S3, E09: Retrogenix®: The Screen Door of Drug Development

Nick Brown (00:02):
We're also very aware that the regulatory sort of environment and demand for regulatory safety and patient safety continues to rise. And of course, this is absolutely critical that it does to make sure that when a patient takes a drug and a therapy, it's going to be as safe as possible. So we really have our ear to the ground really on this, making sure that we comply and really help clients get through, the drug developers get through, these regulatory procedures as smoothly as possible and so they have a molecule that's going to be as safe as possible once they get to that in-human trial and then into the clinic, hopefully as well. So the Retrogenix^® platform is really evolving to meet this ever increasing and ever expanding demand for more confidence in terms of safety standards for patients.

Gina Mullane (01:00):
As anyone in the industry will tell you, the journey of the drug developer is not for the faint of heart. For a drug candidate to finally reach market, it takes an average of 14 years and 2.6 billion dollars. But it's not just about staying power. Nine in 10 drug candidates never win approval, which begs the question who's developing the one in 10 and what is their secret?

I'm Gina Mullane and in this episode of Vital Science, Chris speaks with Nick Brown from Charles River High Peak about the early screening solution being used by the world's top 20 drug developers. We'll learn how the Retrogenix^® platform helps researchers gain valuable insights about their candidate, including potential off targets and safety and vulnerable populations before it ever hits the clinic.

Chris Garcia (01:53):
Nick, welcome to Vital Science. Pleasure to have you here. Can you tell us more about yourself and your role at Charles River?

Nick Brown (02:00):
Yeah. Thank you very much, Chris. It's great to be here. Thanks for having me. I am the group leader of the client services team here at Charles River High Peak. We are a site within the Charles River laboratories family based in the High Peak in England, in the UK, in between Manchester and Sheffield in the north of England to be precise. I have a masters in stem cell regenerative medicine from the university of Sheffield. And I also worked there for a time, looking into stem cell and advanced therapeutic development as well. So I have a background in biological sciences.

I then moved across into the sales and business development side of things for Retrogenix Limited, covering Asia Pacific and also North America as I went along my career. And now, as I say, group leader of the client service team for Charles River. Just as a note there, Retrogenix^® was acquired by Charles River Laboratories last year, and now sits within the Charles River family of technologies as mentioned.

Chris Garcia (02:58):
The Retrogenix^® technology provides the opportunity to generate a greater understanding of potential drug candidates. Can you explain to us how this works?

Nick Brown (03:07):
So this is a really unique platform and it's really exciting for the drug development and discovery community to use. So over 13 years ago, the developers of this platform initially identified targets, basically biological targets, that surround a human cell. And this was done using previous research literature reviews, so reading papers, and also using computers, bioinformatic analysis, to actually generate a list, basically, of these targets that cover a human cell.

These targets are common things that drugs bind to essentially make a response. So this is what drug developers use to influence a change and hopefully resolve an issue or a toxicity that's being developed in a human. So using this list of targets, we then identified a way to essentially represent each of these targets in a synthetic way using a laboratory setting. So without using animal models or humans, we can represent these targets synthetically and we can actually screen drugs and developing molecules and therapeutics over this platform where we have these individually represented targets. And this allows us to confirm that they're binding to the primary targets, what they're intended to bind to, but also potentially binding to something that could be a safety issue, so something that they're not designed to bind to as well.

And this library really covers a huge array of different human targets and allows us to really extensively and comprehensively screen molecules before they go inside humans or even inside animals as well, but for various purposes.

Chris Garcia (04:48):
And why is it important that researchers cast such a wide net at this early stage?

Nick Brown (04:52):
As mentioned, drugs and therapies typically have a target that will cause a therapeutic effect when introduced to the human body. Off targets are unexpected and unintended binding events to other things in the human body. So this platform really provides a tool that helps to check a therapy binds to what it's meant to bind to, and doesn't bind to any of these off targets, which could cause nasty side effects or issues further down the line. And these can vary from kind of minor side effects all the way through to major issues and even fatalities in some cases as well.

So it's absolutely critical that you confirm that the molecule binds to what it's meant to bind to for example, a cancer target, and doesn't bind to a normal target, a normal tissue target, or something that could cause an issue that you're not intending, a toxicity that you're not intending.

Gina Mullane (05:43):
Identifying precisely how a biological or chemical entity interacts with a human cell is fundamental to furthering our understanding of normal, biological and disease processes. It also reveals the mechanism of action of drugs and their potential for toxicity. The cell microarray screening provides a fast, accurate and effective solution for discovering the human cell surface and secreted protein targets of antibodies, proteins, viruses, and small molecules.

What's unique about Retrogenix^® is that it isn't discriminatory. It doesn't target specific tissues like heart or lung tissue. It can be used across therapeutic areas, screening test ligands, or binding against over 6,300 full length proteins that are individually overexpressed in human cells.

