AAN 2023: ALZ-801 for Alzheimer’s found to improve cognition in trial

Treatment for 1 year also seen to reduce levels of disease biomarkers

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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One year of treatment with ALZ-801 (valiltramiprosate) was found in a Phase 2 trial to improve cognition and lower the levels of disease biomarkers among people with early Alzheimer’s with one or two copies of the apolipoprotein E4 (APOE4) disease-associated genetic variant.

Importantly, the investigational therapy from Alzheon did not cause certain side effects, such as brain swelling and bleeds, that have been sometimes linked to anti-amyloid antibody therapies — ones to which APOE4 carriers may be particularly susceptible.

The new findings were detailed by John A. Hey, PhD, chief scientific officer of Alzheon, in an oral presentation at the American Academy of Neurology (AAN) Conference, held April 22-27 in Boston and virtually.

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Trials testing ALZ-801 for patients with APOE4 genetic variant

The ongoing Phase 3 APOLLOE4 trial (NCT04770220) is now seeking to confirm the findings of the Phase 2 trial (NCT04693520) among more than 300 Alzheimer’s patients who each have two APOE4 copies.

The Phase 2 trial will finish later this year, and APOLLOE4 is expected to finish in mid-2024. Alzheon plans to file for regulatory approval of ALZ-801 in 2024, with an expected commercial launch in 2025.

“We are potentially two years from a commercial launch of ALZ-801 in the U.S.,” Martin Tolar, MD, PhD, founder, president and CEO of Alzheon, said in a company press release.

Tolar said trial data so far “position ALZ-801 to potentially become the first oral agent that can slow or even stop and prevent Alzheimer’s pathology [disease mechanisms].”

ALZ-801 is an oral small molecule that works to inhibit the formation of amyloid-beta oligomers, or toxic clumps. These aggregates or clumps form when single amyloid-beta proteins, or monomers, misfold and become prone to sticking together.

Oligomers are known to accumulate in the brains of Alzheimer’s patients and contribute to cognitive decline. Individuals with at least one copy of the APOE4 genetic variant tend to show a particularly high buildup of toxic amyloid-beta in the brain.

Other anti-amyloid antibody therapies work by breaking down amyloid aggregates that have already formed. In contrast, ALZ-801 aims to prevent such clumps from forming by making sure amyloid monomers don’t misfold.

The Phase 2 trial is assessing the safety and efficacy of daily ALZ-801 treatment for up to two years in 84 adults with early Alzheimer’s who have one or two copies of APOE4.

Interim six-month results indicated that ALZ-801 safely lowered the levels of p-tau 181, a key biomarker of neurodegeneration, and led to significant memory improvements.

We are potentially two years from a commercial launch of ALZ-801 in the U.S.

In the AAN presentation, titled “Effects of ALZ-801, an Oral Amyloid Oligomer Inhibitor, on Biomarkers of Alzheimer’s Disease (AD): 12-Month Results of Phase 2 Biomarker Study in Early AD,” Hey reported one-year findings from the Phase 2 trial.

A total of 75 participants completed a year of treatment. These patients had a mean age of 69 and 52% were women.

Blood p-tau 181 levels were significantly reduced with ALZ-801 starting at 13 weeks, or just longer than three months. By one year after the study’s start (baseline), they had generally declined by 41%, reflecting a “profound and sustained effect,” according to Hey.

Moreover, the levels of toxic amyloid-beta species were significantly reduced by about 5% after a year, consistent with the therapy’s expected mechanism of action.

Tissue loss in the hippocampus — a brain region important for memory — was reduced by about 23% compared with data from an external untreated control group included in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Cognitive performance also improved after 13 weeks relative to baseline and remained elevated after a year of treatment. In contrast, those in the external control group saw progressive declines in cognition over a period of one year.

ALZ-801 was well tolerated, with no evidence of vascular edema, or fluid buildup and brain swelling, also known as Amyloid Related Imaging Abnormalities – Edema (ARIA-E).

Together, according to the researchers, the findings support the design of the ongoing APOLLOE4 trial, which includes patients with two copies of APOE4.

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Complications may be more likely for patients with two APOE4 copies

In another poster presentation, titled “Prevalence of Amyloid-Related Imaging Abnormalities in APOE4/4 Homozygotes with Early Alzheimer’s Disease: Baseline Findings from Ongoing Clinical Trials of Oral Anti-Amyloid Agent ALZ-801 (Valiltramiprosate),” researchers discussed baseline imaging findings from APOLLOE4 trial participants prior to starting treatment.

Data indicated these patients showed a high burden of brain lesions associated with amyloid accumulation in blood vessels, and nearly one-third (32%) had signs of microhemorrhages, or small bleeds in the brain resulting from ruptured small blood vessels, which is also known as ARIA-H.

Anti-amyloid antibody therapies are sometimes linked to ARIA-E or ARIA-H because they cause blood vessel inflammation as they work to breakdown amyloid-beta clumps.

The observations support previous findings that patients with two APOE4 copies may be particularly susceptible to these treatment complications, according to the researchers.

Still, the mechanism of ALZ-801 may allow for these types of issues to be bypassed, according to Susan Abushakra, MD, Alzheon’s chief medical officer.

Consistently, ongoing analyses from the Phase 2 and 3 studies “show no increased risk for brain edema and bleeds,” Abushakra said.