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Abstract Details

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)
Aging, Dementia, Cognitive, and Behavioral Neurology
P5 - Poster Session 5 (11:45 AM-12:45 PM)
7-003

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.

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).

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.

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.

 

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.

 

Authors/Disclosures
Sawsan (Susan) R. Abushakra, MD
PRESENTER
Dr. Abushakra has received personal compensation for serving as an employee of Alzheon Inc. Dr. Abushakra has stock in Alzheon Inc. The institution of Dr. Abushakra has received research support from NIA. Dr. Abushakra has received intellectual property interests from a discovery or technology relating to health care.
Rosalind Mandelbaum, PA (Donald S. Marks, M.D., P.C.) No disclosure on file
Jerome Barakos Jerome Barakos has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Jerome Barakos has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen.
Philip Scheltens, MD, PhD, FAAN (Alzheimer Center Amsterdam University medical Center) Dr. Scheltens has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NOVO NOrdisk.
Anton P. Porsteinsson, MD (AD-CARE - University of Rochester School of Medicine) Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ONO Pharmaceuticals. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Porsteinsson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IQVIA. Dr. Porsteinsson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for WebMD. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Otsuka. Dr. Porsteinsson has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Functional Neuromodulation. Dr. Porsteinsson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Xenon Pharmaceuticals. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Porsteinsson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cognitive Research Corporation. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Athira. Dr. Porsteinsson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Porsteinsson has received research support from Alector. The institution of Dr. Porsteinsson has received research support from Eisai. The institution of Dr. Porsteinsson has received research support from Eli Lilly. The institution of Dr. Porsteinsson has received research support from Athira. The institution of Dr. Porsteinsson has received research support from Genentech/Roche. The institution of Dr. Porsteinsson has received research support from Cassava. The institution of Dr. Porsteinsson has received research support from Vaccinex.
David Watson, PhD (Alzheimer's Research and Treatment Center) Dr. Watson has nothing to disclose.
J Emer MacSweeney, MD (Re:cognition Health) Dr. MacSweeney has nothing to disclose.
Marwan N. Sabbagh, MD, FAAN (Barrow Neurological Institute) Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Anavex. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prothena. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cognito Therapeutics. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GSK. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for CervoMed. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheon. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF.
Earvin Liang, PhD (Alzheon) Dr. Liang has received personal compensation for serving as an employee of Alzheon.
Patrick *Use 164469 Kesslak No disclosure on file
Joyce Suhy, PhD (BioClinica) Dr. Suhy has nothing to disclose.
Aidan Power, PhD (Alzheon) Dr. Power has received personal compensation for serving as an employee of Alzheon. Dr. Power has stock in Pfizer. Dr. Power has stock in Alzheon.
John A. Hey, PhD (Alzheon) Dr. Hey has received personal compensation for serving as an employee of Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has received intellectual property interests from a discovery or technology relating to health care.
Martin Tolar, MD, PhD (Alzheon) Dr. Tolar has received personal compensation for serving as an employee of Alzheon. Dr. Tolar has received intellectual property interests from a discovery or technology relating to health care.