BACKGROUND: Alzheimer's disease is characterized by the presence of cortical 
amyloid-beta (Aβ) protein plaques, which result from the sequential action of 
β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a 
small-molecule γ-secretase inhibitor that was developed as a potential treatment 
for Alzheimer's disease.
METHODS: We conducted a double-blind, placebo-controlled trial in which 1537 
patients with probable Alzheimer's disease underwent randomization to receive 
100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in 
cognition from baseline to week 76 were assessed with the use of the cognitive 
subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), 
on which scores range from 0 to 70 and higher scores indicate greater cognitive 
impairment, and changes in functioning were assessed with the Alzheimer's 
Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which 
scores range from 0 to 78 and higher scores indicate better functioning. A 
mixed-model repeated-measures analysis was used.
RESULTS: The trial was terminated before completion on the basis of a 
recommendation by the data and safety monitoring board. At termination, there 
were 189 patients in the group receiving placebo, 153 patients in the group 
receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg 
of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 
6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the 
study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, 
respectively, for the comparison with placebo). The ADCS-ADL scores also 
worsened in all groups (mean change at week 76, -9.0 points in the placebo 
group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; 
P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients 
treated with semagacestat lost more weight and had more skin cancers and 
infections, treatment discontinuations due to adverse events, and serious 
adverse events (P<0.001 for all comparisons with placebo). Laboratory 
abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, 
albumin, total protein, and uric acid and elevated levels of eosinophils, 
monocytes, and cholesterol; the urine pH was also elevated.
CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive 
status, and patients receiving the higher dose had significant worsening of 
functional ability. Semagacestat was associated with more adverse events, 
including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov 
number, NCT00594568.)