Therapeutic Potential of ALZ-801 in High-Risk Alzheimer Disease: Susan Abushakra, MD

WATCH TIME: 5 minutes

"The other exciting thing is that these effects on imaging and cognitive outcomes look very much like our previous data with the old formulation in APOE e4 homozygotes because patients initially showed symptomatic benefit or improvement over their own baseline, and over a year, they remained above baseline. We’ve protected their cognition and that hippocampus for a whole year."

The most common gene associated with late-onset Alzheimer disease (AD) is a risk gene called apolipoprotein E (APOE). It comes in 3 common forms: APOE e2—the least common—reduces the risk of AD; APOE e4—slightly more common—increases the risk of AD and is associated with getting the disease at an earlier age; and APOE e3—the most common—does not appear to affect the risk of AD. Studies suggest that having at least 1 APOE e4 gene can increase the risk of developing AD 2-to 3-fold.

Genetic predispositions can play a major role in the outcomes of therapeutics being assessed for AD. ALZ-801 (Alzheon), a novel, investigational agent in development for AD, aims to be the first disease-modifying therapy specific for those who carry APOE e4/4 homozygotes. In September 2020, the company began a phase 2 open-label biomarker study (NCT04693520), evaluating primary outcomes of change in cerebrospinal fluid phosphorylated tau (p-tau) 181 and adverse events. The study featured 84 patients who had either APOE e4/4 or APOE e3/4 genotype and prior positive amyloid-PET or cerebrospinal fluid (CSF) biomarkers fulfilling amyloid positive and tau positive criteria.

Susan Abushakra, MD, chief medical officer of Alzheon, presented interim 1-year data from the study at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California. All told, treatment with ALZ-801 resulted in a reduction of 41% in plasma p-tau181 (P = .016) after 52 weeks. Additionally, the time course of amyloid-ß (Aß)₄₂ and Aß₄₀ changes in plasma suggested clearance of soluble Aß monomers from brain to plasma, with significant reductions seen at 1 year.

In an interview with NeurologyLive^®, Abushakra provided insight into the results presented at CTAD, including the most notable take-home findings clinicians should be aware of. Additionally, she discussed the importance of biomarker analyses, the role Aß_42/40 has in AD, and the mechanism of action of ALZ-801. She also provided context on the agent’s impact on hippocampal volume, which has been previously associated with cognitive decline and other indicators of AD neuropathology.

Click here for more coverage of CTAD 2022.

REFERENCE
1. Abushakra S, Hey J, Bennow K, et al. Significant effects of oral ALZ-801 on plasma biomarkers of Alzheimer’s disease: 12-month interim analysis of phase 2 biomarker study in APOE4 carriers with early AD. Presented at: 2022 CTAD Conference; November 29-December 2; San Francisco, CA. Abstract OC27