Valiltramiprosate Demonstrates Greater Promise in Earlier Stages of Alzheimer Disease, Phase 3 APOLLOE4 Study Shows

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Key Takeaways

Valiltramiprosate showed significant cognitive benefits in MCI patients, despite not meeting the primary endpoint in mild Alzheimer's disease.
The trial focused on ApoE4 homozygous carriers, who are at high risk for Alzheimer's and have significant amyloid pathology.
Safety profiles were similar between treatment and placebo groups, with some adverse events like COVID-19 and nausea reported.
The study suggests valiltramiprosate may be more effective in early-stage Alzheimer's, particularly in patients with mild cognitive impairment.

Although valiltramiprosate failed to distinguish itself from placebo on the primary end point, the drug performed significantly better among mild MCI participants vs those with mild Alzheimer disease.

Anton Porsteinsson, MD

New data from the phase 3 APOLLOE4 trial (NCT04770220) of valiltramiprosate (Alzheon), a valine prodrug of tramiprosate, showed that the agent did not meet its primary end point in a larger cohort of mild Alzheimer disease (AD); however, did show more prominent benefits in a prespecified mild cognitive impairment (MCI) population.¹

These findings were presented in a plenary session at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria. APOLLOE4, a double-blind, randomized trial, enrolled 325 early AD patients to either valiltramiprosate (n = 163) 265 mg BID or placebo (n = 162) for a 78-week period. At the conclusion of the double-blind period, investigators observed a lack of statistically significance between groups on the primary end point of Alzheimer’s Disease Assessment-Cognitive (ADAS-Cog13) subscale.

Despite the study failing to meet its primary end point, clinical benefits were observed in patients with lesser progressed forms of the disease. Overall, in the prespecified MCI population, there was a nominally significant 52% benefit on ADAS-Cog13 and a 102% improvement on Clinical Dementia Rating-sum of boxes (CDR-SB). In addition, this group demonstrated a 96% slowing (P = .016) on DAD and a 70% slowing (P = .268) in Instrumental Activities of Daily Living (IADL). For comparison, in the full analysis set, comprising both MCI and mild AD, the agent demonstrated an 11% slowing on ADAS-Cog13 (P = .607), 23% slowing on CDR-SB (P = .309), 29% slowing on DAD (P = .279), and a 17% slowing on Mini-Mental State Exam (MMSE; P = .454).

"The APOLLOE4 study is truly one of a kind, focusing exclusively on ApoE4 homozygous carriers—those at the highest risk of Alzheimer's disease,” Anton Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research, and Education Program at the University of Rochester, told NeurologyLive. “These patients not only have significant amyloid pathology but also fragile brain vasculature, making them particularly vulnerable to ARIA when treated with monoclonal antibodies. This study gives us an opportunity to explore an alternative approach that might be safer and more effective for this high-need group."

Coming into the study, 41% of those in the valiltramiprosate group had MCI. The cohort, which comprised patients who have 2 copies of the apolipoprotein e4 allele (APOE4/4 homozygotes), tended to have a high burden of AD pathologies and cerebral amyloid angiopathy (CAA). Prior to randomization, 31% of patients had at least 1 microhemorrhage (MH), 5% had at least 10 MHs, and 10% had siderosis.

Valiltramiprosate failed to perform as well in the mild AD population, with results favoring placebo on all outcomes. In this population, treatment with valiltramiprosate led to an –18% slowing vs placebo on ADAS-Cog13, –7% slowing on CDR-SB, –5% slowing on DAD, –7% slowing on MMSE, and –20% slowing on A-IADL, all favoring placebo. Above all, these data reinforced the finding that greater magnitude of cognitive benefit was achieved at earlier AD stages.

"Valiltramiprosate works by stabilizing amyloid monomers, preventing them from misfolding and forming toxic oligomers,” Porsteinsson added. “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. These findings suggest a potential benefit, particularly in earlier stages of the disease."

In terms of safety, the incidence of amyloid-related imaging abnormalities (ARIA) was similar between the valiltramiprosate (3%; n = 5) and placebo (3%; n = 5) groups. Notably, MH were more frequent in the placebo group (14%; n = 21) than in the active treatment cohort (9%; n = 13). Treatment-emergent adverse events (TEAEs) were slightly higher in the valiltramiprosate group, with the most common being COVID-19 (21%), nausea (26%), weight decrease (14%), decreased appetite (10%), and vomiting (10%).

On volumetric MRI and microstructural DTI results, the therapy outperformed placebo across a number of measures, including in both the overall sample and those with prescpecified MCI. In the overall sample, the study showed 18% slowing in hippocampal volume (HV), 20% slowing in CT whole brain average, 18% slowing in CT Mayo Index, –22% slowing in ventricular volume (VV), and 16% in whole brain volume (WBV), all favoring valiltramiprosate. These effects were more pronounced in the MCI group, with percentage slowing of 26%, 35%, 28%, –29%, and 22%, respectively.

In the MCI group, investigators reported positive effects on grey matter (GM) and white matter microstructure (WMM) by DTI mean diffusivity (MD). On GM, treatment with the investigational agent led to –78% MD reduction in caudate, –89% MD reduction in striatum, and –155% MD reduction in cingulate cortex. On white matter, reported data revealed –123% MD reduction in fornix with valiltramiprosate, –93% MD reduction in whole corpus callosum, and –62% MD reduction in whole corona radiate, relative to placebo.

The previously completed phase 2 trial (NCT04693520) of ALZ-801 achieved its primary endpoint, showing a 31% reduction in plasma phosphorylated tau (p-tau)181 at 104 weeks. The study included 84 participants, with an average age of 69 years and a Mini-Mental State Exam score of 26.0. Most patients (70%) had mild cognitive impairment (MCI). Researchers assessed plasma and clinical outcomes every 13 weeks, while MRI scans were performed annually to monitor biomarker and structural changes.²

Findings presented at the 2024 American Academy of Neurology Annual Meeting revealed that ALZ-801 had a notable effect on Alzheimer disease biomarkers, including amyloid-ß (Aß). Between weeks 52 and 104, treatment led to a 4% reduction in Aß42 levels. Additionally, hippocampal atrophy was measured at 3.6%, approximately 28% lower than rates observed in the Alzheimer Disease Neuroimaging Initiative (ADNI-1) external control group, suggesting a potential slowing of neurodegeneration.

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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.
2. Kesslak JP, Hey JA, Abushakra S, et al. Positive disease modifying effects of oral ALZ-801 on plasma biomarkers, volumetric MRI and cognition at 104 weeks: results of a phase 2 study of APOE4 carriers with early Alzheimer’s disease. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract ES1-001