A Quantitative Framework to Evaluate Proarrhythmic Risk in a First-in-Human Study to Support Waiver of a Thorough QT...

The effects of GS-4997 (apoptosis signal-regulating kinase 1 inhibitor) on cardiac repolarization were evaluated using a systematic modeling approach in a first-in-human (FIH) study. High quality, intensive, time-matched 12-lead electrocardiograms (ECGs) were obtained in this placebo-controlled, single and multiple-ascending dose study in healthy subjects. Model development entailed linearity and hysteresis assessments; GS-4997/metabolite concentration vs. baseline-adjusted QTcF (ΔQTcF) relationships were determined using linear mixed effects models. Bootstrapping was used to obtain 90% confidence intervals (CIs) of predicted placebo-corrected ΔQTcF (ΔΔQTcF). The upper bound of 90% CI for predicted ΔΔQTcF was <10 msec at therapeutic and supratherapeutic GS-4997/metabolite levels, indicating the absence of a QT prolongation effect. Model performance/suitability was assessed using sensitivity/specificity analyses and diagnostic evaluations. This comprehensive methodology, supported by clinical pharmacology characteristics, was deemed adequate to assess the proarrhythmic risk of GS-4997/metabolite by the US Food and Drug Administration and European Medicines Agency resulting in a successful waiver from a dedicated thorough QT (TQT) study.