Lloyd, ChristopherFreskgård, Per-OlaNewton, PhilipLowne, DavidNickson, AdrianBogstedt, AnnaEketjäll, SusannaHöglund, KinaGustavsson, SusanneWelsh, FraserChessell, TharaniMcFarlane, MaryBhat, Ratan V.Turner, RichardPerkinton, Michael S.Valencia, Zulma SantistebanLindqvist, EvaPomfret, MichaelDudley, Amanda D.Vaughan, Tristan J.Groves, Maria T.Natanegara, FanniFeng, YingdongSims, John R.Proctor, Nicholas KyleDage, Jeffrey L.Shering, CraigTan, KeithOstenfeld, ThorBillinton, AndyChessell, Iain P.2024-12-112024-12-112024Lloyd C, Freskgård PO, Newton P, et al. MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients. Alzheimers Dement. 2024;20(11):7762-7776. doi:10.1002/alz.14238https://hdl.handle.net/1805/44941Introduction: 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAmyloid beta 42Drug developmentPharmacodynamicsPharmacokineticsPreclinicalSafetyTolerabilityArticle