ASSESSMENT OF AZELIRAGON QTC LIABILITY THROUGH INTEGRATED, MODEL-BASED CONCENTRATION QTC ANALYSIS

Abstract

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria. Nonlinear mixed-effects modeling was conducted to describe azeliragon concentration-related changes in QT interval, after correcting for heart rate, using Fridericia's criteria (QTcF) and sex-related differences in baseline QTcF. Azeliragon-related changes in QTcF were predicted using 2 methods: simulation and bias-corrected 90% confidence interval approaches. A small positive relationship between azeliragon plasma concentration and QTcF was noted with a slope of 0.059 ms/ng/mL. Simulations predicted mean (90% prediction interval) changes in QTcF of 0.733 milliseconds (0.32-1.66 milliseconds) with the phase 3 dose (5 mg once daily steady state) and 4.32 milliseconds (1.7-8.74 milliseconds) at supratherapeutic doses (20 mg once daily steady state or 60 mg once daily × 6 days). Bias-corrected upper 90% confidence intervals for therapeutic and supratherapeutic doses were 0.88 and 5.01 milliseconds, respectively. Model-based analysis showed a small, nonclinically meaningful, positive relationship between azeliragon plasma concentration and QTcF with a slope close to zero. Neither the prediction interval nor the upper bound of the 90% confidence interval reached 10 milliseconds, demonstrating no clinically meaningful drug-related effect on QTcF at expected therapeutic and supratherapeutic doses of azeliragon.