S2, E09: Can a Repurposed Drug Be the Answer?
About This Episode
What if the cure for your untreatable disease was just waiting on the shelf at your neighborhood pharmacy? Join physician, patient, and researcher Dr. David Fajgenbaum as he shares how his unexpected battle with Castleman disease set him on a journey to find his cure and develop new ways of using existing drugs. Learn how his experience is being applied to severe cases of COVID-19, and explore drug repurposing as an accelerator for the drug development process.
Gina Mullane (00:05):
Hello, and welcome to another episode of Vital Science. Today, we begin a three-part series on drug repurposing. For those not familiar with the term, drug repurposing is the investigation of existing drugs for new therapeutic purposes.
There have been many success stories of drug repurposing. Perhaps the most well-known is Viagra. Originally developed for the treatment of hypertension, clinical trials revealed other surprising benefits. More recently, you have probably heard about existing therapies that have been used to treat symptoms of COVID, and we'll hear about that a little later.
In these cases, physicians feel there is enough data and incentive to try therapy approved for one indication to treat symptoms of other conditions. Both common and rare diseases can benefit from so-called off-label prescriptions. But the process for matching therapies with a wider range of targets is complicated. When the clock is ticking, typically researchers hunting for treatments look to drugs already approved to accelerate the drug development timeline.
There's a lot more to this topic, and what you'll hear today is really just the tip of the iceberg. In this episode, Chris sat down with Dr. David Fajgenbaum, whose inspiring story covers the who, the what, and the why of drug repurposing, and challenges us all to turn hope into action.
Stricken with an episode of life-threatening illness halfway through medical school, David struggled to find an accurate diagnosis and treatment for his condition. I'll let him explain what happened, but the fact that he's here talking to us after five near-fatal relapses of Castleman's disease is a testament to his refusal to accept the status quo.
Dr. Fajgenbaum accounts his journey in an autobiography called Chasing My Cure, which is a fascinating read, if you want to dive deeper into the details. You'll find the links in the show notes.
We'll also hear from our guest, Barbara Killian, Charles River's senior product manager in discovery, whose knowledge of complex biology and discovery platforms will help us to understand the concept of repurposing from a contract research perspective. With that, I'll turn it over to Chris.
Chris Garcia (02:20):
I'd like to welcome to the Vital Science podcast today Dr. David Fajgenbaum, assistant professor of medicine at the University of Pennsylvania, founding director of the Center for Cytokine Storm Treatment and Laboratory, and author of the bestseller, Chasing My Cure; and Barbara Killian, from our discovery division at Charles River.
Barbara, we'll start with you. Can you give us a quick overview of your work at Charles River?
Barbara Killian (02:42):
Hi, Chris. I came to Charles River about three years ago to manage a portfolio of services for the discovery team. These services are at the early stages of drug development: identifying targets, validating targets, optimizing compounds, to ultimately lead them down the pathway to become drug candidates. Most recently, my focus has been on rare disease, helping to connect patients with our scientific network.
Thanks, Barbara. And David, you were a patient, and now you are a survivor and author, a physician, a scientist, and a drug hunter, and we're going to get into each one of those items in more detail today, but let's start from the beginning.
David Fajgenbaum (03:22):
Sure. Well, thank you guys so much for having me. It's really a pleasure and honor to be with you all today. So, yeah, I went from being this healthy third-year medical student. I was training to become an oncologist in memory of my mom, who had passed away a few years before from cancer, to out of nowhere becoming a critically ill patient myself. I was hospitalized for months and months, much of that time without any diagnosis. I was eventually diagnosed with a rare disease, and received many rounds of chemotherapy to save my life. Even had my last rites read to me at one stage, before eventually learning that I would not survive unless I got involved in searching for a treatment that could save my life.
And so, I went on a journey. You mentioned author. My journey was Chasing My Cure, which I described, and it's really this process of trying to find something that could save my life, eventually finding something that could save my life, and then realizing just how important it is that we spread this approach of what's called drug repurposing to other conditions. And so, now I really dedicate my life to chasing cures for other conditions, and for other patients.
