title: Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models.
abstract: BACKGROUND
  Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 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 Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 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 Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 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 Aβ42 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.
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Loureiro
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Dumin
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McKee
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Wesley F
authors.initials: WF
authors.lastname: Austin
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Fuller
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Jed L
authors.initials: JL
authors.lastname: Hubbs
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Ruichao
authors.initials: R
authors.lastname: Shen
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Jonker
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Ives
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
authors.affiliation: Satori Pharmaceuticals, 281 Albany St., Cambridge, MA 02139, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tate