P2-069: Nonhuman primate model for prediction of human Aβ effects. Targeting γ-secretase: Effects of enzyme inhibition vs. modulation of cleavage specificity on CSF and plasma Aβ in conscious rhesus monkeys

Abstract

Alzheimer's Disease is characterized neuropathologically by the presence of amyloid β–peptide–containing plaques along with neurofibrillary tangles in the brain. A novel animal model was established to allow chronic, simultaneous sampling of CSF and plasma from conscious nonhuman primates. The model was validated with an extremely potent γ–secretase inhibitor (GSiA) which showed clear dose–related effects from minimal to near complete reduction of CSF and plasma Aβ40. A dynamic colony of cisterna magna ported (CMP) rhesus monkeys is maintained and used extensively to evaluate the potential of multimechanistic agents to alter CSF and plasma Aβ40 and Aβ42 with simultaneous plasma and CSF compound concentrations. This model allowed the ability to compare and contrast the effects of γ–secretase inhibition vs. modulation of the γ–secretase cleavage site. Crossover studies were conducted with γ–secretase inhibitors of high (GSiB) and moderate (GSiC) potency and a γ–secretase modulator (GSm) compound in an optimized, standard protocol. Baseline CSF and plasma samples were taken prior to single oral dose administration followed by sampling at multiple postdose timepoints over 7 days. Samples were assayed for CSF Aβ40, CSF Aβ42, and plasma Aβ40. Effects on CSF amyloid were seen as dose–related reduction of Aβ40 and Aβ42 by γ–secretase inhibitors and selective reduction of Aβ42 by the γ–secretase modulator. Comparison of these different mechanisms of targeting CNS γ–secretase, showed 25–30% reduction of CSF Aβ42 by all compounds that correlated to 30–40% reduction of CSF Aβ40 with inhibitors and, as predicted, no inhibitory effect on CSF Aβ40 with the modulator. Plasma Aβ40 was affected by γ–secretase inhibitors and was dependent on compound potency, dose and time after dosing; γ–secretase modulator had no effect on plasma Aβ40. As has been observed in humans and other preclinical species, plasma Aβ40 elevated above baseline after γ–secretase inhibition; time and extent of ‘overshoot‘ was dependent upon potency and dose. These comparative results highlight the opportunity to evaluate the amyloid hypothesis with varied mechanisms. CMP rhesus monkey studies are ongoing to address scientific (CSF Proteomics) and development (formulations, dosing regimes) questions with diverse compounds and to establish proof of concept with novel targets.