Yeah, that was a good summary of the book that I read. And it's a complex journey, right? From finding your symptoms, to being diagnosed, to really uncovering and finding a repurposed drug. Walk us through that.
Sure. You're right, it has been a complex journey, and there were a lot of ups and a lot of downs. For me, I was first started on an experimental drug, a drug that we all hoped would be the treatment for Castleman's patients, and that it would be effective for all patients with my particular rare disease, called idiopathic multicentric Castleman disease. And unfortunately, that drug didn't work for me, and I knew that there were no more drugs in development, and there were no more promising leads. And my disease is a very deadly condition. About two-thirds of us will die within 10 years of diagnosis.
I knew that I was not going to survive unless I found a drug that could save my life, but I also knew that I didn't have the time or the money to develop a drug from scratch. That my best bet, my only bet at survival was to better understand what was happening in my immune cells, what was actually happening when my disease flared, and when, in Castleman's disease, your immune system basically attacks your vital organs and causes multi-organ failure.
And so, what was causing those immune cells to get out of control? What, maybe, was going on within those immune cells? And then, I could ask, well, what drugs are already FDA approved that can fix the problem?
Over the course of months, and you mentioned you read Chasing My Cure, I think you said, in record time. I think you mentioned five and a half hours, which I actually do think is the fastest I've ever heard anyone read this book. But of course, the five and a half hours that you read really was years and years of hard work summarized into just a few pages.
But over the course of the years of work, I did eventually find a drug that's been around for decades, that I decided to start to repurpose to save my life, and here I am today.
David, I as read your book I could feel your sense of urgency. You described your life as living on overtime. Can you talk us through what you mean by that?
Sure. I mentioned earlier that I had my last rites read to me when I nearly died the first time from my disease, and I've gone on to unfortunately nearly die four more times. I've really considered that first time that I almost died to be the start of my overtime, and I think all of us are aware, overtime is a time in a game that you didn't think you'd have, so it's extra time. But it's time where every second counts, and you know, you can make a mistake in the first quarter of the game and make up for it, but if you make a mistake in overtime, then that it's it. There's just this incredible urgency that comes with being in overtime.
And so, ever since I had my last rites read to me, I felt this real sense of urgency, that things have to happen now. And I think this has really translated a lot into the way I think about drug development, and just realizing that I think we can all assume that probably all diseases that we currently think of and know about will probably be cured in, let's say, 1,000 years. But that isn't terribly helpful for all of the people with diseases right now.
So, it's not about recognizing that, okay, well, someone's going to figure it out sometime, so let's just kind of keep dealing with the status quo. It's like, yeah, but that's not fast enough. It's not fast enough for me. It wasn't fast enough for my mom. My mom passed away from brain cancer when I was 19. And we have to figure out ways to be faster. It's not about if, but when. Because, like I said, these diseases, they're all going to get cured in the next 1,000 years, but how can we make sure that it's not in 1,000 years? How can we make sure that it's in five years, or five months, or five days?
And so, I think that that sort of urgency, it just became so real. I think all of us in medicine, we all want solutions as quickly as possible. But boy, does it become real when your clock is literally ticking, when you're like, okay, I'm going to relapse, and if I relapse in the next few months for the sixth time, and I'm approaching the lifetime max of my treatment, and there are no more options, I'm going to die, and I'm not going to have another shot to find another drug for me, or find drugs for anyone else with my disease, or other diseases, so I better get going.
And I think that that urgency has been so critical to the progress that we've made, because in medicine, there are so many ways to overthink, and to talk yourself out of and into a lot of different scenarios for why one drug is going to work, or another drug might work. But I think sometimes you've just got to figure out, what is the most effective and efficient path forward to identifying treatments that could be life-saving, and for me, that sort of time constraint gave me real clarity.
