Phase 2 Study Results of Oral ALZ‐801 (Valiltramiprosate) in Early Alzheimer’s Disease Shows Potential Disease Modification Effect: 2‐Year Effect on Plasma Biomarkers, Volumetric MRI, Cognition Outcomes and Clinical Benefit Analysis

Abstract

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‐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). 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‐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). 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‐tau₁₈₁. 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.