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When developing drugs, we rely on animal models to test drugs in an entire system before first-in-human studies. However, animals aren’t human and interspecies differences in pharmacology, physiology, metabolism, and the immune system can lead to drug misclassifications as safe/efficacious or toxic/inactive.
The inconsistencies of animal models, paired with the simplicity of traditional preclinical in vitro assays, has led to a pressing need for more predictive in vitro tools to de-risk the process. Recent focus has centered on the use of Organ-on-a-chip (OOC) technology, or microphysiological systems (MPS), which generate complex and functional human in vitro models that help to circumvent these challenges and guide more informed decision-making.
Despite OOC’s potential, animal models aren’t going to disappear from our workflows in the immediate future as they provide valuable “system level” information that can’t be gleaned using OOC, but what happens when you get conflicting data from different species? Which do you believe? And how can we design preclinical studies more effectively to minimize future animal use? Here we describe two case studies demonstrating how primary human OOC models helped to inform next-step decision making where animal data were conflicting.
> 1. Human OOC models supported Professor Gerard Boss’ lab at the University of California San Diego in their development of the vitamin B12 analog cobinamide as an antidote against toxic chemicals. Previous research established that cobinamide is well tolerated by mice, rats, rabbits and pigs, but causes hepatotoxicity in dogs. Using CN Bio’s Drug-induced liver injury (DILI) Contract Research Services, Boss tested two cobinamide formulations in our PhysioMimix® DILI assay to better inform which could be safe for humans.
> 2. Animal models and 2D hepatocytes were used to test the toxicity of several Antisense Oligonucleotides (ASOs). In their PLOS ONE (2016) publication, Sewing1 et al from AstraZeneca describe poor data translation between the approaches. “A series of reports describe changes observed in rodent and non-rodent studies related to SSO-induced toxicity, but as the safest preclinical candidates progress into the clinic, the human relevance of the observed effects remained unclear so far.” As a result, CN Bio were asked to test two of the ASOs in our PhysioMimix DILI assay. Human relevant markers including ALT and CYP3A4 metabolic activity were able to clearly show and predict human outcomes between ASO-1 (toxic) and ASO-2 (safe). This again gave the authors further clarity regarding which would be safest in humans.
The use of human OOC systems to resolve conflicting data from animal studies can help determine which species more accurately represents the human response. However, the proactive use of both animal and human OOC systems before preclinical development holds even greater potential. Their use can identify and address potential liabilities early, refine preclinical in vivo study design to reduce unnecessary animal use and de-risk first-in-human studies. All of which lead to cost savings and better outcomes. CN Bio presented preliminary animal OOC data demonstrating the translatability of drug responses between animal OOC models and in vivo data at SOT 2024, with more to come at the conference in 2025.
When human and animal OOC are implemented early in the process, there is the opportunity to re-engineer promising drugs to remove potential liabilities. For lead candidates that show promise in human OOC models, pre-testing in animal OOC models will enable the refinement of preclinical in vivo study design to predict potential interspecies differences before in vivo testing, safeguarding unnecessary animal use and avoiding the misclassification of drugs. By being better informed ahead of pre-clinical testing, the approach potentially avoids the need to report negative findings due to interspecies issues within regulatory submissions and de-risks before first-in-human studies for a safer and more efficient process.
Reference
- Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs. Sabine Sewing, Franziska Boess, Annie Moisan, Cristina Bertinetti-Lapatki, Tanja Minz, Maj Hedtjaern, Yann Tessier, Franz Schuler, Thomas Singer, Adrian B. Roth. Published: July 21, 2016
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