E-2012

E-2012 is a novel small molecule developed by Eisai Co., Ltd. primarily for the treatment of Alzheimer's disease. It functions as a gamma-secretase modulator, specifically designed to suppress the production of amyloid-beta 40 (Aβ40) and amyloid-beta 42 (Aβ42) peptides, while increasing shorter amyloid-beta peptides such as Aβ37 and Aβ38, without affecting Notch processing. The accumulation of Aβ peptides is believed to be a key factor in the pathology of Alzheimer's disease. However, preclinical studies in rats revealed that E-2012 also inhibits 3β-hydroxysterol Δ24-reductase (DHCR24), an enzyme involved in cholesterol biosynthesis, leading to lenticular opacity (cataracts) with repeated dosing. This safety concern led to the suspension of its Phase I clinical trials, although they were later permitted to resume after further data submission.