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The COVID-19 pandemic and a ban on non-human primate (NHP) exportation by China have dramatically altered the landscape of NHP use in US biomedical research.1 The worsening NHP shortage along with the FDA Modernization Act 2.0 highlight the need for alternative models to optimize the use of critical animal model resources.
Emulate Organ-Chips allow researchers to more accurately model human biology by combining appropriate human cells, an organ-specific microenvironment, and tissue-relevant mechanical forces such as shear stress and cyclic stretch to mimic peristalsis. The platform employs two parallel independent microfluidic channels separated by a porous membrane, which enables cross-talk between epithelial and endothelial tissues.
Maximizing the efficiency of NHP use
A primary benefit of using Organ-Chips is the ability to optimize NHP usage by reducing the number of compounds that need to be tested in NHPs. For instance, before moving into NHP studies, Moderna uses Organ-Chips to prescreen and capture more clinically relevant data on lipid nanoparticles (LNPs), which are used for mRNA delivery. LNP chemistry is modified to optimize cell- or tissue-specific uptake and expression. However, those modifications might have unintended pathological consequences.
The team set out to use Liver-Chips to model liver fibrosis, predict and de-risk LNPs before NHP studies, and provide mechanistic insights into LNP-mediated and mRNA-induced toxicities. Subsequently, the Liver-Chips allowed Moderna to gauge the risk of liver fibrosis by assessing collagen remodeling and pro-fibrotic gene expression. Using Organ-Chips, they were able to screen a large number of LNPs and move forward to NHP studies with only the most promising candidates.
“Since we’ve had this system in our lab, we have been able to screen 35 novel LNPs, which worked out to ~125 chips [in 18 months]. On the other hand, if we were to run these studies in NHPs, that would take 60 months at a cost of $5.25 million,” emphasized Samantha Atkins, PhD, Senior Scientist at Moderna.
Higher predictive power
In December of 2022, Emulate published a groundbreaking study where they analyzed 870 human Liver-Chips to evaluate the technology’s predictive power for drug-induced liver injury (DILI), a leading cause of safety-related clinical trial failure and global market withdrawals. Results showed 87% sensitivity and 100% specificity when differentiating hepatotoxic from non-hepatotoxic small molecules.
Importantly, all the included 22 hepatotoxic drugs had previously been classified as safe due to a lack of toxicity in animal models. Collectively, these compounds resulted in 242 patient fatalities and 10 liver transplants. A financial framework showed that use of the Liver-Chip in pharmaceutical development programs for new candidate drugs could provide the equivalent of $3 billion in improved R&D productivity.2
Assessing safety of immune-targeting molecules
Traditional drug safety assessment often fails to predict human complications, especially when the drug targets the immune system. A 2021 study led by Roche demonstrated the capability of two different human Organ-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Using in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA), the team discovered that the Lung-Chips and Intestine-Chips could reproduce and predict target-dependent TCB safety liabilities. Results were verified in NHPs.
“With functional features of the human immune system, these models represent a promising alternative platform on which to perform immunotherapeutic safety testing, format selection, and optimization,” said Lauriane Cabon, PhD, group lead at the Institute of Human Biology at Roche, a lead author on the study.3
These models can provide efficient and cost-effective safety and efficacy data before moving to NHP studies. The FDA Modernization Act 2.0 supports exactly this use case by authorizing alternatives to NHPs, such as cell-based assays, computer models, and microphysiological systems like Organ-Chips, as acceptable models for drug development. While Organ-Chips are not yet ready to assume all the roles played by small animal models and NHPs, the technology continues to rapidly evolve.
References
1. Ackley D et al. FDA and industry collaboration: Identifying opportunities to further reduce reliance on nonhuman primates for nonclinical safety evaluations. Regulatory Toxicology and Pharmacology. 2023;138:105327
2. Ewart L et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med 2, 154 (2022).
3. Kerns SJ et al. (2021) Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies. eLife 10:e67106.
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