Alzheon, Inc. reported statistically significant and clinically relevant plasma biomarker reduction, robust preservation of brain volume, and positive memory effects in Alzheimer's patients following 12 months of treatment with investigational agent ALZ-801 in its Phase 2 biomarker trial. ALZ-801 (valiltramiprosate) is an oral agent in Phase 3 development as a potentially disease modifying treatment for AD that blocks formation of neurotoxic soluble beta amyloid (Aß) oligomers causing cognitive decline in Alzheimer's patients. In mechanism of action studies, ALZ-801 fully inhibited the formation of amyloid oligomers at the Phase 3 clinical dose.

ALZ-801 has shown potential for robust efficacy in the highest-risk Alzheimer's population – patients with two copies of the apolipoprotein e4 allele (APOE4/4 homozygotes), and favorable safety with no events of brain vasogenic edema, seen in trials with plaque-clearing antibodies. This population is the focus of Alzheon's pivotal Phase 3 APOLLOE4 trial and has the highest likelihood of demonstrating successful efficacy outcomes. The ongoing, fully enrolled Phase 2 biomarker study is evaluating ALZ-801 in Early AD patients, who carry either one or two copies of the e4 allele of apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively), representing two thirds of Alzheimer's patients.

APOE4 genotype, the leading risk factor for AD after aging, is associated with a several-fold higher brain burden of neurotoxic amyloid oligomers. Phosphorylated tau (p-tau) levels in plasma are a sensitive and specific marker of neuronal stress and brain injury in AD, and considered a highly reliable biomarker of disease pathology. P-tau is produced by neurons as a reaction to formation of toxic beta amyloid oligomers, the key driver of AD pathology and neurodegeneration.

P-tau181 levels rise with AD progression and clinical deterioration of patients, and have been shown to fall in response to clinically effective disease modifying treatments in Alzheimer's. Alzheon's Phase 2 AD biomarker study (NCT04693520) enrolled 84 patients with Early AD, who carry either the APOE4/4 or APOE3/4 genotype and received oral ALZ-801 265 mg twice daily. All analyses of plasma biomarkers were performed at the laboratory of Professor Kaj Blennow at University of Gothenburg in Molndal, Sweden, audited according to Good Laboratory Practice. A total of 75 patients (mean age 69 years, 52% female) completed the Week 52 visit and were included in this pre-specified analysis.

In this population, ALZ-801 demonstrated a significant 41% reduction from baseline in plasma p-tau181 (p=0.016) at 52 weeks. ALZ-801 also significantly reduced the plasma p-tau181/Aß42 ratio by 37% at 52 weeks (p=0.032). Given the importance of p-tau181 and Aß42 as biomarkers of core AD pathology, these results support a disease modifying effect of ALZ-801 in Alzheimer's patients.

ALZ-801 shows rapid and robust plasma p-tau181 reductions at 13, 26 and 52 weeks that correspond with preservation of hippocampal volume and improvements in memory tests. These early p-tau181 effects are enabled by the robust 40% brain penetration of ALZ-801 compared to approximately 1% brain penetration of plaque-clearing antibodies. As p-tau181 is primarily of brain origin and is actively cleared from brain into plasma, the significant lowering of p-tau181 in response to ALZ-801 treatment validates the drug's target engagement and action in AD brain.