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Clinical Trials in a Dish: A Perspective on the Coming Revolution in Drug Development

What if there was a more efficient way to select safer drugs to move into clinical development while reducing attrition? How much time and money could be saved and how much energy could be refocused on enabling safe drugs that address unmet medical needs to reach patients more quickly? Clinical Trials in a Dish (CTiD) studies are poised to revolutionize thinking about practical, immediate and near-term applications in the field of drug discovery and development.

Authors of a recent SLAS Discovery article are executing a strategy to identify, early in the development process, drugs with higher probabilities for clinical success. Clinical trials in a dish (CTiD) allows for laboratory testing medical therapies for safety or efficacy on cells collected from a representative sample of human patients before moving into actual clinical trials.

“I’ve been involved in safety testing for a number of years and an interesting observation is that in the preclinical arena – before drugs move into clinical development – the testing strategies are focused on minimizing dispersion and diversity,” says Bernard Fermini, lead author of the SLAS Discovery article and chief scientific officer and vice president of safety and toxicology assessment at Coyne Scientific (Atlanta, GA, US). “Coyne Scientific is committed to looking at biological diversity in early safety testing.”

Fermini and his team believe that in doing so dollars can be saved for the pharmaceutical industry, but more importantly, getting effective and safe drugs to patients in need can be accelerated.

“This is a difficult field without a doubt, and we don’t have an expectation that we’re going to identify 100 percent of the drugs with safety issues,” Fermini continues. “But you only need to detect a small percentage of the large number of drugs that fail in clinical trials to have a pretty impactful effect. Not only are we contributing in reducing the cost of drug development, but we’re redirecting the efforts of some of the smartest people in the industry to work on drugs that will actually succeed. We can use this brain power for something valuable as opposed to working on something that could have been identified, early in the development process, as likely to fail in the clinic.”

As all who work in drug discovery and development appreciate, the numbers are staggering. Fermini and his co-authors cite studies showing that “of the $2.6 billion spent to achieve a regulatory approval of a single new drug, only about $200 million is spent on the drug that is actually approved. The other $2.4 billion—fully 92 percent of the total investment—is spent on candidate drugs that failed along the way.”

How Does CTiD Work?

Fermini says CTiD is a ‘very different way of thinking’ about preclinical work, but that the time is right to do so because of recent advancements in stem cell science and technology and following a number of recent publications that support the idea. Fermini explains that over the past few years, cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) have shown promise for cardiac safety and toxicology screening during early drug development.

“hiPSC-CMs are attractive because they represent an unlimited source of cells that appear to recapitulate the genetic, physiologic and pharmacological properties of human cardiomyocytes and heart tissue from the donor. The discovery and development of hiPSCs have opened new possibilities of testing that support the concept of large-scale human cell-based safety and toxicity screens, with the potential to reduce attrition of drugs in clinical development. The noninvasive nature and unlimited supply of this patient-derived approach now allows performing surrogate clinical trials in vitro, with consequences that extend well beyond the ability to reduce the attrition of drugs. This new CTiD approach, has potential applications across multiple areas of drug discovery and development – from early stages of lead optimization to regulatory safety assessment.

“What the science is telling us now is that the cells obtained from an individual don’t just represent a random human being; they represent that specific individual. For example, the genes that determine how a person’s heart responds to a given drug are present in the stem cell-derived cardiac cells obtained from that donor and, therefore, will respond pharmacologically in a similar manner. We cite numerous examples in our perspective article – evidence of recapitulation of clinical susceptibility to drug-induced effects using cells derived from both healthy and diseased donors. If you accept the idea that each cell line represents an individual, then you have to accept the fact that different cells lines represent different individuals, and that multiple lines can be considered a surrogate for a population of individuals. And since each line can recapitulate the response of each donor to a given drug, you have the ability to mimic early clinical trials, as the number of participants in those studies is low. But now you can reproduce it in vitro – in a dish.”

The technology around human induced pluripotent stem cells has developed to the point where you now have access to an unlimited number of human cardiac cells available for laboratory use, Fermini states. “Having access to a renewable source of cardiac cells from the same or multiple individuals while having the ability to culture them and study the effects of drugs for an extended period of time at the level of a population is new and exhilarating.”

A French Canadian, Fermini started his career at the Montreal Heart Institute where his team discovered a novel, chamber-specific ion channel in the human heart. This began his journey with cardiac electrophysiology and drug safety.

“This specific ion channel was found in the atrium and not the ventricle, and it became a really intriguing target for the development of drugs to treat atrial arrhythmias,” Fermini explains. “As a result of this discovery, I was recruited to Merck in Pennsylvania to focus on developing antiarrhythmic drugs targeting that newly discovered channel. That was very exciting. I was with Merck for five years. I then went to Pfizer and spent 17 years working mostly in the safety arena and eventually moving up to co-chair the Safety Pharmacology Department as well as head of the Ion Channel Group in that department.”

