From the 10th-14th March, we attended the Society of Toxicology 63rd Annual Meeting and ToxExpo, speaking to safety pharmacology experts about our work unlocking iPSC technology for cardiotoxicity and neurotoxicity models. In this short article, we outline five key takeaways from the event that summarize the current landscape of toxicity testing.

Cardiotoxicity and neurotoxicity are two key challenges for drug discovery, hence their inclusion in the “core battery” of safety pharmacology tests. So with over a decade of experience in the iPSC industry, we were excited to attend SOT and discuss our work using iPSCs for in vitro toxicity models.

With the recent progress in advanced in vitro screening models, regulatory drivers (including the FDA Modernization Act 2.0) and the continued challenges for drug discovery, we spoke to dozens of industry experts about their views on pre-clinical toxicity testing and where safety pharmacology is heading.

#1 Advanced in vitro models are gathering momentum 

The long-standing status quo of animal-based toxicity models is beginning to shift.

With key industry drivers like the Comprehensive in vitro pro-arrhythmic assay (CiPA) initiative and the FDA Modernization Act 2.0, the industry is transitioning to cell-based assays in an effort to close the translational gap from animal models. See key takeaway #5 for more information on this.

Over the past few years at SOT conferences, we’ve noticed an increasing focus on advanced in vitro models and new approach methodologies (NAMs) for safety pharmacology, with more research talks, posters and discussions focusing on alternatives to animal models.

During SOT 2024, we discussed our key safety pharmacology areas:

• Chamber-specific cardiotoxicity models
• Sensory and cosmetic toxicology
• CNS toxicity and epilepsy

Our impression from engaging with safety pharmacology experts was that in vitro models are gaining acceptance thanks to greater regulatory support and strong data– for example, the external CiPA validation of our axoCells ventricular cardiomyocytes.

#2 Better purity and maturity will enhance confidence in cardiotoxicity models 

Cardiotoxicity is responsible for one-third of pre-clinical regulatory clearance failures, which has driven new approaches to cardiac safety pharmacology including the use of iPSC-based screening platforms to detect pro-arrhythmic potential.

The most notable example of this is the CiPA initiative, a 28-compound panel used to test how well a cell-based platform can identify pro-arrhythmic effects. We were delighted to report on the external validation of our axoCells ventricular cardiomyocytes, demonstrating their value in cardiotoxicity platforms.

Building on this momentum, we’ve been looking into the key questions of utility and relevance for iPSC-derived cardiotoxicity models. We’ve therefore produced two discussion documents based on our research in this space:

1. Our ongoing work licensing an innovative protocol developed by a team at The Crick Institute, which aims to produce purer populations of left ventricular cardiomyocytes (click here to read)
2. The identification of a metabolic maturation media to enhance cardiomyocyte maturity (click here to read)

We enjoyed discussing these concepts at SOT as part of our wider work in the cardiac and cardiotoxicity space, and several researchers have since expressed interest in utilizing the outputs of these concepts as an improvement on the traditional mixed-chamber populations used in cardiotoxicity research.

#3 Attention is turning to atrial cardiomyocytes 

While ventricular cardiomyocytes are often used in models, other cardiac cell types (including atrial cardiomyocytes and cardiac fibroblasts) are becoming more popular.

For example, the Health and Environmental Sciences Institute (HESI) held a cardiac group survey in the latter part of 2023, which revealed valuable insights into the thoughts of cardiac safety scientists.

Key results from the survey were:​

• 60% use human cell lines, of which 80% are iPSC in 2D or 3D culture
• Nearly 80% of respondents were interested in using human iPSC-derived atrial cardiomyocytes ​
• 80% would use them to model/investigate AF

In response to this growing momentum towards atrial cardiomyocytes, we launched our axoCells™ Atrial Cardiomyocyte kit, an all-in-one bundle to unlock iPSC technology for in vitro arrhythmia and cardiotoxicity research. We received an overwhelmingly positive response to this new kit and we look forward to supporting researchers looking to build better in vitro models to study atrial fibrillation.

Read more about our axoCells Atrial Cardiomyocyte kit here.

#4 Co-culture neurotoxicity models are gaining interest 

As iPSC-based models gain momentum, safety pharmacology research is beginning to embrace complexity. For neurotoxicity, this is an important factor as the human nervous system is inherently complex with several cell types interacting in the brain, spinal cord and peripheral nervous system. If you want to mimic these system in vitro, then co-culture models offer a step up from simple mono-culture.

We enjoyed speaking about our expertise in this area, including tri-culture epilepsy models (comprising cortical excitatory neurons, cortical inhibitory interneurons and astrocytes) and ALS models (with microglia, motor neurons and muscle cells).

We also discussed our work developing a cortical tri-culture axoModel for compound screening and neurotoxicity, in partnership with Sumitomo Pharma America, Inc., which you can read here.

#5 Regulatory drivers are helping with the transition to in vitro 

As in vitro technology advances in complexity and scale, we recognize the importance of regulatory support to enhance the confidence, consistency and widespread adoption of iPSC-based models.

We spoke to dozens of safety pharmacology researchers about the impact of key regulatory drivers including:

• FDA Modernization Act 2.0 (and, recently, 3.0) driving advancements, confidence and usage of NAMs
• ISSCR Standards Document, for which we have demonstrated excellent compliance
• International Council for Harmonization (ICH) guideline updates to align with advancing technological developments
• HESI toxicology groups facilitating discussions between safety pharmacology researchers and regulatory bodies

Our impression from these discussions is that cardiotoxicity and neurotoxicity researchers are gaining confidence in transitioning from animal models to advanced in vitro platforms due to the increasing support from these regulatory bodies. The key priority for many researchers is ensuring cell-based toxicology models are relevant, translatable and consistent- factors that are enhanced with regulatory oversight and support.

Overall, we enjoyed discussing our work at SOT and will continue to drive progress in the use of iPSC technology for cardiotoxicity and neurotoxicity.

If you’d like to know more about how we can support your in vitro cardiac and cardiotoxicity projects, make sure to download our 2024 Cardiac Guide here: 2024 Axol Bioscience Cardiac Guide

 

Looking to unlock the benefits of iPSC technology for your cardiac or neuroscience research? Get in contact at operations@axolbio.com and let’s discuss how we can help.