Stem Cell Derived Cardiomyocytes in Drug Safety Evaluations: Lessons Learned from the Comprehensive in Vitro Proarrhythmia Assay (CiPA) Initiative
The Comprehensive in Vitro Proarrhythmia Assay (CiPA) represents a new paradigm for directly assessing proarrhythmic risk based upon mechanistic assessments of cellular proarrhythmia linked to Torsades-de-Pointes proarrhythmia. Human stem cell derived cardiomyocytes (hSC-CMs) play a critical role in this initiative, serving to confirm in silico reconstructions of electrophysiologic effects of drugs. The utility of this approach involves consideration of the higher throughput approaches to be used (multielectrode arrays or voltage-sensing optical technologies) as well as consideration of the ability of hSC-CM’s to faithfully and reproducibly recapitulate cellular proarrhythmic events. Multiple publications (as well as a HESI-CiPA Pilot study) point to the utility of hSC-CM’s to detect delayed repolarization as well as other repolarization abnormalities. However, such studies are typically small and conducted unblinded, with a potential bias in the selection of test agents that may not be fully characterized in regards to proarrhythmic risk ranking. Evolving datasets from an ongoing validation study with hSC-CM’s will provide an assessment of the utility of hSC-CM’s for evaluating proarrhythmic liabilities early in drug discovery as well as in later regulatory-approvals of new drugs.