Oral Anti-Amyloid Shows Disease-Modifying Potential: Phase 2 Data

Megan Brooks

April 28, 2023

Results of a phase 2 study demonstrate potential Alzheimer's disease (AD)–modifying effects of an investigational oral anti-amyloid agent, represented by positive changes in plasma and imaging biomarkers of AD pathology.

Use of the drug, ALZ-801 (Alzheon), led to a significant reduction of plasma phosphorylated–tau 181 (p-tau181) , a marker of amyloid-induced neuronal injury in AD, as well as slowing of hippocampal atrophy and stabilization of cognition.

"The 12-month results of our phase 2 trial support the finding that ALZ-801 blocks misfolding of amyloid monomers and subsequent formation of neurotoxic amyloid oligomers, the key initial step in the amyloid aggregation cascade that leads to a rapid and sustained reduction of brain neurodegeneration as measured by plasma p-tau181," John Hey, PhD, Alzheon's chief scientific officer, said in a statement.

"The several-fold greater reduction on the p-tau181 biomarker in plasma compared to plaque-clearing anti-amyloid antibodies, combined with preservation of brain hippocampal volume and their positive correlations with cognitive benefits, further validate the disease-modifying effects of ALZ-801 in Alzheimer's patients," Hey added.

The results were presented here at the American Academy of Neurology (AAN) 2023 Annual Meeting.

Phase 3 Trial Underway

ALZ-801 is an optimized prodrug of tramiprosate that has been shown to inhibit amyloid-beta 42 aggregation into toxic oligomers.

The ongoing phase 2 study is evaluating the effects of oral ALZ-801 (265 mg twice daily) on biomarkers of AD pathology for 84 adults with early AD who have either the APOE4/4 or APOE3/4 genotype. These genotypes represent the majority of AD patients.

The mean age of the cohort was 69 years, and 51% are women; 70% have mild cognitive impairment, and 30% have mild AD. The mean Mini-Mental State Examination score for the cohort was 26.0. Roughly half are taking a cholinesterase inhibitor.

Significant plasma p-tau181 reduction was observed at 13 weeks. Levels were reduced by 41% by 52 weeks (P = .016). There was also a significant 5% reduction in plasma amyloid-beta 42 and 40 at 52 weeks (P = .002 and P = .005), Hey reported.

After 12 months of treatment, hippocampal atrophy was reduced by about 23%, and expansion of ventricular volume was reduced by about 15%, both in comparison with matched controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Composite cognitive Z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks in comparison with matched ADNI controls. "These are very promising data," Hey told conference attendees.

He noted that the safety profile of ALZ-801 remains favorable and consistent with prior safety data. Common adverse events were mild nausea and SARS-CoV-2 infection. There were no drug-related serious events or amyloid-related imaging abnormalities-edema (ARIA-E).

The phase 3 APOLLOE4 study of ALZ-801 is underway. This double-blind, randomized study is comparing oral ALZ-801 to placebo over 78 weeks for roughly 300 adults with early AD who have the APOE4/4 genotype. APOLLOE4 is expected to be completed in mid 2024.

The APOLLOE4 study is supported by a $47 million grant from the National Institute on Aging. The US Food and Drug Administration has granted ALZ-801 fast-track designation.

More Accessible Option?

Reached for comment, Percy Griffin, PhD, Alzheimer's Association director of scientific engagement, noted that the "biggest difference between this drug and others is that it is taken orally, rather than delivered through an infusion. This is important and valuable for reducing patient and caregiver burden and increasing ease of use and access."

It's also noteworthy that ALZ-801 was not associated with ARIA-E, "which has been reported in other anti-amyloid trials and can occasionally be serious," Griffin said.

Overall, he said the results are "encouraging, but more work is needed. If studies results continue to be positive, this treatment may provide a more accessible option for people who are at higher risk of ARIA," Griffin told Medscape Medical News.

The study was funded by Alzheon. Hey is an employee of Alzheon and holds stock in the company. Griffin has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2023 Annual Meeting: Abstract 3243. Presented April 24, 2023.

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