The development of a novel therapeutic through market approval is estimated to cost drug makers $2.6 billion and take over 10 years of research, testing, and regulatory scrutiny combined.1 Organ-on-a-chip (OOAC) technology is gaining momentum as a means to reduce the time and costs associated with drug development. The technology provides a wealth of benefits, spanning factors related to predictability, cost and time efficiency, and avoiding the translation issues often experienced with animal models. Predicting drug effects prior to human clinical trials is paramount in the drug screening and discovery processes. As microscale recapitulations of organs and their complex functions, OOAC systems provide invaluable insights into how human organs will respond to a particular drug or treatment.
Approximately 70% of drugs tested in phase II trials fail, as do approximately 50% of drugs tested in phase III, often due to factors that are impossible to detect in standard in vitro testing. Given the high cost and limited predictability of two-dimensional cell culture and animal models, OOAC technologies offer a more thorough and efficient approach to preclinical drug development — by replicating key aspects of human physiology that are crucial for understanding drug effects before first-in-human studies — in less time and at a lower cost. If OOAC products can make clinical trials even 25% more effective, the cost savings could be greater than $500 million per approved drug. The ability to predict failure earlier and to better understand drug–drug and organ–organ interactions makes OOAC a promising disruptor in the pharmaceutical industry and beyond.
Drug Discovery Powered by Technology
OOAC products vary in their appearances and end-usage capabilities. Often, the product consists of microfluidic channels, organ-specific cultured cells / endothelial cell lines, and superficial vasculature. Mechanical forces can also be applied to mimic organ physical functions— such as a beating heart or breathing lungs. With these static and flexible elements, the chip can act as a three-dimensional cross-section of the actual organ, facilitating specific and highly sensitive drug analysis.
In addition to the dynamic physical functions and cell vasculature, OOACs often include other components to recreate organ physiological processes, such as concentration gradients, fluid shear, and cell patterning. Cell patterning, including both shape and cytoarchitecture, can be made more detailed by incorporating 3D bioprinting to develop multiscale cell patterning with complex channels. Other cellular interactions across multiple tissues, the extracellular matrix, and with other resident or circulating cells may be incorporated to expand the testing potential of an OOAC. Regardless of which combination of components is included, OOACs enable a more physiologically congruent testing environment compared with in vitro tests on simple cell cultures, which do not capture the environment and connections required for organ function in a human body.
In the near term, OOACs have the potential to replace animal testing, develop specific human disease models with faster transitions from lab to clinic, facilitate vaccine development, and improve the underlying technology for better drug discovery and development.
Benefits and Challenges of Multi-Organ OOACs
Another exciting opportunity in the OOAC market is the ability to create multi-organs-on-a-chip (MOC), sometimes referred to as human-on-a-chip (HOC), which allow for more accurate, real-time depictions of drug effects on interconnected organs and even end-to-end human physiological systems. Drug effectiveness is not only measured by its ability to treat one specific condition, but also by the severity of side effects, toxicity levels, and unintended impacts to other organs. MOCs improve PK–PD models by providing critical context for evaluating the potential efficacy of a preclinical therapeutic.
However, emulating entire systems with MOCs still presents several challenges, and it can be very difficult to model end-to-end systems or full-body responses. For example, research suggests that very few companies study the female reproductive system utilizing OOAC technology. Assessing drug impacts to the uterus or ovaries individually may be easier to model, yet measuring the effectiveness of such a drug or treatment targeting a single organ without assessing impacts to the reproductive system as a whole would be significantly less valuable. Another challenging area is the nervous system, as the complex networks of neurons and synapses across the body is difficult to emulate in a representative model. However, there are studies that integrate muscular tissue with neurons to model environments for the investigation of therapies for diseases like multiple sclerosis.
