MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients

Abstract

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ₄₂, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ₄₂ without impacting Aβ₄₀ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n = 57) in single or repeat doses up to 1800 mg intravenously or 200 mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ₄₂, increases in total (bound and free) Aβ₄₂, but no change in total Aβ₄₀ in CSF across doses.

Discussion: MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ₄₂.

Keywords: amyloid beta 42; drug development; pharmacodynamics; pharmacokinetics; preclinical; safety; tolerability.