Prevalence of Amyloid-Related Imaging Abnormalities in APOE4/4 Homozygotes with Early Alzheimer's Disease: Baseline Findings from Ongoing Clinical Trials of Oral Anti-Amyloid Agent ALZ-801 (Valiltramiprosate)
Susan Abushakra1, Rosalind Mandelbaum1, Jerome Barakos2, Philip Scheltens3, Anton P. Porsteinsson4, David Watson5, Emer MacSweeney6, Marwan Sabbagh7, Earvin Liang1, Patrick Kesslak1, Joyce Suhy8, Aidan Power1, John Hey1, Martin Tolar1
1Alzheon, Inc., 2California Pacific Medical Center and Bioclinica/Clario, 3Amsterdam University Medical Centers, Alzheimer Center Amsterdam, 4University of Rochester School of Medicine and Dentistry, 5Alzheimer's Research and Treatment Center, 6Re:Cognition Health, 7Barrow Neurological Institute, 8Bioclinica/Clario
Objective:

To evaluate prevalence of amyloid-related imaging abnormalities (ARIA) in APOE4/4 homozygotes with Early Alzheimer’s disease (AD), including microhemorrhages and siderosis or vasogenic edema (ARIA-H or ARIA-E).

Background:

APOE4 carriers show increased risk of ARIA in AD trials with amyloid-clearing antibodies, the highest in APOE4/4 homozygotes, related to a high burden of aggregated beta amyloid in cerebral microvessels (cerebral amyloid angiopathy, CAA). Trials with amyloid-clearing antibodies exclude subjects with cortical superficial siderosis or >4 microhemorrhages (MH). ALZ-801 (valiltramiprosate) is an oral, highly brain-penetrant inhibitor of formation of soluble neurotoxic amyloid oligomers, which showed promising efficacy in APOE4 carriers with no observed ARIA-E (Abushakra 2016). Two ongoing trials with ALZ-801 focus on APOE4 carriers with Early AD:  Phase 2 enrolled APOE3/4 or APOE4/4, and APOLLOE4 Phase 3 is enrolling only APOE4/4; both studies allow subjects with any number of MH or siderosis.

Design/Methods:

Baseline MRIs were from Phase 2 and 3 studies (MCI or Mild AD, MMSE ≥22), acquired from 1.5T or 3T scanners and centrally evaluated. We report the type and number of ARIA-E/H lesions as of August 2022.

Results:

Baseline demographics of the two studies were similar (~50% female, age 69 years, MMSE 25-26). In 242 homozygotes (211 from Phase 3) there were no subjects with ARIA-E, 72 with any MH, 23 with >4 MHs, of whom 15 had >10 MHs, 2 had macrohemorrhages >1 cm, and 20 had superficial siderosis lesions.

 

Conclusions:

APOE4/4 homozygotes show a high incidence and wide range of CAA-related lesions at the baseline of ALZ-801 studies. Many of these subjects are excluded from amyloid immunotherapy trials due to increased risk of ARIA. ALZ-801 studies include MRI monitoring with 4 scans over 78 weeks of treatment. The favorable ALZ-801 safety profile may provide a treatment alternative for APOE4 carriers at high risk of symptomatic ARIA.

 

10.1212/WNL.0000000000203550