In 2006, induced pluripotent stem cells (iPSCs) were first introduced by Shinya Yamanaka at Kyoto University in Japan. Yamanaka’s discovery, which earned him the Nobel prize in 2012, enabled the use of human cells in stem cell science, bypassing the use of embryonic stem cells (ESCs). As a result of this advance, one of the most important applications for induced pluripotent stem cells has become their use as predictive technologies to support and streamline drug safety testing.
The market for stem cell assays to aid in early-stage drug development is substantial, because stem cells differentiated into tissue specific cells and tissues can form the basis of predictive assays capable of filtering out compounds at an early stage of drug discovery. Historically, the drug discovery and development process has been an extremely expensive and time-consuming endeavor, requiring an investment of 12 to 15 years and a cost of over $800 million per successful drug.[1]
Unfortunately, unexpected serious side effects, usually involving either the liver or heart, cause one of three drugs to fail toxicity requirements in clinical trials. Therefore, the ability to differentiate iPSCs into hepatocytes, neurons, and cardiomyocytes for early-stage toxicity testing has grown into an important area of product development.
Human stem cell-derived cardiomyocytes are particularly important for preclinical cardiac safety assessment. While several independent groups have derived human cardiomyocytes from iPSCs, there are only a few commercial providers that specialize in these cells types. Cellular Dynamics International (CDI) is arguably the best-known American provider, while Axiogenesis has grown into a dominant European provider of these cell types. Both companies specialize in human induced pluripotent stem cell products, including in vitro models of healthy and diseased cell types and tissues.
There are also smaller providers of iPSC-derived cells and assays within the global marketplace, but these companies are the clear market leaders.
Axiogenesis Participates in Validations in Public Consortia
A unique attribute of Axiogenesis relative to other market players is that the company actively participates in validations in public consortia. Specifically, the company is involved in the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, led by the US FDA, Safety Pharmacology Society (SPS), Cardiac Safety Research Consortium (CSRC) and Health & Environmental Sciences Institute (HESI). The CiPA initiative began following a workshop in July 2013 at the U.S. FDA.
CiPA aims to improve current regulatory guidances by introducing predictive technologies, including human stem cell-derived cardiomyocytes into preclinical cardiac safety assessment. The objective of the CiPA initiative is to develop an assay for assessment of the proarrhythmic potential of new drugs to improve specificity when compared to the gold standard, the hERG assay.[2] This assay will ultimately drive the modification or replacement of the existing ICH S7A/B and E14 guidelines, virtually eliminating the need for clinical TQT studies for compounds entering clinical development.
The initial CiPA pilot study comprised a 16 site blinded global study which employed microelectrode array (MEA) and voltage-sensing-optical (VSO) platforms to evaluate the effects of eight compounds with varying cardiac risk (low, medium, high) on human stem cell cardiomyocytes (hSC-CMs) from three global cardiomyocyte providers: Axiogenesis and Cellular Dynamics International provided iPSC-derived cardiomyocytes, while GE Healthcare provided embryonic stem cell (ESC) derived cardiomyocytes.
Axiogenesis Cor.4U human cardiomyocytes were tested at 12 global laboratories, including prominent pharmaceutical, 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.4U cardiomyocytes in these assays were highlighted on multiple occasions at this well-attended workshop.
The key conclusion from these pilot studies is that experimental compound-mediated effects were not only comparable across sites using the same platform, but also among the various platform providers. The results from these proof-of-concept studies emphasize both the reproducibility of the test system (hSC-CMs in higher-throughput electrophysiological assays) across laboratories, as well as the validation of the CiPA model.
Currently, a more comprehensive validation study is ongoing, with results expected in November 2016. In this CiPA II validation study, Axiogenesis Cor.4U cells are one of only two iPSC-derived cardiomyocytes cell models that are funded by the HESI under the FDA grant.
In this study the 5 Core sites will test only CDI and Axiogenesis cells and will use all of the 28 blinded validation compounds in the VSO and MEA technologies. An additional 23 non-core sites (including 7 academic groups) will also participate with Axiogenesis and CDI cells some introducing other related technologies or other cells . These sites will test 4 calibration compounds and 12 blinded compounds selected randomly.
Axiogenesis is a well-represented and 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.
Furthermore, Axiogenesis is an active member of the recently formed HESI Consortium that focuses on establishing novel biomarkers that facilitate improved prediction of neurotoxic effects of drug compounds. Axiogenesis is also involved with the establishment of standards for hiPSCs in the global stem cell market through organizations such as the Standards Coordinating Body (SCB) which liaises with the National Institute of Standards and Technology (NIST), International Society for Stem Cell Research (ISSCR), and the Alliance for Regenerative Medicine (ARM).
To learn more about the role of iPSC-derived cell assays in preclinical safety testing, visit CiPA (http://cipaproject.org/) or Axiogenesis (Axiogenesis.com). BioInformant thanks these groups for their assistance in assessing the market potential for iPSC-derived cell assays. It is our belief that early-stage drug development will be substantially impacted by these predictive technologies as multiple groups and stakeholders collaborate to introduce them to the global marketplace.
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Footnotes:
[1] DiMasi, Joseph A, Ronald W Hansen, and Henry G Grabowski. “The Price Of Innovation: New Estimates Of Drug Development Costs”. Journal of Health Economics 22.2 (2003): 151-185. Web.
[2] “About CIPA | CIPA”. Cipaproject.org. N.p., 2016. Web. 20 June 2016.