Correlations between Clinical and Brain Volume Effects of Oral Valiltramiprosate in APOE4/4 Homozygotes with MCI: Pre-specified Analyses of the Phase-3 APOLLOE4 78-Week Trial in APOE4/4 Homozygotes with Early Alzheimer’s Disease (AD)
Marwan Sabbagh1, Susan Abushakra2, Duygu Tosun3, David Watson4, Aidan Power2, Earvin Liang2, Emer MacSweeney5, Merce Boada6, Karim Bennys7, Jorge Matias-Guiu8, John A. Hey2, Susan Flint2, J. Patrick Kesslak2, Luc Bracoud9, Margaret Bray2, Martin Tolar2
1Barrow Neurological Institute, 2Alzheon, Inc., 3University of California San Francisc, 4Alzheimer’s Research and Treatment Center, 5Re:Cognition Health, 6International University of Catalunya, 7Hopital Gui de Chauliac - CHRU de Montpellier, 8Hospital Clinico San Carlos, 9Clario, Inc.
Objective:
To evaluate valiltramiprosate/ALZ-801 effects on clinical and brain volume outcomes and their correlations over 78 weeks.
Background:
Valiltramiprosate/ALZ-801, an oral small molecule inhibitor of amyloid-beta (Aβ) oligomer formation, was evaluated in APOE4/4 homozygotes with Early AD (NCT04770220). Hippocampal atrophy, an early neuropathological change in AD, is prominent in APOE4/4 homozygotes and is associated with clinical decline.
Design/Methods:
A total of 325 homozygotes (placebo, 265mg BID, randomized 1:1) stratified by MCI (MMSE 27-30) or Mild AD (MMSE 22-26),were enrolled. Primary and key secondary outcomes were ADAS-Cog13 and CDR-SB respectively, DAD was a secondary outcome. Volumetric MRI, collected every 26 weeks, was centrally analyzed for quantitative brain volumes. HV was the main imaging outcome, with secondary measures of cortical thickness (CT) and whole brain volume (WBV). MMRM was main analysis model, analyses by disease stage were prespecified; Spearman’s correlations of drug effects are presented.
Results:
In overall population, primary and secondary clinical outcomes were not significant but all vMRI outcomes showed significant atrophy slowing versus placebo (HV, 18% less atrophy, p=0.017). Prespecified, MCI (N=125), showed positive effects/trends on ADAS-Cog13 (52%, p=0.041), DAD (96%, p=0.016) and CDR-SB (102%, p=0.053); with significant atrophy slowing in HV (26%), CT (35%), both p< 0.01, and in WBV (22%, p=0.027). In MCI group, subject-level correlations between HV-ADAS (r=-0.45), HV-CDR (r=-0.46) were both significant (p<0.0001); clinical correalations for CT, WBV were also significant (correlation coefficients 0.39-0.51).
Conclusions:
In the Phase 3 pre-specified MCI group, valiltramiprosate showed nominally significant cognitive and functional benefits with statistically significant atrophy slowing in all brain compartments (HV 26%, WBV 22%). Hippocampal and whole-brain volume effects showed significant subject-level correlations with cognitive and functional benefits over 78 weeks (correlations 0.45-0.49). These strong subject-level imaging-clinical correlations support the efficacy of valiltramiprosate in APOE4/4 MCI subjects.
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