Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial.

Background: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygotes accumulating a high burden of cerebral beta-amyloid (Aβ) pathology. Valiltramiprosate/ALZ-801 is a small-molecule potent inhibitor of Aβ-oligomer formation. The efficacy, safety/tolerability, and brain volume effects of oral valiltramiprosate were evaluated in this phase III, randomized, double-blind, placebo-controlled, multi-center, 78-week trial in homozygotes with early symptomatic AD.

Methods: The study enrolled eligible APOE4/4 subjects aged 50-80 years with Early AD (Mini-Mental State Examination [MMSE] 22-30), which included mild cognitive impairment (MCI) and mild dementia, Clinical Dementia Rating-Global Score (CDR-G) of 0.5 or 1, who were randomized 1:1 to valiltramiprosate (265 mg twice/day) or placebo. The primary outcome was AD Assessment Scale-Cognitive Subscale (ADAS-Cog13); the key secondary outcomes were CDR-Sum of Boxes (CDR-SB) and Amsterdam-Instrumental Activities of Daily Living (IADL), and a secondary outcome was Disability Assessment for Dementia (DAD). The main imaging outcome was hippocampal volume on MRI; diffusion tensor imaging (MRI-DTI) assessed microstructural tissue integrity. Amyloid-related imaging abnormalities (ARIA) were monitored with MRIs every 26 weeks.

Results: A total of 325 participants enrolled and received study drug. At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290). Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195). The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI. In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes. The most common adverse events were nausea, vomiting, and decreased appetite (more than double placebo rate), with no increased risk of brain edema or microhemorrhages.

Conclusions: The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials.

Trial registration: Clinicaltrials.gov: NCT04770220; EudraCT Number: 2020-005755-20.