Background ABT-494 is a selective Janus Kinase 1 inhibitor currently being evaluated in Phase 3 trials for treatment of rheumatoid arthritis (RA) at doses of 15 mg and 30 mg once daily using the extended-release tablet formulation. Exposure-response analysis of ECG data collected at early stage clinical trials has been recently adopted in regulatory guidelines as a tool to assess the proarrhythmic risk of investigational new drugs.
Objectives The objective of this work was to evaluate ABT-494 QT prolongation potential using exposure-response analysis of data collected in early Phase 1 studies.
Methods Doses of ABT-494 or placebo were administered to healthy subjects in two Phase 1 studies. Evaluated ABT-494 immediate-release regimens ranged from 1 mg to 48 mg single doses under fasting conditions and 3 mg to 24 mg twice daily under non-fasting conditions. Serial triplicate electrocardiograms and pharmacokinetic assessments were conducted. The relationship between change from baseline in Fridericia-corrected QT interval (QTcF) and ABT-494 plasma concentrations was characterized using linear mixed-effects modeling. To evaluate the ECG assay sensitivity, the change in QTcF from baseline to 2 hours post-dose was compared for subjects who received placebo under fasting and non-fasting conditions.
Results There was no statistically significant relationship between the change from baseline in the QTcF interval and ABT-494 plasma concentrations. The point estimate of the effect on QTcF for the highest concentration observed in the evaluated studies, which is approximately 4-fold higher than the mean Cmax of the highest RA Phase 3 dose, is –1.77 msec (with upper bound of the 95% one-sided confidence interval of 3.33 msec; lower than the regulatory threshold of concern of 10 msec). Food shortened the QTcF interval by 5.9 msec (2-sided 90% confidence interval of -9.6 to -2.1 msec), indicating that the ECG assay used in the studies had adequate sensitivity to detect the small change in QTcF caused by food.
Conclusions ABT-494 showed no potential for QT prolongation at the expected therapeutic and supra-therapeutic plasma exposures for the doses being used in Phase 3 RA trials.
Disclosure of Interest M.-E. Mohamed Shareholder of: AbbVie, Employee of: AbbVie, J. Zeng Shareholder of: AbbVie, Employee of: AbbVie, P. Jiang Shareholder of: AbbVie, Employee of: AbbVie, B. Hosmane Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie