Need for Translational Methods in CNS Drug Discovery

Dan Barry:
Welcome to this podcast from Cambridge HealthTech for the 2017 World Preclinical Congress, running in Boston from June the 12th to the 16th. One of the key streams that we have for this year in the conference called Translational Strategies in CNS, and one of the Key Speakers that we have talking about that is Antti Nurmi, who is the Managing Director of Discovery at Charles River.

Antti, thanks very much for joining us today, I thought it would be very useful for our attendees to get a broader perspective of your role within the Charles River organization and some of the responsibilities that you have at the organization.

Antti Nurmi:
Thank you, Dan. It's a pleasure giving this talk with you.

My role at Charles River is to lead our CNS team, so we have decide is this focusing on various CNS disorders of neurology and psychiatry, and we are focusing on all the major neurological diseases that there is a drug development ongoing within the pharma and also in the biotech industry, and we are trying to provide the services to the industry but also to the academia, to understand whether these newly developed molecules or compounds or therapies for these devastating neurological and psychiatric disorders, what are the benefit they actually have in this space, and in here in Kuopio, Finland, we are about 110 people, we have fairly good presentation of long-standing neuroscientists on board, but also during this time this and technical staff who have been working on this CNS models for throughout their careers.

Dan Barry:
With your experience that you've seen within the CNS industry as a whole, how has it changed? How has the CNS drug development industry changed in the last two to three years?

Antti Nurmi:
I think that the field has actually changed quite dramatically, I would say from traditional pharmacology to first of all more to exploratory work, at least here in Kuopio, what we do here at our site, it is also, I would say that the theme of nowadays is that translatability and that's also one of the main topics of this upcoming conference as well, so one of the biggest problems in the field is really to understand that what is the translational value of, for example, animal models what we use here to develop these current therapies for this neurological and psychiatric disorders, and given the older, I would say failures in this CNS space that we have seen over the years. The past couple of years has really shifted also the focus on really understanding these therapeutic targets and also trying to address more specific questions than trying to address a larger disease as a whole, so, many companies are looking at this very specifically from particular angle to try to address these questions that you need to answer in these diseases in order to develop more effective therapies.

Dan Barry:
I assume you'll be addressing some of these in your presentation. You're going to be chairing and speaking in a session titled 'Implementing Successful Translational Strategies'. What do you kind of see as some of the key challenges that still remain when it comes to translating preclinical models in neurological diseases?

Antti Nurmi:
I guess it's when we are in the CNS space. I guess one of the criticisms that we often see in preclinical models, so now I'm talking about the animal models of diseases like Alzheimer's or Parkinson's, is that we are often times looking at the efficacy of the disease from animal behavior point of view and you can imagine that rodent behavior is quite far away from human behavior and, as long as you basically acknowledge that and understand those limitations that basically allows you to use these models to address certain questions, but of course you cannot interpret or translate your preclinical information from animal behavior point of view to clinical situations.

How we are trying to actually address or make the models more translatable is that we're applying certain technologies that are more closer to applications what you would actually use in human situations, so one of those technologies what we actually apply is imaging, and then we can use similar modalities, similar kind of end point in animal models as clinicians would use when they use MRI to look at specific brain lesions or white matter changes in a human brain, or we could use similar kind of head imaging, what you use in human patients to look at their, in certain pathologies you have for example certain changes in the set of receptor occupancies in human patients that you could look at.

We look at the similar kind of things in these disease models in rodents, so we're trying to make some sort of a bridge between the animal models and the human disease, and that's I guess one of the key things what we are trying to really bring this contra-translational bridge as far as we can actually do that, and that lack of translatability's probably the biggest problem what the field actually experiences at the moment, unless those bridges have been actually built.

Dan Barry:
And so do you believe that this is one of the key aspects of advancing CNS drug development to late-stage success? Do you feel the industry needs other things in order for it to progress and for Big Pharma to return big investments for this area?

