Two new approach methodologies (NAMs) predict no clinical QTc prolongation by sisunatovir - Confirmed by TQT study

Abstract

Sisunatovir, an orally administered inhibitor of the Respiratory Syncytial Virus F-protein, inhibits the hERG channel in vitro (IC50 = 1.8 μM), providing a ~ 15× safety margin over the high clinical exposure (hCmax; 118 nM free). A hERG margin <30× generally indicates increased risk for clinical QT prolongation and the arrhythmia Torsades de Pointes (TdP). Sisunatovir also inhibits the cardiac sodium (Nav1.5) and calcium (Cav1.2) channels at 12.1 μM and 19.8 μM, respectively, which may offset the delayed repolarization imparted by hERG block, limiting QT prolongation.

We have previously developed and published two NAMs that provide an integrated assessment of multi-ion channel block. Our human induced pluripotent stem cell cardiomyocyte (hIPSC-CM) model, uses rate-corrected action potential duration (cAPD) changes to estimate the concentration associated with clinical 10 ms QTc prolongation. Our in silico model, trained on a library of clinical compounds with known TdP risk, uses ion channel inputs (hERG binding Ki, Nav1.5 and Cav1.2 functional patch IC50's) to simulate voltage and calcium waveforms based on the O'Hara-Rudy ventricular cardiomyocyte model to predict TdP risk. Here we employed these models to assess the repolarization and TdP risks of a novel compound prior to its examination in a Thorough QT (TQT) study.

The hiPSC-CM model predicted that 30-min sisunatovir exposure would cause a 10 ms increase in clinical QTc at 1.8 μM (>15× hCmax) and that 24-h exposure would cause no clinical QTc prolongation up to 76 μM (>640× hCmax). The in silico model predicted a low risk of TdP at free plasma concentrations ≤1.4 μM (>10× hCmax). These results with preclinical NAMs suggest that sisunatovir is unlikely to result in QTc prolongation or elevated TdP risk at clinically relevant exposures. A TQT study (NCT05878522) confirmed no QTc signal of potential clinical concern. These results demonstrate the utility of NAMs for integrated risk assessment of QTc and TdP.