Sabirnetug (ACU-193): A Selective Amyloid-β Oligomer Antibody for Early Alzheimer's Disease

1. Executive Summary

Sabirnetug (ACU-193) is an investigational humanized monoclonal antibody being developed by Acumen Pharmaceuticals for the treatment of early Alzheimer's Disease (AD).[1] Its therapeutic strategy is centered on the selective targeting of soluble amyloid-β oligomers (AβOs), which are increasingly recognized as key neurotoxic species in AD pathogenesis, distinct from amyloid monomers and plaques.[2] This approach aims to directly address what is hypothesized to be an early and persistent driver of neurodegeneration.[4]

The Phase 1 INTERCEPT-AD trial (NCT04931459), a randomized, placebo-controlled study in patients with early AD, demonstrated that intravenously administered sabirnetug was generally well-tolerated.[1] Importantly, the trial reported low overall rates of amyloid-related imaging abnormalities with edema/effusion (ARIA-E), a notable concern with other amyloid-targeting therapies, particularly in APOEε4 homozygotes who, in this study, did not develop ARIA.[6] The study also provided evidence of dose-dependent central target engagement, with sabirnetug binding to AβOs in the cerebrospinal fluid (CSF).[6] Furthermore, treatment with sabirnetug led to statistically significant reductions in amyloid plaque load at higher doses and modulated downstream biomarkers of AD pathology, including CSF pTau181 and synaptic markers like VAMP2 and neurogranin.[8] These findings suggest a cascade of biological activity, from target engagement to effects on downstream pathology.