Browsing by Author "Ostenfeld, Thor"

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    MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients
    (Wiley, 2024) Lloyd, Christopher; Freskgård, Per-Ola; Newton, Philip; Lowne, David; Nickson, Adrian; Bogstedt, Anna; Eketjäll, Susanna; Höglund, Kina; Gustavsson, Susanne; Welsh, Fraser; Chessell, Tharani; McFarlane, Mary; Bhat, Ratan V.; Turner, Richard; Perkinton, Michael S.; Valencia, Zulma Santisteban; Lindqvist, Eva; Pomfret, Michael; Dudley, Amanda D.; Vaughan, Tristan J.; Groves, Maria T.; Natanegara, Fanni; Feng, Yingdong; Sims, John R.; Proctor, Nicholas Kyle; Dage, Jeffrey L.; Shering, Craig; Tan, Keith; Ostenfeld, Thor; Billinton, Andy; Chessell, Iain P.; Neurology, School of Medicine
    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.