GSM

The neuro-pathological hallmarks of Alzheimer’s disease patients are amyloid plaques and neurofibrillary tangles (NFT), proteinaceous deposits that accumulate over many years. It is believed that amyloid oligomers/fibrils trigger the neuro-degenerative process in AD, including NFT development, and subsequent neuronal death. The finding in 2001 that certain non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, alter the ratio of Abeta42/Abeta40 without affecting the total amount of Abeta produced from APP provoked the search for so called gamma-secretase modulators (GSMs). Gamma secretase modulation reduces Abeta42 production (the desired effect) and increases the production of shorter, more non-amyloidogenic Abeta peptides (e.g., Abeta38). Hence it does not affect the net cleavage of the APP substrate and importantly also spares other gamma secretase substrates, such as Notch. Thus, the GSM mechanism is predicted to produce efficacy comparable to gamma secretase inhibitors with significantly reduced safety risk compared to typical gamma-secretase inhibitors.

EnVivo is advancing its GSM program into preclinical development. EnVivo is highly competitive in this area and aims for “Best in Class”.  The recent failure of Myriad’s flurizan in PhIII highlights the importance of establishing brain penetration of this class of compounds.  EnVivo measures brain penetration directly using bio-analytical techniques and our proprietary compounds lower Abeta after a single dose in wild type and transgenic rodents.