New 12-Month Findings Highlight ALZ-801’s Clinical Effect on Alzheimer Biomarkers, Hippocampal Atrophy

John Hey, PhD

In new 12-month data, ALZ-801 (Alzheon), an investigational oral amyloid oligomer inhibitor, continued to demonstrate its potential as a disease-modifying therapy for Alzheimer disease (AD), represented by reductions in plasma phosphorylated-tau (p-tau)181, slowing of hippocampal atrophy, and stabilization of cognition. The final 24-month data will be released later this year.^1,2

"The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade that leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau181," John Hey, PhD, chief scientific officer, Alzheon, said in a statement.¹ "The several-fold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing anti-amyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in [patients with Alzheimer]."

Presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, the study featured 84 individuals with either apolipoprotein (APOE) e4/4 or APOE e3/4 genotype and prior positive amyloid-PET or cerebrospinal fluid biomarkers fulfilling amyloid positive and tau positive criteria. In total, 75 patients completed 12 months of treatment, 70% of which were in the mild cognitive impairment stage and 30% of which were in the mild AD stage. The mean Mini-Mental State Examination (MMSE) scores were 26.0.

At 12 months, hippocampal atrophy was reduced by 25% compared with matched controls from the Alzheimer’s Disease Neuroimaging Initiative. Plasma p-tau 181, a marker of amyloid-induced neuronal injury in AD, was reduced by 41% by week 52 (P = .016), with significant reductions seen as early as 13 weeks. Furthermore, these reductions correlated with significant reduction in plasma amyloid-ß(Aß)42 and Aß40 at the same time point (–5%; P = .002 and P = .005).

Patients treated with ALZ-801 experienced cognitive improvements at 13 and 26 weeks that remained above baseline at the 1-year evaluation. Furthermore, amyloid-related imaging abnormalities, a concern in the AD community, were not found in the trial. Common adverse events were mild nausea and COVID-19 infection, with no drug-related serious events.

Alzheon also presented baseline characteristics from the ongoing phase 3 APOLLOE4 study (NCT04770220), which completed trial enrollment ahead of schedule in December 2022. The trial, supported by a $47 million grant from the National Institute on Aging, evaluates the effects of 265 mg twice daily oral dose of ALZ-801 in patients with early AD with the APOE e4/4 genotype, for a 78-week treatment period. The primary efficacy outcome assessment is a measure of cognition, through the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13).

In APOLLOE4, imaging findings of individuals enrolled showed that this group exhibits a high rate of cerebral amyloid angiopathy (CAA)-related lesions at baseline, potentially increasing the risk of treatment-induced ARIA lesions. In total, 32% (n = 72) of study participants entered with any microhemorrhages (MH), and 23 had at least 4 MHs. Furthermore, 15 had at least 10 MHs, 2 had macrohemorrhages of at least 1 cm, and 20 individuals had superficial siderosis lesions.³

"Our findings are consistent with the evolving scientific understanding of Alzheimer’s pathology in APOE4 carriers. These individuals frequently present with CAA-like lesions and have a high burden of aggregated amyloid in the vessel walls. When treated with anti-amyloid antibodies that activate microglia and breakdown amyloid plaque, these subjects can develop inflammation in these small vessels, which leads to brain swelling and small bleeds," Susan Abushakra, MD, chief medical officer, Alzheon, said in a statement.¹

She added, "In contrast, the unique upstream mechanism of ALZ-801 has demonstrated the ability to prevent the formation of the neurotoxic oligomers early in the amyloid cascade, without actively breaking down amyloid plaque or inducing inflammation in blood vessels. Our ongoing safety surveillance continues to show no increased risk for brain edema and bleeds in the ongoing phase 2 and 3 studies in Alzheimer disease subjects treated with oral ALZ-801."

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.

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REFERENCES
1. Alzheon to present baseline imaging characteristics from ongoing APOLLOE4 phase 3 trial of oral tablet ALZ-801 (valiltramiprostate) and results of phase 2 biomarker study at American Academy of Neurology conference in Boston. News release. Alzheon. April 18, 2023. Accessed April 20, 2023. https://www.biospace.com/article/releases/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/
2. Hey J, Abushakra S, Blennow K, et al. Effects of ALZ-801, an oral amyloid oligomer inhibitor, on biomarkers of Alzheimer’s disease (AD): 12-month results of phase 2 biomarker study in early AD. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 003243
3. Abushakra S, Mandelbaum R, Barakos J, et al. Prevalence of amyloid-related imaging abnormalities in APOE 4/4 homozygotes with early Alzheimer’s disease: baseline findings from ongoing clinical trials of oral anti-amyloid agent ALZ-801 (valiltramiprosate). Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 003825