After a number of non-cardiac drugs were removed from the market in the 1990s due to increased risk of cardiac arrhythmia, the FDA enacted the ICH E14 guidelines. These guidelines required in vitro hERG screening and in vivo QT prolongation assessment to determine proarrhythmic risk. While considered a success at preventing new withdrawals due to QT prolongation, concern has grown that the assays are highly sensitive and have a low selectivity. As a result, new therapeutics may be prevented from reaching the market.
The FDA’s CiPA initiative calls for a new approach to cardiac drug safety assessment to address these concerns and create a more predictive assay. CiPA proposes a three-tiered approach to testing:
Test activity in select cardiac ion channels Predict the effect with in silico computer modeling Test the in vitro response in human stem cell-derived cardiomyocytes As one of only two technologies approved by the CiPA panel to address in vitro responses, the Maestro MEA platform generates responses similar to a clinical electrodcardiograph (ECG). Cardiomyocyte testing on the Maestro provides a reproducible, whole-cell model of electrophysiological function capable of detecting responses from key cardiac ion channels and molecular pathways. With Axion BioSystems’ Maestro platform, physiologically-relevant cardiac safety data is available in an easy-to-use, data-rich in vitro functional assay.
View the results of the Maestro CiPA pilot study:
To assess the reproducibility and predictive power of human iPSC-derived cardiomyocytes on the Maestro, six sites tested one of three cell lines against eight reference compounds. The reference compounds were picked to validate assay sensitivity across different mechanisms. The Maestro was able to accurately detect the expected response from each compound across each cell line.
Axion BioSystems has developed a cardiac analysis software package included with AxIS software to make cardiac analysis easy and straightforward. AxIS can measure beat rate and rhythmicity, conduction velocity, depolarization amplitude and velocity, and field potential duration. To ensure the most accurate and reproducible results, AxIS offers a variety of quality control options that:
- Isolate the range of maximum beat stability within a recording
- Analyze only from beats originating from the dominant pacemaking site
- Utilize the electrode redundancy to optimize field potential duration measurement
To compliment AxIS, Axion has developed the CiPA Analysis Tool. This tool allows for easy detection and classification of arrhythmia as well as visual inspection and verification of field potential measurements. Quickly and easily compare beating and waveforms between recordings and doses in a user-friendly, visual display. The Axion CiPA Analysis Tool offers everything you need to report in vitro cardiomyocyte-based assay data according to the new FDA guidelines and is included with AxIS.