Background
The Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing ...strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.
Methods
Initial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.
Results
PK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.
Conclusions
chAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.
Background
The Preclinical Testing Core (PTC) of the Model Organism Development for Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a preclinical strategy with go/no‐go decision ...points that permits unbiased assessments of potential therapeutic agents. In models at disease‐relevant ages, this strategy includes: 1) drug formulation, stability, and in vivo pharmacokinetics (PK); and 2) pharmacodynamics (PD) readouts of target engagement and disease modifying activity via non‐invasive PET/MRI, behavior, and transcriptomics. As part of the pipeline validation, verubecestat (VER), a BACE1 inhibitor, was selected for testing in 5XFAD mice.
Methods
PK analysis was performed in 6 month aged 5XFAD mice of both sexes, for both oral gavage (PO) and drug milled into diet (10‐100 mg/kg) with blood and brain concentrations analyzed via LC/MS. PK/PD modeling determined dosing regimen for chronic treatments started at 3 months. All PD endpoints (n = 10‐15/sex/genotype/treatment) were measured at 6‐7 months of age, and included: 18‐FDG PET/MR, 18F‐AV45 PET/MR, autoradiography, immunohistochemistry, and behavioral assessments. Post treatment gene expression profiling was conducted using the nanoString and aligned to AMP‐AD consensus clusters.
Results
Initial PK analysis revealed rapid clearance of VER following PO dosing, thus all PD experiments were performed via chronic exposure to drug formulated in diet (10, 30, and 100 mg/kg/day). Prophylactic treatment with VER produced robust coat color changes consistent with hair color changes reported in the clinic. Moreover, VER resulted in dose‐dependent reductions in amyloid deposition via 18F‐AV45 PET, but did not alter glucose uptake via 18F‐FDG PET. VER failed to improve cognition in 5XFAD mice. Transcriptomics revealed dose depended genes expression that mapped to AMP‐AD consensus clusters for immune response, DNA repair, and RNA metabolism.
Conclusions
The effects of VER dosing on PD endpoints revealed the expected results consistent with clinical findings. Moreover, VER failed to improve cognitive behavior in 5XFAD mice, in line with the lack of cognitive improvement in patients. Together these data positive support for pipeline validation of the MODEL‐AD PTC, and highlight the importance for post‐treatment transcriptomics to align model systems with drug mechanism of actions.
Abstract
Background
The Preclinical Testing Core (PTC) of the Model Organism Development for Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a preclinical strategy with go/no‐go ...decision points that permits unbiased assessments of potential therapeutic agents. In models at disease‐relevant ages, this strategy includes: 1) drug formulation, stability, and in vivo pharmacokinetics (PK); and 2) pharmacodynamics (PD) readouts of target engagement and disease modifying activity via non‐invasive PET/MRI, behavior, and transcriptomics. As part of the pipeline validation, verubecestat (VER), a BACE1 inhibitor, was selected for testing in 5XFAD mice.
Methods
PK analysis was performed in 6 month aged 5XFAD mice of both sexes, for both oral gavage (PO) and drug milled into diet (10‐100 mg/kg) with blood and brain concentrations analyzed via LC/MS. PK/PD modeling determined dosing regimen for chronic treatments started at 3 months. All PD endpoints (n = 10‐15/sex/genotype/treatment) were measured at 6‐7 months of age, and included: 18‐FDG PET/MR, 18F‐AV45 PET/MR, autoradiography, immunohistochemistry, and behavioral assessments. Post treatment gene expression profiling was conducted using the nanoString and aligned to AMP‐AD consensus clusters.
Results
Initial PK analysis revealed rapid clearance of VER following PO dosing, thus all PD experiments were performed via chronic exposure to drug formulated in diet (10, 30, and 100 mg/kg/day). Prophylactic treatment with VER produced robust coat color changes consistent with hair color changes reported in the clinic. Moreover, VER resulted in dose‐dependent reductions in amyloid deposition via 18F‐AV45 PET, but did not alter glucose uptake via 18F‐FDG PET. VER failed to improve cognition in 5XFAD mice. Transcriptomics revealed dose depended genes expression that mapped to AMP‐AD consensus clusters for immune response, DNA repair, and RNA metabolism.
Conclusions
The effects of VER dosing on PD endpoints revealed the expected results consistent with clinical findings. Moreover, VER failed to improve cognitive behavior in 5XFAD mice, in line with the lack of cognitive improvement in patients. Together these data positive support for pipeline validation of the MODEL‐AD PTC, and highlight the importance for post‐treatment transcriptomics to align model systems with drug mechanism of actions.
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