Overviewing Valiltramiprosate’s Therapeutic Impact on Volumetric Imaging MRI, Diffusion Tensor Imaging in Alzheimer Disease

Murali Doraiswamy, MD, MBBS

The 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, was kicked off with a thorough presentation on new data from the phase 3 APOLLOE4 trial (NCT04770220), a large-scale study of investigational valiltramiprosate (Alzheon) in patients with Alzheimer disease (AD) who had 2 copies of the apolipoprotein e4 allele (APOE4/4 homozygotes). In this unique, double-blind study, 325 patients were randomly assigned to either valiltramiprosate (n = 163) 265 mg BID or placebo (n = 162) for a 78-week period, using change in Alzheimer’s Disease Assessment-Cognitive (ADAS-Cog13) subscale as the primary end point.

While the study failed to meet its primary end point, the therapy did show more pronounced clinical benefits in patients with earlier, less progressed of the disease. Among those with mild cognitive impairment (MCI), there was a nominally significant 52% improvement on ADAS-Cog13 whereas in the full analysis set, which comprised by MCI and mild AD, the agent demonstrated an 11% slowing on ADAS-Cog13 (P = .607). Notably, the less progressed group also demonstrated a 96% slowing (P = .016) on DAD and a 70% slowing (P = .268) on Instrumental Activities of Daily Living.¹

The phase 3 trial presentation included several different talks, comprising efficacy and safety, volumetric MRI and diffusion tensor imaging (DTI) results, fluid biomarkers, and clinical meaningfulness and next steps. Following the meeting, NeurologyLive^® reached out to Murali Doraiswamy, MD, MBBS, a professor of psychiatry and geriatrics at Duke University School of Medicine, who presented on the volumetric MRI, DTI results, and their correlations in the study. Doraiswamy, who also serves as the director of the Neurocognitive Disorders Program, shed light on the main findings observed, the significance of impacting brain atrophy, and the potential of hippocampal volumetry as a surrogate biomarker. Furthermore, he spoke on the mechanism and potential role of valiltramiprosate, a valine drug of tramiprosate, in the treatment landscape of AD.

NeurologyLive: Can you provide clinical insights on the volumetric MRI, diffusion tensor imaging results and their correlations?

Murali Doraiswamy, MD: MRI volumetry was a prespecified secondary outcome. Valiltramiprosate showed a nominally significant 18% benefit in slowing hippocampal volume loss compared to placebo in the overall sample. In the MCI subgroup, valiltramiprosate demonstrated a 26% slowing of hippocampal volume loss. Autopsy and longitudinal studies suggest that 10% or more slowing of hippocampal progression is likely to be clinically meaningful. Valiltramiprosate also had nominally significant effects on other pre-specified secondary brain volume measures, including cortical thickness, ventricular volume, and whole brain volume. These changes suggest a broader impact on slowing the neurodegenerative process.

Exploratory results with diffusion tensor imaging (DTI) showed lower mean diffusivity in some gray and white matter regions, indicating better microstructural integrity and network connectivity. This suggests that valiltramiprosate not only slows atrophy but may potentially also benefit cognitive networks.

Lastly, there were clinically meaningful correlations between changes in hippocampal volume and cognitive measures such as ADAS-Cog and CDR-SB. This indicates that the slowing of hippocampal atrophy is associated with better cognitive outcomes, particularly in the MCI subgroup.

What insights do volumetric MRI and DTI give us about how well an agent may perform on patients with early AD?

If an agent shows positive volumetric MRI and DTI results, along with the correlations to cognitive measures, that would strongly suggest that it has a neuroprotective effect.

Taking both data findings in context, what do they tell us about valiltramiprosate and its effect in this subgroup of MCI APOE4/E4?

You have to keep in mind this is a subgroup analyses. Despite that, the robust volumetric MRI results, combined with the clinical correlations, provide internally consistent evidence of valiltramiprosate’s potential efficacy in MCI APOE4/4 homozygotes. They suggest that the drug’s effects are clinically meaningful and not due to effects such as edema or fluid shifts.

What does valiltramiprosate bring to the Alzheimer community that we’ve been lacking?

Protecting against hippocampal and cortical atrophy is particularly important for APOE4/4 homozygotes who are at a higher risk of rapid clinical decline. Today there are no drugs that are proven to protect against cognitive decline as well as hippocampal and whole brain cortical atrophy. Any drug that is confirmed to show that would become the gold standard. Valiltramiprosate’s effects in the MCI subgroup are very promising in this regard.

The drug is given orally and has a favorable safety profile, with no serious ARIA-related side effects. These benefits could potentially address the unmet need for effective and safe treatments in APOE4/4 homozygotes, who are at highest risk of developing AD as well as ARIA.

What are your thoughts on hippocampal volumetry as a surrogate marker?

We have 30+ years of research showing that the entorhinal cortex and hippocampus are the earliest regions impacted by the AD process. This process is accelerated in E4 carriers.Also, hippocampal volume loss has a much tighter link to memory decline than amyloid.Even a 10-15% loss of hippocampal volume can mean the loss of several million critical neurons. As AD advances, the degeneration spreads to other neocortical areas. I think both hippocampal volume and cortical thickness are very robust surrogate markers. Let’s not forget that the N in neurodegeneration is one of the 3 pillars of the ATN framework.

Transcript edited for clarity. Click here for more AD/PD 2025 coverage.

***Dr. Doraiswamy is a professor of Psychiatry and Geriatrics at Duke University School of Medicine. He is a scientific advisor and shareholder in Alzheon as well as a number of other companies in this field. This article was extracted from his presentation at AD/PD***

REFERENCE
1. Inhibition of beta amyloid oligomer neurotoxicity with oral valiltramiprosate/ALZ-801 in APOE e4/e4 homozygotes with early Alzheimer disease. Presented at: 2025 AD/PD Annual Meeting.