S2, E10: Drug Repurposing: Standing on the Shoulders of Giants

Gina Mullane:
Hello and welcome to another episode of Vital Science. Today is the second episode in our three part series on drug repurposing or investigating approved drugs for new therapeutic uses. In our first episode, we heard the inspirational journey of Dr. David Fajgenbaum, who repurposed a drug originally developed for kidney transplants to cure his own Castleman's disease. If you missed that episode, be sure to find time to listen. David's story got us thinking, if there are thousands of approved drugs on the market, many with the potential to be repurposed, how do drug hunters go about finding them? To get the inside scoop on this process, Chris sat down with two drug hunters, Charles River's own Ian Waddell, Chief Scientific Officer, and Vad Lazari, Director of Integrated Biology.

Chris Garcia:
Gina, before we get into my conversation with Ian and Vad, I wanted to say how inspiring it was to hear from David in the series' first episode, he helped us really understand the impact that a repurposed drug can make on a person's life.

Gina:
I totally agree, Chris. This is what keeps us and our scientists motivated every day, these happy endings that come from the work we do. But I think just as important are the sometimes complicated beginnings that get us there.

Chris:
That's right. And from what David said, repurposing is rarely a straightforward process. Remember, he's a patient, a clinician, and even a bestselling author. Even with all of that, he still attributes his success, to the experts and resources that he had access to.

Gina:
A lot of expertise in collaboration is required to bring a therapeutic, even a repurposed one, to market. I think this episode is going to be helpful for our listeners. As we trace a repurposed drug back to its origins, it allows us to pull back the curtain and really understand how does that initial idea come about? How do you know that it's even worth pursuing? How does scientists get from purpose A to purpose B?

Chris:
Those are all great questions, Gina. Let's dive into the episode to get them answered. Chris:
Hello and welcome to episode two in our drug re-purposing series. Again, I am joined by Barbara Killian from Charles River's discovery team. Barbara, super excited to have you back to continue our conversation.

Barbara Killian:
Thank you, Chris.

Chris: We are also joined by two of Charles River's drug hunters, Ian Waddell, Chief Scientific Officer, and Vad Lazari, Director of Integrated Biology. Ian, you've been a Vital Science guest before, but can you reintroduce yourself to our audience?

Ian Waddell:
Certainly Chris. I'm the Chief Scientific Officer in the Adelaide Discovery Parks of Charles River, and that is the park that largely does the discovery part of drug discovery. Prior to that, I spent 20 years working in large pharma, particularly in AstraZeneca, where I was a specialist in oncology, but I did do some work in cardiovascular disease as well. I left AstraZeneca in 2011 and joined a charity. Always in drug discovery, but I worked for Cancer Research UK for about seven years before joining Charles River, initially as the Head of Biology, but laterally as the Chief Scientific Officer.

Chris:
Excellent. Glad to have you here. And Vad, welcome to Vital Science. Can you tell us a bit about yourself?

Vad Lazari:
Thank you. Pleased to be invited. I'm Vad. I'm a Director of Biology here in Charles River. I've been with Charles River for about 10 years. My current role is I have responsibility for assay development and screening, including development of assays to examine repurposed drugs. Prior to that, whilst at Charles River, I was a project manager for a number of projects for the neurodegenerative condition, Huntington's disease. Prior to that, I worked at Pfizer doing both assay development and screening in a range of therapeutic areas.

Chris:
That's great. Thanks, Vad and glad to have both of you here. Barbara, in the last episode, Dr. David Fajgenbaum described how a drug approved for kidney transplants was repurposed to treat his Castleman disease and ultimately saved his life. That's truly an incredible story, but that's not a typical path to repurposed drugs. Right?

Barbara:
That's right Chris. David's story was an incredible story. It was an inspiring story, but not really a typical path. Others in the rare disease community have also been trying to repurpose drugs. As a matter of fact, just last week, the FDA announced it approved a clinical trial for a rare neurological disease, a mutation of the SLC6A1 gene, a disease that's so rare that OneOme says it doesn't even have a name. This mutation has been shown to cause some forms of epilepsy and has been found in some cases of autism.

