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Animal models and their alternatives share the preclinical habitat – Transition from in vivo models to NAMs
Filed under: ADME, Disease modeling, and Safety toxicology
Originally published in Genetic Engineering & Biotechnology News on 1 August 2024.
Animal models are important tools that are extensively leveraged in preclinical drug testing. They have long been established as the gold standard for safety and efficacy testing, especially for small molecule based therapeutics.
However, in recent years there has been a significant push for integrating New Alternate Methodologies (NAMs) such as microphysiological systems (MPS), also known as Organ-on-a-chip (OOC) models into the drug development pipeline – a transition from in vivo models to NAMs. Not only do these “humanized” models better reflect human response but also allows a reduction in animal use – focusing on responsible and ethical use of these models. This aligns with the animal welfare principles known as the “3Rs”: reduction, replacement, and refinement. An alternative set of principles, the “4Rs,” adds another “R”: responsibility. Whichever set of “Rs” is applied, the idea is to solve ethical problems in functional animal experimentation.
Meanwhile, the FDA Modernization Act 2.0 challenges the entrenchment of in vivo animal models in preclinical work and supports development of alternative models. Another piece of legislation, the Biosecure Act, if passed, will significantly impact the sources U.S. researchers use to obtain their animal models.
In response to these shifts, the preclinical landscape is undergoing a transformation. Traditional animal models continue to play an important role, particularly genetically defined and immuno-humanized mice, but there is increasing integration of advanced in vitro systems. Charles River Laboratories has committed hundreds of millions to developing NAMs, including in vitro and in silico tools, while also introducing innovations like the PathogenBinder test that reduces reliance on sentinel animals.
Dr. Emily Richardson, Lead Scientist of Toxicology at CN Bio emphasized that the PhysioMimix® Organ-on-a-chip System supported a successful 2023 regulatory submission for a liver disease candidate, illustrating the regulatory traction of MPS platforms.
“CN Bio recently secured $21 million in Series B investment to expand their design and manufacture of 3D human organ and tissue microphysiological systems (MPSs). The company’s PhysioMimix OOC Higher Throughput System and associated Multi-chip Liver-48 plate was developed in response to market demand. The new plate features a standard SLAS-footprint with 48 miniaturized chips. Three plates can be run simultaneously.
“Importantly, supporting data from the PhysioMimix platform were incorporated into a successful 2023 regulatory submission,” says Richardson. “Inipharm’s INI-822 for a common fibrotic disorder is now in clinical trials. Plus, collaborators at Charles River developed and published a novel genotoxicity application using the system.”
CN Bio also launched a primary gut/liver dual-organ model for improved human ADME and bioavailability estimations. The model was developed with Altis Biosystems, which recreated the intestinal barrier using primary cells isolated from the human jejunum on a biomimetic scaffold (RepliGut). When connected to the Liver-on-a-chip model in the Multi-chip Dual-organ plate, an improved predictive capacity for profiling the ADME behavior of oral drugs was seen as compared to an equivalent Caco-2 Gut/Liver MPS
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“We are expanding our range of all-in-one kits – (NASH in a box, Bioavailability assay kit: Human 18, DILI assay kit: Human 24 )” Richardson asserts. “The kit contains everything required to recreate our models and applications, and to develop preclinical animal MPS models to flag potential interspecies differences and minimize the risk of unforeseen clinical issues.” Initial results demonstrate the translatability of animal MPS data.
This image depicts MASH liver tissue, showcasing the fibrotic phenotype (yellow) associated with the disease. The tissue is composed of primary human hepatocytes, Kupffer cells, and stellate cells. To help researchers model Metabolic dysfunction-associated steatohepatitis (MASH), also known as non alcoholic steatohepatitis (NASH), CN Bio provides the NASH-in-a-box, a modeling kit that is compatible with the both the Single-organ and Multi-organ versions of the company’s PhysioMimix OOC System.
Richardson has seen an upward trend in acceptance following the FDA Modernization Act 2.0 and increased 3R project funding. This trend reflects a growing awareness that ethical considerations can be addressed while practical benefits are pursued, benefits such as lower workflow costs, higher efficiency, and faster clinical translation. The company participates actively in regulatory and standards groups, including the Critical Path Institute, the European Committee for Electrotechnical Standardization, and the IQ-MPS affiliate of the International Consortium for Innovation and Quality in Pharmaceutical Development.
“A growing body of evidence proves that the approach is more predictive than traditional methods and that technologies are being used in a complementary manner,” Richardson declares. “Standardization, a crucial area, needs to be addressed. Existing models will become more comprehensive, and the breadth of models and applications will expand along with more automation solutions.”
Together, these developments reflect a growing consensus: the future of preclinical research lies in a balanced ecosystem where animal models and NAMs work synergistically to improve human relevance, ethical standards, and translational outcomes.
View the full article here.
Dr. Emily Richardson
Lead Scientist (Toxicology)