How Industry Embraces Organ-on-Chips: A 2024 Status Report

Report highlights:

• We are currently at an exciting juncture where several big pharmaceutical companies have started adopting such models and conducted several exploratory studies

• The last 4 years have witnessed at least twofold increase in industrial validation of organ-on-chips across various fields and organ models

• The majority of the studies can be broadly categorized under ADME&T (ADME & toxicity) (55.7%) followed by disease modeling on chips (30%)

• The rigorous industrial testing and strong backing from regulatory agencies indicate, the next 3-5 years can be a favorable investment opportunity in such models.

• Industries and CROs seeking to invest in OoC field should prioritize establishing ADME related organ-models

• Investors can prioritize their investment in the OoC companies that have major focus area in ADME&T sciences

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The pharmaceutical industry faces a significant challenge with high drug attrition rates. Traditionally, animal models have served as the gold standard for pre-clinical testing. However, it is now widely acknowledged that these models do not fully predict human toxicities and efficacies. Particularly concerning is their limited success in predicting liver toxicities. Ethical concerns, especially regarding the use of non-human primates (NHPs), have spurred the development of complex in vitro models derived from human cells. These models, validated for various Contexts of Use (CoUs), offer promising insights in drug discovery.

Organ-on-chips are 3D complex in vitro models that generally incorporate 3D microenvironment, spatially arranged human-derived cells of an organ, and various mechanical cues consisting of organ relevant flow and motion. For instance, lung-on-a-chip may simulate breathing motion and systemic blood flow, featuring human-derived lung epithelium and endothelial cells separated by a membrane or hydrogel.

The last decade witnessed extensive validation of organ-on-chips (OoC) by the academia and OoC makers, setting the stage for broader industry adoption in the current decade. A significant milestone was the passing of the FDA Modernization Act 2.0 law in the United States, signaling a shift toward embracing non-animal methods in drug discovery. The recently introduced legislation, FDA modernization act 3.0, underscores this commitment by outlining detailed guidelines related to the qualification process under which the applicant can request for the eligibility of the non-clinical method.

Recognizing that industry validation is crucial for gauging the translatability of OoC models, collaborative efforts between industry and OoC innovators are underway. Several major pharmaceutical companies have initiated exploratory studies, marking a pivotal moment in OoC adoption. This report outlines these collaborative endeavors and provides insights into the translatability of OoC models.

Figure 1 illustrates a consistent growth in collaborative studies over the years, with a total of 70 publications in the last 10 years. Notably, the past four years have seen a twofold increase in industrial validation across various fields and organ models, peaking in 2022 and 2020. This positive change is partly due to the strong backing from the regulatory agencies and various government initiatives that resulted into promotion of MPS (microphysiological systems) usage in drug discovery. Further, this rigorous industrial testing trend indicates that the next 3-5 years present a favorable investment opportunity in such models.

Figure 1. Number of industrial collaborative publications over the last 10 years

Key industry players embracing OoC models include pharmaceutical giants, contract research organizations (CROs), cosmetics companies, multinational tobacco manufacturers, and biotech firms. Among these, Roche leads with 13 publications, followed by AstraZeneca with 8 publications (Figure 2). Liver-on-chips emerge as the most explored model, followed by gut, cancer, and kidney chips, aligning with the industry's focus on key organs relevant to drug metabolism and toxicity. As liver is the key metabolizing organ for the majority of the drugs, and a sensitive organ to drug induced toxicities, it is not surprising that industries are more inclined to establish liver-chip assays through internal validation.

From the total of 70 publications, most of the studies can be broadly categorized under ADME&T (ADME & toxicity) (55.7%), followed by disease modeling on chips (30%). This trend suggests a strategic investment opportunity in the OoC companies that have their major focus area in ADME&T sciences. Moreover, it can be inferred that industries and CROs seeking to invest in this field should prioritize establishing ADME related organ-models. This is due to the abundance of historical published data on these models, which allows for comparisons of in-house developed model performance during internal evaluation processes. Additionally, CROs aiming to establish MPS labs are likely to receive more inquiries related to ADME.