But a neurologist discovered that a FDA approved drug, Ravicti, which was originally developed for metabolic disorders and has been used successfully in the clinic, that it may also relieve some symptoms of this mutation of the SLCA61 gene. The clinical trials start next month, which you can imagine is really exciting and hopeful news for these families. We're hearing more and more repurposing stories like this in the rare community. But Ian can you describe a typical drug re-purposing project? What are some of the reasons drug developers might choose a repurposing strategy?

Ian:
Certainly, Barbara. To be honest, though, there is no real typical path when we're thinking about re-purposing. What it tends to do is follow the signs. Very often it's a marriaging science in a particular indication or a particular disease setting. Perhaps I can use our collaboration with the PTEN Research Foundation, as an example. Now PTEN is something that's well-known to me in the oncology field as a tumor suppressor. But what we sometimes forget is that it's perfectly possible to have a sematic mutation in PTEN. Children who suffer from that mutation display a syndrome of different biological effects.

Now, our understanding of PTEN means that we have a hypothesis. That hypothesis is we think that by modulating either the PI 3-kinase pathway or the mTOR pathway, we will see beneficial effects. If that is the hypothesis, why reinvent the wheel when there are so many modulators of that pathway that are out there either in clinical trials or some even in patient settings if all we want to do is test the hypothesis? The plan is to test that hypothesis using existing compounds. However, whenever we start a repurposing, that doesn't always mean where we end up. But the benefit of taking a re-purposing stance is that you take a huge leap forward in terms of the drug discovery process, essentially standing on the shoulders of giants. They've done a lot of the hard work.

Barbara:
When you're working on a project, you're collaborating with someone, what prompts you to think that a repurposed drug could be the answer?

Ian:
Barbara, in most cases, it's following the emerging science. Very often when we read the literature around the disease setting that we're talking about, we find that there's a pathway or a particular target that has been looked up before. As soon as we see that, that makes us begin to think that repurposing might be a suitable pathway... Not necessarily to get the final drug, but to get us down so that we can actually test the hypothesis in a complex system as quickly as possible. The quicker we can do that, the quicker we can work out, whether a drug is going to be effective.

Chris:
Vad, we're learning it's not as simple as pulling an approved drug off the shelf at a local pharmacy. What needs to be considered when using an approved drug for another purpose?

Vad:
I think it really speaks to the examples that Ian gave. In terms of understanding both the science around the disease and the science around the drugs that you're looking at testing, the example that Ian used it potentially had an off target effect on a different kinase is a really good example. We're understanding that pharmacology and the biology of the disease gave a very rapid progression of a compound from one indication to another.

Other examples might include for when a drug needs repurposing, it needs a different dose, it might need a different route of administration. For example, for a disease which is a CNS indication, if the drug has a lot of potential, but doesn't get into the brain is there a way of reformulating it or re-dosing it so that it does gain to the brain in sufficient quantity?

I think all of those considerations give it both a deep understanding of the biology and the pharmacology, but also the science of drug discovery and development and how you can then apply all of that knowledge to rapidly move into the clinic.

Chris:
Ian, on our last episode David also gave us an example of thalidomide, which was a drug that was infamously used for morning sickness in the late 1950s. Then it was successfully repurposed in the nineties to treat certain cancers. Again, it's not as simple as taking that drug off the shelf at a pharmacy, but can you describe the work that went into altering that drug to reduce the negative effects?

Ian:
Thalidomide is actually a really interesting case, and it often surprises people that it's still very much in active use in certain cancer settings, particularly in hematological disease, but also in various skin diseases such as leprosy. It's only used under very controlled circumstances.

In order to explain how that came about, I have to talk about some fairly basic chemistry. As it was produced in the 1950s, thalidomide was a racemate. What a racemic means is it's actually a mixture of identical compounds. The easiest way to think about this is to actually look at your hands. Your right hand and left hand are identical in every way, except for one. That is that your left hand is a mirror image of your right hand. It doesn't matter how you contort, how you move your right hand, you can never make it look like your left hand.

Very often molecules that exist in nature... And it goes all the way from very simple sugars. Glucose, for example, has a left-handed version and a right-handed version. Nature loves an equilibrium. Whenever we have a compound that exists as an antimere, an antimere means what either the left hand or the right hand version, they exist in roughly 50/50 mix of the two versions.

