Data Underscore Promise of Satori Pharmaceuticals' Gamma-Secretase Modulator Program in Treatment of Alzheimer's Disease
7/19/2012 10:19:09 AM
CAMBRIDGE, Mass., July 18, 2012 /PRNewswire/ -- Satori Pharmaceuticals, a company dedicated to developing life-changing therapeutics for Alzheimer's disease (AD), announced today that its lead compound, a gamma-secretase modulator (GSM), is efficacious in preclinical models following single or multi-day dosing. This oral presentation, as well as two poster presentations related to the characteristics of Satori's GSMs, was presented at the Alzheimer's Association International Conference (AAIC) in Vancouver, British Columbia.
"These findings help demonstrate that our lead development candidate SPI-1865 has the potential to be an efficacious new therapy for Alzheimer's disease," said Barbara Tate, Ph.D., Vice President of Research for Satori Pharmaceuticals. "SPI-1865 selectively reduces AB42 while sparing total AB, which serves to lower the ratio of this neurotoxic peptide to other AB peptides, returning the levels closer to the ratio seen in healthy human brains. This has advantages when compared with other classes of drugs that cannot selectively target this form of AB that is strongly implicated in plaque formation and neurodegeneration."
Satori gamma-secretase modulators are efficacious in wild type rodents following either acute or steady-state dosing
In an oral presentation on Sunday, July 15, lead study author Robyn M.B. Loureiro presented data that demonstrated Satori's GSM compounds are selective for AB42, penetrate the brain, and are dose responsive at achievable exposure levels.
Sprague-Dawley rats were dosed via oral gavage either in a single acute dose or once a day dosing for six days. Brain AB levels were measured 24 hours post final dose for effects on AB38, AB40 and AB42 using a sensitive plate based ELISA system (MSD).The brain and plasma exposure were assessed by LC/MS/MS.
Notably, SPI-1865 is able to robustly and selectively reduce both AB42 and AB38 while sparing AB40 in vivo, similar to the results in in vitro systems. This effect was shown to be dose-responsive and long-lasting.
An improved cell-based method for determining the gamma-secretase enzyme activity against both NOTCH and APP substrates
In a poster session on Monday, July 16, Timothy D. McKee et al. presented a method that can accurately measure the difference in potency between NICD inhibition and AB42 lowering for therapeutically promising gamma-secretase inhibitors (GSIs) and gamma-secretase modulators (GSMs).
Using the SUP-T1 cell line, which expresses a truncated NOTCH receptor fragment that is a viable gamma-secretase substrate, the researchers have optimized a method to measure both NICD inhibition and AB modulation simultaneously in the same cell line. SUPT1 cells are dosed with test articles for 16 hours, after which time the conditioned media is collected for AB measurement and the cells are collected and lysed for NICD level determination. AB from conditioned media is concentrated using solid phase extraction and detected using a sensitive plate based ELISA system (MSD). The extent of NOTCH processing and subsequent NICD production is determined by immuno-blotting and ELISA using an antibody specific for cleaved NOTCH.
Percent inhibition of AB38, AB40 and AB42, as well as NOTCH cleavage, are plotted relative to vehicle-only samples to establish dose response curves and IC50s for both of the gamma substrates. The fold-difference between NOTCH processing and AB42 IC50s is used to establish the in vitro safety margin between the NOTCH and APP gamma-secretase activities of GSIs and GSMs.
Pharmacokinetic properties of a Satori gamma-secretase modulator, SPI-1865, in multiple animal model systems
In a poster session on Wednesday, July 18, Brian S. Bronk et al. presented data that concludes, based on the preclinical pharmacokinetic profile of SPI-1865, a single daily oral dose is expected to deliver sustained plasma and brain concentrations in humans sufficient to significantly reduce brain AB42 levels.
Multiple preclinical species were dosed with a solution containing SPI-1865 via either an oral gavage or an intravenous route. Plasma from the animals was sampled up to a 240-hour period, brain tissue was collected at the end of select studies, and compound levels were assessed by LC/MS/MS.
SPI-1865 displayed low clearance and a high volume of distribution, providing an extended half-life in all species. Following oral administration, it was also observed that SPI-1865 affords good oral bioavailability and freely accesses the central compartment, providing sustained brain exposures.
About Satori's Gamma-Secretase Modulators
Alzheimer's disease is characterized by the formation of amyloid beta plaques in the brain. Plaques are primarily composed of two main forms of amyloid beta: AB40 and AB42. Satori's program aims to reduce the amount of AB42 in the brain by modulating gamma-secretase, thus lowering brain amyloid, plaque formation and associated damage to normal neuronal function. Studies have demonstrated Satori's proprietary class of gamma-secretase modulators (GSMs) achieve a reduction in AB42 levels without altering total amyloid beta levels in cell lines and animal models of the disease.
About Satori Pharmaceuticals
Satori Pharmaceuticals is developing life-changing therapeutics for Alzheimer's disease. Driven by a world-class team of drug development veterans and advisors, Satori is advancing best-in-industry medicines that aim to slow or stop disease progression. Our drug candidates selectively modulate gamma secretase, the enzyme generating the neurotoxic peptides that form amyloid beta plaques the signature of this debilitating disease. For more information, visit www.satoripharma.com.
SOURCE Satori Pharmaceuticals