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.4U human 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.
Update on the FDA/HESI/CSRC-sponsored Comprehensive In vitro Proarrhythmia Assay (CiPA) initiative.
In mid 2016 a second, more comprehensive follow up validation study began. This study introduced more test drugs with varying proarrhythmic liabilities, increased the number of experimental test sites and test systems. The significant commitment of the Axiogenesis team and success of the Cor.4Ucardiomyocytes in the CiPA studies to date have Axiogenesis positioned on the leading edge of this revolutionary initiative.
New information from current update
Axiogenesis joined other members of the CiPA Myocyte Core Team hosted by FDA and HESI for a face-to-face meeting on April 5 at FDA White Oak Campus in Silver Spring, MD, USA. Axiogenesis was represented by Greg Luerman PhD, Technical Director of North America, and Ralf Kettenhofen, Product Manager Cardiac Cells and Head of Assay Services.
Jennifer Pierson of HESI provided a very detailed summary of the meeting, the highlights of which are included here. First, Gary Gintant reviewed the goals of the validation study (myocyte core sites) which included up to 28 blinded compounds per test site. The overall goal was to establish best practices, calibrate/validate assays, standardize reporting format(s), assess levels & components of variability.
The Myocyte Core team includes 6 MEA and 2 VSO sites and 2 cell providers (Axiogenesis and Cellular Dynamics). Consensus protocols were established prior to the start of the study as well as a common data reporting format. The 28 compounds included 8 high risk, 11 intermediate risk and 9 low risk, each with 4 concentrations that crossed clinical Cmax.
The Core team met on April 5th to review the preliminary data summaries (descriptive statistics and variability across sites) as well as to discuss and finalize the analytical plan (e.g. derive regression models). Additionally, David Strauss provided a brief update on the FDA Advisory Committee Meeting held on March 15, 2017. David also reviewed a potential CiPA Assessment Flow Chart. In this paradigm, stem cell derived cardiomyocytes will be utilized in confirming "low risk" drugs with no pertinent ion channel effects, or conversely, multiple ion channel effects (MICE). It is suggested that if there are any discrepancies, there may be a need to investigate the mechanism further - but it wouldn’t necessarily hold up the drug to study in humans where ECG data would be collected. Additionally, it is also important to note that addressing acute pharmacological behavior is one limiting feature of CiPA. iPS-cardiomyocytes will be important as well for long term/chronic dosing as well as structural cardiotoxicity concerns.
Ultimately, the results from these experiments will be assessed using various regression analyses, logistical models, and other mixed models to understand variabilities and points of error between sites/cell types/instruments. Several predictors (i.e. number of EAD types, number of EADs at each concentration etc.) based on understanding of the biology are needed for model inputs to determine which factors are useful to separate drugs into the risk classifications.
Finally, it was decided that a publication will ensue that will encapsulate these results and statistical modeling. Additional data collected outside of the CiPA core team studies may provide as a “test” against this model. Importantly, the participating CiPA myocyte sub team members agreed neither publish, nor present their data prior to the primary publication. Thus, no data summaries were included within this summary.