Alzheon, Inc. announced two scientific publications of results from the Phase 2 biomarker trial showing statistically significant and clinically relevant reduction in plasma biomarkers of neurodegeneration, preservation of brain volume, and positive cognitive effects in Early AD patients who are carriers of apolipoprotein e4 allele (APOE4) following 24 months of treatment with investigational oral agent ALZ-801/valiltramiprosate. The research papers, ?Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer?s Disease? and ?Analysis of Cerebrospinal Fluid, Plasma ß-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer?s Disease Using Quantitative Systems Pharmacology Model?

were published in the scientific journal Drugs, and are available through open access at: https://doi.org/10.1007/s40265-024-02067-8 and https://doi.org/10.1007/s40265-024-02068-7, respectively. ALZ-801/valiltramiprosate is an investigational oral disease-modifying therapy in Phase 3 development for the treatment of Early AD. In mechanism of action studies, ALZ-801 fully blocked the formation of neurotoxic soluble beta amyloid (Aß) oligomers at the Phase 3 clinical dose.

ALZ-801 has shown both potential for clinical efficacy in the highest-risk and most fragile Alzheimer?s population ? patients with two copies of the apolipoprotein e4 allele (APOE4/4 homozygotes) and favorable safety with no increased risk of vasogenic brain edema. This population is the focus of the pivotal 78-week APOLLOE4 Phase 3 trial, which is fully enrolled with topline data expected in the third quarter of 2024.

The Phase 2 biomarker study was designed to inform the development of ALZ-801 in the broader population of APOE4 carriers, which represents ~65% of all patients with AD. The open-label, multicenter, single-arm Phase 2 trial evaluated the effects of ALZ-801 265 mg administered orally twice daily on plasma AD biomarkers, hippocampal volume (HV) as measured by magnetic resonance imaging (MRI), and clinical tests of learning and memory, as well as safety and tolerability, over 104 weeks. The trial enrolled 84 patients ages 50 to 80 years with early AD (MMSE 22-30), who carry either one or two copies of the e4 allele of the apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively), and showed positivity for amyloid and tau biomarkers in cerebrospinal fluid (CSF).

APOE4 genotype, the leading risk factor for AD after aging, is associated with a several-fold higher risk of symptomatic AD and higher brain burden of neurotoxic amyloid oligomers and of aggregated amyloid in cerebral microvasculature (cerebral amyloid angiopathy, CAA). The study was designed to provide evidence of target engagement to support initiation of a pivotal Phase 3 trial in APOE4 carriers. This positive Phase 2 study evaluating oral ALZ-801 in APOE4 patients with early AD achieved its primary efficacy endpoint of reduction in plasma p-tau181 over two years, suggesting a robust decrease in amyloid-induced brain neurodegeneration and target engagement.

A significant 31% reduction (p=0.045) in plasma p-tau181 from baseline to 104 weeks started at 13 weeks and was sustained at every visit through 104 weeks. HV atrophy was significantly reduced by 25% (p=0.0014) compared to a matched external control from ADNI-1, an observational AD study. Memory scores showed improvement from baseline at 26 weeks and thereafter showed minimal decline from baseline at 104 weeks.

These cognitive effects correlated significantly with decreased HV atrophy (p=0.002). The most common treatment-emergent adverse events were nausea and urinary tract infections, and no drug-related serious adverse events were reported. Of 14 early withdrawals, six were due to non-serious treatment-emergent adverse events and there was one death due to COVID-19 (not related to study drug).

No vasogenic brain edema (amyloid-related imaging abnormalities with brain edema, ARIA-E) was observed on MRI over 104 weeks. After completion of the core study, a long-term extension of an additional 104 weeks was initiated and is in progress to allow long-term assessment of plasma biomarkers, hippocampal volume, cognitive tests, and safety over four years of treatment. In the Phase 2 trial, oral ALZ-801 showed early and sustained significant reduction of plasma p-tau181 and plasma Aß42 levels over 2 years, suggesting alleviation of neurodegeneration due to toxic effects of soluble amyloid oligomers.

The quantitative systems pharmacology (QSP) biomarker analysis supports the positive therapeutic effect of ALZ-801, with evidence of arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent aggregation of amyloid monomers into soluble neurotoxic oligomers. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory of memory decline, suggesting that the clinical benefits are consistent with its mechanism of action. The QSP analysis provides supportive amyloid fluid biomarker and clinical evidence for ALZ-801 as a potential first-in-class, oral small-molecule anti-Aß oligomer agent with disease modification potential in AD.