Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer's disease

Background: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (A beta) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce A beta formation may be of therapeutic benefit. Objective: This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139). Methods: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. Results/conclusions: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain A beta in a dose-dependent manner in animals and plasma and cerebrospinal fluid A beta in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.