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3D Bioprinting Could Speed Up Drug Development

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By Cindy Dubin, Contributing Editor

Three-dimensional (3D) printing is a 20-year-old technology whose time finally seems to have arrived. Interest in the equipment rose sharply last year; in 2012, the market for 3D products reached $777 million and could reach $8.4 billion by 2025 as medical uses for the printers are being developed, according to Lux Research.

One company focused on the medical use of these printers is San Diego-based Organovo Holdings, a biotech firm that designs and creates functional, 3D human tissues for medical research and therapeutic applications. In January 2014, Organovo delivered its first 3D liver tissue to an outside laboratory for experimentation, marking a milestone toward commercial launch of a 3D liver tissue product. "These 3D human tissues have the potential to accelerate the drug discovery process, enabling treatments to be developed faster and at lower cost," explains Keith Murphy, Organovo's CEO and president, who previously worked at Alkermes and Amgen.

A Toxicity Predictor
Organovo has focused its attention on the liver because, as Murphy explains, about 10 percent of all drugs in Phase 3 clinical testing fail due to liver toxicity. "One reason for that failure is because we currently test the drugs on animals or on cells on a Petri dish surface, and that just doesn't work for liver testing," he says. "We see projects get green-lighted to move into clinical trials, but subtle effects of the drug on the liver come out over time."

As an alternative to animal testing and Petri dishes, Organovo is building what Murphy claims is a better model of the human liver. The company's proprietary bioprinting platform enables the reproducible, automated creation of living human tissues that mimic the form and function of native tissues in the body. The 3D bioprinted human tissues are constructed from tiny building blocks made of living human cells using a process that translates tissue-specific geometries and cellular components into 3D designs that can be executed by an Organovo NovoGen Bioprinter. Once built, the bioprinted tissues share many key features with native tissue, including tissue-like cellular density, presence of multiple cell types, and the development of key architectural and functional features associated with the target native tissue.

Organovo's 3D human tissues offer many advantages over standard cell-culture platforms due to the fact that three-dimensionality is achieved without dependence on biomaterial or scaffold components that would not be found in native tissues. Organovo's bioprinting technology was developed by the company's scientific founder, Prof. Gabor Forgacs, at the University of Missouri Medical Center at Columbia in 2003.

The living cells, taken from an individual, are bioinked (i.e., cells are treated and formulated to form the bioink), loaded into a cartridge, and inserted into the 3D printer, which is about 2' x 2' x 1.5'. If printing liver tissues, a 24-well plate is printed in about 45 minutes and usable for testing in just two days.

"Three-dimensional bioprinted tissues can help pharmaceutical companies speed up the drug discovery process allowing R&D teams to test new and promising drugs on functional human tissues during hit-to-lead (H2L) and lead optimization stages of drug development," says Murphy. "This will help identify potential toxicity and efficacy issues before drugs ever enter clinical studies." In addition, these tissues last more than 40 days, which is a vast improvement over their 2D counterparts, which can only last for 48 hours. This would enable researchers to dose, monitor, and sample the same tissue over a longer period of time, allowing them to detect more subtle or longer-term effects.

In addition to liver tissues, Organovo can biopsy cancer cells from a patient, grow them, and make 3D bioprinted tumors to test new drugs. Entering into 3D bioprinting at the right stage of drug development is critical. For instance, it would not make sense to pursue 3D bioprinting for a pharmaceutical or biologic company that wanted to screen 10,000 compounds. Doing so would be too costly to build the tissues at a reasonable price. A better scenario would be if there were 100 or fewer compounds to test, and the company was seeking the perfect molecule to move forward with — without liver toxicity issues. "The model allows a company to put its faith in a molecule that represents the desired potency and efficacy to move into a clinical trial," says Murphy. "While the current drug discovery process typically takes between three and six years, this would help pharmaceutical companies reject an ineffective or dangerous drug in a matter of months."

Building The Data
The benefits of rapid drug discovery and early identification of toxicity issues have caught the attention of pharmaceutical companies. For instance, Organovo signed a collaborative research agreement with Roche last year. While Murphy cannot describe the scope of the work, it is presumably to test Roche's compounds.

Unrelated to Roche, Organovo has released quite a bit of data on its 3D liver model. Organovo's 3D liver tissues exhibit dose-dependent responses to acetaminophen, a known liver toxicant. And Murphy explains that the liver tissues successfully produced albumin, fibrinogen, and transferrin. The bioprinted liver tissues also possess the ability to synthesize cholesterol.

While Murphy admits that no test can be 100 percent accurate, he says 3D bioprinting represents a huge leap forward from animal testing and Petri dishes. For example, he says the small tissue being created is indeed representative of the larger tissue. "We are starting from a place where it's so bad that slight improvements are incredibly good, and we're creating what we think is a dramatic improvement," he says. "We may fall short of being perfect, but we are so much closer to perfect than the available methods that the benefit is huge."

Murphy says the promising data is not only a story to be shared with pharma, but also with federal regulators. "Remember that regulators are scientists, and they want to see good data. That is what they will use to determine a drug's approval. The bottom line is if we provide the scientific value that we think we can, which is a better model than some of the existing animal models, the FDA should be extremely comfortable letting people move forward."

Organovo has already been speaking with the FDA. Murphy says the agency is aware of how the company's science works and how it can potentially be beneficial. "If we show that 3D bioprinting is a predictive tool, the FDA will accept the test and could theoretically ask that pharma use the technology," he says.

Figuring Out Why Green-Lighted Drugs Go Bad
But until that point is reached, more work needs to be done. Going forward, Murphy says Organovo will test drugs that failed in the clinic but were initially green-lighted based on the results of animal models and 2D cell-culture testing. "We want to discern what things light up that we could have seen to help pharmaceutical development become more predictive."

Organovo will also commence the commercial launch of its 3D liver and start generating revenue through a contract research service model before the end of the year whereby a pharma client would provide its compounds and Organovo will perform a set of tests for the client. While the cost for such a service will depend on the tissue, Organovo will work with each customer on an individual basis and build tissue specifically to a client's need. Murphy does say, though, that the cost for tissue for liver fibrosis would be different than tissue for liver toxicity testing.

While Organovo anticipates that preclinical toxicology testing services could command prices in the high tens of thousands per compound for standard liver screening alone, Murphy points out that the cost of drugs that fail is estimated at about 40 percent of all drug spending. "So if the drug spending is more than $50 billion per year, there is an opportunity to save more than $20 billion. Even if using 3D bioprinting testing only causes modest improvement, there is significant potential benefit."

"Three-dimensional bioprinted tissues can help pharmaceutical companies speed up the drug discovery process."

Keith Murphy
CEO and President, Organovo Holdings

And Murphy says that, under the right circumstances and with the right partner, Organovo could license the bioprinting technology to a life sciences company to perform its own testing.

Organovo also plans to release additional data in 2014 on its 3D kidney tissues and breast cancer tissues, which are now in development.

Organovo is about six years away from entering clinical studies to make tissues for surgical implant. "Everyone quickly thinks about large organs; bioprint an organ and implant it into the body. But, instead, we are focused a little smaller. Think of a 3D bioprinted liver patch to help repair a damaged liver. We could take cells from the patient to create the patch, which would almost assure no immune response."

The applications and the implications are plentiful. Organovo will continue to work with liver and kidney tissue, but other 3D bioprinting research will include oncology, lung tissue, muscle tissue, and blood vessels.

Murphy says: "Three-dimensional bioprinters are a powerful tool, and while they might not solve every issue in drug development, they can be leveraged to make headway in areas where traditional animal models and 2D cell-culture methods aren't allowing pharma to make good progress.

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