Metrion’s human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte assay represents an advanced and cutting-edge tool that provides for early cardiac derisking in drug discovery. This revolutionary model can play a vital role in the evaluation of novel pharmaceutical compounds during the early stages of drug development by enabling researchers to predict potential cardiac risks with higher accuracy and efficiency.

As the pharmaceutical industry continues to innovate and discover new compounds, ensuring their safety profile is a paramount concern. Drug-induced cardiac events, such as arrhythmias and QTc prolongation, remain among the leading causes of late-stage trial failures. Metrion’s hiPSC-derived cardiomyocyte assay offers early-stage data that can help mitigate these risks, significantly improving drug safety and reducing the reliance on traditional, costly animal studies.

Our clinically translatable cardiomyocyte model offers early decision-making data regarding the potential cardiac risks associated with new compounds. By utilising a hiPSC-derived cardiomyocyte assay, researchers can obtain predictive data on how a compound might affect cardiac function in humans before it enters clinical trials. This data can ultimately prevent late-stage drug development failures and avoid the substantial costs associated with such failures.

In addition to providing valuable information about drug-induced cardiac effects, this advanced model can improve the overall efficiency of the drug discovery process. By detecting potential safety issues early, researchers can make informed decisions about whether to proceed with a compound or pursue other options.

Metrion’s hiPSC-derived cardiomyocyte assay is a higher-throughput, 96-well plate-based system designed to assess changes in action potential morphology, which is a key indicator of cardiac function. The assay can be used to evaluate both acute and chronic exposure to compounds, providing comprehensive safety pharmacology and toxicology data over a range of exposure durations (24 hours or greater). This is especially important for detecting chronic toxicities that may not be apparent during short-term testing.

Highly cost-efficient cardiomyocyte assay

The 96-well plate format makes the assay highly cost-efficient and suitable for higher-throughput screening.

• Ideal for rapidly evaluating larger numbers of compounds.
• The system’s ability to provide data on action potential morphology is vital for assessing how compounds interact with ion channels and their potential to disrupt normal cardiac function, which could lead to adverse events such as arrhythmias.
• Simultaneous high-resolution measurement across 96 well plate at 10,000 Hz
• Recordings using voltage-sensitive dye that deliver patch-clamp equivalent quality
• Multiple endpoints evaluated (APD_20/50/90, rise time, beat rate, triangulation)
• Measurement of acute (30min) and chronic (24h/48h) effects
• Predicts clinical exposure associated with 10ms QTc prolongation
• Defines exposure associated with QRS probability
• Highlights unknown acute/chronic toxicity

The assay is aligned with current International Council for Harmonisation (ICH) S7B guidelines for non-clinical cardiac safety testing and adheres to the principles outlined in the FDA Modernization Act 2.0. These guidelines are designed to ensure that drugs are evaluated in ways that are relevant to human health, improving the overall safety and efficacy of new therapeutics. Read about the need to embrace the future of preclinical drug discovery safety.

A critical feature of Metrion’s hiPSC-derived cardiomyocyte assay is its ability to assess the impact of compounds on action potential morphology. Changes in the shape and duration of the cardiac action potential are key indicators of potential toxicity or arrhythmia risk. By examining how compounds affect ion channel activity and their interactions with critical cardiac proteins such as hERG, researchers can gain insight into whether a compound might cause harmful effects on the heart.

Recordings using voltage-sensitive dye (VSD) with quality equivalent to patch-clamp are valuable for assessing cardiovascular risk in drug discovery. They provide a high-fidelity, high-throughput alternative to traditional electrophysiology techniques.

VSD-based recordings offer:

• Non-invasive, high-resolution measurements of membrane potential changes across a large number of cells or wells simultaneously, enabling faster and more efficient cardiac safety screening.
• Precise detection of drug-induced effects on cardiac ion channels, such as hERG (IKr), Na_V5, and Ca_V1.2, which are critical for evaluating proarrhythmic risk.
• The ability to achieve patch-clamp-equivalent data quality enhances predictive accuracy, reducing false negatives and late-stage failures, and supports safer drug development with improved preclinical-to-clinical translation.

Figure 1. Representative traces from the assay clearly demonstrate how selective ion channel blockers or hERG trafficking block agents influence the action potential morphology of hiPSC-derived cardiomyocytes. This enables detailed analysis of how different compounds might cause changes in the duration and characteristics of the action potential, providing a clearer understanding of their potential risks before clinical testing. Peter Kilfoil, Shuyun Lily Feng, Asser Bassyouni, Tiffany Lee, Derek Leishman, Dingzhou Li, David J. MacEwan, Parveen Sharma, Eric D. Watt, Stephen Jenkinson, Characterization of a high throughput human stem cell cardiomyocyte assay to predict drug-induced changes in clinical electrocardiogram parameters, European Journal of Pharmacology, Volume 912, 2021.

