title: Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings.
abstract: 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.
  
  
  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.
authors.affiliation: Lilly Research Laboratories , Indianapolis, IN , USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Henley
authors.forename: Karen L
authors.initials: KL
authors.lastname: Sundell
authors.forename: Gopalan
authors.initials: G
authors.lastname: Sethuraman
authors.forename: Sherie A
authors.initials: SA
authors.lastname: Dowsett
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
mesh_terms: D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000503:physiopathology; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017063:Outcome Assessment, Health Care; D018570:Risk Assessment
chemical_list: D001381:Azepines; 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; D018697:Nootropic Agents; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine
keywords: Adverse events; Alzheimer’s disease; Gamma-secretase inhibitor; Notch; Safety; Semagacestat; Tolerability