Drug Development.

Background: ALZ-801 (valiltramiprosate), an oral brain-penetrant amyloid-oligomer inhibitor in Phase 3 testing in APOE4/4 homozygotes (APOLLOE4 trial). A 2-year Phase 2 biomarker study was completed evaluating ALZ-801 (265 mg BID) on plasma biomarkers, MRI, cognition, and clinical benefit in EAD APOE4 carriers. At trial end, subjects could enroll in a 1-year long-term extension with an ongoing biomarker and cognition analysis.

Method: 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 occurred every 13 weeks; MRI every 52 weeks. Primary outcome was plasma p-tau; 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). Hippocampal volume and cognitive tests were compared to matched group from ADNI-1 observational study using simple matching (age, APOE4 genotype, disease stage) and propensity scores as covariates in the MMRM analysis. Clinical and HV benefit was determined by Cohen's d score. For plasma biomarkers, observed data changes-from-baseline were analyzed with 2-sided simple t-tests.

Result: 84 subjects were enrolled; 51% female, 69 years, MMSE 26.0, 70%/30% had MCI/Mild AD; 70 completed 104-weeks. Plasma p-tau 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). Hippocampal atrophy (3.6%) was ∼28% lower than matched external control (ADNI-1). RAVLT-total memory and DSST remained above/at baseline through 104 weeks; Cohen's d clinical benefit effect in RAVLT and hippocampal volume ranged from 0.5 to 0.7. 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). Most common TEAE was mild nausea, and no ARIA-E was observed.

Conclusion: Over 2 years, oral ALZ-801 reduced plasma p-tau. Cognitive stabilization correlated with reduced brain atrophy, showing treatment benefit compared to external controls. Cohen's d values for hippocampal volume and cognition suggest strong clinical benefit. No ARIA-E/vasogenic edema was detected. These biomarker results support the disease-modifying effects of ALZ-801 in Early AD with promising clinical efficacy and favorable safety in APOE4 carriers. A Phase 3 78-week trial in APOE4/4 homozygotes Early AD (EAD) is ongoing with results expected in 2024.