Exposure-response analyses of QT data from early-stage clinical studies 
represent a valuable tool to assess the QT prolongation potential for drugs in 
development in lieu of standalone thorough QT (TQT) studies. However, 
demonstrating adequate electrocardiogram assay sensitivity can be challenging in 
the absence of a positive pharmacological control. Upadacitinib is a Janus 
kinase 1 inhibitor currently being evaluated in phase III rheumatoid arthritis 
trials. Exposure-response analyses to evaluate the QT prolongation potential for 
upadacitinib from phase I trials and the utility of the effect of food on QTcF 
to demonstrate ECG assay sensitivity are presented. The analyses demonstrated no 
effect of upadacitinib on QT interval and confirmed the sensitivity of the ECG 
assay to detect the small QT shortening effect caused by food. Lack of bias from 
manual ECG adjudication was also demonstrated. These analyses supported 
requesting a waiver for the regulatory requirement for a dedicated thorough QT 
study for upadacitinib.