Alzheon, Inc. reported a clinically relevant and statistically significant plasma biomarker reduction and memory improvement in Alzheimers patients following 6 months of treatment with oral tablet ALZ-801 (valiltramiprosate) in its Phase 2 biomarker trial. ALZ-801 is an oral agent in Phase 3 development as a potentially disease modifying treatment for AD that blocks the formation of neurotoxic soluble amyloid oligomers that lead to cognitive decline in Alzheimer's patients. In mechanism of action studies, ALZ-801 has been shown to fully inhibit the formation of amyloid oligomers at the Phase 3 clinical dose.

ALZ-801 has shown potential for robust efficacy and favorable safety in the highest-risk Alzheimer's population patients with two copies of the apolipoprotein ε4 allele (APOE4/4). This population is the focus of Alzheon's pivotal Phase 3 APOLLOE4 trial and has the highest likelihood of demonstrating a successful outcome. 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 ε4 allele of apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively).

APOE4 genotype, the leading risk factor for Alzheimer's after aging, is associated with a several-fold higher brain burden of neurotoxic amyloid oligomers. Phosphorylated tau (p-tau) levels in plasma and CSF are sensitive and specific markers of brain injury and neurodegeneration in AD. P-tau is produced as a reaction to toxic beta amyloid (Aβ) oligomers.

P-tau181 levels rise with AD progression and clinical deterioration, 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 the APOE4/4 or APOE3/4 genotype and received oral ALZ-801 265 mg twice daily. The primary outcome for this interim analysis was change from baseline in plasma p-tau181. All analyses of plasma biomarkers were performed at the laboratory of Professor Kaj Blennow at University of Gothenburg in Molndal, Sweden.

A total of 80 patients (mean age 69 years, 51% female) completed the Week 26 visit and were included in this analysis. In this population, ALZ-801 demonstrated a significant 29% reduction in plasma p-tau181 (p=0.028) at 26 weeks, and 18% reduction at 13 weeks (p=0.038). ALZ-801 also significantly reduced the plasma p-tau181/Aβ42 ratio by 30% at 26 weeks (p=0.022), and by 21% at 13 weeks (p=0.018).

Given the importance of p-tau181 and Aβ42 as biomarkers of core AD pathology, these results support a disease modifying effect of ALZ-801 in Alzheimer's. ALZ-801 shows early and robust plasma p-tau181 reductions at 13 and 26 weeks with improvements in memory. These early p-tau181 effects are likely enabled by the robust 40% brain penetration of ALZ-801 compared to approximately 1% brain penetration of antibodies. As p-tau181 is primarily of brain origin and actively clears 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 the AD brain.

In addition to the biomarker outcomes, the Phase 2 study included a standard learning and memory test, Rey Auditory Verbal Learning Test (RAVLT), as a secondary outcome. Analysis of RAVLT total memory scores, whichincluded both immediate and delayed recall, showed a significant improvement from baseline to Week 26 (p=0.002). In the overall 84 subjects who received ALZ-801, the most common adverse event was mild nausea.

There was no evidence of vasogenic edema and no drug-related serious events. The safety and tolerability profile was favorable and consistent with prior data from more than 2,000 AD patients in Alzheons safety database. With support from the National Institute on Aging in the form of a $47M grant to fund the APOLLOE4 Phase 3 study with ALZ-80, Alzheons drug candidate is well positioned to become one of the first disease-modifying treatments approved for slowing and even preventing cognitive decline in Alzheimers patients.

Pioneering a precision medicine approach in Alzheimers, the APOLLOE4 Phase 3 trial is enrolling the highest-risk APOE4/4 AD patients and incorporates the latest biomarkers to track patient benefit p-tau181 in cerebrospinal fluid and blood, synaptic and inflammatory biomarkers, hippocampal volume, and cortical thickness measures, along with the gold-standard primary clinical endpoint, ADAS-Cog 13 (Alzheimer's Disease Assessment Scale-Cognitive Subscale).