Prophylactic evaluation of verubecestat on disease‐ and symptom‐modifying effects in 5XFAD mice

Abstract

Introduction Alzheimer's disease (AD) is the most common form of dementia. Beta‐secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under‐investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late‐Onset Alzheimer's Disease (MODEL‐AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F‐florbetapir (AV‐45/Amyvid) (18F‐AV45) and 18‐FDG (fluorodeoxyglucose)–PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results Prophylactic verubecestat treatment resulted in dose‐ and region‐dependent attenuations of 18F‐AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose‐dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F‐FDG uptake. Discussion Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL‐AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early‐stage AD.

STOP‐AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease

“…In addition, to validate the pipeline, 22 VER and LEV were selected for screening based on their scores and were evaluated through the PTC pipeline. Importantly, consistent with its inhibition of BACE1, VER showed reductions in amyloid via 18F‐AV45 PET/MRI and dose dependent changes across 38 genes studied, but did not show alterations in 18F‐FDG PET/MRI or behavior measures with 3 months of prophylactic treatment starting in 3 months old 5XFAD mice 19 . Similarly LEV, a synaptic vesicle 2A antagonist (SV2A), showed significant dose and sex dependent changes in 18F‐FDG PET/MRI uptake, and differential gene expression which aligned to accelerating medicines partnership for AD (AMP‐AD) consensus clusters B (immune) and C (neuronal system).…”

“…Importantly, consistent with its inhibition of BACE1, VER showed reductions in amyloid via 18F-AV45 PET/MRI and dose dependent changes across 38 genes studied, but did not show alterations in 18F-FDG PET/MRI or behavior measures with 3 months of prophylactic treatment starting in 3 months old 5XFAD mice. 19 in 5XFAD mice. 20 Combined, these studies recapitulate the clinical findings and side-effect profiles and help to validate the PTC pipeline and the STOP-AD drug selection process.…”

“…18 In addition, recent work from our group has prioritized translationally relevant PD endpoints over animal behavior. 4,19,20 Combining these aforementioned approaches permits evaluation of the drug candidate across a spectrum of methods, modalities, and scales to provide a more comprehensive view of the drugs likelihood of clinical success.…”

“…For drugs targeting the CNS, examination of physicochemical, in vitro absorption, distribution, metabolism, elimination and transporter (ADMET) attributes and in vitro potency property space for a set of CNS drugs and candidates have been explored 18 . In addition, recent work from our group has prioritized translationally relevant PD endpoints over animal behavior 4,19,20 . Combining these aforementioned approaches permits evaluation of the drug candidate across a spectrum of methods, modalities, and scales to provide a more comprehensive view of the drugs likelihood of clinical success.…”

The 5XFAD mouse model of Alzheimer’s disease displays age-dependent deficits in habituation to a novel environment

“…Verubecestat is a beta-secretase (BACE) inhibitor that dose-dependently inhibits the production of Aβ in 5XFAD mice. In the original analyses of these open field data, verubecestat did not alter total distance moved in the open field [23] . A one-way ANOVA (F(4,160) = 4.943) on intrasession habituation data revealed that 5XFAD mice treated with vehicle or the low dose (10 mg/kg/day) of verubecestat had significantly increased activity change ratios (p = 0.0014 and 0.0235, respectively), while 5XFAD mice treated with the high dose (100 mg/kg/day) of verubecestat had reduced activity change ratios compared to vehicle-treated 5XFAD mice (p = 0.0467) ( Fig.…”