Disrupting the Animal Testing Model
Perhaps the most near-term benefit of OOACs is disrupting the reliance of animal models on drug testing, reducing costs and improving efficiency, particularly in early discovery. Some of the costs associated with animal testing include animal procurement, nutrition, preparation, and active pharmaceutical ingredients (APIs). The United States government spends over twice as much on animal testing as all pharmaceutical and biotech companies combined, and the National Institutes of Health (NIH) spends about half of its annual operating budget — roughly $16 billion — on animal testing.3 Animal testing can cost anywhere from 1.5 to 30 times the cost of in vitro testing. The exorbitant costs and high likelihood of preclinical and clinical trial failures indicate a tremendous opportunity for companies and health entities to save money and improve testing outcomes by leveraging OOAC systems.
Although scaling an animal model presents logistical challenges (it can be extremely costly, and resources may be too scarce to procure enough animals (and/or API) to conduct statistically relevant testing), there are many tailwinds supporting reducing reliance on animal testing. First, there are significant regulatory hurdles, as many countries, states, and locales have stringent animal testing laws — many of which ban it altogether. There are noteworthy ethical concerns and staunch opposition from individuals and animal rights organizations like PETA and the Humane Society of the United States, which are constantly lobbying against animal testing. Finally, drug testing results from animal models often do not translate well to humans; sometimes drugs can cause undesired or harmful side effects in humans even though they did not exhibit the same effects in animal testing, and vice versa. Each of these favorable factors support greater acceptance, integration, and use of OOACs for drug testing.
OOACs enable a more physiologically congruent testing environment compared with in vitro tests on simple cell cultures, which do not capture the environment and connections required for organ function in a human body.
Early Adopters and Innovators
The OOAC market is still relatively new and major market leaders have yet to emerge. There have been no significant acquisitions or mergers yet, and companies are still in early to middle stages of product development. Many of the more promising, headlining companies are gaining traction in the cardiac, liver, and kidney spaces, with some well-known institutions like the Wyss Institute and MIT serving as incubators for companies pushing to be first to market. The Harvard/Wyss Institute-supported startup Emulate, Inc. has licensed OOAC technology that works as an automated instrument to link multiple organ chips together by transferring fluid between their common vascular channels.4 This instrument is designed to mimic whole-body physiology and controls fluid flow and cell viability while allowing for real-time observation of the cultured tissues and the ability to analyze complex interconnected biochemical and physiological responses across 10 different organs.
Other companies innovating in the OOAC space with liver-on-a-chip models that Dynamk has been following include Hepregen, spun out of an MIT incubator, and Hurel Corporation, originally funded and incubated by Merck and now counting the Humane Society of America as a participating investor. Nortis, a spin-out from the University of Washington, is focused on a disposable kidney-on-a-chip. TissUse, a spin-off from the Technische Universität Berlin has launched a two-organ product that has been successfully applied in more than 20 academic and industrial research projects. AxoSim was developed in a Tulane University lab and is focused on nerve-on-a-chip technology in a three-dimensional model. Two companies that have been doing fascinating work in the cardiac drug discovery space are CuriBio, a provider of biomimetic cell-based assay products and services, and TARA Biosystems, with a heart-on-a-chip product that can actually mimic a beating heart. Given that heart disease is a global leading cause of death, heart-on-a-chip products have great potential if companies can achieve proof of concept and researchers can utilize the technology to achieve drug efficacy.
Revenue Models and Future Generations
Companies in the OOAC space typically provide OOACs as a service for researchers or produce devices designed to capture and measure results of OOAC studies. At a high level, the market can expect several generations of market growth. In the near term, OOACs have the potential to replace animal testing, develop specific human disease models with faster transitions from lab to clinic, facilitate vaccine development, and improve the underlying technology for better drug discovery and development. In the midterm, experts expect that OOACs will expand into precision medicine applications, engineering stem cells that differentiate into highly functional, specialized cells on chips. Finally, in the long term, there is the potential to enable synthetic manufacturing of human tissues leveraging 3D bioprinting capabilities.
