Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer’s Disease

  • A. H. Burstein
  • M. Sabbagh
  • R. Andrews
  • C. Valcarce
  • I. Dunn
  • Larry AltstielEmail author


Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer’s disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and a 1 point change in CDR-sb in favor of drug. Azeliragon 5 mg/day delayed time to cognitive deterioration (7-point change in ADAS-cog from baseline, logrank p=0.0149). Based on promising results from the Phase 2b study, a Phase 3 registration program (STEADFAST) is being conducted under a Special Protocol Assessment from FDA. The ongoing Phase 3 program, if successful may demonstrate azeliragon can slow cognitive decline in mild AD patients.

Key words

Azeliragon RAGE Alzheimer’s disease 

List of abbreviations


Alzheimer’s disease


advance glycation endproduct


receptor for advanced glycation endproducts


long-term potentiation


flurodeoxyglucose positron emission tomography


Alzheimer’s Disease Assessment Scale cognitive portion


Clinical Dementia Rating Scale Sum of Boxes


mini-mental state examination


Alzheimer’s Disease Cooperative Study–Activities of Daily Living


neuropsychiatric inventory


controlled oral word association test


category fluency test


Resource Utilization for Dementia


Dementia Quality of Life


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Copyright information

© Serdi and Springer Nature Switzerland AG 2018

Authors and Affiliations

  • A. H. Burstein
    • 1
  • M. Sabbagh
    • 2
  • R. Andrews
    • 1
  • C. Valcarce
    • 1
  • I. Dunn
    • 1
  • Larry Altstiel
    • 1
    • 3
    Email author
  1. 1.vTv Therapeutics Inc.High PointUSA
  2. 2.Barrow Neurological InstitutePhoenixUSA
  3. 3.vTv Therapeutics LLCHigh PointUSA

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