This focus on safety testing led Fermini to his current position at Coyne Scientific.

“The standard way of thinking when you are testing a drug is to optimize your assays to minimize variability in your data,” Fermini says. “However, by doing, so you end up excluding diversity. For example, currently, stem cell cardiomyocyte studies are usually executed using a single-cell line or a line derived from a single individual. Moreover, animal studies that are performed in the pharmaceutical industry ignore the problem of individual-to-individual variation in drug response among humans and suffer from the use of very much in-bred animals. Therefore, the genetic diversity is lost.

“However, once you’ve gone through all this extensive preclinical testing, the first thing you do in clinical trials is to expose your highly prized lead candidate drug to the most diverse biological system that exists – humans,” Fermini continues. “You’ve eliminated most if not all diversity from preclinical testing and then you move the drug into the clinic. That’s when unexpected safety issues happen and you’re left wondering ‘how could we have missed that?’ Testing drugs against multiple cell lines with CTiD is similar to testing drugs against multiple humans with unknown genetic susceptibility to drug effects, just like it’s done in early clinical testing.

“But, you’re doing that before you go into the clinic. You then begin to see not only the magnitude of effects but also, and for the first time, the dispersion of the effects across a sample of the population, similar to what you can expect when administered to a number of different individuals. Everybody responds differently to medication, and some are more prone to adverse effects than others. But this difference is never considered or explored in preclinical testing. We now have the ability to generate cell lines from a number of different donors, similar to a Phase I clinical trial, allowing you to quantify the distribution of effects in a population as opposed to a single individual. In our validation work we’ve observed that some drugs result in little dispersion of effects across numerous individuals, while others show a large dispersion suggesting that more individuals may be affected by the latter drug than the former. That’s important to know early in the process. When you’re developing a drug, a major concern is the safety of that drug. A main reason for preclinical testing is to detect issues and define safety margins before going into man. A safety margin is defined as the difference in concentration or exposure where a drug shows efficacy, and that where adverse effects are observed. That ratio – that window – is your therapeutic index, or your safety margin. By documenting the dispersion of responses as opposed to looking at data from a single cell line, you’re able to define with more certainty the safety margin within a population and identify drugs that have a safer profile and a higher probability of succeeding in clinical development.   

“Not only that, but you’re also able to determine the incidence of effects,” Fermini continues. “Let’s say that for budgetary reasons you are asked to select only one of three promising drugs to move into clinical development. All three drugs are from the same therapeutic class, show similar efficacy and adverse effect profiles, based on the information in hand. Which one would you choose and why? Using our approach, you could test all three drugs on a number of different cell lines and endpoints and look for differentiation. For example, let’s say that you see effects in three or four of those lines with one drug, no effects in 15 lines with the second drug and finally 12 out of 15 lines respond negatively with the third drug. Suddenly the choice becomes much more obvious. You now have the ability to rank order your three drugs based on a more complete safety profile obtained from human material, as you are provided with a realistic projection of the adverse effect profile you can expect in clinical testing. Tackling the issues of dispersion of effects and incidence in preclinical testing is a new concept, and that’s why we think it’s exciting and potentially very impactful. And it probably explains, at least in part, why we had over a thousand downloads of the article within the first two weeks of its release in SLAS Discovery.”

What About Those Cell Lines?

Fermini acknowledges there are several contract research organizations offering stem cell testing services, but he says Coyne Scientific is the only one offering multiple stem cell line testing and the CTiD approach.

“These lines have to be prepared in ways that are very consistent,” he says. “If your goal is to look at the effect of genetic diversity – and not diversity in epigenetics – then you have to control the conditions under which you acquire, induce, differentiate, culture and maintain the cells. In the field right now, some scientists are reporting different responses with the same drugs when tested across a number of lines obtained from different vendors. We believe there are several reasons for this. One is that each vendor prepares their cells in a different way, from protocols for induction of pluripotency to time in culture, to number of passages, etc., leading to inconsistent results in the field. Another important aspect is that the tissue source, the donor behind each line, is different. Therefore, each vendor has a very different human being used as testing material, and that introduces significant diversity (male vs. female; young vs. elderly; healthy vs. diseased…). In our case, we try to control as many of the extrinsic factors as possible. The original starting material is cord blood. Therefore, the age of each donor is known and is very consistent across all lines – and that’s unique in the industry. Because of the origin of the tissue, there is very little impact of epigenetics – we know these donors haven’t smoked and they haven’t been laying in the sun for years and developed skin cancer, or any other disease that can affect the DNA in their cells. Our focus is on genetic as opposed to epigenetic diversity. We do all of the cell differentiation, maintenance and culture work in house under very defined and controlled conditions. Consequently, the material we work with is much more homogeneous than if you were to go out and purchase a number of lines from a number of different vendors. It’s a lot of work, and it’s an expensive proposition but in the end it’s worth it. That’s probably, in part, why we are currently the only vendor offering CTiD.”