And I should mention that, too, when you hear the concept of overtime, I think a lot of people say, oh my gosh, that must be terrifying, and how do you even decide what you're going to do every day, if you feel like you're in overtime? And they're right. I mean, it is scary to be in overtime. It is terrifying. But for me, my life really changed when I was able to turn from overtime being scary to overtime being clarifying. To say, okay, my clock is ticking, my time is limited, so rather than being afraid and not sure what to do today or tomorrow, I'm going to use that to help me to have some clarity around what do I need to do? What is the most important thing for me to do today, tomorrow, and the next day? And then, as we discussed earlier, then just start doing.
As Dr. Fajgenbaum mentioned, Castleman's disease is a rare disorder of the immune system. Its cancer-like features and lymph node involvement have long made it difficult to diagnose, but David's investigations, in collaboration with the leading Castleman's researcher, Frits van Rhee, and others, have led to established diagnostic criteria for the multiple forms of this rare condition.
Idiopathic multicentric Castleman's disease, David's form, is the most deadly, involving numerous lymph nodes that mobilize the immune system, releasing proteins called cytokines that attack the body's major organs all at once. As with cancer, treatment with intensive chemotherapy can help shut down the cytokine storm, but chemotherapy itself has its limitation, and it's not curative.
We use the term idiopathic to describe the fact that Castleman's origins are unknown, and David continues that despite ongoing research, we still haven't pinpointed what activates the immune system. As we've heard, Castleman's is episodic in nature. David has successfully survived five relapses with chemotherapy and drugs that are currently on the market, but there still isn't a cure that works for everyone, and you'll soon hear the relapsing, remitting nature of the disease makes research challenging.
And like you said, I mean, time is ticking. According to the book, you had five of these episodes, which again, each of those could have been the deadly one. The drugs that you were being tested on, you have to be under the condition. You have to have the symptoms up here, right? It wasn't like something you could just test as is. You have to be having the symptoms of Castleman's to be able to test the drug.
Exactly, yeah. To be able to be able to get a sense for whether the drug was really working or would work, you would need to test it in the midst of one of these relapses, and these relapses are frightening. So, basically, my immune system becomes hyper-activated, and then starts to attack all of my vital organs. And actually, it's called a cytokine storm, and up until about a year ago, people would look at me funny when I talked about cytokine storms. I run a center called the Center for Cytokine Storm Treatment and Laboratory at Penn.
But unfortunately, the whole world has been introduced to what a cytokine storm is through what happens in the most severe COVID-19 patients. So, COVID patients get really, really sick, the ones that are in the ICU, they're experiencing a cytokine storm. Their immune system is out of control, and in an effort to control this virus, it ends up destroying the whole body. While in Castleman's disease, we don't know why the immune system has gotten started in the first place. There's no evident virus that we could fine, but the immune system is just totally out of control, wreaking the same havoc that we see in sever COVID-19 patients.
So, that, I think, can probably help you get a sense for what's happening when I'm having these relapses, and you're exactly right: getting those precious samples, and for me, banking on my blood samples, banking lymph node tissue, bone marrow, I knew when I had this fifth deadly flare that I was running out of time, out of options, and the only way that I could possibly survive was if I could bank those samples, put them in the freezer, and then if somehow I was lucky enough to survive, then I could go back to those samples and start running experiments on them, and see if I could find something that could save my life.
David, it's amazing that your work with Castleman can be applied to COVID-19. Are there any other repurposing stories you can share?
Sure. There are a lot of examples of drugs that were developed for one indication, and were eventually tested and tried in another disease area. Not enough, as you've heard me say throughout this podcast, but there certainly are some really good examples. One of my favorite examples is a drug called thalidomide. Thalidomide was originally developed for morning sickness for pregnancies back in the '50s. What happened was just tragic. It turned out that thalidomide causes horrible birth defects, so countless children were born missing limbs because of thalidomide, because it was given to mothers for morning sickness.
