Effects of Oral Valiltramiprosate on Clinical Efficacy, Safety, and Brain Volume Outcomes in APOE4/4 Homozygotes with Early Alzheimer’s Disease (AD): Topline Results of the 78-week Phase 3 APOLLOE4 Trial
Susan Abushakra1, Sharon Cohen2, Marwan Sabbagh3, David Watson4, Aidan Power1, Anton Porsteinsson5, Emer MacSweeney6, Merce Boada7, Pierre Jean Ousset8, Earvin Liang1, Susan Flint9, J. Patrick Kesslak1, Adem Albayrak9, Margaret Bray1, John A. Hey1, Martin Tolar9
1Alzheon, Inc., 2Toronto Memory Program, 3Barrow Neurological Institute, 4Alzheimer’s Research and Treatment Center, 5University of Rochester School of Medicine, 6Re:Cognition Health, 7Ace Alzheimer Center, Barcelona, 8Toulouse Gerontopole & Alzheimer’s Clinical Research Center, 9Alzheon
Objective:
To evaluate valiltramiprosate/ALZ-801 effects on clinical and brain volume outcomes in the prespecified MCI group.
Background:
Valiltramiprosate/ALZ-801, an oral small molecule inhibitor of amyloid-beta oligomer formation, was evaluated in a randomized, double-blind, placebo-controlled, 78-week trial in APOE4/4 homozygotes with Early AD (NCT04770220).
Design/Methods:
This trial randomized subjects 1:1 to placebo or valiltramiprosate 265 mg BID; stratified by MCI (MMSE 27-30) or Mild AD (MMSE 22-26). ADAS-Cog13 was the primary outcome, CDR-SB key secondary, functional DAD secondary outcomes, and hippocampal volume (HV) the main imaging outcome. MMRM was the main analysis model.
Results:
Safety population (N=325) was 51% females, mean age 69 years, MMSE 25.6, with 39% MCI and 61% Mild AD. In overall analysis population (N=320), ADAS-Cog13 placebo-adjusted effect favored drug non-significantly vs placebo (12%, p=0.61) and secondary outcomes were nonsignificant; however HV favored drug significantly (18% less atrophy, p=0.017). Prespecified Mild AD favored placebo nonsignificantly, but showed HV numerical benefit (12% less atrophy, p= 0.115). In prespecified MCI, all clinical outcomes favored drug (nominal p-values): ADAS-Cog13 (-2.14,p=0.042; 52%); CDR-SB (-0.65,p=0.053, 102%); DAD (+6.1, p=0.016, 96%). HV showed significant benefit versus placebo (108 mm3, 26% less atrophy, p= 0.004), with 35% and 22% less cortical and whole brain atrophy. Nausea (mostly mild) was the most common adverse event; ARIA-E incidence was same as placebo.
Conclusions:
The overall population did not achieve significance on primary/secondary clinical outcomes, but showed significant slowing of hippocampal atrophy on valiltramiprosate (18% p=0.017). The pre-specified MCI group showed nominally significant positive effects on cognitive and functional outcomes, with 52% less cognitive decline, functional stabilization, significant slowing of hippocampal (26%) and whole brain atrophy (22%) over 78 weeks. Overall safety was favorable with no increased ARIA-E or ARIA-H. In the high-risk APOE4/4 population, this positive benefit-risk profile supports valiltramiprosate’s potential as an oral disease-modifying treatment for APOE4/4 homozygotes with MCI.
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