Deposition of amyloid beta (Abeta) peptide into plaques is one of the two hallmark features of Alzheimer's disease. These plaques, typically concentrated in the spaces between nerve cells in the brain parenchyma and cerebral blood vessel walls, are thought to impede nerve cell function and promote neuronal degeneration in Alzheimer's disease brains. According to current thinking, AD etiology is explained by the amyloid cascade hypothesis, whereby overproduction of Abeta protein, or alternatively the failure to clear this protein, leads to the accumulation of amyloid deposits and contributes to the formation of neurofibrillary tangles. These lesions are associated with neuronal cell death, which manifests as loss of memory. Thus strategies to prevent the formation, accumulation or cytotoxic effects of Abeta are being actively pursued. Several potential interventions have been proposed to delay the onset or prevent the appearance of Alzheimer's disease, including Abeta production inhibitors (beta- and gamma-secretase inhibitors, statins, etc.); Abeta aggregation inhibitors; Abeta deposit-dissolving agents; and immunization with Abeta peptide. Furthermore, antiinflammatory therapies and metal chelating agents may minimize the brain's reaction to Abeta (Integrity^® Disease Briefings: Alzheimer’s Disease).

In the spring of 2008, Lilly initiated its first phase III clinical trial of semagacestat (LY-450139) for the treatment of mild to moderate Alzheimer's disease. Semagacestat is being tested to see if it can slow the progression associated with Alzheimer's disease by inhibiting gamma-secretase, an enzyme that contributes to the formation of amyloid beta. The trial, called IDENTITY, is a randomized, double-blind, placebo-controlled trial that will be conducted in the U.S. and 21 additional countries and will evaluate 1,500 patients for 21 months. An open-label extension will be available to all participants completing the study. Patients who are taking currently available symptomatic treatments for Alzheimer's disease can continue treatment during their participation in IDENTITY. Because the IDENTITY study also incorporates a randomized delayed start design, even those subjects initially assigned to the placebo arm of the study will be started on active semagacestat treatment sometime before the end of the 21-month study period. Both the subjects and investigators will be blinded to the exact timing of this delayed start of study drug administration (ClinicalTrials.gov NCT00594568). Semagacestat was originally codeveloped by Lilly and Elan.