Now, the reason I say that this is an important example of drug repurposing is because decades later, a researcher in Little Rock, Arkansas figured out that thalidomide, this awful drug that no one wants to touch with a 10-foot pole, is actually a lifesaving treatment for multi myeloma, one of the most common blood cancers, and it has gone on to get approval for multi myeloma and literally save tens, maybe hundreds of thousands of lives of cancer patients. And of course, this drug, thalidomide was developed morning sickness. It turned out to be the worst drug you could ever imagine for morning sickness, but it went on to become this lifesaving drug for cancer, just highlighting again that drugs approved for one thing can be lifesaving in other ways.
And of course, the drug I'm on, Sirolimus, was developed for kidney transplantation 30 years ago. It suppresses the immune system by inhibiting this one part of the immune system, and that works really well to prevent your immune system from rejecting an organ like a kidney, but it also saves my life with Castleman disease, which is a disease where the immune system is out of control, as well. So, we can't just focus on what one person decided, or one company maybe decided the first disease is for a drug to be used in, and we need to keep an open mind that just because that drug hasn't yet been tried for the disease doesn't mean that it won't work.
I mean, I can tell you that I was a medical student when I first got sick with Castleman disease, and when my doctor explained to me that there were no more drugs in development, and that there were no approved drugs, I assumed that meant that there were no drugs that could be effective. But it wasn't that there weren't drugs that couldn't be effective, it was just that they maybe hadn't been tried yet. And so, I think that's a frame shift that we need to get into, which is we recognize that just because there's nothing currently available that's known to be effective doesn't mean that there isn't something currently available; we just don't know that it's effective yet.
As you might imagine, battling a disease for which there is no cure creates a definite urgency to find a therapy that might work to treat symptoms or reverse a condition. Traditional drug development follows a typical arc of identifying a target for therapy, identifying compounds or biologic molecules that act on that target, then putting the candidate through its paces to assure its efficacy and safety. While robust and usually well-funded, this approach can take years of time that patients with rare diseases just don't have, and as David points out, limited patient pools and sample sizes can make it difficult to confirm whether a therapy works.
Repurposing takes advantage of drugs that have already been approved for other indications, often shaving critical time off the process of testing. In this next segment, you'll hear about the different approaches to discovering repurposed drugs, and learn why identifying new uses for existing therapies is so important.
And with time ticking, I mean, for your disease, for COVID patients, for other rare diseases, you mentioned drug repurposing. Thousands of FDA drugs are approved right now, so any one of those could possibly help another disease. Barbara, I'm going to turn to you. Can you describe a classic drug repurposing screen?
Sure, Chris. There's many different paths to finding a repurposed drug. One is high-throughput screening, or we call it HTS, and the first step of any screen is to identify a target for that drug. What molecule, protein or pathway can be impacted to induce some kind of therapy with that? A common example of this is to measure changes in something like kinase activity. This new acid that you've developed us then run against what we call a compound library. For a repurposed drug, that compound library will be made up of hundreds to thousands of drugs that have already been approved by the FDA, or sometimes even drugs that made it pre-clinical, but for some reason never made it to market.
So, during these screens, any of these compounds impact the cell. In this example, let's say the enzyme activity went up. That's considered a hit. What we'll then do is take those hits and move them along the drug development pipeline. Now, with the repurposed library, the advantage is, those hits have already gone through the drug development process, so we have a lot of history with them, a lot of data, a lot of characterization, so there's a lot of work that we don't have to do, and we can take time out of the drug development pipeline. It's been said, from these repurposed libraries, having that data from the hit can allow us to take 5-7 years out of that drug development time.
It may sound simple, but the more complex the disease, the harder it might be to find a target, and also the harder it might be to develop an assay. But the principle is the same for all screens: you identify target, you develop an assay, you run the screen, you find a hit, and you move the best hit along the pipeline. With a repurposed library, these hits have been well-established. That could really speed up drug development.
So now, David, your approach is a little different, but it was the same in theory. I'm sure it helped that you have samples from your last infection to use for your screens. Can you tell us how you used those?
Sure. So, yeah, at the end of the day, I think that we're all shooting for the same thing, and that's that every drug that's approved for one thing, or one disease, should be used for every other disease that it could be helpful for. But of course, when you develop a drug for a condition, you don't know all of the other conditions or diseases that might benefit from that drug unless research is done.
And so, one way to figure out additional uses for a drug that's approved for one thing is to do a high-throughput drug screen, just like you described. Figure out some sort of a readout for what you're looking at and testing in the dish, throw drug on, and see if that drug does the thing that you're hoping that it does. That's a really important approach. You don't really know what drugs are going to work in a certain way, and who knows, maybe a drug that you never even anticipated can work, and maybe it does in this particular cell line, or in the dish.
Another approach, maybe you call a little bit more of a focused approach, or a translational approach, is the one that we took, which is where you do really in-depth profiling of human samples. So in our case, we had as many blood samples and lymph node samples from me as I could. And you do what's called multiomic profiling. We've all heard of genomics, but there's also transcriptomics and proteomics, so tools to basically characterize what's going on in those cells. For me, we did serum proteomics. We measured all the proteins in my blood. We did something called flow cytometry, looking at various immune cell populations. We measured a bunch of what are called cytokines in my blood.
And when we pooled all that information together, we utilized some new tools called pathway analysis tools, where basically you ask the data, what are some almost themes in the data? What are some insights you can get from all of this data you just generated? And these tools will give you a sense that maybe there's a particular signaling pathway or communication line in your immune system that's turned on, or maybe there's a pathway that's turned off.
And in my case, we found that there was a particular communication line in my immune system that seemed to be turned on. It's called the mTOR pathway. MTOR is really important for immune cells to proliferate and to get activated. And so, it kind of made sense. We said, well, my disease is a disease where my immune system gets out of control, and all of this data, when we crunch it, it tells us that maybe this one particular part of the immune system is turned, and that's really what I would consider a hit, just like Barbara mentioned.
But that hit is only so helpful. You need to progress these hits. And so, for us, we then went forward and went to my lymph node tissue, and we confirmed it. We did a validation experiment where we said, okay, the data is telling me that this particular communication line is turned on, but I'm going to go into my tissue, I'm going to run an experiment to ask, is it actually turned on?
And so, we did that, and when we confirmed that this particular part of my immune system was on, we then said, okay, well, what drugs exist that can turn this thing off? If the thing that's on is called mTOR, is there an mTOR inhibitor out there that could maybe turn this off, and maybe that could be helpful. And thankfully there is, and thankfully this drug's been around for decades, and so I found out about it, and I said, all right, we're going to try this.
So, it's an approach where basically, you're figuring out what's wrong, and then you say, well, what drugs can fix it? Versus the approach that Barbara described, which is basically, we're not sure exactly what's wrong, but let's throw every drug you could ever imagine at these cells, and see if they change the cells in a meaningful way, or correct the problem in some way.
There's a third approach, too, that's gaining more and more attention, and that's an artificial intelligence-driven approach, where you use AI and machine learning to basically look across the literally millions and millions of published papers to look for connections between the published literature that can maybe suggest that a new drug, or a new pathway or communication line could be important to one disease or another. It basically asks the question, maybe a drug like mine, Sirolimus is effective for a disease like Castleman disease, but as humans, we would have to read millions and millions of papers to find this related disease that would connect to Castleman's, but you can use machine learning to try to do that for you.
So, I always think about drug repurposing, and everything I do, try to kind of turn into a system, and in particular, when I think about drug repurposing, the first part of the system is, how are you going to find that hit? And any one of those three approaches, the approach I described, the one Barbara described, or the artificial intelligence approach, is going to give you a hit. But once you have a hit, in order to move it forward, you need to validate it in some way. You need to do an experiment in the lab to confirm it, and then you need to continue to move it down. So, maybe you need to give it to a human. Maybe it needs to be first in human. Maybe you need to do a large, randomized controlled trial. But there are a number of steps that have to be followed to move this idea forward.
And you really had the benefit of using diseased cells. We don't always have that benefit for some diseases, so the fact that you were able to save your samples and use them for your own screen like that, that was such a time saver, I'm sure.