Now, the interesting thing is long after the toxic effects were observed, it was discovered that a single enantiomer, so a single version of the drug had the teratogenic effects. The toxicity crowds the other hand, if you like to think of it that way, still had the biological efficacy. The drug that is used today is specifically purified to be a single enantiomer, so a single handed version of the original drug.

However, it's not as simple as that. As I said before, nature loves an equilibrium. As soon as you introduce a complex biological system, such as the human body, there is a potential for that single enantiomer to recreate a racemate. That is why, even today, there is no safe dose of thalidomide and it can really only be administered and used under very specific conditions and in very specific indications.

Barbara:
Wow. Ian that just goes to show how complex both the biology of the disease is, but also the complexity of these drugs that we're using to treat these diseases. It sounds like in some cases, in this one, it was dividing the two enantiomers, but in some cases when there is either toxicity or there is something that may need to be changed on a drug, I've often heard of that you've need to reinvent a drug. Can you explain a little bit of that to us? Why repurposing sometimes also includes reinventing?

Ian:
Certainly Barbara. Let me take you back to what I think both Vad and I mentioned earlier. Re-purposing is a fantastic tool to get us very quickly down the path in terms of drug discovery. I often use the phrase standing on the shoulders of giants, but that doesn't necessarily mean that it will get you all the way there in the sense of it will be right for the new disease setting or the new characteristics of the biological effect that we're trying to create. Very often, we've got to alter the compound to make it better in that therapeutic setting. That means that often we've got to add what we call an inventive step. It is not always at the pharmacophore so that is the bit of the molecule that drives the biological effect. Very often, it's about making the compound have a longer half-life or making it more lipophilic so it has better tissue penetration as we move to a different disease setting.

Barbara:
As we mentioned in the last episode, repurposing drugs can take five to seven years out of the drug development process, but that just shows that you're right. It doesn't take all the time away, but as you say, it really gives them a nice heads start.

Ian:
Absolutely.

Gina:
Ian provides some nice insight there. A repurposed drug may not be used in the same dose or even in the same form, and in the case of thalidomide, could require a lot of bench work to be reworked in a way that is valuable and safe in another context. It's a good reminder that repurposing isn't always as simple as it sounds. It's not as easy as just switching out a label.

Chris:
It always requires some level of innovation. In some cases that will mean looking at the drug through a different lens to see the potential of an off target effect. But in other cases, you'll need to reinvent the drug by possibly reordering the chemical components to achieve your goal.

There are also instances when the repurposing track is just the first leg of a journey, an efficient way to test the hypothesis. Often this allows researchers to fail faster in one approach before settling on another, which can be valuable in itself. No matter the outcome, there's clearly a lot of effort involved, even if, as Ian said, you're standing on the shoulders of giants.

Gina:
It also makes you wonder how did drug developers find these giants in the first place? Let's hear from Vad on how scientists go about identifying compounds that might be candidates for repurposing.

Chris:
Vad I learned that compounds are screened using something called a repurpose compound library. I incorrectly imagined bookshelves full of pill bottles, but what does a repurpose compound library actually look like?

Vad:
A repurpose library is essentially a small collection of drug or drug like molecules called compounds that are as well characterized as is possible to be. As Ian pointed out, a number of repurposing efforts have been with drugs that are currently on the market or variants of drugs that are currently on the market. As he correctly pointed out, this can shave a number of years off that discovery and development process, because a lot of the hard work has been done for you.

In terms of the repurpose library, it's a much smaller collection. Some of our HTS collections, which are much more varied because they're focused in on drugs or drug like molecules that are already proven to be safe, effective, have got known modes of action, and potentially some known off target modes of action as well... That process of characterization development of those molecules can be short-cutted.

Barbara:
As I said earlier, I've been following these repurposing drugs stories. The example I gave earlier was a drug for a metabolic disease that will be hopefully used for a neurological disorder. When you're trying to pull these libraries and choose which compounds to screen, is it typical to hunt for a drug that might be in a different therapeutic area, for example, a cancer compound used for a neuro screen? How do you choose these repurpose libraries?

Vad:
That's actually a really good example. We've just completed a paper published with CHDI, who are a Huntington's disease charity. It's doing exactly that. There was an observation made in Huntington's disease that there were effects in the DNA damage response in both patient derived cells and animal models of Huntington's disease.