Let's hear more from Nick on one therapeutic area where this technology has been a game changer.

Nick Brown (06:46):
I think a major space that we cover is the cancer oncology space. So really these advanced therapeutics that it's absolutely critical that you make sure that they're safe and they're able to be applied to obviously usually very sick and immunocompromised patients who may have various forms of cancer. So some of these advanced therapeutics are starting to come into the clinic now, but as I mentioned, oncology is a very prominent area that we work in. But across the board, this platform can be used for various different indications and different types of drugs as well.

Chris Garcia (07:21):
Retrogenix^® offers one of the largest protein libraries. What is unique about it? And how does it enhance large molecule cell therapy, discovery and preclinical safety capabilities?

Nick Brown (07:32):
A key time that this library is used is in the preclinical space. So in a drug discovery and development program, you have various stages and, I guess, well, hurdles is a bit of a negative word, but various stages that a molecule has to go through before it gets to the end points, which is in clinic and being delivered to human patients.

So one area that we specialize in and we focus in is the preclinical development space, which is before the molecule has got into the clinical trials, which listeners may be familiar with. And this is where we start to test the molecule, how it actually interacts with humans and how it actually potentially affects humans positively and negatively. So it's important to gain as much data as possible in the preclinical stage, so that you're confident that the molecule can progress into in-human trials.

So we specialize in this preclinical stage and kind of we can be used as a final safety check before a molecule progresses into the in-human testing phases. So we can support other techniques, other more traditional techniques, but also in some cases, we can provide a potential alternative to other more traditional techniques as well.

So this platform doesn't use any human tissue or any animal models. In terms of ethical considerations, it's a very simplistic platform. It can be used readily and the lead times are low as well. So it's really accelerating the process in terms of getting that molecule to the clinic and to patients, which is obviously the goal of this drug development process.

Gina Mullane (09:11):
The Retrogenix^® platform also provides a powerful alternative to animal testing, which is in line with a philosophy embraced by the pharmaceutical research community known as the 3Rs. The 3Rs is an ethical framework for performing more humane animal research that has been embedded in international legislation and regulations, as well as the policies of organizations that fund or conduct animal research. According to the 3Rs, researchers should whenever possible attempt to replace the use of animals in research, reduce the numbers of animals in a study and, or refine processes to minimize harm to research animals.

Chris Garcia (09:53):
So Nick, it's clear that this technology is making a huge difference in the research community. What does all this mean for patients?

Nick Brown (10:01):
So this technology really allows drug developers to produce safer drugs and get them to the clinic and to the patients more quickly as well. This is particularly important, as I say, for therapies like oncology therapies, where you're dealing with very vulnerable patients, immunocompromised patients, but also for other vulnerable groups, it's important as well. So an example of how we're adapting the technology to cover more vulnerable patients potentially is the introduction of the prenatal protein library, which is a relatively new introduction. And we've essentially identified key targets within a certain developmental window of prenatal patients and we now overexpress these targets and include these targets in our platform. So this allows us to increase the confidence that when we screen a drug over them, before it gets in-human, the chance of an adverse off target interaction is lower and we have that increased confidence before it sees that in-human trial.

A good example of that is something called an antibody drug conjugate, which essentially combines the power of targeting with an antibody with a more aggressive payload, which is more of a traditional cancer therapeutic. With molecules like this, it's very critical that you have that targeting and make sure that it's hitting the things that you expected to hit. So, as I say, if that goes into a vulnerable patient, it could be a real issue.

An example of how we're addressing this as well is the prenatal protein library, which is a relatively recent addition to the Retrogenix^® platform. And this is where we've identified critical targets in a certain window of developments in a prenatal person, a prenatal mother. And we actually have covered these targets in our library now, so when we screen a therapeutic over our library, we're ticking off those targets and saying, "Your molecule does not hit these. Therefore, we expect the risk of targets to be low in our hands."

And this allows a greater level of confidence that these vulnerable patients can be included in clinical trials, because you already have that data there that says, 'Yes, this molecule is safe and it's able to be able to be taken by these vulnerable patient groups." So that's already happened with a drug that we know of. I'm sure there will be future drugs where this is also applied to.

Gina Mullane (12:27):
Because there are many ethical considerations to weigh for this vulnerable and scientifically complex population, pregnant subjects have traditionally been an underrepresented group in human trials. Safety is of utmost importance and the risks and benefits of treatment versus no treatment are closely scrutinized in clinical research design. By first conducting a screening with the Retrogenix^® platform, researchers can gain insight into the safety profile of their drug in pregnant women and potentially other vulnerable populations, giving them confidence in their decision when it comes time for clinical trials.

Chris Garcia (13:07):
We've talked quite a bit about clinical and preclinical research, but what impact does a screening library have on earlier stage therapeutic testing and their development?

