Oral valiltramiprosate/ALZ-801, an amyloid oligomer formation inhibitor, is in development as a disease-modifying Alzheimer’s disease (AD) treatment. In this Phase 2 single-arm study in APOE4 carriers with Early AD (NCT0493520), valiltramiprosate showed cognitive stability over 104 weeks (2 years, Hey 2024). We here report the long-term safety and MMSE effects over 208 weeks.

Phase 2, single-arm, study enrolled 53 APOE3/4 and 31 APOE4/4 Early AD subjects with MCI (MMSE >26) or Mild AD (MMSE 22-26) and CDR-G of 0.5 or 1. Subjects had positive CSF biomarkers at baseline or a historically positive amyloid-PET scan and received 265mg BID over 208 weeks. MMSE responders  were defined as MMSE change from baseline ≤4-point at 104, 156 and 208 weeks, using observed case analysis.

84 subjects enrolled; 51% female, mean age 69 years, MMSE 26.0, 36/84 had MCI at baseline; 70, 65 and 51 subjects completed 2, 3 and 4 years on valiltramiprosate.In the overall population, MMSE response rate was 74%, 55% and 43% at Weeks 104, 156 and 208, and similar between genotypes. The MCI group showed higher responder rates of  84%, 70% and 58% at Weeks 104, 156 and 208, respectively. APOE4/4 MCI group showed 73% responders at 208 weeks. Adverse events in >10% included COVID-19, nausea, urinary tract infection, decreased appetite, decreased weight and vomiting. There was no ARIA-E or symptomatic ARIA-H.  

Amyloid positive, APOE4 carriers with Early  AD treated with valiltramiprosate show high rate of stabilized MMSE scores (responders) over 4 years, particularly in subject with MCI (58% at 4 years). Long-term safety over 4 years of treatment was favorable with no ARIA-E or symptomatic ARIA-H. Analyses of Additional clinical, volumetric and biomarker analyses are in progress. These results suggest a favorable benefit-risk profile of valiltramiprosate with long-term APOE4 carriers treatment .