Biomarkers

Background: ALZ-801 (valiltramiprosate) is an oral inhibitor of amyloid oligomer formation in development as a disease-modifying AD treatment, including a fully enrolled APOLLOE4 Phase 3 trial in 325 APOE4/4 homozygotes. A Phase 2 study is evaluating ALZ-801 effects on plasma biomarkers, brain volumes and cognitive outcomes in APOE4 carriers. Plasma p-tau₁₈₁ reduction over 104 weeks is primary endpoint. A study extension includes active treatment over additional 104 weeks for a total of 208 weeks (4 years). Long term analyses include plasma p-tau₁₈₁, Aβ42/40, p-tau₂₁₇, GFAP and other emerging biomarkers. Hippocampal volume and cognition are additional outcomes.

Method: This active study enrolled 84 APOE4 carriers (MMSE ≥22; positive CSF+ biomarkers) who receive ALZ-801 265 mg BID. CSF/plasma biomarkers were conducted at Dr. Blennow's laboratory (Simoa, EuroImmun assays). MRIs analyzed by Clario at baseline, 52, 104, and in the long-term extension (LTE); cognitive and biomarker tests are every 26 weeks. Biomarkers are analyzed on observed cases, hippocampal volume (HV) and cognitive tests are analyzed by MMRM with two-sided p-values; with Spearman's correlations of biomarker-clinical outcomes.

Result: Baseline mean age was 69 years, MMSE 26, 51% females, and 70% MCI; and 83 subjects had any post-treatment efficacy assessment. Total of 75 and 70 subjects completed 52 and 104 weeks. At 104 weeks, plasma p-tau₁₈₁ reduction was 31% (p=0.045), Aβ42 reduction was 4% (p=0.042). Hippocampal volume (HV) versus untreated matched subjects from ADNI showed ∼20% less atrophy (p<0.002). Immediate and delayed memory scores (Rey test) remained at baseline levels versus 21% decline in matched ADNI subjects (p<0.0001). Memory stabilization correlated with reduced HV atrophy (r= 0.44, p=0.0002). In the 66 ongoing LTE subjects, cognitive and HV ADNI comparisons and biomarker-cognitive correlations at 130 weeks will be reported. Most common TEAE was mild nausea, with no ARIA-E.

Conclusion: Biomarker positive APOE4 carriers showed significant plasma p-tau₁₈₁ and Aβ42 effects, with promising HV effects that correlated with cognitive benefit. Sustained long term benefits on these outcomes over 2.5 years could support disease modification with a continued favorable safety profile of ALZ-801. Correlations of plasma biomarkers to long-term clinical and imaging outcomes provides valuable insights into ALZ-801 effects in AD.