Absolutely. I mean, I think frankly, if I had a disease that I wasn't able to get my hands on readily, and then get a drug into me quickly to test, I just wouldn't be alive today. We wouldn't be having this podcast. Chris wouldn't have read my book in five and a half hours. None of that would be the case if I had not been able to get my hands on my samples, and then start testing the drug on myself, just in a matter of weeks, actually, from starting the research, and then now, here it is, over seven years in remission.
A remarkable story, to be sure. It would seem that the most advantageous approach to repurposing drugs would be some combination of traditional screening, the multiomics analysis that David mentions, and insights drawn from artificial intelligence. When you consider the complexity of biology, and the multiple layers of activity that could factor into disease, tools like bioinformatics, or the mining and analysis of vast datasets, and artificial intelligence, can help us make the most of the sample data we collect. In fact, as a discrete discipline, bioinformatic analysis of genomic, proteomic, and transcriptomic data is gaining traction as a powerful tool for novel drug discovery, as well. Barbara asked David about his experience in this realm.
We kind of touched on this, but I've been in this field quite awhile, and I've been amazed how quickly new technologies are adapted when they've been proven successful, and we're now in the middle of a new technology boom with bioinformatics. I can imagine, in the years just since you've been doing this program, this boom has helped your research. So, you described it a bit, but how else has bioinformatics changed the way you shift your data?
You're totally right, it is such a game changer. When you do something like serum proteomics or transcriptomics, there are so many genes and proteins that are just incredibly different from one sample to the next, and to try to figure out, is the fact that there's increased expression or levels in one sample versus another, is it meaningful, or is it just random chance? Is there something about that sample? Is there something about the way that it was processed? There's just a million reasons why two samples might be different.
But the power of bioinformatic tools is to ask, is it more different than you would expect from random chance alone? And so, you can start to get some percentages, or some probabilities that the things you're finding to be different are real differences that maybe are meaningful. And you can go even further. There are these amazing database of information about drugs that are known to increase or decrease the expression of one gene or another gene.
And basically, it's so much information at such high dimensional levels that no human brain could wrap one's head, or at least my brain certainly couldn't. I don't know, maybe there are others that could. But no human brain, I believe, can really wrap their head around the countless dimensions of information around the way that certain genes function with other genes, the way that proteins interact with other proteins, and the drugs interact with those proteins and genes. It just, it's really impossible to wrap your head around.
But that's where these tools become so powerful, because if we can generate the data, and then we can ask the right questions, we can utilize these bioinformatic tools, then we can gain insights that can literally save lives, and of course, I'm just one example of it.
Those screens can give us so much data, thousands of data points. Multiple hits, some strong, some stronger than others. Which one would have the most promise. So, using bioinformatic tools to analyze data, that alone can take so much time out of the drug development process, and maybe there's some other steps that we can apply bioinformatics to, as well.
I totally agree, and I think, I mean, this first... you don't get a drug to save someone's life until you get a hit, and so the first thing, you need a hit. But there are way more hits than there are drugs to save people's lives. And so, this is step one, and you want to be nimble, you want to be quick on figuring out what looks promising, what's a hit, or what is a candidate.
And then, you need to be incredibly rigorous with pushing that candidate forward, and saying, okay, it looks promising in the dish. It looks promising in my hands. But let's see what happens as we progress this forward. Can we validate this hit. Does it really look like it's going to stand the test of time? And then, can we give it to humans? What happens when we give it to humans? Maybe it's already been given to humans with that disease. Is there some data we can get our hands around to see how patients did?
And that sort of data is really important, because that gives us a sense for, does it make sense to move this drug forward to a large clinical trial? And then we do. Then we do move it forward to clinical trials. So, it's this very translational program, and you can tell. I mentioned a number of different things that we do, and of course, we have a number of people that are involved in each one of those things that we do, and of course, we wouldn't be able to do it if I didn't have an amazing team.
It's also interesting that you say when a doctor does it off-label, then you move into clinical trials. That what works for one patient isn't going to work for all patients, and there needs to be continued studies on those compounds.
