Azeliragon

Overview

Azeliragon (TTP488) is an orally bioavailable small molecule that inhibits the receptor for advanced glycation endproducts (RAGE).

RAGE is  an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery (Yan et al., 1996; Schmidt et al., 2009),  RAGE is found on the cells of the neurovascular compartment:  endothelial cells and microglia prominently express RAGE whose expression is upregulated in AD (Yan et al., 2007; Yan et al, 2009).  RAGE ligands include Aβ, S100b, HMGB1, and Advanced Glycation Endproducts (AGEs).  RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation, and AD (Stern et al., 2002; Bierhaus et al., 2005).  RAGE has been proposed to contribute to AD pathology by:  promoting vascular leakage, promoting influx of peripheral Aβ into brain; mediating Aβ induced oxidative stress, mediating AGE induced hyperphosphorylation of tau (Li et al., 2011) and Aβ mediated neuronal death (Deane et al., 2003; Carrano et al., 2011; Hartz et al., 2012; Kook et al., 2012; Li et al., 2011).

The pleiotropic role of RAGE in AD pathology has been described using rodent models.  Mice expressing the human amyloid precursor protein (APP) transgene in neurons develop significant biochemical and behavioral changes reminiscent of human AD.  Double transgenic mouse overexpressing wild type RAGE in the APP transgene background exhibit accelerated behavioral changes, whereas double transgenic animals expressing a dominant negative mutant of RAGE are protected (Arancio et al., 2004).  This data suggests that RAGE plays a role in augmenting the chronic inflammatory state caused by overproduction of Aβ.

RAGE is thought to be involved in the transport of Aβ from peripheral to central nervous system compartments (Tanzi et al., 2004).  In vivo, Aβ uptake into brain is dependent on RAGE as shown in RAGE null mice (Deane et al., 2003).  Similarly, Aβ uptake in brain can be inhibited using either the secreted, soluble form of RAGE (called sRAGE) or an anti-RAGE antibody (Deane et al., 2003).  In addition, plaque formation in a mouse model of cerebral amyloidosis was inhibited using sRAGE (Yan et al., 2000; Rocken et al., 2003).  These data suggest that RAGE is intimately involved in the pathogenesis of AD, and that sustained Aβ interaction with RAGE on blood-brain barrier and/or neuronal cells is an important element of amyloid plaque formation and chronic neuronal dysfunction.

Additionally, RAGE is believed to be involved in mediating advanced glycation endproduct induced tau hyperphosphorylation (Li et al., 2011).  In vivo, injection of advanced glycation endproducts induced tau hyperphosphorylation, memory deterioration, decline of synaptic proteins and impairment of long-term potentiation.   These effects are attenuated following blockade of the RAGE receptor with a RAGE antibody.  

These data taken together suggest that inhibition of RAGE with an orally available small molecule inhibitor presents an attractive therapeutic rationale for the treatment of Alzheimer’s disease.

> RAGE Mechanism Publications

  1. Walker D, Lue LF, Paul G, Patel A, Sabbagh MN. Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer's disease. Expert Opin Investig Drugs. 2015 Mar;24(3):393-9. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/25586103
  2. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005 Nov;83(11):876-86. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/16133426
  3. Li XH, Lv BL, Xie JZ et al.  AGEs induce Alzheimer’s-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation.   Neurobiology of Aging 2012;33:1400-14210. Abstract link: http://www.ncbi.nlm.nih.gov/pubmed/21450369
  4. Lue LF, Walker DG, Jacobson S, Sabbagh M.  Receptor for advanced glycation endproducts: its role in Alzheimer’s disease and other neurologic diseases.   Future Neurol 2009;4(2):167-177. Abstract link:    http://www.ncbi.nlm.nih.gov/pubmed/19885375
  5. Perrone L, Sbai O, Nawroth PP, Bierhaus A.  The complexity of sporadic Alzheimer’s disease pathogenesis: The role of RAGE as therapeutic target to promote neuroprotection by inhibiting neurovascular dysfunction.  In J Alzheimers Dis 2012;;2012:734956. doi: 10.1155/2012/734956. Epub 2012 Mar 11. Abstract link:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310161/
  6. Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM. The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer’s disease. Curr Opin Investig Drugs. 2009 Jul;10(7):672-80.  Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/19579173
  7. Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings. Adv Drug Deliv Rev. 2002;54(12):1615-25. Abstract link: http://www.ncbi.nlm.nih.gov/pubmed/12453678
  8. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996 Aug;382(6593):685–691. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/8751438
  9. Yan SD, Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF. RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med. 2007;7(8):735-42. Abstract Link :  http://www.ncbi.nlm.nih.gov/pubmed/18331231
  10. Yan SD, Bierhaus A, Nawroth PP, Stern DM. RAGE and Alzheimer’s disease: a progression factor for amyloid-beta-induced cellular perturbation? J Alzheimers Dis. 2009;16(4):833-43. Abstract link:  http://www.ncbi.nlm.nih.gov/pubmed/19387116

 

STEADFAST Study

The STEADFAST study, two independent and identical randomized, double-blind, placebo-controlled Phase 3 trials (Part A and Part B), was designed to investigate the safety and efficacy of azeliragon as a potential treatment for patients with mild Alzheimer’s disease. The 18-month study targeted enrollment of 800 patients (400 in each trial). The first trial enrolled patients in the United States and Canada who had a clinical diagnosis of mild Alzheimer's disease and an MRI consistent with this diagnosis. Enrollment of the second trial included study sites in the United Kingdom, Ireland, Australia, New Zealand and South Africa.

Part A and B of the STEADFAST study did not meet either co-primary efficacy endpoint. Patients taking azeliragon compared with placebo did not improve in cognitive or functional outcomes as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb). However, findings from the STEADFAST study suggest that lower maximal plasma concentrations of azeliragon are associated with improvements in efficacy relative to placebo. These findings are consistent with published data from the phase 2b study (Burstein et al. BMC Neurology 2014, 14:12).

Relying upon the program’s Fast Track Designation status and study results to date, the Company will pursue expedited discussions with the Food and Drug Administration (FDA) to propose a pathway for further clinical development in support of regulatory approval of azeliragon.

Publications

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics