Population PKPD modeling of BACE1 inhibitor-induced reduction in Aß levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig.

PURPOSE: The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid ß (Aß) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel ß-secretase (BACE1) inhibitors. METHODS: BACE1-mediated inhibition of Aß was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aß production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach. RESULTS: Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aß40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells. CONCLUSION: The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.

AZ-4217: a high potency BACE inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice.

Aß, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). ß-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aß peptides. Small molecule BACE1 inhibitors are expected to decrease Aß-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aß production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

Has inhibition of Aß production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.

PURPOSE: To date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aß in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aß effects. METHODS: A model-based-meta analysis on Aß levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752). RESULTS: The clinical data available did not show any significant or robust reduction of CNS Aß over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aß levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations. CONCLUSIONS: More substantially, CNS Aß-lowering drugs are needed to test whether inhibition of Aß production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design.