Building better human disease models with hiPSC-derived cardiomyocytes

Between the FDA Modernization Act 2.0 and the ISSCR Standards Document, there’s a growing industry trend toward developing robust in vitro models for drug discovery and toxicity screening. Recently, an important study was published taking an objective view of a range of human iPSC-derived cardiomyocytes, and their pro-arrhythmia sensitivities, through the use of computational methods to aid the cardiac safety decision-making process. In this article, we explore this evolving landscape and look at the utility of human iPSC-derived cardiomyocytes for cardiotoxicity screening.

Cardiotoxicity: a billion-dollar problem

Adverse effects on the heart cause one-third of regulatory clearance failures; clearly, cardiotoxicity is a major challenge for drug development and discovery 1. Predicting cardiotoxic liabilities earlier in drug development could both accelerate and de-risk drug development. Considering the average drug can cost over $2 billion to develop, there is enormous interest in developing new methods to “fail faster” 2.

Biopharma has developed and utilized a range of models to identify cardiotoxic effects, including in vivo (animal) models, primary cell models (using cells taken directly from humans or animals) and in vitro immortalized cells transfected with particular ion channels to screen candidate therapies.

While these models have offered some value, the translational gap has persisted, sparking increasing interest in more human-relevant in vitro models.

The utility of human iPSC-derived cardiomyocytes

There has been increasing interest in the potential of iPSCs for better models for drug screening and discovery. By taking human cells and reprogramming them into iPSCs, you can potentially recapitulate the in vivo environment to a better degree than existing models.

The 2019 FDA Workshop Report outlined several promising applications for human iPSC-derived cardiomyocytes, including the identification of drug-drug interactions and the identification of side effects missed by animal models 3. This was followed by the announcement of the FDA Modernization Act 2.0, which opened the door for human-relevant testing methods (such as cell-based assays and microphysiological systems) to be used instead of, or alongside, the traditional animal testing for drugs and biosimilars.

Fig. 1: The effect of Nifedipine, an L-type Calcium channel blocker, on axoCells^TM ventricular cardiomyocytes, as part of the CiPA initiative. axoCells cardiomyocytes demonstrate expected response to increasing Nifedipine concentrations: progressive reduction in action potential duration until quiescence at 1 micromol.

The FDA also introduced the Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative, which encouraged the generation of functional data via a “cardiotoxicity in a dish” model. Our axoCellsTM human iPSC-derived cardiomyocytes demonstrated excellent performance in the twenty-eight compound assay, correctly identifying cardiotoxic liability. Further MEA studies confirmed the correct response to all the major classes of cardioactive drugs.

Clearly, there is promising industry momentum toward the use of human iPSC-derived cardiomyocytes in cardiotoxicity models.

New evidence: human iPSCs pro-arrhythmia sensitivity

Recently, an important study was published taking an objective, view of a range of human iPSC-derived cardiomyocytes 4. The report analyzed 5 commercially available iPSC-derived cardiomyocytes (including axoCells cardiac cells) assessing their pro-arrhythmia sensitivities with 10 compounds. Using computational population modeling of the 5 data sets with each compound, Bayesian bootstrapping increased sample numbers to 1000 and enabled objective classification and ranking of compound-induced sensitivities of cell lines.

While there were differences in compound-induced pro-arrhythmia sensitivities between cell lines, they all exhibited an expected elongation or shortening of calcium transient duration. The authors concluded that “a well-characterized specific cell line to generate standard data and calibrate diverse test approaches” should be used, which is in line with the ISSCR Standards Document mentioned above. However, they also state that “giving too much weight to data from a single cell line may miss cardiac safety issues caused by the diversity of human genetics”.

Overall, this demonstrates that, while there is no single commercial supplier whose cells work perfectly across all compounds as yet, iPSC-derived cardiomyocytes can be used to build robust models for cardiotoxicity screening with the application of quantitative data science tools to facilitate the decision making process for individualized cardiac safety analysis.

Key highlights

• There is considerable momentum from the industry toward using human iPSCs for cardiotoxicity and drug discovery, buoyed by the FDA Modernization Act 2.0, the CiPA initiative and the recent ISSCR Standards Document
• A recent study looked at 5 commercially available iPSC-derived cardiomyocytes (including axoCells) and demonstrated their utility as models for cardiotoxicity testing using data-driven methods to analyze liabilities and facilitate the cardiac safety decision making process
• As iPSC enthusiasts with CiPA-validated ventricular cardiomyocytes, we see tremendous value in using human iPSC-derived cardiomyocytes as models for cardiotoxicity testing

Bibliography

1 Francis Grafton, Jaclyn Ho, Sara Ranjbarvaziri, Farshad Farshidfar, Anastasiia Budan, Stephanie Steltzer, Mahnaz Maddah, Kevin E Loewke, Kristina Green, Snahel Patel, Tim Hoey, Mohammad Ali Mandegar (2021) Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes eLife 10:e68714 https://doi.org/10.7554/eLife.68714

2 DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ. 2016 May;47:20-33. doi: https://doi.org/10.1016/j.jhealeco.2016.01.012. Epub 2016 Feb 12. PMID: 26928437.

3 Pang L, Sager P, Yang X, Shi H, Sannajust F, Brock M, Wu JC, Abi-Gerges N, Lyn-Cook B, Berridge BR, Stockbridge N. Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms. Circ Res. 2019 Oct 11;125(9):855-867.   Epub 2019 Oct 10. PMID: 31600125; PMCID: PMC6788760.

4 Wakatsuki, T., Daily, N.J., Hisada, S., Nunomura, K., Lin, B., Zushida, K., Honda, Y., Asyama, M., & Takasuna, K. (2023). Bayesian Approach Enabled Objective Comparison of Multiple Human iPSC-derived Cardiomyocytes’ Proarrhythmia Sensitivities. bioRxiv. doi: https://doi.org/10.1101/2023.05.14.540739