Gamma secretase modulation (GSM) is a promising new approach to reducing Abeta42 production and increasing production of shorter, non-amyloidogenic Abeta peptides. GSM does this by modulating, rather than directly inhibiting, the activity of gamma secretase, one of the key amyloid-processing enzymes. This enzyme is key in producing the Abeta42 peptide, which is a primary pathologic constituent of the amyloid plaques that characterize Alzheimer’s disease. By modulating—and not inhibiting—gamma secretase, GSMs could offer new treatments with comparable efficacy, but with significantly reduced safety risks compared to gamma secretase inhibitors (GSIs). Data suggest that GSIs may not be tolerated for the long-term treatment of Alzheimer’s disease.
The lead investigational compound in the GSM program is FRM-0962, a specific and potent gamma secretase modulator that has shown activity in both cells and preclinical transgenic mouse models of Alzheimer’s disease.
In January 2013, the company initiated a Phase 2 clinical trial of FRM-0962 in healthy volunteers and in volunteers with mild cognitive impairment or early Alzheimer’s disease. The Phase 2 trial is a randomized, double-blind, dose-escalating study to assess the safety, tolerability, pharmacokinetics, and effects of FRM-0962 on cerebrospinal fluid amyloid concentrations.