One of the targets of the enzymes involved in a DNA damage response is a kinase called ATM. They were molecules that were published that were known ATM inhibitors, but the properties of those molecules weren't perfect. They weren't brain penetrant. They weren't quite post or selective enough. Through re-purposing we use the molecules that were available in the public domain to test the hypothesis and show that we were able to inhibit ATM and effect that signaling pathway. Through our chemistry and screening capabilities, we optimize those molecules to create the much more potent and selective variants of those ATM inhibitors that were potential therapies for Huntington's disease.

Barbara:
Wow. That's a great example of reinventing exactly what Ian mentioned before, the need to reinvent a drug when you find that hit. I can imagine some of the tools that you have available now that maybe weren't available before to help you with things like reinventing drugs. What other new technologies are out there that kind of helped you repurpose and reinvent these drugs?

Ian:
Barbara, one of the things I wanted to talk about was the use of artificial intelligence and machine learning. This is an area that both Vad and I, our working in. To be honest, it really has the potential to transform the way we do drug discovery, not just the way that we do re-purposing.

In the hope of not overly simplifying things, it's essentially the use of large datasets of either public or private data to try and make models that predict the biology in the therapeutic setting that we're interested in. Now, this can range from virtually fitting compounds into non-binding seeds, all the way to actually modeling how the compound will actually interact with pathways in a complex biological system.

At the moment where it's particularly helping in a re-purposing sense is actually looking for so-called off target effects, where the compound is doing something other than it was originally hypothesized. Now off target effects are extremely important because they could lead to toxicity. However, very often that off target effect is actually beneficial, and it's helping us understand where those beneficial off target effects might be... I think is driving repurposing.

Barbara:
That's so interesting, Ian, because I've never thought of off target effects as a positive before, but great example. Going to rethink the way I use that term. And Vad...

Vad:
Yeah, I would agree with Ian. I think the other area where artificial intelligence and complex model building will be more influential in the future is, is the opposite of that, which is the biology. With the PTEN example that Ian used early on in this discussion, the understanding of that pathway and the interactions, there are reasonably well known in the context of that disease.

Whereas for other diseases, for example, constructing that model and that pathway could be something that then reveals areas of biology that are able to be drugged. Therefore, we can then apply that model to identify targets that then we can run either high throughput screens or look for repositioned drugs that can influence that pathway. That can give us a really good early understanding of both the disease and also the potential pathways that we can influence to affect the pathology or the outcome of that disease.

Chris:
Vad, any other new technologies supporting drug repurposing projects?

Vad:
Yeah, a really good example of that is some of the advances that have been made in the field of proteomics and compound off target identification. As Ian and Barbara both quite rightly said, the identification of modes of action outside of that, for which a compound was originally designed as a drug, can be a really good lead into a re-purposing campaign.

Where we do see compounds that potentially are working in a disease model, but perhaps through some careful science, are not believed to be interacting with the target that they were designed for. One of the things that we can use is a proteomics assay where the compound is synthesized with a method of capturing both the compound itself, but also the protein target that it's bound to.

Then we can use our proteomics facility to identify that protein. By doing that, it gives us real strength that the off target is the more relevant one, but it also then tells us how we can then go about making a drug that's actually better for that disease and the original one that's been repurposed.

It's a kind of two-step process. First of all, identifying that compound that is the kind of seed to showing that the biology can be influenced by a small molecule, but then taking that small molecule, finding its real protein target, and then making a better drug for that disease or that condition.

Barbara:
So reinventing and optimizing?

Vad:
Absolutely.

Chris:
It sounds like AI and machine learning are proven to be game-changing technologies for drug repurposing.

Gina:
Yes. And a large part of drug hunting involves sifting through existing data sets to find the potential for something completely novel. Automating that process in some fashion can save scientists a significant amount of time.

Chris:
Time is something these patients often do not have. Shaving years off the development timeline for therapeutic can be life-changing, especially for patients living with a rare disease for which there is little or no treatment for.

Gina:
In the case of a global pandemic, scientists were racing against the clock to develop a COVID vaccine last year. An ANI was hugely helpful in enabling the re-purposing of existing compounds. Let's hear more on this from Ian and Vad who were directly involved in these efforts.

