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, Emily Liffick, J. Eads, A. M. Wessels, S. Monk, J. Schumi, J. Mullen

Research output: Contribution to journalReview article

7 Citations (Scopus)

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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Alzheimer Disease
Serum Amyloid A Protein
Phase III Clinical Trials
Amyloid beta-Protein Precursor
4-methoxy-5'-methyl-6'-(5-(prop-1-yn-1-yl)pyridin-3-yl)-3'H-dispiro(cyclohexane-1,2'-inden-1',2'-imidazol)-4'-amine
Cerebrospinal Fluid
Healthy Volunteers
Guinea Pigs
Dogs
Brain
Enzymes
Therapeutics

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., ... 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

Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). / 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, Emily; Eads, J.; Wessels, A. M.; Monk, S.; Schumi, J.; Mullen, J.

In: The journal of prevention of Alzheimer's disease, Vol. 4, No. 4, 01.01.2017, p. 247-254.

Research output: Contribution to journalReview article

Sims, JR, Selzler, KJ, Downing, AM, Willis, BA, Aluise, CD, Zimmer, J, Bragg, S, Andersen, S, Ayan-Oshodi, M, Liffick, E, Eads, J, Wessels, AM, Monk, S, Schumi, J & Mullen, J 2017, 'Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814)', The journal of prevention of Alzheimer's disease, vol. 4, no. 4, pp. 247-254. https://doi.org/10.14283/jpad.2017.38
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, Emily ; Eads, J. ; Wessels, A. M. ; Monk, S. ; Schumi, J. ; Mullen, J. / Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). In: The journal of prevention of Alzheimer's disease. 2017 ; Vol. 4, No. 4. pp. 247-254.
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