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Cardiomyocytes from human iPSCs are valuable tools to assess non-clinical cardiotoxicity

Jan Turner

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an innovative platform for the prediction of drug-induced adverse effects (AEs) on the heart.

Recently, the United States Congress passed the FDA Modernization Act, which will allow non-clinical human-relevant testing methods, like cell-based assays, microphysiological systems (such as Organ-Chips), bioprinted, or in silico models to be used instead of, or alongside, the traditional animal testing for drugs and biosimilars. This paves the way for researchers and drug developers to undertake cardiotoxicity studies using human iPSC-CMs – something hugely important when assessing safety and making subsequent regulatory decisions on potential human treatments.

Here we’ll take a look at a new review exploring existing submissions to the FDA that use human iPSC-CMs.1 The researchers have shone a very interesting light on both the power and limitations of these cells for predicting human cardiac safety.

Drug-induced cardiac AEs are a big problem

When it comes to developing a new drug, AEs that impact cardiac function are among the main reasons for drug attrition since these can result in proarrhythmia and life-threatening serious adverse events (SAEs). Being able to predict these AEs early in drug development could therefore not only speed up the time it takes to bring a drug to market but save vast amounts of money.2

Traditional approaches to safety testing of compounds for cardiotoxicity have known limitations and in the search for better models, scientists figured out how to reprogram somatic cells into pluripotent stem cells and from there how to differentiate cardiomyocytes from iPSCs. A very promising in vitro cardiac model was on the horizon with the potential to detect AEs at both a scale and speed traditional models just couldn’t reproduce.

There are now multiple protocols available using human iPSC-CMs in drug safety assessment. Since the first use of human iPSC-CMs in a submission to the FDA in 2012, and adoption of the comprehensive in vitro proarrhythmia assay (CiPA) from 2013, these cells have been used in an increasing number of FDA regulatory applications, some of which have made a regulatory impact via an integrated non-clinical risk-assessment approach.

But while human iPSC-CMs show promise for predicting drug-induced cardiac AEs, how they may be used with confidence for non-clinical testing, and in what contexts, is important for regulators such as the FDA and EMA, now more than ever in light of the FDA Modernization Act moving forward and the European Parliament voting, by a clear majority, a resolution on plans and actions to accelerate the transition to innovation without the use of animals in research.

Human iPSC-CMs in practice: FDA submission case studies

These case studies demonstrate the potential of hiPSC-CMs to be a valuable tool for predicting drug-induced adverse effects and support their use as part of a tiered testing strategy.

Case 1: Human iPSC-CMs aid in labeling recommendation for a hERG-blocking drug

Pitolisant is a histamine 3 (H3) receptor antagonist that can cause mild-to-moderate QTc prolongation at high doses, and was approved with a warning for QT prolongation. The sponsor integrated non-clinical and clinical data to more comprehensively assess the risk of delayed ventricular repolarization, including studies suggested by the CiPA initiative.  The sponsor also investigated the proarrhythmia risk through hERG inhibition and the blockade of other cardiac ion channels, yet results from hiPSC-CMs were inconclusive.

Overall, the results from the non-clinical studies, using human iPSC-CMs, in silico modeling, and Purkinje fibers from rabbits, correlated well with those from the clinical QT studies using traditional ICH S7B assays,3 and showed that pitolisant has a low pro-arrhythmic risk at therapeutic concentrations. These combined data resulted in the prescribing information featuring a warning that pitolisant prolongs the QT interval, and that some patients should be carefully monitored.

Case 2: Unravelling drug-drug interactions postmarketing using human iPSC-CMs

In 2013, the drug sofosbuvir was approved for the treatment of chronic hepatitis C virus (HCV) infection. However, in 2015, the FDA issued a warning following unexpected cases of serious symptomatic bradycardia that had been reported when sofosbuvir was co-administered with the anti-arrhythmic drug amiodarone. It was difficult for the FDA and the applicants to develop a strategy to address this novel and complex issue. Since then, mechanistic and non-clinical studies have been conducted to evaluate the mechanisms of drug-drug interactions between sofosbuvir and amiodarone, with and without other anti-HCV direct-acting antivirals.

Drug-drug interaction studies using human iPSC-CMs showed that sofosbuvir inhibited human L-type calcium channels in the presence of amiodarone, suggesting a pharmacodynamic drug-drug interaction.4 However, human iPSC-CMs assayed highlighted an increased beat rate and shortened field potential duration, which is in contrast to the slowed heart rate seen in clinical presentation. This may be due to the human iPSC-CM cultures lacking atrioventricular and sinoatrial nodes along with their immature phenotype.5

But in general, human iPSC-CM functional assays could rapidly assess the mechanisms underlying changes in heart rate and represent a useful alternative method to answer important drug safety questions.