Interestingly, all 11 reported publications of liver-chip were related to ADME&T. The major applications explored using liver-on-chips were: DILI (drug-induced liver injury) predictions, hepatic clearance predictions, NASH (nonalcoholic steatohepatitis) models, and DDI (drug-drug interactions) predictions. Out of 10 reported gut-chip publications, 5 publications were related to modeling of IBD (inflammatory bowel disease). Apart from IBD, gut-on-chips have been validated for studying compound permeability, anti-inflammatory compound testing, and anti-cancer drug induced side effects.

Moreover, most of the cancer-on-chips studies (publications: 5) tested the efficacy of immunotherapies. From the reported publication of kidney-chips, 57% of the publications can be classified under ADME&T. Kidney-on-chips have been majorly used to study antisense oligonucleotides uptake mechanism, nephrotoxicity, renal ischemia/reperfusion injury, Lowe syndrome and Dent II disease. Out of 7 published studies related to blood vessel, 6 studies can be classified under disease modeling. Similarly, all 3 lung-chip publications were also related to disease modeling.

All studies involving skin-liver models fall under the category of ADME&T. These models represent a particularly interesting and promising subset within organ-on-chip technology. Cosmetic industries, such as L'Oréal and Beiersdorf AG, are leveraging skin-liver models to explore the toxicity and route-specific metabolism of cosmetic ingredients. All four studies focusing on the blood-brain barrier (BBB) can be categorized under ADME&T. Notably, two of these studies investigated the permeability of biologics, specifically therapeutic antibodies, across the BBB using these chips.

In multi-organ models, liver-chips feature prominently in combination with other organ models such as skin, pancreas, thyroid, lung, heart, muscle, cancer, and gut, highlighting their versatility and relevance in complex drug testing scenarios.

Figure 2. Data from the industry standpoint: Details of the organ-model used by the industries.

Figure 3 showcases the major OoC model providers validated by industries. We found that Mimetas’ devices have been widely validated by industries (publications: 24), followed by TissUse GMBH (publications: 12) and Emulate Inc. (publications: 8). Moreover, we can gain valuable insights into the most sought-after model offered by each company, as featured in at least one industrial collaborative study. This information serves as a helpful guide for investors, enabling them to identify key players and understand their primary areas of focus:

• Liver-chips: CN Bio, Emulate and Javelin Biotech have widely validated their liver models.
• Kidney-chips: Nortis Bio has focused more on validating kidney chips with industry partners.
• Tumor-chips: AIM Biotech is at the forefront of validating tumor models.
• Multi-organ models: Hesperos and TissUse have dedicated their resources more on developing multi-organ models with industry partners,
• BBB-chips: Mimetas is involved widely in validating BBB-chips.
• Gut-chips: Emulate and Mimetas have validated their models thoroughly with industry partners.
• Lung-chips: Alveolix models have been tested widely.
• Skin-liver models: They are more popular from TissUse.

Finally, Neuronal, cardiac and muscular models have been successfully validated by Hesperos with industry partners.

Figure 3. Data from OoC makers’ standpoint: Details of the most prominent models offered by each OoC maker used in collaborative studies

Some of the future trends gleaned from this data suggest that predicting ADME properties will emerge as a pivotal focus area for industries. Therefore, OoC makers should prioritize demonstrating the repeatability and reproducibility of their chip models involved in ADME. Liver toxicity prediction stands out as another crucial area of interest for industries, given the persistent DILI concerns. Hence, the OoC makers should extensively validate liver-chips with a large dataset of drugs with low, moderate and high DILI risks.

Furthermore, with the growing number of drug discovery programs centered around large molecules, OoC models should undergo validation with newer modalities such as PROTACS, antibody-drug conjugates, peptides, etc. Finally, disease modeling on chips will be another major area of interest, offering insights into new drug targets for the industry through omics approaches.

Some of the current challenges of OoC models include lack of regulatory guidelines, lack of standardization, additional investment to acquire skilled labor, concerns related to reproducibility and robustness of the OoC data, risks and uncertainties involved with new OoC models. Hence, the majority of drug development industries are cautiously evaluating these models, assessing their strengths and weaknesses through internal validation. Further, many of these companies are using MPS models for internal decision making, mechanism of action studies, and identifying new targets through disease modeling. However, industries are currently skeptical in reporting such data in their regulatory filings. It is expected that with FDA modernization act 3.0, increasing number of pharmaceutical companies will be motivated to include MPS data in regulatory filings.

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