1. N Engl J Med. 2013 Jul 25;369(4):341-50. doi: 10.1056/NEJMoa1210951.

A phase 3 trial of semagacestat for treatment of Alzheimer's disease.

Doody RS(1), Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, 
Sun X, Thomas RG, Aisen PS; Alzheimer's Disease Cooperative Study Steering
Committee, Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group.

Author information: 
(1)Alzheimer's Disease and Memory Disorders Center, Department of Neurology,
Baylor College of Medicine, Houston, TX 77030, USA. rdoody@bcm.edu

Comment in
    N Engl J Med. 2013 Oct 24;369(17):1661.
    N Engl J Med. 2013 Oct 24;369(17):1660-1.
    N Engl J Med. 2013 Oct 24;369(17):1661.

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.)

DOI: 10.1056/NEJMoa1210951 
PMID: 23883379  [Indexed for MEDLINE]