Analytical thinking: a focus on cell & gene therapeutic analysis

Absorption Systems works collaboratively with biotech and pharma companies. Dealing with their future therapeutics, the company’s analytical research services help customers streamline and simplify the approval process. Lu Rahman found out more from CEO Patrick Dentinger.

LR: Describe Absorption Systems’ analytical testing expertise in relation to cell and gene therapy

PD: As an analytical lab, customers provide us with what they believe will be their future therapeutic — in this case, viral vectors carrying a specific gene or cells that perform certain functions. These vectors and cells can exhibit potential variation during the development process, so the first step is to measure and quantitate the material so that we know if each batch conforms to the same descriptors. To do this, we delineate its particle size dimensions and take note of its surface markers, its stability, its response to freeze-thawing, etc. It is important that a company can consistently and repeatedly produce the same analytical results in order to ensure stability and secure regulatory approval.

The next step is to analyse the product to see if it successfully does what is intended. Taking gene therapies as an example, we look at the properties of the vector and determine whether it can deliver its contents into the cell. Then, once it’s inside the cell, we need to establish if it integrates into the cells’ machinery, produces the desired intermediates (e.g., mRNA), and generates a functional molecule (e.g., protein) that interacts with other proteins and/or functions as an enzyme or ion channel.

This whole process is rather challenging, and many of the analytical tools we use are now being pushed to their limits because of the level of scrutiny required to assure reproducibility. Because of the ‘newness’ of the regulatory scrutiny we now need, best practices around handling, processing, and characterising these materials are evolving. We at Absorption Systems pride ourselves on having the know-how and tools required to effectively analyse cell and gene therapeutics, providing our customers with a much-needed service.

LR:What challenges are associated with the analytical testing of cell and gene therapies?

PD: Unlike small molecules, cell and gene therapies are dynamic, being created from living systems that, upon entering a patient, can create a cascade of events which, in turn, go on to produce the desired effect. This mode of action is considerably more complex than that of the mechanism of small molecule drugs and is unlike anything else the industry has come across before. As more cell and gene therapies approach the market, the goal is to establish a body of evidence where standard operating procedures and best practices are established to the level of the small molecule space. At this time, the industry as a whole is still learning that there are a lot of unknowns, particularly as more drug developers look toward reproducibly, stability, scale-up and commercialisation of these cell and gene therapies.

LR: In what ways does Absorption Systems’ expertise help drug development companies navigate the path to market?

PD: In the cell and gene therapy space, there are several examples of established companies making good headway toward commercialisation. The majority of developers are either universities/ research hospitals, spin-offs, or start-ups. These organisations are research-centric and have a great understanding of the science of their therapeutic, but they understandably lack commercialisation experience. At Absorption Systems, we work across the boundary between research and industry and use our experience and expertise to help guide drug developers through to market.

A lot goes into preparing for regulatory review and approval. Understanding what testing is required and how and when to do it is essential. But it’s also essential to present your data in a way that convinces a regulatory authority that your data and processes are reliable enough for approval.

Absorption Systems has extensive experience and expertise in presenting complex experimental data detailing mechanisms of action within in vitromodels. For example, during the mid-2000s the FDA and EMA produced a guidance document calling for a detailed explanation from applicants addressing whether a therapeutic small molecule interacts with drug transporters — membrane-bound proteins that either allow uptake of a drug or prevent its entry. At Absorption Systems, we developed a whole series of stable transporter models in cell culture. These enable us to effectively evaluate a drug and establish its interaction with specific transporters. We can then consider whether a second drug uses the same transporter, giving rise to drug-drug interactions. In this fashion, we can establish a pattern and a series of rules that we can apply over and over again, providing the FDA and EMA with the quality data they need.

LR: What sets Absorption Systems’ capabilities apart from other competing companies?

PD: I think what sets us apart is our level of experience: we’ve been doing this for quite some time, starting in 1996. We have proven expertise in drug permeability, drug transporter, and gene therapy potency assay measurements, having developed advanced in vitro testing methods that help push the industry forward. These experimental approaches allow us to demonstrate that, when we test a small molecule or viral vector in vitro, the outcome is relevant to what happens in humans.

As further evidence of our continued commitment to creating predictive models for human outcomes, in the early 2000s, the FDA released a guidance document that provided an opportunity for companies to use cultured cells to replace in vivo bioequivalence testing, based on in vitro measurements of drug product dissolution, and drug substance solubility and permeability. If a company can demonstrate those three properties, the regulatory agencies will waive human bioequivalence testing, which has the potential to expedite product development. We have unparalleled knowledge in this area and have been successfully enabling clients to overcome the need for human bioequivalence testing since 2001.

LR: You work with customers to overcome complex barriers whendeveloping drugs. What are these barriers and how you are ensuring that they are being resolved?

PD: Up until the FDA guidance issued ca. 2001, it was necessary to test the bioequivalence of generic drugs in healthy human volunteers. These clinical trials are very costly and can cause timeline delays, resulting in challenges for drug developers. More worrying, though, was that cytotoxic cancer drugs and antipsychotic drugs also had to be tested on healthy volunteers, which is ethically unacceptable. So, in response, we developed in vitro tools as an alternative to testing in human subjects. Again, for our cell-based systems that predict a human outcome, the market is continually expanding, encompassing products such as topical medications delivered to the eye or the skin.

Effectively correlating laboratory bench work to human outcomes has been our business model since our inception, and today we are recognised in the industry for this expertise. This enables us to efficiently move clients through the FDA and the EMA, and that’s where our global recognition comes from.

In the coming years, we intend to carry this approach forward. We must continue to develop new techniques that are more predictive and clearly address the demands of the market. There is a constant need to push the limits; we have to look at the tools we have now and imagine how to keep making them better. Essentially, with our work so far, we have short-circuited the path to getting therapeutics into humans, and I would argue that this is not a trivial accomplishment.

LR: Can you briefly talk about any examples of how Absorption Systems has supported its clients to bring cell and gene therapeutics to market more rapidly?

PDI can’t talk specifically about most of our clients, but to get a flavour of the value we bring to our customers, you can check out our work with Spark Therapeutics for the development of a gene therapy for retinal degeneration. We supported Spark by working with them to create a potency assay, which is a key requirement ahead of commercialisation.

LR: What are the greatest challenges that you see drug developers facing in the cell and gene therapy space in the next five to ten years, and how is Absorption Systems preparing to meet those challenges?

PD: Again, one of the core challenges we will face is the need to develop more precise predictive analytical tools, and to optimise the way we leverage them. Inevitably, it will take time to collate and analyse the data from these testing techniques, and ultimately assess which approaches offer the most value and should be carried forward. But, with the wealth of promising clinical information we currently have, and the growing enthusiasm and resources flowing into the cell and gene therapy sector, we simply can’t turn back.

Additionally, with the majority of cell and gene projects focusing primarily on rare diseases, we need to find ways to overcome the difficulties of testing in incredibly small patient populations while enabling a fair return on drug developers’ investments and ensuring patient safety. What’s exciting now, however, is that we have several companies in late-stage clinical development targeting broader markets, and that can only help to bring more excitement and investment into this space.

As the outsourcing model of drug development continues to grow, CROs have a unique opportunity and responsibility to address several of these challenges. Having worked with a wide range of clients across varying projects for the last 20 years, Absorption Systems is well-positioned to develop and drive the testing innovation that the industry will require in the coming decade. With that expert know-how, we’ll be spearheading the effort to get the best treatments to those that need them the most in the shortest amount of time. That’s what this is all about.

Image: Alexandru Goman

Patrick Dentinger is CEO and Co-founder of Absorption Systems, where he has overseen consistent organic growth of top-line revenue and bottom-line profit for the last 25 years. He has an undergraduate degree in pharmacology from the University of California, Santa Barbara and has extensive experience in business development and licensing in biotechnology and clinical research. Dentinger was a 2002 recipient of the Ernst and Young Entrepreneur of the Year award.  






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