DEVELOPMENT REVIEW OF THE BACE1 INHIBITOR LANABECESTAT (AZD3293/LY3314814)
J.R. Sims, K.J. Selzler, A.M. Downing, B.A. Willis, C.D. Aluise, J. Zimmer, S. Bragg, S. Andersen, M. Ayan-Oshodi, E. Liffick, J. Eads, A.M. Wessels, S. Monk, J. Schumi, J. Mullen
J Prev Alz Dis 2017;4(4):247-254
Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer’s disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.
J.R. Sims ; K.J. Selzler ; A.M. Downing ; B.A. Willis ; C.D. Aluise ; J. Zimmer ; S. Bragg ; S. Andersen ; M. Ayan-Oshodi ; E. Liffick ; J. Eads ; A.M. Wessels ; S. Monk ; J. Schumi ; J. Mullen (2017): Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.38