Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing
Stephanie Villarreal1, Fuqiang Zhao2, Lynn A Hyde3
1Neuroscience, MRL, West Point, PA, USA.
Abstract:
Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice. Animals were treated with verubecestat or controls including the anti-Aβ antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Aβ40 and Aβ42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Aβ treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Aβ antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Aβ immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Aβ peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials.
Insights
Verubecestat, an investigational Alzheimer's drug, did not worsen amyloid-related imaging abnormalities (ARIA-H) in mice. The BACE1 inhibitor effectively reduced amyloid pathology without increasing microhemorrhage risk.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaque accumulation.
- BACE1 inhibitors aim to reduce Aβ production as a therapeutic strategy for AD.
- Anti-amyloid immunotherapies can cause adverse events like amyloid-related imaging abnormalities (ARIA).
Purpose of the Study:
- To evaluate if verubecestat exacerbates microhemorrhage (ARIA-H) in a mouse model of AD.
- To assess the impact of verubecestat on amyloid pathology and ARIA-H.
- To compare verubecestat's safety profile regarding ARIA-H with anti-Aβ antibody treatment.
Main Methods:
- A 12-week nonclinical study using Tg2576-AβPPswe mice.
- Treatment groups included verubecestat, anti-Aβ antibody (3D6), and controls.
- ARIA-H assessment via longitudinal T2*-MRI and Prussian blue histochemistry.
- Quantification of Aβ peptides in plasma and cerebrospinal fluid.
- Analysis of brain Aβ plaque load and Thioflavin S staining.
Main Results:
- Verubecestat significantly reduced plasma and CSF Aβ40 and Aβ42 levels.
- No significant difference in ARIA-H was observed between verubecestat-treated mice and controls.
- Anti-Aβ antibody treatment significantly increased ARIA-H but did not alter plaque status.
- Verubecestat significantly suppressed brain Aβ accumulation and reduced plaque load.
- Reduced Aβ immunoreactivity and plaque number were observed in verubecestat-treated animals.
Conclusions:
- Verubecestat treatment did not exacerbate ARIA-H in mice.
- The BACE1 inhibitor effectively reduced central nervous system amyloid pathology.
- These findings support verubecestat's therapeutic mechanism for Alzheimer's disease.
- Data will be compared with ongoing clinical trial MRI profiles.
