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

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.

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

“…Four drugs targeting the inflammation/ infection/immunity (17.6% of all agents) are currently in phase 3 clinical trials. The first is ALZT-OP1 (cromolyn + ibuprofen) aiming to increase the clearance of Aβ by modulating the microglia activation; the next is azeliragon, a RAGE antagonist, aiming to reduce Aβ load and neuroinflammation in the brain; 371 the third is masitinib, a tyrosine kinase inhibitor, aiming to reduce the Aβ charge and tau phosphorylation; and the last is COR388, a bacterial protease inhibitor targeting gingipain, aiming to reduce neuroinflammation and hippocampal neurodegeneration. Other potential candidates did not seem to lead to conclusive results and were halted.…”

“…For the sake of brevity, we will not explain the method in great detail but rather refer the reader to our recent article that gives an insight of TDA and how it can be applied to high-dimensional and multiscale data. 371 However, in brief, TDA extracts topological and geometrical features that persist across spatial scales (hence beyond classical network analysis). These persistent features correspond to invariances of the data and are summarized in specific diagrams as shown in Figure 1 (right panel, A and B).…”

Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets

“…However, contradictory findings have been published and other studies have shown that RAGE inhibition, elicited either through genetic deletion or through the use of anti-RAGE or anti-HMGB1 antibodies, was associated with unchanged or decreased bacterial dissemination 17,38,39 . Indeed, although trials in patients with mild Alzheimer's disease did not support clinical efficacy of azeliragon (TTP448, vTv Therapeutics, High Point, NC, USA), an inhibitor of RAGE-amyloid β protein interactions, no obvious safety issues were associated with its use (5 mg orally once daily for 18 months) in human patients [40][41][42] . Future research should therefore investigate the extent to which our current findings might translate to the treatment of critically ill patients with ARDS in terms of the timing, dosing and methods of administration of RAGE inhibition candidates, with a focus on their efficacy and safety profiles.…”

Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease

“…RAGE is over expressed in the brain tissues of AD patients. Azeliragon has been shown to slow down the progression of AD [ 118 ]. It was developed by vTv Therapeutics® (Originator) and was studied in the phase 3 clinical trials for the treatment of Alzheimer’s type dementia (STEADFAST).…”