Preclinical Validation Of A Potent Gamma-Secretase Modulator For Alzheimer'S Disease Prevention

A potent gamma-secretase modulator (GSM) has been developed to circumvent problems associated with gamma-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit gamma-secretase activity but rather allosterically modulate gamma-secretase, reducing the net production of A beta 42 and to a lesser extent A beta 40, while concomitantly augmenting production of A beta 38 and A beta 37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUC(effective), the systemic exposure required for reducing levels of A beta 42 in rat brain by 50%.