I had the honor of interviewing Patrick Dentinger, President and CEO of ACF Bioservices, an Absorption Systems company whose mission is to develop innovative research tools that can be used to accurately predict human outcomes. The company has facilities in Philadelphia, PA, Medford, MA, San Diego, CA, and Panama City, Panama.
In this fascinating interview, we discuss Mr. Dentinger’s background, the establishment of ACF, its origins in parent company Absorption Systems, and the critical role it is playing within the rapidly expanding cell- and gene-therapy industry.
Interview with Patrick Dentinger, President and CEO of Absorption Systems
Patrick Dentinger: Dr. Ismael Hidalgo and I founded Absorption Systems in 1996. We met through a mutual friend. At the time, Ismael was working in a pharmaceutical company and I had left my position at an international CRO, with the intention of starting my own company. The more I learned about Ismael’s scientific background, it became clear that there was an opportunity to establish a business based on some of the work he had done.
In the late 1980’s, as a post-doctoral researcher, Ismael had characterized the functionality of a unique cell line. The cell line was derived from an adenocarcinoma of the colon, but its functional phenotype resembled many of the characteristics of the human ileum. When cultured properly, the cells form a monolayer, with a tight intercellular barrier. His interest with this cell line was to understand whether he could use it to predict the extent to which a drug would be absorbed in the human intestine. Once he had demonstrated that, and it was replicated by independent labs, Ismael had essentially created an in-vitro tool for predicting drug absorption in humans.
Ismael’s research interests fit well with my background in drug delivery systems. Back then, the industry was struggling to find better methods for predicting drug absorption. The opportunity, we realized, was to use this unique cell-based model as a laboratory bench tool to accurately predict the permeability characteristics of a molecule. The real significance was that it represented a shift in the industry from solely relying on animal testing to trusting the predictive utility of a human cell-based test system. Previously, drug researchers were left with many unanswered questions about the absorption of a molecule, its distribution, and how it is excreted, because of the many variables inherent in animal testing.
For example, the journey of an orally administered drug takes it through the acidic stomach to the small intestine, where typically most drug absorption occurs. By this time, the active ingredient should have dissociated itself from the tablet or capsule, its formulation, into a soluble form that can be absorbed across the intestinal mucosa. Once the drug molecule crosses the wall of the small intestine, the portal vein takes it directly to the liver, the chief metabolic organ of the body. The drug has to make it past the liver, preferably intact unless it is a pro-drug that has to be metabolized to the active moiety, before entering the general circulation and ultimately reaching its intended target.
Cade Hildreth: What a valuable convergence of events that led you to form Absorption Systems. I am glad that you and Ismael were introduced to one another.
Patrick Dentinger: When we started in the mid-90’s, combinatorial chemistry was an emerging technology with high hopes for becoming a game-changer for the industry. Chemists had figured out how to combine advances in chemical synthesis with automation to produce thousands upon thousands of unique chemical compounds in a very short time. With concurrent advances in automation and protein chemistry, the industry quickly figured out how to test the massive numbers of chemicals against drug targets in a process known as high-throughput screening. By combining high-throughput screening with combinatorial chemistry, the industry was poised to change the way “hits” (chemicals that bind to a drug target) were discovered.
Hits are exciting, but they are just chemicals that bind to targets. To become a drug, a hit needs to have “drug-like” properties. For example, if intended to be taken orally, a hit needs to be stable in acid, soluble, permeable (across the gut wall), metabolically stable (it gets past the liver mostly unchanged) and have enough drug left to enter the bloodstream and make it to its target.
Ismael and I planned to offer our clients in-vitro tests that could be formatted to screen lots of hits rapidly, and to do so with small quantities of the chemicals, which was necessary because the combinatorial chemistry approach did not produce a lot of material.
We knew we had a clear advantage over the traditional approach of animal dosing because animal models were not compatible with the large numbers of hits being generated. The cost, the time, and the amount of material needed for testing in animals was not going to be practical. In-vitro techniques provided several solutions to the combinatorial approach to drug discovery: most of the cell-based and subcellular fraction-based assays were of human origin, the assays were performed on the benchtop with some automation, and the tests did not require much material. Upon completion of these screening tests, hits could then be categorized for their “drug-like” characteristics. This was the convergence of factors that convinced us to launch the company.
Things did not work out as we planned. Combinatorial chemistry did not evolve into the paradigm-shifting format that many people had anticipated. The strategy of producing thousands of compounds quickly faded as in-silico tools for drug design improved and the industry drifted toward more focused medicinal chemistry, which emphasized a slower design-for-purpose approach. As a result, we had to change our business focus to emphasize the predictive nature of our assays more than the speed and cost.
Cade Hildreth: You spoke briefly about your background as you described Absorption Systems’ unusual history. Are there other aspects of your background that led you to forming the company?
Patrick Dentinger: I started out as a bench scientist, transitioned into licensing of technology, and then into sales. While working for these companies, I realized that the underlying issue was our limited understanding of why many drugs fail to reach their target. This is the dilemma that connected me with Ismael. We recognized that we needed better tools to assess how a drug gets to its site of action and to identify barriers that prevent it from doing so.
Cade Hildreth: Fascinating. As a non-clinical CRO, what problems do you solve for your clients?
Patrick Dentinger: We currently solve a multitude of dynamic problems in two main categories: 1) providing scientific expertise in the form of experimental design and experimental interpretation, and 2) overcoming their capacity constraints. Within these two categories, we provide distinct advantages by continuing to offer proprietary and innovative tools, as well as optimized and highly qualified test systems. When we started, we had at most, two commercial competitors in our market segment. At the time, the bulk of in-vitro biology work was being performed in academia, and it was just trickling out into industry. Large pharma companies were getting more involved, but there was undeniably an opportunity to provide contract-based, non-clinical services. Additionally, we were confident that we had expertise that hardly anyone else had.
Over twenty years later, we still have advantages to successfully solve problems for our clients. We continue to innovate and utilize our expertise in cell biology and molecular biology. Our expertise is now matched by experience over a wide range of molecular entities. Even though we had to change course from our original concept for the business, we did get one thing right: we did predict the emergence of the specialty contract research organization.
Cade Hildreth: That all makes enormous sense. What types of clients do you serve?
Patrick Dentinger: Among approximately 400 clients per year, we work with the full range from large pharma, biotech, to virtual companies around the globe.
Each of our clients have different needs. The big guys often have capacity issues, but more and more even they are seeking the expertise of specialty CROs. The mid-size companies and the smaller companies usually don’t have the resources or the technical expertise at their current level of development, so they have relied on outsourcing more heavily.
Cade Hildreth: Interesting. What locations do you have, and how did you choose those specific sites?
Patrick Dentinger: Our headquarters are just outside of Philadelphia, PA, mainly because that is where Ismael and I live. We also have laboratories in San Diego, CA, Medford, MA, just 3 miles outside of Cambridge, and Panama City, Panama.
Cade Hildreth: Why Panama?
Patrick Dentinger: One of the unique aspects of our business is our track record for helping companies with non-clinical approaches to drug approvals. We have a distinct advantage, because of our expertise, in helping generic and re-purposed drugs achieve market approval without human equivalence testing. Generic drug approvals historically required human testing, whereby the generic drug was compared to the branded drug in what are referred to as bioequivalence studies. With certain generic or re-purposed drugs, the FDA has established a regulatory approval process known as the Biopharmaceutics Classification System or BCS. The BCS can replace the traditional clinical bioequivalence study in select cases. Our expertise in this area has been instrumental in helping clients achieve market approval while avoiding unnecessary human bioequivalence trials. The real benefit for our clients is time to market. Every day a client’s drug is not on the market is extremely costly.
Central America and South America are growing markets with a rising middle class of consumers. They are beginning to embrace this FDA-established regulatory pathway to more rapidly and cost-effectively get generic drugs to their patient population. Panama was a natural choice because it is a business-friendly country, and Ismael is Panamanian so he knows the country well.
Cade Hildreth: Interesting.
Patrick Dentinger: It all circles back to the cell line that Ismael had characterized when he was a post-doc. Today, we are the world’s leader for providing this type of characterization service. If a generic drug meets the criteria for a BCS study, the generic sponsor company can receive what’s called a “biowaiver” and waive human testing prior to marketing approval. We are exceptional at determining the potential for a biowaiver, as well as performing the work and delivering an ironclad report, ready for regulatory submission.
What’s really interesting is that the FDA has driven this, so essentially, they have accepted the replacement of human testing with an in-vitro cell-based model, a prime example of translational medicine. As I mentioned, not every drug meets the criteria for the BCS pathway, but for those that do, it is a fast, efficient way of getting a generic drug approved. To date, our in-vitro testing has never missed a proper classification in the sense that it has never generated a false positive.
Cade Hildreth: Wow, incredible track record. What is the focus of your Boston facility?
Patrick Dentinger: Our Boston-based laboratory is TGA BioServices. The acquisition of TGA BioServices was part of our overall strategy to even further expand our capabilities for large molecule therapeutics and the cell and gene therapy sector.
TGA adds GLP and GMP immunoassay expertise to our capabilities, including assay development using ELISAs and flow cytometry. They also bring additional cell culture expertise necessary for the development of potency assays, as well as expertise in identifying markers within the cell. We also wanted a footprint in the Boston area because it is so close to much of our client base.
Cade Hildreth: Very interesting. What is the importance of ACF Bioservices as a division of Absorption Systems?
Patrick Dentinger: Up to now, we’ve been talking about the non-clinical utility of one particular cell-based model,, which is mostly relevant for small-molecule therapeutics. ACF is a new division that focuses on large molecules, and cell and gene therapy services; specifically, we wanted to establish a dedicated and access-controlled space for GMP potency and release assays to meet regulatory requirements.
The evolution of our service offerings into cell and gene therapy was logical and is still based on our core expertise. All of it is based on our advanced understanding of cell behavior. For example, one of the challenges in working with cells is that they have a tendency to change behavior over time, referred to as phenotypic drift. This type of drift comes in many forms, so it is important to monitor the characteristics of cells and identify when drift is occurring. The in-vitro cell work that we perform for non-clinical studies and especially for biowaiver approvals utilizes cells that need to be tightly controlled. Because these cells are used in regulatory filings, the FDA is free to audit any studies we have performed and submitted to the agency. Our first audit was in the early 2000s, I think it was 2002. The FDA came in and audited our cell culture processes and procedures as part of their overall audit.
Then, new developments in the mid-2000s significantly impacted our business. The FDA and EMA began to understand and appreciate the role that drug transporters play in the disposition of drugs throughout the human body. Drug transporters reside in cell membranes, and they can determine whether a drug gets into a cell. The reason the FDA and EMA are interested in transporters is that the presence of transporters often explains pharmacokinetics, that is, how drugs enter or leave cells in the human body.
Transporters can also explain another aspect that the agencies are concerned with, drug-drug interactions. When you take two drugs at the same time, the pharmacokinetics of one drug may be altered by the presence of the other. If one drug is eliminated through a certain pathway, whether by metabolism or through a transporter, a second drug that uses the same pathway may cause complications. For example, one or both of the drugs may reside longer in the body than intended. The theory of drug dosing is that we want the drug to get in, do its job, and then we want it eliminated. Having a drug circulating in your body longer than intended is rarely good. When this happens, we start seeing drug-drug interactions.
To build transporter research tools, we took a cell-based assay approach. We focused on cells that did not have the desired transporter, and we inserted a specific transporter gene to express the desired transporter protein. We characterized the functionality of that protein and when we were done, we had a cell-based assay for the activity of that transporter. We developed an entire suite of cell lines to look at specific transporters, in some cases by taking the opposite approach, which is by silencing a specific transporter gene. Although we were focused on drug transporters, this approach is similar to the mechanism by which gene therapy companies deliver their therapeutic genes.
So, we have expertise in culturing cells, we have been audited by the FDA for our cell manufacturing, and we have a highly advanced understanding of how to characterize the performance of a functional protein in a cell. Expanding our service offerings into cell and gene therapies was logical because we have been performing these activities for the better part of twenty years. For the cell and gene therapy space, we refer to this as Potency Assay services.
It’s also important to note that in this space, potency assays are not exactly the same as traditional potency assays in the large molecule space. Conceptually similar, but we have direct experience and I can tell you that due to unknowns, establishing a tight and reproducible potency assay with a well-defined mechanism of action requires deep expertise and control of the cell line. The advantage we have is that thorough characterization of the test system is our sweet spot.
Both the FDA and EMA have clearly stated that the submission of a new cell or gene therapy, for late-stage clinical trials or commercial product release, requires testing to verify the mechanism by which the therapy works. They want potency assays.
Cade Hildreth: What other types of testing services do you offer that are specific for cell and gene therapy companies?
Patrick Dentinger: The specific services we offer include immunological assays to detect isolated proteins or proteins expressed in cell systems. We do thes by using binding assays, ELISA, and flow cytometry. We offer cell line selection and optimization for potency assay development. We look at transduction efficiencies of delivery systems using viruses and other transfecting agents. We can study the neutralizing effect of serum or plasma on gene vectors using the same cell-based system. We can also study mRNA expression, protein formation, and functionality.
Cade Hildreth: I fully understand. What are the advantages of working with ACF Bioservices and Absorption Systems, versus other players in the industry?
Patrick Dentinger: What is interesting about the cell and gene therapy space is that the first ever gene therapy product approval in the United States occurred just several months ago. Shortly thereafter, two additional approvals occurred. The treatments are quite amazing and the FDA is working to make this happen. We have been involved with the FDA for the last 15-16 years, so we have extensive experience with their justifiable expectations for scientific rigor in regulatory submissions. Our scientific expertise in potency model selection, our expertise in model characterization and validation, and our GLP and GMP capabilities are distinct in this space and a differentiator for us in the marketplace.
With regard to Absorption Systems, it truly comes down to the proven reliability of our work, which is rooted in our expertise with cell culture, supplemented by our more than 20 years of experience with in-vitro and in-vivo studies, and complemented by our continuous efforts to innovate test systems to improve prediction of human outcomes. The reliability of our assay designs and results is critical for helping our customers determine the fate of their drug candidate faster. The quality of our services is evidenced by our track record for helping customers achieve successful regulatory submissions and helping customers gain market approval.
Cade Hildreth: Since you are so deeply entrenched within this industry, what trends are you seeing in the cell and gene therapy industry at large?
Patrick Dentinger: The excitement of the approvals and the unmet medical conditions that these approved therapies are treating is absolutely remarkable. Investor money is flowing into the space and there is a lot of excitement at the moment.
The challenge for everyone is to more fully understand how all this works. Can companies consistently and cost-effectively manufacture these unique therapies? Can we better predict when a therapy will work for a given patient and when it won’t? Will the benefits of the therapy last in the patient or will the patient revert back to an original disease state? Can we better predict side effects of the therapies?
In industry, we often see a therapeutic result in humans that cannot be re-created by the hypothesized mechanism in cultured cells, for a variety of reasons. For ACF, we aspire to improve the correlation between cell culture models and human outcomes, remaining true to our mission.
Cade Hildreth: What trends are you seeing in terms of how the FDA is treating cell and gene based therapies?
Patrick Dentinger: We have interacted with the FDA for the past 15-16 years and
I think the FDA has been very open and supportive to all of these new therapeutic approaches. We can see the interactions between the FDA and our clients, and it has been very positive. Of course, there is caution, because the regulators are tasked with protecting the public safety so they are going to demand more rigorous testing as knowledge in these fields grows. From my perspective, the public should be made aware that there is a deep fascination and commitment on their part to try to make cell and gene therapies happen. Their interest and commitment will put a great burden on ACF to validate the science behind the therapy.
Cade Hildreth: It is a truly remarkable time in history. Since you are at the right place at the right time, what are your 5-year goals for ACF Bioservices and Absorption Systems?
Patrick Dentinger: From our inception, we have been committed to creating innovative tools for predicting human outcomes. We commit a lot of research dollars and expertise to this effort. Our goal is quite clear and will remain so for the next five years, and that is to help our clients demonstrate how their technology works in a predictive and correlative way using laboratory science. We are committed to doing this for our small molecule, large molecule, and gene and cell therapy clients.
Cade Hildreth: Interesting. Do you serve companies largely in the US, or are you global in reach?
Patrick Dentinger: We provide our services globally to all the major pharmaceutical development markets: Japan, Australia, India, Europe, North America, and Central and South America.
Cade Hildreth: Fantastic, you are global in reach. I will conclude with the most important question. How can people get in touch with you or learn more about ACF Bioservices and Absorption Systems?
Patrick Dentinger: They can find us at absorption.com or sales@absorption.com.