Drug Development.

Background: Oral ALZ-801 (valiltramiprosate), a brain-penetrant agent that inhibits amyloid-oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer's disease (AD). ALZ-801 effects on plasma AD biomarkers were evaluated in a 104-week Phase 2 study in APOE4-carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid-related imaging abnormalities (ARIA) in AD patients. Incidence of ARIA-H (microhemorrhages, MH; superficial siderosis, SS) and of ARIA-E (edema/effusion) was analyzed.

Method: This study enrolled 84 subjects (31 APOE4/4, 53 APOE3/4) MMSE ≥22 and CDR-G 0.5 or 1.0, with positive amyloid and CSF p-tau181 ≥60 pg/ml. Subjects received ALZ-801 at 265 mg BID over 104 weeks, with MRI at baseline, 52 and 104 weeks following a standardized protocol including 2D FLAIR and T2* Gradient Echo. Study allowed subjects with any number of MH, but ARIA-E and SS lesions >1cm were exclusionary. Data were evaluated centrally by Clario neuroradiologists for eligibility assessment and ARIA safety monitoring. The study's primary outcome was plasma p-tau reduction at 104 weeks.

Result: At baseline, mean age and MMSE were 69 years and 26 respectively, with 52% female and 70% MCI subjects. Of 84 enrolled, 83, 75 and 69 subjects had baseline, 52-week and 104-week MRI. Baseline MRIs showed >1 MH in 7/83 (8%), and 6/75 subjects (8%) with post-treatment MRI developed new MH, all asymptomatic. At baseline, 5 subjects had 1-4 MH, of whom 2 developed new MH (3-4); 1 subject had >10 MH and developed 29 new MH. 3 subjects developed de novo MH (1-3). There was no SS or ARIA-E. Study primary outcome was achieved with significant p-tau181 reduction (31%, p = 0.045) and 4% Aβ42 reduction (p = 0.042), with memory stabilization over 2 years (Hey, ADPD 2024).

Conclusion: The Phase 2 APOE4-carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA-E. This 265 mg BID ALZ-801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ-801 in APOE4 carriers with Early AD.