To evaluate ALZ-801’s effects on plasma and imaging biomarkers of Alzheimer’s disease (AD).

ALZ-801 (valiltramiprosate), an oral brain-penetrant amyloid-oligomer inhibitor is completing a Phase 3 78-week trial in APOE4/4 homozygotes Early AD (EAD) subjects. The Phase 2 study evaluated its effects (265mg BID) on plasma biomarkers, MRI and cognition in EAD APOE4 carriers over 2 years. Plasma p-tau181 is elevated in AD and reduced by efficacious doses of lecanemab and aducanumab.

This 104-week, open-label study enrolled 84 subjects (MMSE 22-30, CDR-G 0.5-1, positive amyloid-PET or CSF biomarkers). Plasma and clinical testing were every 13 weeks, MRI every 52 weeks. Primary outcome was plasma p-tau181, cognitive tests were Rey Auditory-Verbal-Learning-Test (RAVLT) and Digit-Symbol-Substitution-Test (DSST). Dr. Blennow’s Laboratory (Sweden) conducted plasma biomarker analyses (Simoa, EuroImmun assays). Observed data changes-from-baseline were analyzed with 2-sided simple t-tests.

84 subjects were enrolled (51% female, age 69 years, MMSE 26.0, 70%/30% had MCI/Mild AD;70 completed 104-weeks. Plasma p-tau181 showed significant reductions at all timepoints reaching 31%-43% over 52-104 weeks (p=0.045), Aβ42 decreased ~4% over 104 weeks(p=0.042). Hippocampus atrophy (3.6%) was ~28% less than matched external control (ADNI-1 study). RAVLT-total memory and DSST improved at 26 weeks, remaining above/at baseline at 104 weeks; 50% and 33% of MCI and Mild AD subjects maintained their CDR-G stage. Cognitive stabilization correlated with decreased hippocampal atrophy (Spearman’s r=0.38-0.43, p≤ 0.002); and cortical thinning (r=0.35-0.58, p≤ 0.004). COVID-19 infection, nausea, decreased appetite were the main AEs, with no ARIA-E.

Over 2 years, oral ALZ-801 reduced plasma p-tau181 and Aβ42 significantly suggesting improved amyloid clearance. Cognitive stabilization correlated strongly with reduced brain atrophy, both showing treatment benefit compared to external control. No ARIA-E/vasogenic edema was detected. These biomarker results support the disease-modifying effects of ALZ-801 in Early ADwith promising clinical efficacy and favorable safety in APOE4 carriers.