Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking

Abstract

Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening. : Kopljar and colleagues developed a scoring system to evaluate the potential cardiac hazard of drugs using a hiPSC-CM-based screening assay. This approach allows translation of various pharmacological responses in hiPSC-CMs into a single hazard label. Early evaluation of thousands of new chemical entities within drug discovery and development should enhance the development of new drugs with a favorable cardio-safety profile. Keywords: cardiomyocytes, stem cells, drug discovery and development, drug screening, cardiac safety, cardiac hazard, pharmacology, arrhythmia, torsade de pointes, hERG