Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-A?PPswe Mice Without Inducing Microhemorrhage.

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-A?PPswe mice. Animals were treated with verubecestat or controls including the anti-A? 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 A?40 and A?42 by?>90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-A? treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-A? antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain A?40 and A?42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of A? 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 A? 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.

SUBMITTER: Villarreal S 

PROVIDER: S-EPMC5611839 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature