Responding to the need for more predictive preclinical assays for cardiac liability, ACEA Biosciences introduced a “ground-breaking” device the company describes as “next generation.” Designated the xCELLigence RTCA CardioECR System, it is building on the success of its impedance-only RTCA Cardio System, ACEA says. Combining impedance and field potential recording technology with a pacing function, the RTCA CardioECR system is said to be the first platform to allow simultaneous cardiomyocyte contractility and field potential measurement in one assay.
With the added field potential measurement and pacing stimuli, ACEA’s system allows for a deeper, faster assessment of cardiac toxicity mechanisms. According to ACEA, the field-potential electrode technology provides a measure of the integrated ion channel activity in cardiomyocytes that may be impacted by the tested compound. Meanwhile, the pacing function allows for controlling the rate of contractility “for a more controlled assay,” says ACEA. The system’s combined dual readout system also delivers a longer-term measurement of cardiomyocyte viability — something that has the potential to identify compounds that can cause longer-term structural damage to cardiomyocytes. With its ability to accelerate cardiomyocyte evaluation across multiple compounds by orders of magnitude, the platform introduces distinct “Fail-it-Fast” innovation to R&D operations.
Yama Abassi, ACEA Biosciences’ vice president of global operations agrees: “There has been a push by the pharmaceutical industry over the last few years to pursue a ‘fail early, fail cheap’ strategy. The earlier that one can eliminate a compound that may have potential [negative] side effects, the better it is. I think it’s obviously the earlier one can kill a compound with some potential toxicities, the better.”
That concept, says Abassi, is the model now “but the most important thing about it is that you want to have a very predictive assay. The danger is that you don’t want to kill good compounds. But if your assay is not predictive enough, the likelihood that you will eliminate some really good beneficial compounds is also very high. That’s the dangerous side of the ‘fail fast, fail cheap’ mentality. It’s really important for the pharma industry to use highly, highly predictive assays that are really reflective of the human condition. For example, if they’re using cells, it has to be very relevant cell types. In this case, once again, we are using human stem cell-derived cardiomyocytes. I just cannot see this type of assay being done even five years ago. Five years ago these technologies were not available.”
Founded in 2002, ACEA Biosciences has been developing and commercializing cell analysis platforms for life science research. According to ACEA, researchers are continuing to advance their studies via the 1,300-plus instruments the company has sold for a broad range of diverse applications. According to Abassi, the technology has been cited in more than 600 peer-reviewed publications. ACEA’s innovation in life science began with the introduction of its RTCA xCELLigence technology and continues with the recent introduction of NovoCyte flow cytometers.
CARDIOVASCULAR TOXICITY BAD
Cardiovascular toxicity is consistently identified as a leading cause of drug attrition and withdrawal, notes Abassi, explaining that “a number of drugs have been withdrawn from the market due to the risk of causing a potentially fatal form of ventricular arrhythmia referred to as Torsades de Pointes (TdP). The xCELLigence system provides a higher throughput and more predictive approach that can be used earlier in drug development to reduce both cost and risk.” Abassi says the company is confident the new system will deliver significant benefit to the pharmaceutical industry and that it is well-aligned with the FDA CiPA initiative. With its purported speed, combined readout abilities and fortune-telling predictive analysis capabilities, the RTCA CardioECR System is indeed revolutionary and Abassi explains why:
“I would describe it as cutting-edge as one can get, says Abassi. “It’s absolutely revolutionary in the sense that it combines multiple technologies to give additional information about the risk of compounds.” Abassi notes ACEA’s system uses human-induced pluripotent stem cell-derived cardiomyocytes. “Obviously with the emergence of [these types of stem cells] the application that everybody thought about was more therapeutic in nature, but the more immediate application is to use stem cells to derive relevant human cell types, such as liver cells and cardiomyocytes for evaluating the potential side effects of pharmaceutical compounds in development.”