Antti Nurmi:
Yes, I think the understanding first of all your therapeutic targets well, in humans, and then contra-translating that, or back-translating that, to the animal models is very important, so these are, I'm now mostly talking about my experiences, where my background comes from is the animal models of disease and not that much on the in vitro systems, or more simplified systems. I think that there will be much more weight put on computational systems, in silico systems, but also to use in vitro systems and especially this human-derived stem cell lines and things what there are simple but they have been derived more closer to resemble human tissue or human brain in this case.

So, these kind of things coming together will definitely drive also the development of future therapies, and I see that there's also companies, academia and an industry in general is going to invest more, I would say, more broadly to explore these alternatives also than the animal models that what have been traditionally been used or, I would say, traditional in vitro systems that have been used historically much more in the drug development space.

Dan Barry:
So do you believe that we have the right targets at the moment? Do we need new targets, new ways to develop new targets? Or is it very much a translational aspect is the bottleneck that this area has been struggling with?

Antti Nurmi:
I think that we need to have both, so of course because that we have such a powerful tool in terms of understanding the genetics also behind these diseases, so we definitely need to look for alternative, or new targets so to say, but at the same time we also need to be able to have better translatability in the tools what we have so that we could somehow maximize the predictability of our, basically, how successful we will be in the end in the process of having the drug on the market and I guess everything comes down to minimizing the effort, or essentially stopping your programs the earlier the better because it's a very time consuming and also expensive to do drug development, so the earlier you can make a decision whether you are going to meet your milestones or whether you will actually get a success, the earlier you can actually discontinue your programs the better you're off. So that is also one way of looking at it, is that you're trying to maximize your chances of success, having good, hopefully also good novel targets but also that if you will have a good translatable tools that you are applying in order to maximize your success.

Dan Barry:
I just also wanted to ask a little bit more about Charles River's involvement in this space, and maybe you could give me a little bit example of how things have progressed within the company, and really what your aim as a company is for people working within this space.

Antti Nurmi:
Charles River is a global organization, especially now I'm referring to Charles River Discovery, for which our site is part of. It's part of the global organization whose mission is to really be there on the frontline on developing therapies, not only in the CNS but in other therapeutic areas as well. Really be that the partner, and in the frontline to develop novel therapies for these devastating diseases that we have out there.

We have kind of a global commitment from our side to really be partners and participate, and be proud of being part of this process, to be there, to see these new therapies coming hopefully in the future. Also in the CNS space, which has notoriously been a lot of failures in our history, so we are really committed to be there, to support our sponsors or the industry, and also academia and in being involved with the academia also to understand what do we need to develop in order to make those drug development projects successful.

Dan Barry:
Is there any particular presentations or sessions within that conference track that you're particularly keen to attend, or excited to see some of the data coming out of that?

Antti Nurmi:
Yes, one of the big challenges what we encounter especially in the in vivo space, and of course this applies to the CNS drug development in a broader terms, is that the issue with the blood-brain barrier. So one of the limitations of various therapies of not being successful or not being efficacious, that they have a low penetrance in the CNS, and this means that basically the tissues that would need to have the drug in place do not actually get that because of the blood-brain barrier. So understanding the dynamics of the blood-brain barrier, how that works, how we can for example facilitate these treatments or therapies of passing this blood-brain barrier is very helpful and it would be beneficial for the field in general, so I'm looking very much forward to seeing that what kind of advancement has been actually made in a preclinical setting in understanding the animal models and how we could actually utilize that also to understand the things that are happening in human patients in these diseases.

Dan Barry:
Well, Dr. Nurmi, thank you very much for your time answering the questions that we had for you today. The blood-brain barrier conference will be part of the World Preclinical Congress, and there's been a popular package that we've been offering as well as the translational strategy in the CNS conference so, for those who are interested in the conference, please make your way towards our website, and Dr. Nurmi, I'd like to thank you again very much for your time and this afternoon.

Antti Nurmi:
Thank you, it was pleasure.

Dan Barry:
Thank you very much.