Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

Background and Purpose Translation of nonclinical markers of delayed ventricular repolarization to clinical QTc prolongation (a biomarker for Torsades de Pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. A retrospective analysis of 150 submitted drug applications in a US-FDA database was conducted to determine the utility of established nonclinical in vitro iKr current (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The diagnostic and prognostic performance of three nonclinical assays were compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operator curves (ROC), positive and negative predictive values, and likelihood ratios. Key Results Nonclinical assays demonstrated robust specificity (ability to identify drugs without clinical QTc prolongation) but poor sensitivity (ability to identify drugs eliciting clinical QTc prolongation) at low to intermediate (1x-30x) clinical exposure multiples. The QTc assay provided the most robust positive and negative predictive values (ability to predict clinical QTc prolongation). Receiver operator curves (defining overall test accuracy) and likelihood ratios (ability to influence post-test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best results at 30x exposures) while the APD assay demonstrated minimal value. Conclusions and Implications The diagnostic and prognostic value of hERG, APD, and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates devoid of clinical QT prolongation, the hERG and QTc repolarization assays provide greater value compared to the APD assay.