma p-tau181, a marker of amyloid-induced neuronal injury in AD, as well as slowing of hippocampal atrophy at 1 year and cognitive stabilization, suggesting a disease modifying effect in AD patients. These biomarker and clinical effects are being confirmed in the Phase 3 trial.