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
- 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
- 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
- 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
- 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
- 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/
- 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
- 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
- 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
- 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
- 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
Azeliragon has completed phase 1 studies in healthy volunteers and 10 week (Sabbagh et al, 2011) and 18 month (Galasko et al 2014, Burstein et al 2014) Phase 2 studies in patients with mild to moderate Alzheimer’s disease. Studies have supported identification of a safe, well-tolerated and efficacious dose for further study in the Phase 3 registration trial.
Our completed Phase 2b clinical trial, TTP488-203, was a randomized, double blind, placebo-controlled trial assessing the safety and efficacy of azeliragon in 399 patients with mild-to-moderate AD. Azeliragon or placebo was added to stable doses of acetylcholineserase inhibitors (AchEIs) and/or memantine. Patients were randomized to receive an oral dose of 20 mg per day (following a loading dose of 60 mg/day x 6 days) of azeliragon, 5 mg per day (following a loading dose of 15 mg/day x 6 days) of azeliragon or placebo.
The primary endpoint was the change in ADAS-cog at 18 months. The secondary endpoints included the changes in global, functional, cognitive and behavioral attributes as measured by CDR-sb, ADCS-ADL, MMSE, and NPI.
Efficacy in Mild to Moderate AD Patients
Despite the 20 mg/day dose being stopped by the DMC due to acute, reversible, concentration dependent cognitive worsening and the study being prematurely stopped for apparent futility, the study achieved its pre-specified objective demonstrating a statistically significant 3.1 point difference (p = 0.008) favoring azeliragon 5 mg/day over placebo at 18 months in patients with mild to moderate AD.
While the study was not powered to show significant differences for global, functional, cognitive and behavioral secondary endpoints, after 18 months the CDR-sb, ADCS-ADL, MMSE and NPI demonstrated numerical improvement for 5 mg/day when compared to the placebo arm. In particular, the CDR-sb score was improved by 0.7, the ADCS-ADL score improved by 1.47, the MMSE score improved by 1 and the NPI score improved by 1.2.
In addition, azeliragon 5 mg/day decreased the incidence of psychiatric adverse events, including a statistically significant decrease in anxiety symptoms. The results of the secondary endpoints are summarized in the following figures.
Efficacy in Mild AD Patients
Azeliragon 5 mg/day demonstrated greater efficacy for mild AD (MMSE score 21-26) than patients with moderate AD (MMSE score 14-20). The ADAS-cog11 showed a statistically significant 4.0 difference (p=0.018) for 5 mg/day relative to placebo.
The difference in CDR-sb between 5 mg/day and placebo at 18 months was also statistically significant showing a 1.0 difference (p=0.02). Additional secondary endpoints (ADCS-ADL, MMSE, NPI) demonstrated directional improvement as mean improvement of 3.2 for the ADCS-ADL score, 1.1 for the MMSE score and 3.1 for the NPI score in the 5 mg/day group compared to placebo. The results of the primary ADAS-cog11 endpoint in the mild AD population are summarized below.
Azeliragon has been granted Fast Track designation by the United States Food and Drug Administration and has successfully completed an End of Phase 2 meeting. A phase 3 trial, the STEADFAST Study, under a Special Protocol Assessment (SPA) is ongoing.
Based on the Phase 2b clinical results, concentration effect analyses to support dose selection and discussions with the FDA, we commenced the STEADFAST Study in the second quarter of 2015.
The STEADFAST Study is a multi-center, randomized, double-blind, placebo-controlled, parallel group 18 month study to establish the efficacy of azeliragon in patients with mild AD (MMSE 21-26) receiving stable doses of an acetylcholinesterase inhibitor and/or memantine. The single protocol will enroll 800 subjects divided into two independent sub-studies. Each subject will receive either a 5 mg/day dose of azeliragon or the placebo, each added to stable doses of acetylcholinesterase inhibitor and/or memantine. The sub-studies are independently powered to demonstrate statistically significant differences in co-primary endpoints of ADAS-cog and CDR-sb at the 18th month timepoint.