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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 Altstiel
Review

Abstract

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

AD

Alzheimer’s disease

AGE

advance glycation endproduct

RAGE

receptor for advanced glycation endproducts

LTP

long-term potentiation

FDG-PET

flurodeoxyglucose positron emission tomography

ADAS-cog

Alzheimer’s Disease Assessment Scale cognitive portion

CDR-sb

Clinical Dementia Rating Scale Sum of Boxes

MMSE

mini-mental state examination

ADCS-ADL

Alzheimer’s Disease Cooperative Study–Activities of Daily Living

NPI

neuropsychiatric inventory

COWAT

controlled oral word association test

CFT

category fluency test

RUD

Resource Utilization for Dementia

DEMQOL

Dementia Quality of Life

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References

  1. 1.
    Lane CA, Hardy J, Schott JM. European J Neurol. Alzheimer’s disease. doi: 10.1111/ene.13439Google Scholar
  2. 2.
    Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. 2016 Oct;139 Suppl 2:237–252.CrossRefPubMedGoogle Scholar
  3. 3.
    Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging. 2015;32(2):139–147.CrossRefPubMedGoogle Scholar
  4. 4.
    Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 2005; 83: 876–886.CrossRefPubMedGoogle Scholar
  5. 5.
    Schmidt AM, Yan SD, Yan SF, Stern DM. The multi-ligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001;108:949–955.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hori O, Brett J, Slattery T, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995;270:25752–25761.PubMedGoogle Scholar
  7. 7.
    Hofmann MA, Drury S, Fu C, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999;97:889–901.CrossRefPubMedGoogle Scholar
  8. 8.
    Donato R. RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med 2007;7:711–724.CrossRefPubMedGoogle Scholar
  9. 9.
    Chavakis T, Bierhaus A, Al-Fakhri N, et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003;198:1507–1515.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    He M, Kubo H, Morimoto K, et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep. 2011;12:358–364.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996;382:685–691.CrossRefPubMedGoogle Scholar
  12. 12.
    Ding Q, Keller JN. Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim Biophys Acta 2005; 1746, 18–27.CrossRefPubMedGoogle Scholar
  13. 13.
    Fang P, Schachner M, Shen YQ HMGB1 in development and diseases of the central nervous system. Mol Neurobiol 2012; 45(3):499–506.CrossRefPubMedGoogle Scholar
  14. 14.
    Shepherd CE, Goyette J, Utter V, et al. Inflammatory S100A9 and S100A12 proteins in Alzheimer’s disease. Neurobiol Aging 2006;27: 1554–1563.CrossRefPubMedGoogle Scholar
  15. 15.
    Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001; 280:E685–E694.CrossRefPubMedGoogle Scholar
  16. 16.
    Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996;382:685–691.CrossRefPubMedGoogle Scholar
  17. 17.
    Yan SF, Yan SD, Ramasamy R, Schmidt AM. Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation. Ann Med 2009;41:408–422.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mackic JB, Stins M, McComb JG, et al. Human blood-brain barrier receptors for Alzheimer’s amyloid-beta 1–40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell menolayer. J Clin Invest 1998;102(4):734–743.PubMedGoogle Scholar
  19. 19.
    Giri R, Shen Y, Stins M, et al. beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am J Physiol Cell Physiol 2000;279(6):C1772–C1781.CrossRefPubMedGoogle Scholar
  20. 20.
    Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003;9(7):907–913.CrossRefPubMedGoogle Scholar
  21. 21.
    Mattson MP, Camandola S. NF-kappa-B in neuronal plasticity and neurodegenerative disorders. J Clin Invest 2001;107:247–254.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. Cell Biochem 2001;81(1):102–13.CrossRefGoogle Scholar
  23. 23.
    Li XH, BL Lv, Xie JZ, Liu J, Zhou XW, Wang JZ. AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging 2012;33(7):1400–10.CrossRefPubMedGoogle Scholar
  24. 24.
    Deane R, Singh I, Abhay PS, et al. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 2012; 122(4):1377–92.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kostura MJ, Kindy MS, Burstein A, et al. Efficacy of RAGE antagonist in murine model of Alzheimer’s disease. Alzheimers Dement 2014;10(4, Suppl):638–639.CrossRefGoogle Scholar
  26. 26.
    Sabbagh MN, Agro A, Bell J, Aisen PS, Schweizer E, Galasko D. PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer’s disease. Alz Dis Assoc Disord 2011;24(30):206–212.CrossRefGoogle Scholar
  27. 27.
    Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988;24:637–9.PubMedGoogle Scholar
  29. 29.
    Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Aβ interacations in Alzheimer disease. Neurology 2014;82(17):1536–42.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Burstein AH, Grimes I, Galasko DR, Aisen PS, Sabbagh M, Mjalli AM. Effect of TTP488 in patients with mild to moderate Alzheimer’s disease. BMC Neurol 2014;14:1212.doi: 10.1186/1471-2377-14-12.CrossRefGoogle Scholar
  31. 31.
    Burstein AH, Lamson MJ, Sale M, Brantley SJ, Gooch A, Dunn I, Altstiel LD. Effect of CYP2C8 and CYP3A4 inhbition and CYP induction on the pharmacokinetics of azeliragon. J Prev Alz Dis 2017;4(4):336.Google Scholar
  32. 32.
    Gooch A. Burstein AH, Brantley SJ, Lamson MJ, Dunn I, Altstiel L. Effect of mild or moderate hepatic impairment on the clearance of azeliragon. J Prev Alz Dis 2017;4(4):335–6.Google Scholar
  33. 33.
    Burstein AH, Brantley SJ, Dunn I, Altstiel LD, Schmith V. Assessment of azeliragon QTc liability through integrated, model-based concentration QTc analysis. Alz Dementia 2017;13(7, supplement): 262–3.CrossRefGoogle Scholar
  34. 34.
    Vellas B, Andrieu S, Cantet C, Dartigues JF, Gauthier S. Long-term changes in ADAS-cog: what is clinically relevant for disease modifying trials in Alzheimer? J Nutr Health Aging 2007;11(4):338–41.PubMedGoogle Scholar
  35. 35.
    Mehta D, Jackson R, Gaurav P, Shi J, Sabbagh, M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opinion on Investigational Drugs 2017; 6: 735–739.CrossRefGoogle Scholar
  36. 36.
    Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimer’s Research & Therapy 2016; 8:39–51.CrossRefGoogle Scholar
  37. 37.
    Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol 2017;133(2):155–175.CrossRefPubMedGoogle Scholar

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
  1. 1.vTv Therapeutics Inc.High PointUSA
  2. 2.Barrow Neurological InstitutePhoenixUSA
  3. 3.vTv Therapeutics LLCHigh PointUSA

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