Organ-on-a-chip technology helps bridge the gap between animal and human models in drug development, Audrey Dubourg reports
Sadly, 90% of drugs entering clinical trials ultimately fail, with insufficient efficacy remaining a leading cause for these failures despite years of R&D and millions of pounds invested.
This harsh reality points to the fact that the preclinical tests used to discover and develop drugs do not accurately reflect human outcomes. Unfortunately, all industry-standard models have flaws; traditional in-vitro assays are too simplistic and in-vivo animal models are too ‘animal’. The problem is now exacerbated as new advanced drug modalities, with human-specific modes of action becoming more prevalent in drug pipelines. So, what can be done to overcome these limitations and bring much needed therapeutics to market in fast and cost effective ways - especially for diseases that are becoming more widespread? The answer: Make use of a an innovative new solution called the ‘organ-on-a-chip’ (OOC).
New approach methodologies
The complementary or alternative use of New Approach Methodologies (NAMs), such as organ-on-a-chip (OOC), offer a path forward in situations where model translatability to humans is predicted to be poor, or for testing advanced drug modalities where human-specific targets and pathways are required.
The aim of OOC is to accurately replicate human physiology and function in vitro by culturing physiologically relevant combinations of primary human cells together in a perfused environment supplied by fluidic flow. Using OOC, it is now possible to recreate healthy and diseased human organ mimics in the laboratory.
Non-alcoholic Steatohepatitis
One area of growing global concern is the metabolic disorder Non-alcoholic steatohepatitis (NASH), also known as Metabolic Dysfunction-associated Steatohepatitis (MASH). NASH is the most common form of chronic liver disease worldwide. Despite much R&D effort, there is only one approved therapeutic.
This is mainly owing to the inability of traditional in-vivo approaches to accurately predicting the human response to this complex metabolic disease.
CN Bio’s highly characterised and validated PhysioMimix NASH assay is comprised of primary human hepatocytes, stellate and Kupffer cells that form 3D microtissues capturing key stages of disease progression, intracellular fat accumulation, inflammation and fibrosis. The OOC model supports development of drugs targeting NASH by enabling the precise mechanistic effects of drug efficacy to be uncovered.
Bridging the gap between humans and animals
Whereas animal models capture the complexity of a full organism, OOC demonstrates how a disease mechanism, or the effects of a drug, will differ in a human setting. The combination of the two gives a much broader preclinical insight into a drug’s potential.
In conjunction with the PhysioMimix OOC, CN Bio’s product and service portfolio offer flexible solutions to researchers to fast-track the incorporation of OOC technologies into drug discovery workflows.
An ‘in a box’ solution from CN BIo
The company’s ‘in-a-box’ solution provides a straightforward and quick route to recreating its industry-proven models and assays, and through its Contract Research Services (CRS), the team can tailor each experimental design to deliver unique human-translatable insights and actionable data within weeks, while saving significant time and cost versus animal studies.
In December 2023, the company announced its CRS had supported the characterisation of a NASH drug candidate targeting human metabolism. As metabolism in mice is very different from human, OOC offered a path forward. Compound efficacy data derived using this NASH assay was used to support the initiation of Inipharm’s Phase 1 clinical trial for INI-822. The submission represents the first example of an OOC provider’s data supporting the clinical progression of a drug for a complex metabolic liver disease and demonstrates the transformative potential of these models to provide human-relevant insights within preclinical programs. Looking to the future, the body of evidence demonstrating OOC’s superior performance versus traditional approaches is destined to continue growing since these technologies are in a unique position to help pave the way for more much-needed therapeutics to progress into the clinic, and beyond.
Audrey Dubourg is product manager for CN Bio
Alternative applications for OOC technology
OOC technology can help oncology researchers study the impact of specific tissue components, investigate the role of the tumor microenvironment (TME), or visualise how cancer cells behave over time when interacting with stromal and immune cells. Similarly OOC is better able to reproduce the complexity that influences cancer behavior in vivo, and appropriately model more recent advancements in cancer therapeutics than conventional in-vitro models.
Similarly, OOC can help with inflammatory diseases. Inflammation plays a role in many conditions including Alzheimers and Inflammatory Bowel Syndrome (IBS). However, modeling complex immune response in vitro can be difficult owing to the fundamental differences in the immune systems of animals and humans. OOC allows researchers to incorporate the cellular diversity seen in vivo into a tissue-specific microenvironment that more closely emulates the complex cell-cell interactions involved in inflammation in a closely controlled environment.
