Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease

Abstract

Eli Lilly & Co is developing semagacestat, an inhibitor of the gamma-secretase enzyme. This enzyme is pivotal in the generation of beta-amyloid (A beta), a neurotoxic endogenous peptide believed to be involved in the pathogenesis of Alzheimer's disease (AD). In animals, semagacestat reduced A beta levels in the plasma, CSF and brain; however, studies have not reported on cognitive effect of this compound. Phase I clinical trials in healthy volunteers have evaluated doses ranging from 5 to 140 mg/day and phase II trials in patients with AD have evaluated doses ranging from 30 to 140 mg/day for up to 14 weeks. Trials in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A beta levels, and a recent trial in healthy volunteers demonstrated a robust, dose-dependent inhibition of newly generated A beta in the CSF after single oral doses. The main adverse events involved the gastrointestinal tract. In 2008, two large phase III clinical trials in patients with mild-to-moderate AD were initiated by Eli Lilly. Semagacestat is the most advanced gamma-secretase inhibitor and represents a major hope among therapies designed to slow the rate of cognitive decline of patients with AD.