Drug toxicity is a pervasive issue in the pharmaceutical drug development process, which is difficult to avoid but needs to be identified and mitigated. Failure to recognize such toxicities during the course of drug development can pose a great risk to the target patient population, as well as a serious challenge to drug developers faced with an unforeseen drug withdrawal from the market. The potential for clinical manifestation of ventricular arrhythmias, commonly known as “Torsade de Pointes” (TdP), can be caused by new pharmaceuticals, and continues to be a major concern for both the pharmaceutical industry and regulatory agencies. The Food and Drug Administration (FDA) established the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative through a public/private partnership, whose charter is to examine the possible modification to existing regulatory guidelines.
On the non-clinical side, CiPA proposes to utilize three complementary approaches which include: (i) additional ion channel screening above and beyond hERG; (ii) an in silico cardiac modeling approach which can be used to integrate and model the data from the ion channel screening; (iii) a relevant human cardiomyocyte model system such as hiPSC-CMs to assess the effect of pharmaceutical compounds.
The multi-site validation study, which was published recently in “Cell Reports”, focused on assessing the potential of using hiPSC-CMs with either in vitro-based microelectrode array (MEA) technology, including the xCELLigence CardioECR system from ACEA, or voltage-sensing optical (VSO) techniques. Standardized protocols were used to assess drug-induced altered repolarization, and to identify important hiPSC-CM assay endpoints associated with high, intermediate, and low TdP risk using linear regression models.
“Selecting the xCELLigence RTCA CardioECR system as one of the main platforms in the Core Sites for evaluation of Phase II validation set is a vote of confidence for our technology,” said Dr. Yama Abassi, Vice President at ACEA Biosciences. “Additionally, as a validation site, ACEA executed studies confirming the electrophysiological effects, as well as sensitivity, specificity and reproducibility of hiPSC-derived cardiomyocytes in response to 28 well-characterized drugs through the observation of concentration-dependent effects on repolarization and of arrhythmia-related events consistent with known ionic mechanisms of single and multi-channel blocking drugs.”
During this CiPA Phase II study, two commercial human cardiomyocyte lines were used with 5 devices across 10 sites. A statistical model was established to predict proarrhythmic risk from electrophysiological responses. The results from this study could be used as the basis for possible modification of the existing regulatory guidelines for cardiac assessment of pharmaceutical compounds.