Nick Brown (13:16):
So, so I mentioned previously that we have the different stages in the drug development process. I've talked about the preclinical stage and the sort of preclinical trial stage, which is the final tick as I described earlier. We can actually apply this platform at an even earlier stage than this. So before, typically a drug developer will start with thousands of molecules and whittle this down over time and over testing to a handful, maybe even one, and this will be the molecule that progresses into the clinical trial and then into the clinic if it's safe.

What we can do is actually apply this at the handful of molecule stage to check they're all safe, but we can actually apply it at an even earlier stage. So this gives a drug developers information even earlier to say which molecules are suitable for progression and which are safe. Again, safety being the key thing here. Which molecules are actually viable candidates to then progress into the later stages of preclinical testing, for example.

So really, the main goal is to knock out unviable candidates using our platform. You can say candidate A is safe, that's clean. Candidate B hits something you don't want it to hit, so we can get rid of that one. And so on and so forth. This can really reduce the time commitments for this testing, so again, this molecule can get through to clinic more quickly and start treating patients more quickly, but also just building up that understanding and that data set of each molecule is really valuable and it helps, as I say, drug developers to pick the best candidates to move forward with, and again, increase the confidence that they're going to be safe and efficacious once they get through to the clinic.

Chris Garcia (14:56):
And Nick what's next for the Retrogenix^® library?

Nick Brown (15:01):
Yeah. So we're always looking to be as comprehensive and high quality as possible. So really we want to give our clients and drug developers the best chance of spotting off targets at whatever stage that they decide to screen with us. So it's really this balance and this focus on both the size and how comprehensive the library is versus the quality of the library as well. So we want to make sure that what we have in terms of our targets are as high quality as possible and we don't give a set of data that's going to be confusing or challenging for people to interpret.

We're also very aware that the regulatory sort of environment and demand for regulatory safety and patient safety continues to rise. And of course, this is absolutely critical that it does to make sure that when a patient takes a drug and a therapy, it's going to be as safe as possible. So we really have our ear to the ground, really, on this, making sure that we comply and really help clients get through, the drug developers get through, these regulatory procedures as smoothly as possible and so they have a molecule that's going to be as safe as possible once they get to that in-human trial and then into the clinic, hopefully as well. So the Retrogenix^® platform is really evolving to meet this ever increasing and ever expanding demand for more confidence in terms of safety standards for patients.

So alongside the evolving industry and regulatory standards, there's also a ever expanding range of different types of molecules that drug developers are making to really increase and maximize how a molecule actually interacts with a patient and get that result that we're looking for in terms of treating the disease or the illness. So I mentioned a molecule type earlier in ADC, antibody drug conjugates, but there's also cell therapies, gene therapies, lots of other types of therapies that are more advanced. And from what we're seeing in terms of the initial data, actually showing more of a response in terms of what they're actually treating for these patients. So more of a response to cancer treatments, more of a response to other treatments as well.

So to be able to screen all of these new types of molecules again on the platform, really boosts how it can be used by the drug developers to ensure that these different types of molecules are all safe, or as safe as possible, again, before they're treated in patients as well. And of course, the amount of data that we have on these molecules is less than the more traditional types of molecules, so it's really critical that we have this data set using the Retrogenix^® platform, which, as I say, doesn't use human tissues or animal models, to really boost the confidence that they're going to be safe once they get into the final consumer, the patient, at the end of the day.

And finally, the great thing about being part of Charles River now, as I mentioned from the acquisition last year, we now integrate into the wider process and process map that Charles River has. So we have a huge array of different services and studies that we can perform for drug developers and we can take a molecule all the way from drug discovery and development at the very start, right the way through to the clinical trials and into clinic at the end. So we can really work with drug developers to make a molecule as powerful and as efficacious and as safe as possible. And the Retrogenix^® library and platform really fits very nicely into this workflow. Again, to make sure you have that confidence and de-risking that molecule before it gets into the patient at the end of the day.

Chris Garcia (18:36):
Well, from everything we've covered, it sounds like the Retrogenix^® platform and technology will do great things for drug discovery. Nick, thanks for spending some time with us today on Vital Science.

Nick Brown (18:47):
No problem. Thank you very much for having me.

Gina Mullane (18:49):
Nick Brown is group leader of the client services team at Charles River High Peak.

In our next episode of Vital Science, we'll learn about how Valo Health's human centric data and AI powered computation are expected to revolutionize the drug discovery process. If you'd like to help support Vital Science, you can rate and review our show on Apple Podcasts. And if you haven't already, please subscribe to our show on Apple Podcasts, Spotify, or wherever you download podcasts.

Do you have a suggestion, idea or a great story to tell? Share it with us at [email protected]. Also be sure to check out our sister podcast, Sounds of Science, focusing on innovation and trends in the life science industry. Thanks for listening to this episode of Vital Science. I'm Gina Mullane.