How our license with The Francis Crick Institute could de-risk drug development

Following the exciting announcement of our exclusive license with The Francis Crick Institute, we'd like to outline what this means for cardiomyocyte research, drug discovery and tackling the biopharma cardiotoxicity challenge.

The problem: cardiotoxicity costs

Cardiotoxicity, whereby a drug exerts adverse effects on the heart, is responsible for?one-third?of regulatory clearance failures, placing it amongst the biggest challenges in drug development?1 . Being able to predict liabilities earlier in drug development could therefore not only speed up the time it takes to bring a drug to market, but 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 .

The challenges themselves have been well-characterised; fatal arrhythmias such as Torsades de Pointes have been responsible for 14 major drug withdrawals while structural heart problems like myocarditis are particularly problematic for anti-cancer drugs?3 ?4 .

Throughout its modern history, Biopharma has utilised and developed a range of models to identify cardiotoxic effects, including:

• In vivo?(animal) models
• Primary cell models, using cells taken directly from humans or animals
• In vitro?immortalised cells transfected with particular ion channels to screen candidate therapies

While these models offer value to a certain degree,?there is still?a distance between 'the bench' and the 'clinic'.?The evidence gathered over decades?shows?that animal models offer only partial insights into how potential drugs interact?in vivo,?while cell lines transfected with only one ion channel gene can miss other important ion channel?effects?(which may compensate for those single ion channel effects) and therefore, offer limited translational capabilities?1 ?3 .

So what would a better human model look like and how could it potentially de-risk drug development?

The potential of human iPSCs

For many years now, labs around the world have been exploring the potential of iPSCs in producing 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.

As suppliers of human iPSC derived cardiomyocytes, we can see the enormous potential and understand the industry shift towards?in vitro?cell-based assays. But we also appreciate that human iPSCs bring their own challenges, most notably maturation. Maturation of iPSCs is crucial to ensure they behave as close to?in vivo?as possible.

Our axoCells? human iPSC-derived cardiomyocytes have?already?demonstrated excellent performance in the CiPA twenty-eight compound assay, correctly identifying cardiotoxic liability. Further MEA studies have confirmed the correct response to all the major classes of cardioactive drugs.

In the broader human iPSC cardiomyocyte space, we've seen an industry shift towards cell-based models for cardiotoxicity in drug screening. 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.?5

The trend towards?in vitro?models has been best demonstrated by the FDA Modernisation Act 2.0 which encourages the use of non-animal models for drug testing, including cell-based assays.

The next generation of iPSC derived cardiomyocytes, using the Crick protocol

We're delighted to have agreed on an exclusive license with The Francis Crick Institute for an enhanced iPSC protocol, maximizing our capabilities in the cardiomyocyte and cardiotoxicity spaces. The IP exclusivity gives us the freedom to operate in the market and deliver on our mission to produce better human models for cardiotoxicity testing and disease.

The protocol itself will enable us to use human iPSCs to produce purer, more mature populations of left ventricular cardiomyocytes, reducing readout errors and improving robustness. This ultimately improves cardiotoxicity models, as demonstrated by:

• Correct gene expression of specific marker genes
• Clear structural markers (such as myocyte striation patterns)
• Robust functional data (e.g., from MEA and contraction velocity studies)

You can read the full scientific paper here:?Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells: Cell Reports Methods

The near-homogeneous left ventricular populations also give us the flexibility for chamber-specific modelling, a current gap in cardiotoxicity screening. This is even more exciting when you consider chamber-specific diseases such as Brugada syndrome (right ventricle-dominant) and hypertrophic cardiomyopathy (left ventricle-dominant), which cannot be distinguished with current mixed chamber cardiomyocyte protocols.

This agreement will ultimately help us in aim to produce better, more physiologically relevant models for cardiotoxicity testing and drug screening, whilst enabling us to work with a world-class research institute under the combined mission of better human disease models.

Read the full press release here:?https://axolbio.com/publications/crick-axol-bioscience-press-release-april-24th-2023/

Key takeaways

• Cardiotoxicity remains one of the biggest challenges in bringing new drugs to market
• Axol has agreed an exclusive license with The Francis Crick Institute for an enhanced iPSC cardiomyocyte methodology
• The license will help us in our mission to build better models for cardiotoxicity, whilst giving us the freedom to operate in the market and deliver on our mission

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?Blinova K, Dang Q, Millard D, Smith G, Pierson J, Guo L, Brock M, Lu HR, Kraushaar U, Zeng H, Shi H, Zhang X, Sawada K, Osada T, Kanda Y, Sekino Y, Pang L, Feaster TK, Kettenhofen R, Stockbridge N, Strauss DG, Gintant G. International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Rep. 2018 Sep 25;24(13):3582-3592. doi:?https://doi.org/10.1016/j.celrep.2018.08.079 . PMID: 30257217; PMCID: PMC6226030.

4?Stella Stoter AM, Hirt MN, Stenzig J, Weinberger F. Assessment of Cardiotoxicity With Stem Cell-based Strategies. Clin Ther. 2020 Oct;42(10):1892-1910. doi:?https://doi.org/10.1016/j.clinthera.2020.08.012 .?Epub 2020 Sep 13. PMID: 32938533.

5?Li Pang,?Philip Sager,?Xi Yang,?Hong Shi,?Frederick Sannajust,?Mathew Brock,?Joseph C. Wu,?Najah Abi-Gerges,?Beverly Lyn-Cook,?Brian R. Berridge?and?Norman Stockbridge. Originally published 10 Oct 2019https://doi.org/10.1161/CIRCRESAHA.119.315378 ?Circulation Research. 2019;125:855–867