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

Ivan Kopljar,Fetene Tekle,Ard Teisman,Karel Van Ammel,David J Gallacher,Martin Otava,Hua Rong Lu

doi:10.1016/j.stemcr.2018.11.007

Ivan Kopljar, Fetene Tekle + Show 5 more

Open Access

https://doi.org/10.1016/j.stemcr.2018.11.007

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Abstract

SummaryHuman 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.

Highlights

Assessment of cardiac safety liabilities within drug discovery and development is essential to advance promising new chemical entities (NCEs) into clinical evaluation
We used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities
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

Summary

Introduction

Assessment of cardiac safety liabilities within drug discovery and development is essential to advance promising new chemical entities (NCEs) into clinical evaluation. Inhibition of the hERG channel (gene: KCNH2), a voltage-gated K+ channel that conveys the cardiac rapid delayed rectifier potassium current (IKr), is the main mechanism associated with drug-induced QT prolongation. Beyond QT prolongation, these additional pharmacological actions can result in drug-induced cardiac liabilities such as QT shortening and QRS widening, which are associated with bradycardia and cardiac arrest, and non-TdP ventricular tachycardia or ventricular fibrillation. These cardiac liabilities not related to prolongation of repolarization need to be considered during cardiac safety evaluation in pharmaceutical research and development (R&D) (Lu et al, 2008, 2010)

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