Oral Amyloid Oligomer-Targeting Agent Slows Brain Atrophy in APOE ε4 Homozygotes with Early AD
Results of a study evaluating the efficacy and safety of the oral amyloid oligomer-targeting agent ALZ-801 (valiltramiprosate; Alzheon, Framingham, MA) in individuals with early Alzheimer disease (AD) who are homozygous for the ε4 allele of the apolipoprotein (APOE) gene showed significant slowing of hippocampal atrophy as well as cognitive and functional benefits. These results were presented at the 18th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference. ALZ-801, an investigational oral amyloid-targeting treatment, is a valine-conjugated prodrug of tramiprosate with improved pharmacokinetic profile and gastrointestinal tolerability.
In the randomized, 78-week, phase 3 APOLLOE4 trial (NCT04770220), researchers evaluated treatment with ALZ-801 265 mg twice daily vs placebo in APOE ε4homozygotes with early AD (Mini-Mental State Examination [MMSE] scores of 22 to 30) across 77 sites in North America and the European Union (N=325). Participants were stratified by disease stage into mild cognitive impairment (MCI; MMSE 27 to 30) or mild AD (MMSE 22 to 26). Primary and secondary outcomes included change from baseline in the 13-item Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Disability Assessment for Dementia (DAD) scores at 78 weeks, which were analyzed using a mixed-effect model with repeated measures. MRI-based hippocampal volume was the main imaging outcome, with volumetric and safety MRIs conducted every 26 weeks.
Key findings include the following:
- ALZ-801 treatment was associated with an 18% reduction in hippocampal atrophy vs placebo in the overall study population (P=.017).
- The ADAS-Cog13 placebo-adjusted effect (least squares means of difference between ALZ-801 and placebo) favored individuals treated with ALZ-801 but was nonsignificant (delta, -0.5; 11% less decline; P=.61).
- All secondary clinical outcomes (CDR-SB, DAD) in the overall study population were statistically nonsignificant.
- In the MCI subgroup, cognitive decline was reduced by 52% in individuals treated with ALZ-801 vs placebo (P=.042).
- In the MCI subgroup, all clinical outcomes showed nominally significant improvements in individuals treated with ALZ-801: ADAS-Cog13 (delta, -2.14; P=.042; 52% difference vs placebo); CDR-SB (delta, -0.65; P=.053; 102% difference vs placebo); DAD (delta, +6.1; P=.016; 96% difference vs placebo).
- Brain imaging in the MCI subgroup showed 26% less hippocampal atrophy and 35% less cortical thinning in MCI participants treated with ALZ-801 vs placebo.
ALZ-801 was well-tolerated, and the most common treatment-emergent adverse events included mild nausea, appetite changes, and weight loss. No increase in ARIA-E or ARIA-H was observed in the ALZ-801–treated group compared with placebo, and no deaths occurred during the study.
Source: Abushakra S, Watson D, Power A, et al. Effects of oral valiltramiprosate on clinical efficacy, safety and brain volume outcomes in APOE4/4 homozygotes with early AD: topline results of APOLLOE4 randomized, placebo-controlled 78-week multi-center trial. Presented at: 18th annual Clinical Trials on Alzheimer’s Disease Conference; December 1-4, 2025; San Diego, California.