Leaving hERG in the Rearview Mirror
The Comprehensive in vitro Proarrhythmie Assay (CiPA) initiative, led by the US FDA, Safety Pharmacology Society (SPS), Cardiac Safety Research Consortium (CSRC) and Health & Environmental Sciences Institute (HESI), aims to improve current regulatory guidances by introducing predictive technologies, including human stem cell-derived cariomyocytes (hSC-CMs), into preclinical cardiac safety assessment. This assay, designed to assess proarrhythmic risk during new drug development, will ultimately drive the modification or replacement of the existing ICH S7A/B guidelines and elimination of E14 guidelines, virtually eliminating the need for clinical TQT studies for compounds entering clinical development.
The initial 16 site blinded global pilot study employing microelectrode array (MEA) and voltage-sensing-optical (VSO) platforms evaluated the effects of eight compounds with varying cardiac risk (low, medium, high) on hSC-CMs from three global cardiomyocyte providers (iPSC: Axiogenesis, Cellular Dynamics Int.; and ESC: GE Healthcare).
Axiogenesis Cor.4Uhuman cardiomyocytes were (or are currently being) tested at 12 global laboratories, including prominent pharaceutical, contract research organizations and academic institutes. The pilot tests included analysis of 8 blinded compounds on both microelectrode array (MEA) and voltage sensitive optical imaging platforms. Preliminary data were presented on December 11, 2014, at the CiPA Update Workshop. The physiologically-relevant, reproducible performance of the Cor.4Ucardiomyocytes in these assays were highlighted on multiple occasions at this well-attended workshop.
The pervasive message from these pilot studies is that experimental compound-mediated effects were not only comparable across sites using the same platform, but also amongst the various platform providers. The results from these proof of concept studies both emphasize the reproducibility of the test system (hSC-CMs in higher throughput electrophysiological assays) across laboratories as well as help to validate the CiPA model going forward.
Currently, a more comprehensive validation study is plannes for mid-late 2015. This study will likely introduce more cardiomyocyte cell providers and will most certainly the number of experimental test sites and test systems. Axiogenesis is a well-represented and is an influential presence on the myocyte committee responsible for establishing the basic (biological, pharmacological, quality control) criteria for inclusion in these larger validation studies. These criteria will also help to establish rules and requirements for the use of cardiac myocytes in future CiPA-related investigational new drug (IND)-enabling studies.
The significant commitment of the Axiogenesis team and success of the Cor.4Ucardiomyocytes in these CiPA studies have Axiogenesis well positioned on the leading edge of this revolutionary initiative.