Case 3: hiPSC-CMs as a tool for proarrhythmia risk assessment

In 2012, the development of BMS-986094, an antiviral HCV NS5B drug class, was stopped after a patient experienced rapidly progressive reduced cardiac function and death, along with additional cases of unexpected cardiac AEs.6 A similar drug, referred to as Drug A, was also placed on partial clinical hold due to concern for similar risk.

In response, the sponsor submitted summary data of the 50% cytotoxic concentrations in hiPSC-CMs to support the claim that Drug A had a lesser degree of cytotoxic potential compared to BMS-986094. However, the predictive performance of human iPSC-CMs for cardiotoxicity, particularly for mechanisms other than ion channel blockers, had not been adequately investigated or validated. Therefore, using human iPSC-CMS to determine the compound cytotoxicity was deemed insufficient to describe the clinical cardiotoxic potential of drug A, and the sponsor withdrew their investigational new drug application.

It’s worth noting that the mechanisms of the cardiotoxicity of drug A and BMS-986094 remain unknown. Several non-clinical studies have tried to deduce this but haven’t been able to find a clear mechanism.

Here the research was unable to identify a clear cause for the cardiac toxicity and highlights some of the limitations of hiPSC-CMs as a tool for understanding cardiac toxicity in this drug class. It’s hoped that future studies with human iPSCs can improve the understanding of the mechanisms of cardiotoxicity associated with this class of drug.

Early steps toward better in vitro testing

Despite some challenges, the use of human iPSC-CMs in cardiotoxicity screening has the potential to provide rapid and accurate insight into cardiotoxicity potentials and mechanisms of new drugs. It’s now important for organizations like the FDA and the scientific community to work collaboratively toward reducing variability and increasing confidence in the use of human iPSC-CM technology for regulatory submissions. This means fully understanding both the potential and limitations of these cells and working within a standardized testing environment to account for those.

The FDA has an impressive track record of pushing the translation of new technologies like in vitro methods to improve safety predictions, and their Modernization Act is the most recent example of this. There is clearly an appetite to incorporate tools like human iPSCs-derived cells more widely into testing and it’s wonderful to see both the FDA and scientific communities moving in the same direction.

These are only the early steps, but the foundations are laid and progress is there to be made. We feel privileged to not only be early promoters of human iPSC-derived cells for non-clinical work but as leaders in making this technology accessible to a broader audience – through both cells and custom laboratory services. One of the common issues we’ve seen in the literature around human iPSC-CMs has been their immature phenotype. However, new techniques and reagents, such as the media and supplements we have developed are helping to generate more mature, more human-relevant cardiomyocytes.

There are lots of hurdles still to overcome – translating in vitro results into in vivo predictions will always be a challenge – but it’s a hurdle we’re excited to jump.

References

 

  1. Yang, X., Ribeiro, A. J. S., Pang, L. & Strauss, D. G. Use of Human iPSC-CMs in Non-clinical Regulatory Studies for Cardiac Safety Assessment. Toxicol. Sci. 190, 117–126 (2022).
  2. Pang, L. et al. The FDA Workshop on Improving Cardiotoxicity Assessment with Human-Relevant Platforms. Circ. Res. 125, 855–867 (2019).
  3. Ligneau, X. et al. Non-clinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. Br. J. Pharmacol. 174, 4449–4463 (2017).
  4. Millard, D. C. et al. Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes. Toxicol. Sci. Off. J. Soc. Toxicol. 154, 174–182 (2016).
  5. Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).
  6. Gill, M. et al. From the Cover: Investigative Non-clinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor. Toxicol. Sci. Off. J. Soc. Toxicol. 155, 348–362 (2017).

Press enquiries

Jan Turner

Axol Bioscience
jan.turner@axolbio.com

NOTES TO EDITOR

About Axol Bioscience

Axol is a leading provider of product and service solutions in the iPSC-based neuroscience, immune cell, and cardiac modeling for drug discovery and screening markets. Our custom research capabilities in gene editing, electrophysiology, reprogramming, and differentiation means we can offer customers validated ready-to-use cell lines and a suite of services bolstered by deep scientific expertise and robust functional data – all with shorter lead times. To find out more, visit axolbio.com.

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