Targeting Amyloid-ß Oligomers With Investigational Alzheimer Disease Therapy Valiltramiprosate

Sam Gandy, MD, PhD

(Credit: Mount Sinai)

Alzheon’s valiltramiprosate, formally known as ALZ-801, is an oral therapy currently being assessed in a phase 3 clinical trial (NCT04693520) for the treatment of APOE4 carriers, an at-risk population, with early-stage Alzheimer disease (AD). At the recently concluded 2025 Alzheimer’s Association International Conference, held July 27-30, in Toronto, Canada, the company presented data on valiltramiprosate, which included clinical and volumetric MRI findings observed among patients with mild cognitive impairment who carried 1 or 2 copies of the APOE4 gene.^1,2

An investigational therapy, valiltramiprosate is designed to bind to monomeric ß amyloid to prevents the formation of soluble oligomers. In a quantitative systems pharmacology analysis, findings revealed that a reduced formation of toxic amyloid oligomers was associated with preservation of hippocampal volume, attenuation of neurodegeneration across all brain regions, and slowing of disease progression. These effects were most pronounced in the high-risk APOE4/4 population, which carries a greater burden of neurotoxic amyloid oligomers.

Alzheimer expert Sam Gandy, MD, PhD, director of the Center for Cognitive Health at the Icahn School of Medicine at Mount Sinai and others presented these findings during a symposium at AAIC 2025. Following the session, Gandy, who also serves as the associate director of the Mount Sinai Alzheimer's Disease Research Center, spoke with NeurologyLive^® to offer insights on the recent findings on amyloid-ß oligomers discussed at the symposium, highlighting their toxicity, resistance to current detection methods, and role in AD progression. He also discussed preclinical data suggesting that valiltramiprosate could prevent oligomer and fibril formation in vitro, as well as research into mitochondrial activation as a potential neuroprotective strategy.

NeurologyLive: Could you provide an overview of the valiltramiprosate symposium presented at AAIC 2025?

Sam Gandy, MD, PhD: The symposium was dedicated to these unusual structures of the amyloid-ß peptide called oligomers and they’re challenging in several ways. The first is that they’re not readily detectable. There’s no standard way of detecting them in spinal fluid or with PET scans during life. The second is that they’re toxic—just as toxic, or maybe even more so, than the standard amyloid fibrils. Because of that, we won’t be able to be sure that we’ve gotten rid of all amyloid-ß toxicity until we find a way to monitor these and either expel them from the brain or neutralize their toxicity and that’s their importance. Most particularly, these standard amyloid PET scans that are used to detect amyloid will not pick up oligomers because the ligands used for PET scans now only bind the fibrils.

How did your presentation reflect on the mechanism of action of this investigational therapy?

I showed some results both from the literature and from our lab. From the literature, it’s important to see that there are patients with certain forms of AD—for example, the form associated with the Arctic mutation—whose amyloid scans will never become positive no matter how long they have the disease, despite the fact that they’re just as impaired as people who have positive scans. That’s because the mutation that causes Arctic familial AD is in the middle of the amyloid-ß domain and prevents fibrils from forming, so they form only oligomers. We’ve been studying a mouse that accumulates only oligomers and using that to try and get to the mechanism to find out where in the cell the oligomers are poisoning nerve cells. We have some evidence that it involves mitochondria, and we’re looking at new ways of activating mitochondria to try and neutralize amyloid-ß toxicity or oligomer toxicity.

What were the implications of the findings that were presented at the conference?

Well, the new compound that Alzheon is working on targets oligomers and their folding. There was another speaker in the symposium who had nice video evidence of watching oligomers and fibrils form in a dish as a sort of movie. And you can watch that if, when the drug was added, the oligomers and fibers didn’t form. So certainly, in that situation, the medicine looked really promising in terms of being able to stop the formation of oligomers and fibrils in a dish.

I mean, there are still additional trials that have to be performed to confirm the results and to get more evidence on the mechanism, but the data that are accumulating so far certainly make it worthwhile to pursue further. Another thing that’s going to be done is to try and measure the standard blood and spinal fluid biomarkers that we’re using now to diagnose AD and see how these medicines affect those biomarkers.

Do you have any closing remarks on the presentations given at AAIC this year in general?

There certainly are a lot of new leads. I think that we’ll eventually need some medicine to target inflammation, and that’s certainly part of how AD causes damage to the brain. The use of small interfering RNAs—siRNAs—to knock down levels of amyloid and tau has been remarkably well tolerated and has durable effects, so they don’t get discussed as much as the antibodies, but these siRNA strategies are also very promising.

Transcript edited for clarity. Click here for more coverage of AAIC 2025.

REFERENCES
1. Cohen S, Gandy S, Ono K, Geerts H, Hey J. Inhibition of Beta Amyloid Oligomer Neurotoxicity with Oral Valiltramiprosate. Presented at: 2025 Alzheimer’s Association International Conference; July 27-31; Toronto, Canada.
2. Alzheon to Present Insights into Oral Valiltramiprosate/ALZ-801 Mode of Action and Clinical Efficacy at Dedicated Symposium at Alzheimer’s Association International Conference in Toronto on July 30th, 2025. News Release. Alzheon. Published July 15, 2025. Accessed August 11, 2025. https://alzheon.com/alzheon-to-present-insights-into-oral-valiltramiprosate-alz-801-mode-of-action-and-clinical-efficacy-at-dedicated-symposium-at-alzheimers-association-international-conference-in-toronto/