MEDI1814 Selectively Reduces Free Aβ42 in Cerebrospinal Fluid of Non-Clinical Species and Alzheimer's Disease Patients.

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.