Continuing to Validate

“Our claim is that we have the ability to do clinical trials in vitro, and there’s no doubt that this is a new way of thinking and it will take some time before it’s fully adopted in the industry. But, again, as I like to say, you eat an elephant one bite at a time and that’s kind of where we are now – taking the first few bites,” Fermini says. 

Announcing their efforts in the SLAS Discovery perspective is the first step in generating discussion in the field. Coyne Scientific team members have been working further to disseminate their ideas through presentations, scientific posters and interacting with research scientists at meetings of the Society of Toxicology, Safety Pharmacology Society and World Pharma Congress, for example.

The company also is working in collaboration with pharmaceutical companies.

“We’re testing drugs that were relatively clean from a safety perspective in preclinical testing but when they went to a Phase I clinical study, they showed unexpected issues,” Fermini says. “Our goal is to test these drugs in our assays and see if, using a population approach, we can detect at exposure levels that are clinically relevant, effects that were missed in the standard preclinical testing package.”  

He cites an example. One pharmaceutical company that plans to work with Coyne Scientific went through preclinical testing of a candidate drug with no issues but once in Phase I studies, several patients developed arrhythmias.

“We’re thinking they might have missed this adverse effect as they studied the drug in a single cardiac cell line, a single patient. One person is not representative of the human race,” he explains. “When using a single cell line, the results are often binary; there is an effect or there is no effect – period. What we hope to show as we look for effects in multiple cell lines, hence multiple humans, is a signal in one or more of our lines that they weren’t able to detect because of the lack of diversity in their approach.”

Fermini is All In

“I’ve been involved in cardiovascular safety testing pretty much my entire career. I feel very privileged and very lucky. I’ve worked and interacted with some of the smartest people in the field and in some of the greatest Institutions one can hope for. I’ve always had a sense of purpose and felt like I was contributing to “something,” making an impact. Stem cell-derived cardiomyocytes have developed into key research material over the past few years, and there’s a large number of investigators using these cells to predict cardiac arrhythmias. While that’s important, I’ve always felt that more could be done with these cells. This is human material so it’s completely relevant to human findings, and there are many novel ways to study these cells. I spent my whole career working with cardiac tissue, isolated cardiac cells and even tissue from human hearts, but stem cell cardiomyocytes open up new and exciting avenues to study cardiac safety and toxicity.  

“It’s a world that I’ve always been passionate about – being able to work with cardiac cells in a more chronic way,” he continues. “If you’re able to keep cells in culture a long time then you’re able to mimic drug exposure for a long time, and for oncology compounds that’s the key. Concerns with these drugs have shifted from a focus on benefit to an emphasis on risk. We now successfully treat various cancers or prolong life expectancy significantly with new drugs, but you want to make sure to maximize the quality of life of the patients after the treatment as well and not induce long lasting, life threatening health issues. With many oncology drugs, adverse effects on the heart develop over time. The use of stem cell cardiomyocytes now offers new opportunities to study oncology drugs in ways that were not possible even a decade ago – that’s a major impact!

“Diversity has been eliminated from preclinical testing, and it probably plays a major role in drugs failing in clinical trials. We now have the tools to really test for diversity and we can do it in the lab, at a fraction of the cost of clinical trials and outside the rigid and heavily regulated environment of clinical testing. I believe that this is just the beginning. The state of stem cell science today is unquestionably imperfect, and clearly there are important issues that need to be addressed. But in five to ten years from now, they’re going to continue to improve and provide novel insights in translating preclinical data to clinical outcome. I feel like we’re at the beginning of something big and I have this unbelievable opportunity to contribute my knowledge and expertise to move the field forward. That’s what drives me; that’s what gets me to work every morning. It’s very risky; there are no guarantees but I am willing to take the risk because opportunities like this don’t come around often in one’s career.”

Read the SLAS Discovery Perspective for Free

“Clinical Trials in a Dish: A Perspective on the Coming Revolution in Drug Development” by Bernard Fermini, Shawn T. Coyne and Kevin P. Coyne is available for free public access at SLAS Discovery Online. Join SLAS today for full access to all peer-reviewed scientific content in SLAS Discovery (Advancing Life Sciences R&D) and/or SLAS Technology (Translating Life Sciences Innovation).

August 13, 2018