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

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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 Aβ 42 , the pathogenic self‐aggregating species of Aβ. RESULTS MEDI1814 reduces free Aβ 42 without impacting Aβ 40 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 Aβ 42 , increases in total (bound and free) Aβ 42 , but no change in total Aβ 40 in CSF across doses. DISCUSSION MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ 42 .