Barbara:
In the last episode, we also learned that over 400 drugs are repurposed to treat COVID-19 patients. I just want to ask the two of you, what lessons did you learn from COVID-19 re-purposing that you see maybe could be the future of global health? Any lessons learned that you take into your drug development?

Ian:
You're absolutely correct. That is something that the Vad myself and many of our colleagues at Charles River were involved in. Whilst it's true that there were over 400 compounds that were repurposed to treat COVID, one of the things we need to remember is that the vast majority have not and sadly will not be successful. When I say that, I actually do not see that as a failure.

Drug discovery is incredibly hard and what was really pleasing in the pandemic was that the global community actually came together and collaborated to fight the disease. For me that's the real lesson is what we can achieve when we work more collaboratively and openly.

One of the reflections I have is, I think back to being at a conference in 2019. We were talking about new modalities. One of the modalities that we were talking about was MRE as a therapeutic entity, but I'm not sure that very many of us were thinking that by the first half of 2021, hundreds of millions of us would actually have taken them.

When you think about either the Pfizer BioNTech or the Moderna vaccine in its simplest sense, that is exactly what happened. For me, it's all about working collaboratively and working faster to get therapeutics to patients quicker.

Barbara:
Yeah. Let's hope that continues. Vad, any lessons you're going to take?

Vad:
One Of the things that was really positive about the clinical trials that were run during the pandemic was the identification of agents that did work. Dexamethasone is a very good example where it treats the inflammatory condition caused by both the COVID virus and the body's response to it.

Identifying dexamethasone and sharing that information rapidly meant that it was able to be used to treat a vast number of patients. Also, by doing the trials in a correct manner and sharing data that didn't work. It meant the effort was then spared in treating patients with drugs that didn't work in favor of ones that did.

Barbara:
I was amazed how quickly and how widely all those results of those trials were shared. That's another collaborative effort of the openness of this data.

Chris:
Ian, I'll start with you as a drug hunter, What excites you most about drug repurposing?

Ian:
It's actually exactly what Barbara just said. It's about working collaboratively. It's following the emerging science, working collaboratively to speed up the whole drug discovery process by not constantly reinventing the wheel.

Chris:
That's great. And VAD...

Vad:
I think it's the speed at which we're able to potentially help people. Also, knowing that there are a number of diseases where there are no known treatments being able to apply that knowledge to try and help people

Chris:
For me, what I learned and was excited most from our talk today was really standing on the shoulders of giants. Ian, what you said about getting that head start, and again I love the fact that through the pandemic, the collaboration that we've seen globally of lessons learned as has really helped accelerate, whether it's a vaccine or a therapeutic to help us.

I want to think Ian, Vad, and Barbara for their time today. I really hope our listeners learned a bit more from this episode about how drugs are repurposed by our drug hunters.

Ian:
Thanks, Chris. I really enjoyed the conversation.

Vad:
Thank you very much.

Barbara:
I look forward to our next episode.

Gina:
Thank you Vad, Ian, and Barbara for grounding us in the science behind repurposing a drug. As we learned today, the road from purpose A to purpose B is rarely as simple as applying the same route and dose to a new disease. First its potential must be recognized. Then only through innovation, resourcefulness, and troubleshooting is it able to be re-imagined as a repurposed, but wholly unique therapeutic. Not an easy process to be sure, but the payoff is worth it.

In reviewing the groundwork that's already been laid scientists can leverage existing research to push their drug development forward in a more efficient ways. Repurposing allows researchers to learn from fellow drug hunters and to sidestep avoidable pitfalls in bringing treatments to market more quickly. As Barbara mentioned in this episode, one drug that was being used to treat metabolic disease is now being repurposed in the clinical trial for a neurological disorder. This condition is so rare. It doesn't even have a name.

Imagine the potential we would have to treat human disease if we could find ways to pool our collective expertise and make it easily accessible to researchers. This is why many individuals in the field are focused on developing tools to facilitate drug repurposing and enable collaboration among drug hunters across the globe.

Among these trailblazers is Sanath Ramesh, a tech engineer and father working to help his son as well as other families who are battling a rare disease. Next episode, Sanath will tell us more about his personal quest for a cure and his inspiration for open treatments, the new platform he's developed to support others in their re-purposing journey. Until next time. Thanks for listening.