Two recent peer-reviewed publications underline the predictive value of Axiogenesis Cor.4U iPSC-derived cardiomyocytes (iPSC-CMs).
There was a publication earlier this year by Astra Zeneca researchers that resulted in a somewhat negative perception (mostly by iPS cell skeptics) of iPSC-derived cells. The predictive value of iPSCs was questioned, with the abstract stating, “iCell® cardiomyocytes have limited value as an integrated QT/TdP assay, highlighting the urgent need for improved experimental alternatives that may offer an accurate integrated cardiomyocyte safety model for supporting the development of new drugs without QT/TdP effects.”
This was research performed using iCells, which in that paper do not sufficiently predict QT prolongation using field potential duration (FPD) as a readout properly. In addition, they show arrhythmic behavior induced by a drug that is considered safe in the clinic (ranolazine). In another recent publication from Merck researchers using a different assay technology, iCells again showed arrhythmias induced by ranolazine.
Given this context, it was vital for both the FDA and the drug discovery community to identify what cardiac cell models are predictive.
Therefore, it is of great significance that a recent FDA publication announced that Cor.4U cells by Axiogenesis reliably predict clinical results. The finding was further confirmed by researchers at Clyde Biosciences in a publication released September 22, 2016.
The importance of these findings to the drug development community is that there is growing evidence to suggest that Axiogenesis’ COR.4U cardiomyocytes may have a greater predictive value than other commercially available options.
Axiogenesis, World’s 2nd Largest Supplier of iPSC-Derived Cells, Including COR.4U Cardiomyocytes
For those not familiar with Axiogenesis, the company was founded in 2001 and is headquartered in Cologne, Germany. At the time of this article, Axiogenesis is the second largest provider of iPSC-derived cell types and tissue for large pharmaceutical companies.
After Yamanaka’s groundbreaking iPSC technology became available, Axiogenesis was the first European company to license and adopt Yamanaka’s iPSC technology in 2010. Now Axiogenesis specializes in human iPSC products, including in vitro models of healthy and diseased cell types and tissues. Axiogenesis’ current focus lies on preclinical drug discovery and drug safety through the development of functional assays using human neuronal and cardiac cells, although it is expanding into new areas.
Its flagship offering is its Cor.4U human cardiomyocyte product family, including cardiac fibroblasts. Cor.4U cells are used in applications for single cell analysis to high-throughput screening (HTS) in early cardiac safety and safety assessment, as well as in cardiovascular drug development.
To explore the importance of this product family to the drug discovery community, we review two recent peer-reviewed publications that underline the predictive value of Axiogenesis Cor.4U iPSC-derived cardiomyocytes (iPSC-CMs), relative to other commercial options.
Key observations and conclusions of these papers are discussed below.
1. FDA Publication: Comprehensive Translational Assessment of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias
Ksenia Blinova and coworkers from FDA, as well as contributors from Zenas, University of Glasgow and Axion Biosciences, provide the to-date perhaps most comprehensive and clinically translational pharmacological assessment of iPSC-CMs.
In this report 26 drugs and 3 drug combinations, most with known QT prolongation and torsade de pointes (TdP) risk, were tested on iPSC-CM from two different commercial providers (Axiogenesis, CDI) using both high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) technologies. These assays are currently being validated for use in the Comprehensive in vitro Proarrhythmia Assay (CiPA).
Importantly, the concentrations used in these experiments began at clinical (Cmax) values and were increased to supraphysiological doses as an example of a “safety margin” assessment. Ultimately, this study focused on the correlation of in vitro action potential (APD) and field potential (FPD) duration to clinical QT prolongation. These results were correlated with experimentally determined ion channel block to provide insight into iPSC-CMs as an integrative model demonstrating multiple ion channel effects (MICE).
In the head-to-head comparison (see table above, reproduced from supplemental data, table IV), both cell types correctly did not identify any false positives (specificity = 1). Axiogenesis Cor.4U cardiomyocytes demonstrated better sensitivity than the iCells for predicting clinical APD90/FPDc prolongation as more true positives and fewer false negatives were identified.
Similarly, baseline inter- and intra-assay variation (COV) were also lower for Cor.4U as well and demonstrated good cross-platform consistency.
Importantly, the dual blocker ranolazine did not elicit arrhythmias in Cor.4U cells, whereas it did at higher doses in the iCells. This is consistent with a previously characterized, detectable late sodium current in Cor.4U and underscores the need for a physiological cell system to assess Multiple Ion Channel Effects (MICE).
For more details read the full article “Comprehensive Translational Assessment of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.”
2. The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye DI-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent stem Cell-Derived Cardiomyocytes
This report evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM.
The objective of the study was to demonstrate that optical VSD dye recording from hiPSC-derived cardiomyocytes is a suitably assay system for CiPA and for drug discovery. Using this assay, the authors compared electrophysiological characteristics of two commercially available hiPSC-derived cardiomyocytes cell types (Cor.4U and iCells), “both of which are thought to represent a stable paradigm of human-derived cardiomyocytes.”
The effect of 3 blinded reference compounds nifedipine (L-type calcium channel blocker), E-4031 (pure hERG blocker), and ranolazine (hERG and late sodium current blocker) were assessed.
Cor.4U and iCells responded similarly to nifedipine. However, only Cor.4U cells revealed a statistically relevant shortening of the APD90 at lower concentrations.
Ranolazine, a clinically safe drug, did not induce arrhythmias in Cor.4U even at the highest test dose of 100 µM – i.e. Cor.4U predicted the clinic accurately. In contrast, iCell cardiomyocytes reveal induction of EAD and tachy-arrhythmic beating patterns (see figure 9 of the paper, with ranolazine effect depicted below).
According to the authors, “The mechanisms responsible for the complex cellular proarrhythmia observed with some (iCell) myocytes at supratherapeutic exposures of ranolazine are unclear.”
Taken together, the study by Hortigon-Vinagre clearly indicates that Cor.4U cardiomyocytes are the preferred cell model to assess cardiac pro-arrhythmic potential in vitro.
For more details read the full article here.