Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models

INTRODUCTION: Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ(42 )peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ(42 )levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ(42 )and Aβ(38 )while sparing Aβ(40 )and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. METHODS: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. RESULTS: In wild-type mice using either dosing regimen, brain Aβ(42 )and Aβ(38 )levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ(40 )was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ(42 )and Aβ(38 )were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. CONCLUSIONS: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ(42 )in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.