New data from Alzheon's phase 3 APOLLOE4 trial revealed that valiltramiprosate (ALZ-801) failed to meet its primary endpoint in mild Alzheimer's disease but demonstrated significant benefits in patients with milder forms of the disease, particularly those with mild cognitive impairment (MCI).
The findings, presented at the 2025 AD/PD International Conference on Alzheimer's and Parkinson's Diseases in Vienna, Austria, highlight a potential new treatment approach for high-risk patients who are often excluded from other therapies.
Significant Benefits in Early-Stage Disease
The double-blind, randomized APOLLOE4 trial enrolled 325 early Alzheimer's patients who received either valiltramiprosate 265 mg twice daily (n=163) or placebo (n=162) for 78 weeks. While the study did not achieve statistical significance on its primary endpoint of the Alzheimer's Disease Assessment-Cognitive (ADAS-Cog13) subscale in the overall population, a prespecified analysis of the MCI subgroup showed remarkable results.
In patients with MCI, valiltramiprosate demonstrated:
- A nominally significant 52% benefit on ADAS-Cog13
- A 102% improvement on Clinical Dementia Rating-sum of boxes (CDR-SB)
- A 96% slowing (P=.016) on the Disability Assessment for Dementia (DAD)
- A 70% slowing (P=.268) in Instrumental Activities of Daily Living (IADL)
"The APOLLOE4 study is truly one of a kind, focusing exclusively on ApoE4 homozygous carriers—those at the highest risk of Alzheimer's disease," said Anton Porsteinsson, MD, director of the Alzheimer's Disease Care, Research, and Education Program at the University of Rochester. "These patients not only have significant amyloid pathology but also fragile brain vasculature, making them particularly vulnerable to ARIA when treated with monoclonal antibodies."
Novel Mechanism of Action
Unlike anti-amyloid monoclonal antibodies such as Leqembi (lecanemab) and Kisunla (donanemab), which target amyloid plaques, valiltramiprosate works by stabilizing amyloid monomers to prevent them from misfolding and forming toxic oligomers.
"In patients with mild cognitive impairment, we saw a robust response—a 2.1-point difference on the ADAS-Cog at 78 weeks, with separation from placebo emerging as early as week 13," Porsteinsson noted. "These findings suggest a potential benefit, particularly in earlier stages of the disease."
Favorable Safety Profile for High-Risk Patients
A key advantage of valiltramiprosate is its safety profile, particularly regarding amyloid-related imaging abnormalities (ARIA), a concern with monoclonal antibodies. The incidence of ARIA was similar between the valiltramiprosate (3%; n=5) and placebo (3%; n=5) groups, with microhemorrhages actually more frequent in the placebo group (14%; n=21) than in the treatment group (9%; n=13).
This safety profile is especially significant for APOE4 homozygotes, who have a high burden of Alzheimer's pathologies and cerebral amyloid angiopathy (CAA). Prior to randomization, 31% of patients had at least one microhemorrhage, 5% had at least 10 microhemorrhages, and 10% had siderosis.
The most common treatment-emergent adverse events included COVID-19 (21%), nausea (26%), weight decrease (14%), decreased appetite (10%), and vomiting (10%).
Biomarker and Imaging Evidence
Valiltramiprosate also showed positive effects on volumetric MRI and microstructural DTI results. In the overall sample, the therapy demonstrated:
- 18% slowing in hippocampal volume loss
- 20% slowing in cortical thickness whole brain average
- 18% slowing in cortical thickness Mayo Index
- 22% reduction in ventricular volume expansion
- 16% preservation in whole brain volume
These effects were more pronounced in the MCI group, with percentage improvements of 26%, 35%, 28%, 29%, and 22%, respectively.
Additionally, the drug showed positive effects on grey matter and white matter microstructure by DTI mean diffusivity, with significant reductions in the caudate, striatum, cingulate cortex, fornix, corpus callosum, and corona radiata relative to placebo.
Market Potential and Future Directions
The oral administration of valiltramiprosate gives it a competitive advantage over injectable monoclonal antibodies in terms of ease of use for patients. GlobalData forecasts that valiltramiprosate could generate US sales of approximately $663.3 million in the MCI patient populations by 2033, accounting for 82% of potential total early Alzheimer's sales.
Given the APOLLOE4 results, Alzheon may focus regulatory approval efforts on the MCI patient population rather than mild Alzheimer's disease. The company is also planning to evaluate valiltramiprosate in additional patient populations, with prevention in APOE4 homozygotes as a promising option, since the results showed greater efficacy when the drug was administered earlier in the disease course.
These findings build on previous phase 2 results, which showed a 31% reduction in plasma phosphorylated tau (p-tau)181 at 104 weeks and approximately 28% lower hippocampal atrophy compared to an external control group.
For patients with APOE4 homozygosity who are often excluded from treatment with monoclonal antibodies due to ARIA risk, valiltramiprosate could potentially fill a significant unmet need in the Alzheimer's treatment landscape.
