ALZ-801 Shows Reduction in Relevant Alzheimer Biomarkers, Clearance of Amyloid After 2 Years

James P. Kesslak, PhD

Two-year data from a phase 2 study (NCT04693520) showed that treatment with ALZ-801 (Alzheon), an oral, investigational agent, resulted in significant reductions in relevant Alzheimer disease (AD) biomarkers such as phosphorylated tau (p-tau)181 and amyloid-ß (Aß)⁴² . Coupled with effects seen on cognitive stabilization and reduced brain atrophy, investigators concluded the results point to a disease-modifying impact with the therapy.¹

These findings were presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, by lead author James P. Kesslak, PhD, vice president of Clinical Development and Medical Affairs at Alzheon. Among 70 patients who completed the 104-week period, findings revealed significant reductions of plasma p-tau181 reaching 31%-43% over weeks 52-104 of the study (P = .045). Throughout that time, Aß⁴² levels decreased by 4% in treated patients.

The trial originally enrolled 84 individuals who had an average age of 69 years and an average Mini-Mental State Exam (MMSE) score of 26.0. Comprised of mostly those with mild cognitive impairment (70%), patients were tested on plasma and clinical outcomes every 13 weeks, with MRI conducted every 52 weeks. The primary outcome was plasma p-tau181, with other tests like the Rey-Auditory-Verbal-Learning-Test (RAVLT) and Digit-Symbol-Substitution-Test (DSST) to measure change in cognition.

In addition to changes on p-tau and Aß42, patients on the therapy had 3.6% hippocampus atrophy, which was around 28% less than those from the Alzheimer Disease Neuroimaging Initiative (ADNI-1) study, an external control. RAVLT, a comprehensive test that evaluates short-term memory, working memory, and long-term memory, was also improved at 26 weeks, and remained above/at baseline at 104 weeks. Similar observations were seen for the DSST, a validated and sensitive measure of cognitive dysfunction.

In total, 50% and 33% of patients with MCI and mild AD, respectively, maintained their Clinical Dementia Rating stage throughout treatment. Additional findings showed that cognitive stabilization correlated with decreased hippocampal atrophy (Spearman’s r = 0.38-0.43; P <.002) and cortical thinning (r = 0.35-0.58; P ≤.004). In the original data readout from September 2023, findings also showed significant correlations between hippocampal volume vs RAVLT Total Score (r = 0.44; P = .0002), hippocampal volume vs MMSE (r = 0.43; P = .0003), hippocampal volume vs DSST (r = 0.38; P = .002), cortical thickness vs RAVLT Total Score (r = 0.35; P = .004), cortical thickness vs MMSE (r = 0.58; P <.0001) and cortical thickness vs DSST (r = 0.55; P <.0001).

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In terms of safety, the most commonly observed adverse events were COVID-19 infection, nausea, and decreased appetite. Notably, as reported in the original readout, there were no cases of amyloid-related imaging abnormalities (ARIA), a common concern for novel AD therapeutics.

ALZ-801, an oral brain-penetrant amyloid-oligomer inhibitor, is currently being assessed in the phase 3 APOLLOE4 trial (NCT04770220). The study, fully enrolled with 325 individuals with early AD, randomly assigns patients to ALZ-801 at 265 mg twice daily (BD) or placebo for 78-week treatment period, with change on the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as the primary end point. In addition, the trial looks at several secondary end points of function, activities of daily living, and behavior, along with other biomarker end points that evaluate tau181, Aß42, Aß40, and MRI hippocampal volume.

APOLLOE4 includes those with early AD who are homozygous for the ε4 allele of the apolipoprotein gene (APOE4 homozygous or APOE4/4). Patients must have an MMSE score at screening of 22-30 and a CDR global score of 0.5 to 1. In addition, to be included, patients must have an RBANS delayed memory index score of less than 85 and have evidence of progressive memory loss over the last 12 months per investigator assessment. In the early imaging findings, the patient population of APOLLOE4 exhibited a high rate of cerebral amyloid angiopathy-related lesions at baseline, making them more susceptible to treatment-induced ARIA of brain edema and microhemorrhage.²

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REFERENCES
1. Kesslak JP, Hey JA, Abushakra S, et al. Positive disease modifying effects of oral ALZ-801 on plasma biomarkers, volumetric MRI and cognition at 104 weeks: results of a phase 2 study of APOE4 carriers with early Alzheimer’s disease. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract ES1-001
2. 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. News release. Alzheon. April 18, 2023. Accessed April 15, 2024. https://www.businesswire.com/news/home/20230418005109/en/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