Lecanemab: Amyloid Reduction and Evidence of Downstream Biomarker Modification

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils) which has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in a Phase 3 Study in early AD (Study 301). The objective of this analysis is to report biomarker results from Study 301.MethodsStudy 301 was a double‐blind, randomized, placebo‐controlled study of 1875 patients with early AD randomized to 10 mg/kg IV lecanemab or placebo for 18 months of treatment. Plasma, CSF, and imaging biomarkers of amyloid, tau, neurodegeneration, and gliosis were assessed.ResultsLecanemab met all primary and key secondary clinical endpoints with a high degree of statistical significance. Lecanemab improved markers of amyloid with reduction of brain amyloid by PET in as early as 3 months and improvement in CSF Aß42 and plasma Aß42/40. Biomarkers of tau showed improvement in CSF and plasma p‐tau181, and slowing of tau accumulation relative to placebo in the medial temporal regions by tau PET. For biomarkers of neurodegeneration and gliosis, there was improvement in CSF t‐tau, CSF neurogranin, and plasma GFAP. There were no significant differences in CSF or plasma Nf‐L between lecanemab and placebo. Volumetric MRI results were inconsistent, with reduced hippocampal atrophy on lecanemab, but greater cortical volume loss relative to placebo, possibly “pseudoatrophy” related to amyloid mobilization.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Improvements in biomarkers of amyloid, tau, neurodegeneration, and gliosis provide a biological basis for the treatment effects consistent with disease modification.