title: A phase 3 trial of semagacestat for treatment of Alzheimer's disease.
abstract: 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.)
authors.affiliation: Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. rdoody@bcm.edu
authors.forename: Rachelle S
authors.initials: RS
authors.lastname: Doody
authors.forename: Rema
authors.initials: R
authors.lastname: Raman
authors.forename: Martin
authors.initials: M
authors.lastname: Farlow
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.forename: Steven
authors.initials: S
authors.lastname: Joffe
authors.forename: Karl
authors.initials: K
authors.lastname: Kieburtz
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Sun
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thomas
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Eric
authors.initials: E
authors.lastname: Siemers
authors.forename: Gopalan
authors.initials: G
authors.lastname: Sethuraman
authors.forename: Richard
authors.initials: R
authors.lastname: Mohs
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood; D001381:Azepines / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms / Q000139:chemically induced; D017211:Treatment Failure; D015431:Weight Loss / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D001381:Azepines; D015415:Biomarkers; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine