Organ Model: Liver

Featured session at Bethesda MPS Day, which took place on 11/9/2023.

Drug-induced liver injury (DILI) is a potentially lethal condition that heavily impacts the pharmaceutical industry, causing approximately 21% of drug withdrawals and 13% of clinical trial failures. Recent evidence suggests that the use of Liver-Chip technology in preclinical safety testing may significantly reduce DILI-related clinical trial failures and withdrawals. However, drug developers and regulators would benefit from guidance on the integration of Liver-Chip data into decision-making processes to facilitate the technology’s adoption.

This perspective builds on the findings of the performance assessment of the Emulate Liver-Chip in the context of DILI prediction and introduces two new decision-support frameworks: the first uses the Liver-Chip’s quantitative output to elucidate DILI severity and enable more nuanced risk analysis; the second integrates Liver-Chip data with standard animal testing results to help assess whether to progress a candidate drug into clinical trials.

There is now strong evidence that Liver-Chip technology could significantly reduce the incidence of DILI in drug development. As this is a patient safety issue, it is imperative that developers and regulators explore the incorporation of the technology. The frameworks presented enable the integration of the Liver-Chip into various stages of preclinical development in support of safety assessment.

Webinar Abstract

Adeno-associated virus (AAV)-derived vectors have emerged as a promising gene delivery vehicle for a broad range of clinical indications. The liver in particular is an interesting target as it is easily transduced with AAV vectors and allows a persistent expression of the transgene. However, off-target gene transduction remains a significant challenge in the development of successful gene therapeutics; thus, it is crucial to develop efficient organ-specific promoters for gene therapy constructs. While simple in vitro 2D cell culture models are useful for initial higher throughput screening, their limited complexity often results in responses that do not translate to animal models or human patients. Organ-on-a-Chip technology is helping to bridge this gap by enabling researchers to assess gene therapy constructs in a more physiologically relevant microenvironment. 

In this webinar, Dr. Rui Sun, Research Scientist at Bayer AG, presented on how he applied the Emulate Liver-Chip to evaluate the transduction efficiency and selectivity of liver-specific AAV promoters.

Learn how the Liver-Chip can be used to:

• Improve the evaluation of AAV vector transduction efficiency 
• Rank order various candidate promoter constructs 
• Quantify transgene expression efficiency and specificity 
• Investigate transduction efficiency by cell type
• Evaluate promoter efficacy in a liver disease model

Webinar Abstract

Drug-induced liver injury (DILI) is a potentially lethal condition that heavily impacts the pharmaceutical industry, causing drug withdrawals and approximately 13% of clinical trial failures. The prevalence of DILI in clinical settings exposes the limitations of preclinical toxicology models, which fail to capture the complexity of human liver physiology and its response to drug exposure.  

Recent evidence suggests that adopting the Emulate Liver-Chip into preclinical workflows may reduce DILI-related clinical trial failures. Here, we present a quantitative framework for integrating Liver-Chip data into the pharmaceutical decision-making process. This new Liver-Chip DILI score enables researchers to categorize tested compounds into standard DILI risk categories utilizing human Liver-Chip and animal in vivo data.  

During this webinar, topics that were covered included: 

• Characterization results of the Emulate Liver-Chip within the context of use of DILI prediction 
• Where in the preclinical workflow the Liver-Chip can be deployed 
• How the Liver-Chip’s quantitative readouts can be used to map prospective therapeutics into standard DILI risk categories  
• Methodology for combining Liver-Chip data with animal in vivo data, allowing for a more holistic assessment of DILI risk ahead of clinical trial testing
  

The presentation was followed by an informative Q&A session.

Originally presented at Global MPS Day 2023

In this on-demand webinar, Heidrun Ellinger, Ph.D., of Bayer talks with Emulate Principal Scientist Sasha Berdichevski about a phase two clinical trial that was voluntarily withdrawn due to a liver toxicity signal.

Organ Model: Liver

Application: Toxicology

Abstract: Organ-on-a-chip platforms are utilized in global bioanalytical and toxicological studies as a way to reduce materials and increase throughput as compared to in vivo based experiments. These platforms bridge the infrastructure and regulatory gaps between in vivo animal work and human systems, with models that exemplify active biological pathways. In conjunction with the advent of increased capabilities associated with next generation sequencing and mass spectrometry based ‘-omic’ technologies, organ-on-a-chip platforms provide an excellent opportunity to investigate the global changes at multiple biological levels, including the transcriptome, proteome and metabolome. When investigated concurrently, a complete profile of cellular and regulatory perturbations can be characterized following treatment with specific agonists. In this study, global effects were observed and analyzed following liver chip exposure to the chemical warfare agent, VX. Even though the primary mechanism of action of VX (i.e. acetylcholinesterase inhibition) is well characterized, recent in vivo studies suggest additional protein binding partners that are implicated in metabolism and cellular energetic pathways. In addition, secondary toxicity associated with peripheral organ systems, especially in human tissues, is not well defined. Our results demonstrate the potential of utilizing an organ-on-a-chip platform as a surrogate system to traditional in vivo studies. This is realized by specifically indicating significant dysregulation of several cellular processes in response to VX exposure including but not limited to amino acid synthesis, drug metabolism, and energetics pathways.

Organ Model: Liver

Application: Toxicology

Abstract: Drug-induced liver injury (DILI), both intrinsic and idiosyncratic, causes frequent morbidity, mortality, clinical trial failures and post-approval withdrawal. This suggests an unmet need for improved in vitro models for DILI risk prediction that can account for diverse host genetics and other clinical factors. In this study, we evaluated the utility of human liver organoids (HLOs) for high-throughput DILI risk prediction and in an organ-on-chip system.

Webinar Abstract

In December 2022, two milestone papers were published: “Predictive validity in drug discovery: what it is, why it matters and how to improve it” in NRDD and “Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology” in Communications Medicine, part of Nature Portfolio. In addition, President Biden signed the FDA Modernization Act 2.0 into law. This groundbreaking advancement allows researchers to leverage Organ-on-a-Chip technology data as part of a novel IND submission, breaking the 1938 Food, Drug, and Cosmetic Act (FDCA) mandate that required all new drugs be tested on animals.

To say the least, it was an exciting way to close out the year. However, these milestones are sparking many questions across the industry: What’s next, how does this impact my work, and how do I get started with Organ-on-a-Chip technology?

Watch this on-demand fireside chat to see industry experts discuss:

• What is predictive validity in drug discovery, why is it important, and how can we improve it?
• The recent Communications Medicine publication demonstrated that the Emulate human Liver-Chip was able to correctly identify 87% of the tested drugs that caused drug-induced liver injury in patients despite passing animal testing evaluations—and did not falsely identify any drugs as toxic, leading to a 100% specificity rating. We will discuss how this will help your decision-making criteria to improve patient safety and increase your confidence that a viable candidate drug will not be de-prioritized due to a false positive.
• How could an improvement in sensitivity and specificity lead to a $3B increase in R&D productivity for small molecule drug development?
• And lastly, what can we expect with the passing of the FDA Modernization Act and the growing global movement to eliminate animal testing mandates?

Abstract

As cannabinoid use expands, there grows a need to evaluate cannabidiol (CBD) and cannabinol (CBN) for toxicity potential. This study set out to meet this need using the Emulate human Quad-Culture Liver-Chip to evaluate these two compounds for hepatotoxicity potential.

Communications Medicine, part of Nature Portfolio (2022)

KEY Takeaways

• 870 Liver-Chips were used to evaluate the toxicity of 27 known hepatotoxic and non-toxic drugs.
• The Liver-Chip outperformed spheroids and animal models, with a sensitivity of 77% and specificity of 100% against the full set of 27 drugs tested on a single donor.
• Across a subset of 18 drugs tested on two donors, the Liver-Chip yielded a sensitivity of 87% and specificity of 100%.
• Economic analysis indicates routine use of the Liver-Chip could generate $3 billion per year to small-molecule drug development through an increase in R&D productivity​.

Abstract

Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realized in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips’ predictive value have not yet been reported.