Alzheon's ALZ-801, an oral agent, has shown promising results in a Phase 2 biomarker study for Alzheimer's disease (AD), demonstrating a significant reduction in phosphorylated tau (p-tau181) levels and improvements in memory. The study, involving 84 patients with early AD, revealed a 29% decrease in p-tau181 concentrations (p=0.028) at 26 weeks and an 18% reduction at 13 weeks (p=0.038). This suggests a potential disease-modifying effect of the drug.
The study focused on patients carrying one or two copies of the ε4 allele of the apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes). The APOE4 genotype is a major risk factor for Alzheimer's, increasing the brain burden of neurotoxic amyloid oligomers.
ALZ-801 is designed to inhibit the formation of these neurotoxic soluble amyloid oligomers, which are believed to mediate cognitive decline in Alzheimer's patients. The oral agent targets amyloid oligomers at the phase 3 clinical dose and has shown safety and efficacy, particularly in patients with two copies of the apolipoprotein ε4 allele (APOE4/4).
Impact on Biomarkers and Cognition
The Phase 2 study also assessed the plasma p-tau181/Aβ42 ratio, revealing a 30% reduction at 26 weeks (p=0.022) and a 21% reduction at 13 weeks (p=0.018). Furthermore, a Rey Auditory Verbal Learning Test, used as a secondary outcome, indicated improvements in immediate and delayed recall at week 26.
According to Martin Tolar, MD, PhD, Founder, President, and CEO of Alzheon, "The several-fold greater reduction on p-tau181 biomarker compared to anti-amyloid antibodies provides further support for superior clinical benefit observed in Alzheon’s prior Alzheimer’s studies."
Safety and Ongoing Phase 3 Trial
The safety profile of ALZ-801 appears favorable, with no reports of vasogenic edema or drug-related adverse events. Mild nausea was the most commonly reported side effect. These findings align with previous data from over 2,000 AD patients in Alzheon's safety database.
A Phase 3 study of ALZ-801 is currently underway in APOE4/4 early AD patients, who constitute approximately 15% of the AD population. This randomized, controlled trial is comparing the oral agent with a placebo over a 78-week period, evaluating efficacy, safety, and biomarker/imaging effects at a twice-daily dose of 265 mg. The APOLLOE4 Phase 3 study is supported by a $47 million grant from the National Institute on Aging.
The Phase 3 trial incorporates a comprehensive set of biomarkers, including the ADAS-Cog 13 (Alzheimer’s Disease Assessment Scale-Cognitive Subscale) as the primary outcome, as well as p-tau181 in cerebrospinal fluid and blood, synaptic and inflammatory biomarkers, hippocampal volume, and cortical thickness measures.
Expert Commentary
Kaj Blennow, MD, PhD, a member of Alzheon’s Scientific Advisory Board, stated, "Upon analysis of the plasma p-tau181 data in our laboratory, we have observed an unprecedented reduction in this leading biomarker of Alzheimer’s pathology in patients taking ALZ-801 tablet for 6 months. This suggests a downstream effect on neuronal function and the potential for clinical efficacy of this novel treatment."
Plasma and CSF concentrations of phosphorylated tau (p-tau) are considered sensitive and specific markers of AD brain injury and neurodegeneration, resulting from a reaction to toxic beta-amyloid (Aβ) oligomers. Levels of p-tau181 increase with AD progression and clinical deterioration but can decrease with clinically meaningful AD-modifying treatments.