A significant challenge in drug development is the potential for novel compounds to cause QTc prolongation or QRS interval widening, both of which are associated with a higher risk of arrhythmias and sudden cardiac events. Accurate prediction of these issues is essential for identifying and mitigating cardiac risks early in the development process.

Metrion’s hiPSC-derived cardiomyocyte assay:

• Is an invaluable tool for predicting QTc and QRS liabilities.
• Uses high-frequency (10kHz) measurements using voltage-sensitive fluorescent dyes to capture high-fidelity action potential waveforms across all wells of a 96-well plate.
  • This enables real-time, accurate measurement of action potential duration (e.g., APD90), rise time, and beat rate, which are critical endpoints in assessing the cardiac effects of compounds.
• Can predict the free clinical exposure levels associated with a 10 ms change in the QTc interval, offering valuable data for early-stage decision-making.
  • This is especially important because even slight changes in the QTc interval can lead to significant clinical implications, including sudden cardiac death in extreme cases.

Figure 2. Metrion’s hiPSC cardiomyocyte assay highlights QRS risk. An ROC analysis of 22 QRS positive and 12 QRS negative compounds clearly defines the ability of the assay to define the free clinical exposure associated with QRS with high accuracy.

Another significant advantage of Metrion’s hiPSC-derived cardiomyocyte assay is its ability to assess compounds over extended periods, up to 48 hours, in serum-free conditions. This allows for the evaluation of chronic toxicities and other long-term effects that might not be detectable in shorter, serum-containing assays. Extended testing durations are critical for assessing the full impact of drugs that may require prolonged exposure to cause adverse effects.

Metrion’s hiPSC-derived cardiomyocyte assay is designed to be reliable, reproducible, and highly translatable to human clinical data. This is particularly important as drug developers are under increasing pressure to ensure that their preclinical studies are predictive of human clinical outcomes. The use of hiPSC-derived cardiomyocytes provides a more accurate representation of human cardiac function compared to traditional animal models, which can often have species-specific differences in ion channel expression and drug response.

Our assays demonstrate the cardiac safety of therapeutic compounds in accordance with current regulatory guidelines, including those set forth within ICH S7B.

Figure 3. Assessing the effect of compounds on the ventricular action potential waveform in a plate-based human stem cell cardiomyocyte model.

The hiPSC-derived cardiomyocyte model offers several key advantages, making it an essential tool for early cardiac derisking in drug discovery:

Human relevant cardiac safety model

The assay provides a human-relevant model that better reflects the response of human hearts to therapeutic compounds, which is critical for improving the predictability of drug safety in clinical trials. Traditional animal models, such as those using rats or dogs, do not always replicate human cardiac physiology accurately.

Reduction of animal testing in drug discovery

The use of hiPSC-derived cardiomyocytes significantly reduces the need for animal testing, which aligns with the ethical principles of the 3Rs (Replacement, Reduction, Refinement) in animal research. This reduction in animal testing not only improves the ethical standards of drug development but also reduces costs and enhances the sustainability of the drug discovery process.

Early detection of cardiotoxicity in preclinical drug discovery

By identifying cardiotoxic compounds early in the drug development process, Metrion’s VOLTA hiPSC-derived cardiomyocyte assay helps to avoid late-stage failures that can be costly and time-consuming. Early detection of cardiac risks allows for more informed decision-making and resource allocation, ultimately saving time and money in the long run.

Versatile assay for comprehensive cardiac safety assessment

This assay can be used in conjunction with other types of cardiac assessments, such as electrophysiological studies, contractility assays, biochemical analyses, and even in vivo studies. Its flexibility makes it an invaluable tool that can complement other experimental systems and provide a comprehensive view of a compound’s cardiac safety profile.

As the FDA embraces non-animal testing methods, Metrion’s Volta assay offers a human-relevant, clinically translatable solution for early cardiac safety assessment in drug development. Using hiPSC-derived cardiomyocytes and high-frequency optical recording, the Volta assay reliably predicts key cardiac risk markers like QTc prolongation, aligning with FDA-endorsed New Approach Methodologies (NAMs) and the CiPA framework. Scalable, reproducible, and validated, it provides an ethical and efficient alternative to animal models, helping sponsors reduce costs, accelerate timelines, and meet evolving regulatory expectations in a post-animal testing era. Read more about embracing the future of preclinical drug discovery safety in a post-animal testing era.

As the FDA embraces non-animal testing methods, Metrion’s Volta assay offers a human-relevant, clinically translatable solution for early cardiac safety assessment in drug development. Using hiPSC-derived cardiomyocytes and high-frequency optical recording, the Volta assay reliably predicts key cardiac risk markers like QTc prolongation, aligning with FDA-endorsed New Approach Methodologies (NAMs) and the CiPA framework. Scalable, reproducible, and validated, it provides an ethical and efficient alternative to animal models, helping sponsors reduce costs, accelerate timelines, and meet evolving regulatory expectations in a post-animal testing era. Read more about embracing the future of preclinical drug discovery safety in a post-animal testing era.