Amyloid-Beta MAbs Offer Little Benefit in Alzheimer’s, but ALZ-801 Shows MCI Efficacy
A Cochrane review of 17 trials finds amyloid-beta-targeted monoclonal antibodies offer negligible benefit in MCI or mild Alzheimer’s. In a phase 3 trial, the oral agent valiltramiprosate (ALZ-801) showed significant cognitive and functional improvements in the MCI subgroup, with no brain swelling risk. The company plans another phase 3 study in 2026.
A systematic review of amyloid-beta-targeted monoclonal antibodies found negligible or little effect for patients with mild cognitive impairment (MCI) or mild Alzheimer’s disease, while an investigational oral therapy, valiltramiprosate (ALZ-801), demonstrated significant cognitive and functional benefits in a prespecified MCI subgroup of a phase 3 trial, with no increased risk of brain edema.
The Cochrane review, published April 15 in the Cochrane Database of Systematic Reviews, included 17 randomized controlled trials lasting at least 12 months with 20,342 participants. It compared amyloid-beta-targeting monoclonal antibodies to placebo or no treatment. Results showed probably little to no difference in cognitive function as measured by the Alzheimer’s Disease Assessment Scale-Cognitive scale (standardized mean difference [SMD], −0.11) and little to no difference in dementia severity as measured by the Clinical Dementia Rating Sum of Boxes scale (SMD, −0.12). Amyloid-beta-targeting monoclonal antibodies probably resulted in little to no difference in functional ability measured on the Alzheimer’s Disease Cooperative Study (ADCS)-Activities of Daily Living scale (SMD, 0.09), and may yield a small increase if measured by the ADCS-Instrumental Activities of Daily Living scale or ADCS-Activities of Daily Living for Mild Cognitive Impairment scale (SMDs, 0.21 and 0.23, respectively). “There is now a convincing body of evidence converging on the conclusion that there is no clinically meaningful effect,” the researchers stated.
In contrast, the oral anti-amyloid oligomer agent valiltramiprosate (ALZ-801) showed nominally significant benefits in the MCI stage of Alzheimer disease in the APOLLOE4 phase 3 trial. ALZ-801 is designed to inhibit the formation of neurotoxic soluble beta amyloid oligomers, and preclinical studies showed complete blockade of oligomer formation at the phase 3 dose. The agent received FDA fast-track designation in 2017. The APOLLOE4 trial enrolled 325 APOE ε4/ε4 homozygotes aged 50–80 with early Alzheimer disease (Mini-Mental State Examination score 22–30, Clinical Dementia Rating-Global Score 0.5–1). Participants were randomized to ALZ-801 265 mg twice daily or placebo.
At 78 weeks, the overall trial population did not show a significant effect on the primary endpoint, ADAS-Cog13 (11% slowing, p=0.607), but did show significant slowing of hippocampal atrophy (18%, p=0.017). In a prespecified analysis of the MCI subgroup (MMSE >26, n=125), ALZ-801 significantly slowed cognitive decline on ADAS-Cog13 by 52% (p=0.041) and improved functional abilities on the Disability Assessment for Dementia (DAD) scale by 96% (p=0.016). The Clinical Dementia Rating-Sum of Boxes showed a positive trend (102% slowing, p=0.053). Hippocampal atrophy was slowed by 26% (p=0.004), and positive microstructural brain changes were observed on diffusion tensor imaging. The drug’s cognitive benefits correlated with imaging outcomes. Common adverse events included nausea, vomiting, and decreased appetite, with no increased risk of brain vasogenic edema or microhemorrhages.
Alzheon’s CEO stated, “Valiltramiprosate has emerged as the only late-stage oral treatment with a potential to materially change the Alzheimer therapeutic landscape in the near future,” and announced plans for a next phase 3 study in 2026 based on the APOLLOE4 results and its long-term extension.