Identifying Acute Cardiac Hazard in Early Drug Discovery Using a Calcium Transient High-Throughput Assay in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Hua Rong Lu; Mohamed Kreir; Van Ammel Karel; Fetene Tekle; Danny Geyskens; Ard Teisman; David J Gallacher

doi:10.3389/fphys.2022.838435

Identifying Acute Cardiac Hazard in Early Drug Discovery Using a Calcium Transient High-Throughput Assay in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Front Physiol. 2022 Apr 25:13:838435. doi: 10.3389/fphys.2022.838435. eCollection 2022.

Authors

Hua Rong Lu¹, Mohamed Kreir¹, Van Ammel Karel¹, Fetene Tekle², Danny Geyskens¹, Ard Teisman¹, David J Gallacher¹

Affiliations

¹ Global Safety Pharmacology, Predictive, Investigative and Translational Toxicology, Nonclinical Safety, Beerse, Belgium.
² Discovery and Nonclinical Safety Statistics, Statistics and Decision Sciences, Quantitative Sciences, Janssen R&D, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.

Abstract

Introduction: Early identification of cardiac risk is essential for reducing late-stage attrition in drug development. We adapted the previously published cardiac hazard risk-scoring system using a calcium transient assay in human stem cell-derived CMs for the identification of cardiac risks recorded from the new hiPSC-CM line and investigated its predictivity and translational value based on the screening of a large number of reference and proprietary compounds. Methods: Evaluation of 55 reference drugs provided the translation of various pharmacological effects into a single hazard label (no, low, high, or very high hazard) using a Ca²⁺-sensitive fluorescent dye assay recorded by -by FDSS/µCell Functional Drug Screening System (Hamamatsu on hiPSC-CM line (FCDI iCell Cardiomyocytes²). Results: Application of the adapted hazard scoring system in the Ca²⁺ transient assay, using a second hiPS-CM line, provided comparable scoring results and predictivity of hazard, to the previously published scoring approach, with different pharmacological drug classes, as well as screening new chemical entities (NCE's) using a single hazard label from four different scoring levels (no, low, high, or very high hazard). The scoring system results also showed minimal variability across three different lots of hiPSC-CMs, indicating good reproducibility of the cell line. The predictivity values (sensitivity and specificity) for drug-induced acute cardiac risk for QT-interval prolongation and Torsade de pointes (TdPs) were >95% and statistical modeling confirmed the prediction of proarrhythmic risk. The outcomes of the NCEs also showed consistency with findings in other well-established in vitro and in vivo cardiac risk assays. Conclusion: Evaluation of a large list of reference compounds and internal NCEs has confirmed the applicability of the adaptations made to the previously published novel scoring system for the hiPSC-CMs. The validation also established the predictivity for drug-induced cardiac risks with good translation to other established preclinical in vitro and in vivo assays, confirming the application of this novel scoring system in different stem cell-CM lines for early cardiac hazard identification.

Keywords: HTS assay; cardiac hazard risk; cardiomyocytes (hiPS-CMs); stem cells; translation.