Journal Article

Developing Topics

Geerts, Hugo, Power, Aidan, Tolar, Martin, Short, Shaina M, Schaefer, Jean, Yu, Jeremy, Abushakra, Susan, Hey, John A

2025

Overview

The central hallmark of Alzheimer's disease (AD) is progressive brain atrophy accompanied by amyloid and tau pathologies. Valiltramiprosate is an oral, small-molecule inhibitor of amyloid oligomer formation in development as a disease-modifying treatment for AD. Whereas APOLLOE4 did not meet the primary endpoint of cognitive slowing in overall Early AD population, valiltramiprosate produced a meaningful improvement (ΔADAS-Cog13 = -2.144, p =0.041) and function (ΔCDR-SB = -0.646, p =0.053) in the prespecified Mild Cognitive Impairment (MCI) subjects. Valiltramiprosate consistently reduced atrophy in hippocampus (-26%, p =0.0042 in MCI) and other brain regions, indicating substantive neuroprotective benefits. We report a subpopulation of early symptomatic super-responders in the APOLLOE4 Phase 3 study that exhibited full prevention of hippocampal atrophy and improved cognition over 78 weeks. The multicenter, randomized, double-blind, placebo-controlled APOLLOE4 Phase 3 trial was conducted in 325 APOE4/4 homozygotes with MCI or Mild AD (MMSE ≥22 and CDR-Global 0.5 - 1.0). The valiltramiprosate dose was 265 mg BID for 78 weeks. The primary outcome was ADAS-Cog13, and volumetric hippocampal volume (HV) MRI was an imaging endpoint. The subpopulation reflects AD subjects with an increased HV at 78 weeks over baseline. Eleven super-responder subjects (MMSE 27.7 ± 0.6; 6 males and 5 females) in the active treatment group and two female placebo subjects (MMSE 28.0 ± 0.0) exhibited a greater HV at 78 weeks than baseline. This represents ∼15% and 6.5% of the active MCI and Mild AD subject populations, respectively. There was an increase of 66.0 ± 20.4 mm (mean ± SEM) HV at 78 weeks vs. baseline in the active super-responders. Also, the active super-responders exhibited a younger age (63.7 ± 2.4 years), higher MMSE, and less baseline hippocampal atrophy (8511.6 ± 348.7 mm ) compared to the overall Early AD population (7045 ± 1002 mm ). The prevention of atrophy by valiltramiprosate treatment corresponded with cognitive and functional benefit (ADAS-Cog13, CDR-SB). Valiltramiprosate demonstrates potential for preventing hippocampal atrophy and stabilization of cognitive and functional decline in earliest symptomatic APOE4/4 AD. The results support a potential disease stabilization benefit of oral valiltramiprosate as a prevention therapy in presymptomatic AD.

• Subject: Aged / Alzheimer Disease - drug therapy / Alzheimer Disease - genetics / Alzheimer Disease - pathology / Apolipoprotein E4 - genetics / Atrophy / Brain - drug effects / Brain - pathology / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - pathology / Double-Blind Method / Female / Hippocampus - drug effects / Hippocampus - pathology / Humans / Magnetic Resonance Imaging / Male