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

Research output: Contribution to journalReview article

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)247-254
Number of pages8
JournalThe journal of prevention of Alzheimer's disease
Volume4
Issue number4
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Alzheimer’s disease
  • BACE1 inhibitor
  • Lanabecestat
  • MCI due to AD
  • mild AD

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sims, J. R., Selzler, K. J., Downing, A. M., Willis, B. A., Aluise, C. D., Zimmer, J., Bragg, S., Andersen, S., Ayan-Oshodi, M., Liffick, E., Eads, J., Wessels, A. M., Monk, S., Schumi, J., & Mullen, J. (2017). Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). The journal of prevention of Alzheimer's disease, 4(4), 247-254. https://doi.org/10.14283/jpad.2017.38