Valiltramiprosate Demonstrates Beneficial Imaging Impacts on Less Progressed Subgroup of APOE4 Homozygotes

Susan Abushakra, MD, chief scientific officer at Alzheon

In a pre-specified cohort of patients with mild cognitive impairment (MCI), results from the phase 3 APOLLOE4 trial (NCT04770220) showed that investigational valiltramiprosate (Alzheon) had significant impacts on imaging outcomes such as hippocampal volume (HV), cortical thickness, and whole brain volume. Investigators concluded that these strong correlations seen at the MCI stage support its efficacy and are consistent with its proposed mechanism of inhibiting amyloid oligomer formation.¹

In this double-blind, randomized trial, patients with early-stage Alzheimer disease (AD) who had 2 copies of the apolipoprotein e4 allele (APOE4/4 homozygotes) were randomly assigned to valiltramiprosate (n = 163) 265 mg BID or placebo (n = 162) for a 78-week period. The pre-specified MCI group included 125 patients (58 on placebo; 67 active), while the imaging population included 54 patients on placebo and 62 on active drug. Within this subgroup, there were significant slowing of HV by 26% (P = .004), cortical thickness by 35% (P <.0001), and whole brain volume atrophy by 22% (P = .027).

Presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada, the MCI subgroup demonstrated positive effects on ADAS-cog/Disability Assessment for Dementia (DAD; nominal P <.05) and a trend on Clinical Dementia Rating-Sum of Boxes (CDR-SB; P = .053), the study’s primary and key secondary outcome, respectively. In the study, lead investigator Susan Abushakra, MD, chief scientific officer at Alzheon, and others, used Spearman’s correlations to determine drug-effect correlations while pre-specifying each analysis based on disease stage.

In the analysis, results showed those randomized to active treatment had changes in HV that correlated significantly with change in ADAS-cog13 (r = –0.40; P <.005), CDR-SB (r = –0.45; P <.005), and DAD (r = 0.33; P = .018). For cortical thickness, the correlations were also significant: ADAS-Cog13 (r = 0.34; P = .015), CDR-SB (r = 0.49; P <.005), and DAD (r = 0.40; P <.005). Notably, whole brain volume treatment effect also correlated with clinical outcomes (P ≤.01).

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A second analysis presented at AAIC 2025 looked at valiltramiprosate’s effects on microstructural integrity of grey and white matter in both those with MCI (n = 84) and mild AD (n = 122). In the overall population, using mean water diffusivity (MD), treatment with the agent resulted in positive trends (P <0.1) on cingulate/occipital cortex and caudate/striatum relative to placebo, as well as significant effects on white matter (WM) structures such as corpus callosum genu (P <.001) and fornix (P = .007).²

The mild AD group showed positive trends on occipital cortex and significant WM effects (GCC: P = .005; fornix: P = .019), while the MCI group showed significant effects in cingulate (P = .031) and WM (GCC/whole CC: P = .003/0.013) as well as fornix (P = .032). In the MCI active arm, dMRI effects showed significant correlations with both clinical and volumetric measures, including frontal cortex mean diffusivity with ADAS-Cog13/CDR-SB (P < 0.05) and with hippocampal volume and cortical thickness (both P = 0.002), as well as WM-GCC diffusivity with hippocampal volume (P = 0.03) and cortical thickness (P = 0.006).

The first data release for APOLLOE4 was presented earlier this year at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria. In the study, valiltramiprosate, a valine prodrug of tramiprosate, did not meet its primary end point of change in ADAS-Cog13; however, did show more prominent benefits in the prespecified MCI population. In this group, investigators observed a nominally significant 52% benefit on ADAS-Cog13 and a 102% improvement in CDR-SB.³

Additional data from the original release showed a 96% slowing (P = .016) on DAD and a 70% slowing (P = .268) in Instrumental Activities of Daily Living. For comparison, in the full analysis set, comprising both MCI and mild AD, treatment with the agent resulted in an 11% slowing in ADAS-Cog13 (P = .607), 23% slowing on CDR-SB (P = .309), 29% slowing on DAD (P = .279), and 17% slowing on Mini-Mental State Exam (P =.454).

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REFERENCES
1. Abushakra S, Doraiswamy M, Liang E, etl al. Correlations of Valiltramiprosate Effects on Hippocampal Volume and Cortical Thickness with Clinical Outcomes in the Pre-Specified MCI Group: Subgroup Analysis from the 78-Week APOLLOE4 Phase 3 Trial in APOE4/4 Homozygotes. Presented at: AAIC 2025; July 27-31; Toronto, Canada. ABSTRACT 108827
2. Liang E, Abushakra S, Doraiswamy M, et al. Valiltramiprosate Effects on Microstructural Integrity of Grey and White Matter in APOE4/4 Homozygotes with Early AD and their Correlations to Clinical Outcomes: MRI Mean Diffusivity Results from the 78-Week APOLLOE4 Phase 3 Trial. Presented at: AAIC 2025; July 27-31; Toronto, Canada. ABSTRACT 108716
3. 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.