Abassi says that with these model systems the industry is now in a position to start testing the toxic side effects of drugs because relevant human model systems are commercially available and viable; previously the pharmaceutical industry had to rely on animal testing. “Now we have relevant human model systems in scalable quantities that we can use for high-throughput screening potentially to screen hundreds, if not thousands, of compounds on a daily basis and get [large amounts] of relevant information from them.”
ACEA’s xCELLigence is groundbreaking considering it can generate incisive information from cardiac cells which are basically grown in a dish but ones that behave very much like a normal human heart. For example, the cells beat spontaneously in culture, just like a regular, normal cardiac cell. Abassi explains that the system’s sensors are a key element of the testing platform. “These sensors allow us to look at both the contractility of cardiomyocytes and its electrophysiological aspects,” says Abassi. “We can quantify cardiomyocyte contraction and derive critical information from it, including the beating rate.” The other sensor provides mechanistic information about how the compound may be impacting these cells at the molecular level.
“We can look at two things — contractility on one hand, the typical beating of the heart cells; and on the other, we can look at it from an electrophysiological angle, which gives us once again, more mechanistic information about the proteins or molecules that are actually involved,” notes Abassi. “You get a really quick and clear view of any compound’s effect on cardiac cells, hence the human heart.”
The system is designed around a microtiter plate format with multiple wells. “You can test lots of compounds,” says Abassi, and “you can test different concentrations.” Noteworthy also is the fact that the system’s sensors generate a readout noninvasively, which means the sensors themselves will not harm the cells. The noninvasive nature of the testing regime means study times can be extended, which is especially important when it comes to understanding toxicity. A lot of people, including the pharma industry, tend to look at toxicity on a minute-to-hour scale. But a lot of times toxicity actually emerges after many days or even many weeks.
“Sometimes toxicities take time to accumulate,” says Abassi. “With our system, we can follow how people actually take the drug in the clinic. We can do chronic dosing and see if, over time, there is a cumulative toxicity that could be extracted. With one dose or two doses, you may not see the toxicity, but over time as the dose is continued you might see a cumulative type of toxicity. Otherwise, with other assays one can miss this easily.” Because ACEA’s system is noninvasive, a lab technician can continue to monitor cells over hours, days or weeks and beyond.
Each of the wells, 48 to be precise, can be treated essentially as a separate experiment. A scientist can seed the cells in each of the wells, and let the cells grow. “Because these are cardiac cells,” explains Abassi, “we allow them to become synchronous — in terms of beating. Just like a heart cell. Then we monitor that and can quantify it using the system’s software.” According to Abassi, the system is straightforward to configure and to use. The typical workflow involves plating the cells onto the microtiter plates, then placing the system inside a CO2 tissue culture incubator to grow the cells.
Abassi contends the economies and efficiencies that this will allow downstream in the development process will quickly provide any lab deploying the technology a return on the investment. “Without a doubt, it’s a cost-effective alternative,” says Abassi, explaining that without ACEA’s system, the alternative is to use whole heart systems from rabbits or monkeys. “Can you imagine how much time and effort it takes to obtain animal hearts and to infuse them with drugs? You can only do that procedure one at a time,” notes Abassi. “The time, effort, energy [and money] that’s spent is enormous.”
That’s why, Abassi explains, pharma companies wait a long time before they attempt these types of tests because it costs so much. “They can do it with only a handful of compounds. Now because these tests are available in large enough quantities in the drug discovery process, [researchers] can start screening these compounds much earlier and gain a lot of information about the compounds that are being taken through the development phase, says Abassi. “That’s the really nice aspect; the alternative’s cost — and the system’s benefits especially justify the upfront investment.”
According to ACEA the FDA also has taken notice of this technology (see sidebar), especially because of the availability of stem cell-derived cardiomyocytes. “What the FDA wants to do is actually include these tests as part of the safety guidelines, explains Abassi. “The FDA typically issues these guidelines for testing pharmaceuticals. Now the FDA is evaluating our technology as well as other technologies for safety assessment. If all goes well, they can actually recommend these kinds of tests as part of the cardiac safety guidelines, which will come out in 2016.”