Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814)

Area of Science:

• Neuroscience
• Pharmacology
• Clinical Drug Development

Background:

• Alzheimer's disease (AD) lacks effective disease-modifying treatments.
• Amyloid-beta (Aβ) production is a key target for AD therapeutics.
• Lanabecestat is an oral, brain-permeable BACE1 inhibitor designed to reduce Aβ production.

Purpose of the Study:

• To review the development of lanabecestat, a BACE1 inhibitor for Alzheimer's disease.
• To summarize preclinical and clinical findings for lanabecestat.
• To describe ongoing Phase 3 clinical trials supporting lanabecestat's registration.

Main Methods:

• Lanabecestat's mechanism as a BACE1 inhibitor was assessed.
• Preclinical studies in mice, guinea pigs, and dogs evaluated Aβ reduction.
• Phase 1 studies in healthy subjects and AD patients assessed Aβ levels in plasma and CSF.

Main Results:

• Lanabecestat demonstrated dose- and time-dependent reduction of soluble Aβ and sAPPβ in animal models.
• Significant reductions in plasma and CSF Aβ1-40 and Aβ1-42 were observed in Phase 1 studies.
• Three ongoing Phase 3 trials (AMARANTH, AMARANTH-EXTENSION, DAYBREAK-ALZ) are evaluating lanabecestat in early AD.

Conclusions:

• Lanabecestat effectively reduces Aβ production, supporting its investigation as a disease-modifying AD treatment.
• Clinical studies show promising Aβ reduction, warranting further evaluation in large-scale Phase 3 trials.
• Ongoing trials are crucial for establishing lanabecestat's efficacy and safety in mild cognitive impairment and mild AD dementia.