High Prevalence of CAA-Related Lesions in APOE ε4/4 Homozygotes With Early Alzheimer disease

Susan Abushakra, MD

Recent imaging results from the phase 3 APOLLOE4 trial (NCT04770220) investigating ALZ-801 (Alzheon), an investigational oral amyloid oligomer inhibitor, showed that patients with early-stage Alzheimer disease (AD) who are apolipoprotein ε4 allele (APOE4/4 homozygotes) carriers had a high prevalence of cerebral amyloid angiopathy (CAA)-related lesions at baseline.¹ These findings suggest that these patients would be more susceptible to treatment-induced brain edema and microhemorrhage (MH), known as amyloid related imaging abnormalities (ARIA).

At least 1 lobar MH was present in about 32% of a 325-patient cohort, including 9% of patients with greater than 4 microhemorrhages (MH) and 9% of patients with superficial siderosis, with the most common locations of these lesions in the occipital and frontal lobes. Notably, 2 participants had macrohemorrahages and a majority of the participants had white matter disease.

“High prevalence of CAA-related lesions in APOE4/4 patients with AD is consistent with the emerging safety risks of plaque-clearing antibodies in large pivotal AD trials, showing how helpful oral ALZ-801 treatment could be even just from the safety standpoint in APOE4 patients, who represent 65-70% of AD population,” lead author Susan Abushakra, MD, chief medical officer at Alzheon, said in a statement.²

Presented at the 2023 Alzheimer’s Association International Conference, July 16-20, in Amsterdam, the Netherlands, the APOLLOE4 trial fully enrolled 325 APOE ε4/4 homozygotes patients with earlier AD who had a Mini-Mental State Exam score of at least 22 points. Abushakra and colleagues investigated the prevalence of MH and CAA lesions in this patient sample at the baseline (mean age 69 years; women, 51%; MMSE, 26; white, 82%; MCI, 65%). The baseline MRIs were obtained from 1.5T/3T scanners which were centrally evaluated by Clario, collecting reports on the number and locations of the CAA lesions.

ARIA-E was also reported in APOE e4/4 carriers treated with placebo in lecanemab (Leqembi; Eisai) & gantenerumab (Eli Lilly) trials (4%-6%). This background ARIA likely reflects spontaneous CAA-related inflammation commonly reported in APOE ε4 carriers.3 Oral ALZ-801 in the ongoing studies has not shown increased ARIA risk, and has safety advantage over amyloid antibodies especially for APOE ε4/4 homozygous patients.

“APOE4/4 individuals have a high burden of aggregated amyloid plaque in brain vessels, which leads to the CAA lesions seen on MRI scans, and this pathology contributes to an increased risk of developing brain edema and bleeds when treated with anti-amyloid antibodies,” Abushakra said in a statement.² “The unique upstream mechanism of action of ALZ-801 has demonstrated the ability to prevent the formation of the soluble neurotoxic oligomers, while avoiding the breakdown of amyloid plaque in blood vessels, and ongoing safety surveillance in our clinical trials continues to show no increase in brain edema and bleeds in APOE4/4 homozygous AD patients, who are at the highest risk of symptomatic ARIA with anti-amyloid antibodies.”

ALZ-801 acts through a novel enveloping molecular mechanism of action to fully block formation of neurotoxic soluble amyloid oligomers in the human brain associated with the onset of cognitive symptoms and progression of AD. APOLLOE4, which spans 85 sites in the US, Canada, and Europe, is expected to be complete by June 2024. If successful, findings will support the potential commercial launch of the agent in 2025.

At the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, Alzheon presented 12-month results from its phase 2 biomarker study (NCT04693520) assessing its investigational agent ALZ-801.4 At the meeting, NeurologyLive® sat down with John Hey, PhD, chief scientific officer at Alzheon, to gain a better understanding of the characteristics for the APOLLOE4 cohort. Hey provided commentary on the high levels of CAA-related lesions, and why ALZ-801 may be more suitable to this patient population.

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REFERENCES
1. Abushakra S, McLaine R, Barakos J, et al. Prevalence of Cerebral Microhemorrhages and Cortical Superficial Siderosis in APOE4/4 Homozygotes with Early Alzheimer's disease: Baseline Findings from Phase 3 Trial of Oral ALZ-801 in APOE4/4 Homozygotes (APOLLOE4). Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 82916.
2. Alzheon to Present Baseline Imaging Characteristics from Ongoing APOLLOE4 Phase 3 Trial of Oral Tablet ALZ-801 (Valiltramiprosate) and Positive Biomarker/Clinical Correlations from Phase 2 Biomarker Study at Alzheimer’s Association International Conference in Amsterdam. News Release. Published July 11, 2023. Accessed July 25, 2023. https://alzheon.com/alzheon-to-present-baseline-imaging-characteristics-from-ongoing-apolloe4-phase-3-trial-of-oral-tablet-alz-801-valiltramiprosate-and-positive-biomarker-clinical-correlations-from-phase-2-biomarker-s/
3. Regenhardt RW, Thon JM, Das AS, et al. Association Between Immunosuppressive Treatment and Outcomes of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2020;77(10):1261-1269. doi:10.1001/jamaneurol.2020.1782
4. Alzheon to present baseline imaging characteristics from ongoing APOLLOE4 phase 3 trial of oral tablet ALZ-801 (Valiltramiprosate) and results of phase 2 biomarker study at American Academy of Neurology Conference in Boston. News release. Alzheon. April 18, 2023. Accessed July 25, 2023. https://www.businesswire.com/news/home/20230418005109/en/Alzheon-to-Present-Baseline-Imaging-Characteristics-from-Ongoing-APOLLOE4-Phase-3-Trial-of-Oral-Tablet-ALZ-801-Valiltramiprosate-and-Results-of-Phase-2-Biomarker-Study-at-American-Academy-of-Neurology-Conference-in-Boston