Economic case for MPS
Typically more than 45% of drug development failures occur in the three clinical phases, highlighting the need for better systems for preclinical testing.
The primary goal of life science companies is to successfully translate research and development into clinical applications. The cost of creating a single molecular entity from the bench to the bedside is approximately US$2.87 billion, so it is important to fail early in order to manage costs.
In vitro cell-based and in vivo animal models have low translational value for human clinical trials. A study conducted by M.J. Waring, Professor of Medicinal Chemistry at Newcastle University, and others in 2015 analyzed data from several pharma companies including AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer, revealing an attrition rate of 25% in phase I and II clinical trials indicative of limitations of preclinical validation based on standard systems.
Microphysiological systems (MPS) or organs-on-chips lie at the intersection of science and bioengineering. These models provide an efficient toolkit for tissue engineering, biological studies, single cell analysis, and drug development. MPS use normal human or patient derived cells to create a 3D physiological environment by incorporating cell-cell interactions, perfusion, or vasculature tissues. Such platforms may be used to model individual organisms or study the interconnected function of an entire system; thus, can lower the long drug development cycle time and high costs and improve the probability of clinical success. Dr. Uwe Marx, leader of the “Multi-Organ-Chip” development program at the Technische Universität Berlin, and others estimated that MPS platforms may reduce the drug development cycle time from 13.5 years to less than six years. The Transatlantic Think Tank for Toxicology (T4) further predicted that this would significantly help identify drugs that are likely to fail in the clinic before they are validated more comprehensively.
As regulatory agencies are beginning to embrace the concept of MPS, the growth of the MPS stakeholder community is accelerating. In Europe, organizations like the EUSAAT are focused on reducing vivisection, the use of live animals for the purpose of scientific research. In North America, the Community called NA3RsC (Reduce, Reuse, Recycle) seeks to promote MPS platforms as an alternative to animal models. In particular, the Community banned the use of animal testing for cosmetics in 2012. That same year, the US Defense Advanced Research Projects Agency (DARPA) acknowledged the role of MPS in the research and development of drugs. It invested in “human-on-a-chip” to develop MPS for engineering at least 10 human organ systems for testing drugs safely. DARPA helped strategize the goals for MPS and provide much-needed support for early investigators in the US and some of the beneficiaries include the Wyss Institute at Harvard University and companies like Emulate Inc.
The academic community has been at the forefront of new technological developments in MPS systems including the development of predictive biomarkers. The Wyss Institute at Harvard University has developed multiple organ-on-chip models including lung alveolus, lung airways, and small and large intestines. Recently, they created human intestine chips that were lined with cells from patient-derived organoids, and a heart-on-chip to model abnormal heart structure and function in the case of Bath Syndrome. In 2017 at Duke University, Leigh Atchison and others developed a blood vessel model to study the Hutchinson-Gilford progeria syndrome, a rare ageing disorder. In 2019 Aaron Glieberman and colleagues at Harvard developed a human islet-on-chip that helped study the effects of insulin and scale the results for manufacturing.
The biopharma community are starting to adopt MPS platforms for preclinical development as well. For example, MIMETAS OrganoPlate is used by Galapagos Pharma for modeling scleroderma, a disease that involves tightening of the skin, and inflammatory bowel disease (IBS). Philip Morris International designed a 3D human microvessel-on-chip system that simulates the cardiovascular disease-related inflammatory mechanisms involved in initiating atherosclerosis for assessing the risks of consumer products.
Scientists are integrating MPS platforms into the drug development continuum and it is increasingly becoming more evident that MPS platforms significantly improve preclinical validation studies while saving time and budget, and in the long term, improve clinical success and save lives
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- Rudmann, Daniel G. "The Emergence of Microphysiological Systems (Organs-on-Chips) as Paradigm-Changing Tools for Toxicologic Pathology.” Toxicologic Pathology, vol. 47, no. 1, 2018, pp. 4–10., doi:10.1177/0192623318809065
- Waring, Michael J., et al. “An Analysis of the Attrition of Drug Candidates from Four Major Pharmaceutical Companies.” Nature Reviews Drug Discovery, vol. 14, no. 7, 2015, pp. 475–486., doi:10.1038/nrd4609
- Materne, Eva-Maria, et al. “The Multi-Organ Chip - A Microfluidic Platform for Long-Term Multi-Tissue Coculture.” Journal of Visualized Experiments, no. 98, 2015, doi:10.3791/52526
- Atchison, L., Zhang, H., Cao, K. et al. A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells. Sci Rep 7, 8168 (2017). https://doi.org/10.1038/s41598-017-08632-4
- Glieberman AL, et al. Synchronized stimulation and continuous insulin sensing in a microfluidic human islet on a chip designed for scalable manufacturing. Lab Chip. 2019;19(18):2993–3010. https://pubs.rsc.org/en/content/articlelanding/2019/lc/c9lc00253g/