OBJECTIVE: Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable 
risk-benefit profile in a Phase 3 study of patients with Alzheimer's disease 
(IDENTITY trials), and clinical development was halted. To assist in future 
development of γ-secretase inhibitors, we report detailed safety findings from 
the IDENTITY study, with emphasis on those that might be mechanistically linked 
to γ-secretase inhibition.
RESEARCH DESIGN AND METHODS: The IDENTITY trial was a double-blind, 
placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537 
patients age 55 years and older with probable Alzheimer's disease were 
randomized. Treatment-emergent adverse events (TEAEs) are reported by body 
system along with pertinent laboratory, vital sign, and ECG findings.
RESULTS: Semagacestat treatment was associated with increased reporting of 
suspected Notch-related adverse events (gastrointestinal, infection, and skin 
cancer related). Other relevant safety findings associated with semagacestat 
treatment included cognitive and functional worsening, skin-related TEAEs, renal 
and hepatic changes, increased QT interval, and weight loss. With few 
exceptions, differences between semagacestat and placebo treatment groups were 
no longer significant after cessation of treatment with active drug.
CONCLUSIONS: Many of these safety findings can be attributed to γ-secretase 
inhibition, and may be valuable to researchers developing γ-secretase 
inhibitors.