OOAC technology has potentially extensive applications that extend beyond traditional drug development and end-users. In addition to therapeutics, the technology shows promise across industries that must pass fastidious safety regulations for products that are ingested, inhaled, or topically applied. Cosmetic companies can use OOACs to test skin interactions; food and beverage companies can test how their products impact the gastrointestinal and vascular systems; chemical manufacturers can test the impact on lung function through inhalation studies. Once the technology is perfected, OOACs have the potential to disrupt traditional testing methods globally and across several industries.
Support from Market Regulators
OOAC technology is quickly making its way into the regulatory framework for assessing the safety and risk of new compounds. On September 12, 2018, the U.S. Food and Drug Administration (FDA) held a public hearing to garner feedback from stakeholders on the agency’s Predictive Toxicology Roadmap, which was created to “invigorate and strengthen the FDA’s long commitment to promoting the development and use of new technologies to better predict human, animal, and environmental responses to a wide range of substances relevant to the FDA’s regulatory mission.”5 The FDA Commissioner at the time, Dr. Scott Gottlieb, opened the hearing by expressing the agency’s support for moving OOAC technology forward across the product life cycle and alluded to the agency’s work on intestinal OOACs, or “gut chips” in the FDA’s parlance.
Current Limitations Temper Near-Term Expectations
OOAC technology is essentially still in its infancy, and a proof of concept has not yet been fully established. Most of the companies in the space are not in proof-of-concept phases, but rather focused on repeatability and building relationships with key clients, who would ultimately demonstrate their products’ viability through drug efficacy studies. Gaps in engineering still remain, as full emulation of complex systems remains a work in progress. Animal testing is still the industry standard, and, in order to disrupt the practice, companies will have to be able to prove their products and processes, particularly as it pertains to the reliability of toxicity data. However, despite these remaining hurdles, OOAC remains an extremely promising concept, and, at Dynamk Capital, we believe it will become a market disruptor in the years ahead.
The Role of Dynamk Capital
Life science entrepreneurs with highly disruptive, market-defining tools, technologies, and services have long struggled to secure the right mix of capital and expertise. We address this gap with deep domain and technical expertise, coupled with the strategic and commercialization experience to help these companies realize full potential. We are passionate about creating the future of biotech and life sciences and believe in innovative services, tools, and technologies that are critical for the discovery, development, and production of life-saving therapies. Dynamk partners with life-science visionaries whose market-defining ideas are shaping the future of how therapeutics are being developed, increasing global access for patients, and reducing costs. We invest in growth, early and seed stage companies developing novel life-science tools, technologies, and services — the underlying technologies needed to discover, develop, and manufacture biotherapeutics.
The OOAC space that focuses specifically on the development cycle of therapeutics is of special interest for Dynamk as we see great promise in the technology of these products and with increased focus from federal agencies such as the NIH and the FDA, who have also issued grants for research in OOAC. We believe companies that continue to grow and achieve proof-of-concept will gain acceptance of government agencies and disrupt markets in very positive ways.
Sullivan, Thomas. “A Tough Road: Cost To Develop One New Drug Is $2.6 Billion; Approval Rate for Drugs Entering Clinical Development is Less Than 12%.” Rocketpointe Corporation. 21 Mar. 2019. Web.
Kimura, Hiroshi; Sakai, Yasuyuki; Fujii, Teruo. “Organ/body-on-a-chip Based on Microfluidic Technology for Drug Discovery.” Elsevier Ltd. Feb. 2018. Web.
Bellotti, Anthony. “A 2018 Challenge to Government Animal Experiments: Find Your Own Funding.” Capitol Hill Publishing Corp. 16 Jan. 2018. Web.
“Human Organs-on-Chips.” Wyss Institute. 2020. Web.
Rein, Judy. “Organs on a Chip! FDA’s Predictive Toxicology Roadmap.” Food and Drug Law Institute. 2020. Web.