Yeah, I think that we've learned, COVID has been just awful in every possible way. However, and it's weird to say however after saying a statement like that, but I'm hopeful that there are some important learnings that we can take from COVID as a medical system. I mean, one of them is that there's been a tremendous amount of drug repurposing. I mean, there literally have been over 400 different drugs given to humans with COVID to try to treat COVID. Hundreds. Over 400 have been given. And we've heard about some of the successes, like dexamethasone. It cuts mortality rates by a third if you're on a ventilator. It cuts your mortality by 20% if you're in the hospital.
But then, we've also heard about ones that were not so successful, where many folks got really excited about a drug from really preliminary, early data, drugs like hydroxychloroquine, which didn't actually turn out to be effective when large trials were done. There have been 18 different randomized, controlled trials looking at hydroxychloroquine, and only one out of 18 have shown a benefit. And so, it shows to go that drug repurposing is promising and important, and it's literally saving tens of thousands of lives of COVID patients, but it has to be done right, and it has to be data-driven.
And where does all that information sit, that others have access to it?
For COVID, it didn't sit anywhere until we launched the Corona Project, and for just about every disease, there isn't a central place that keeps track of this. But back, March 13th, you'll probably remember, Friday the 13th of March last year was when the US really shut down because of COVID. And I found myself that night, I was sitting next to my wife and my daughter, and we were watching the news. They actually were both asleep, and I was hoping so badly that some researcher somewhere would follow the steps that we've taken for Castleman's and apply it to COVID. And then, I was thinking to myself, I hope that they read our papers. We've written about how we profiled the immune system of Castleman's patients, and we found drugs. I hope that those researchers will even read my book and know the steps that we went through, follow our blueprint.
And then, about a minute later, I was like, wait, why am I hoping that some research somewhere follows our blueprint of drug repurposing? Maybe we should just do it. I mean, we've spend the last almost decade trying to understand why the immune system gets out of control in the context of Castleman's, and now it's become very clear that a very similar set of circumstances occur in COVID.
And so, we started the Corona Project. It's currently the world's largest database tracking drugs being used for COVID-19. It's primarily focused on drugs given to humans with COVID, but we also are beginning to expand it into preclinical data, so when drugs are tested in a lab. The idea is that you need to have in one place all of the data on drugs that have been given to humans, whether it's in a clinical trial or not in a clinical trial, and you need to be able to synthesize that in a simple and easy way, so that people can understand the totality of evidence, without needing to read the 29,000 papers that our team has read. So, you can either read 29,000 papers that have been published over the last year, or you can go to this website, CCN.org/corona, and you can access all of the data from the 29,000 papers.
That actually brings me to another question. Your lab was focused on Castleman, and then you pivoted a little bit to focus on COVID-19. Are there any other rare diseases that you were looking at, or hoping to look at, before all of this happened?
Yeah. I think about my work, and our team's work, really in three buckets. The first is thinking about cytokine storm disorders. These are diseases where the immune system gets out of control. Cytokines are proteins that your immune system produces when it's activated. And cytokines are really important for fighting off infections. You need some cytokines, but you don't need too many cytokines. And so, I guess I would say initial and primary focus has really been around understanding what is happening in cytokine storm disorders, understanding what drugs are already FDA-approved that could be effective to save patients' lives that experience these cytokine storm disorders.
The second area is around rare diseases beyond Castleman's or other rare cytokine storm disorders. And when we talk about rare diseases, it's less about doing work in the lab on a given rare disease, and more about creating the environment and the ecosystem so that rare disease research progresses as quickly as possible. And we've come up with a new sort of approach to rare disease research called the collaborative network approach. I run a foundation called the Castleman Disease Collaborative Network that I started back in the early parts of my journey chasing a cure for Castleman's, and we've spearheaded this really new approach. What you really need is, you need to leverage the whole, entire crowds. You need to leverage all of the key stakeholders to determine what should be done, and you need to then go recruit the best people to do it.
And so, for that second area, it's really, for me, focusing around how do you create the tools and the systems so that rare disease research progresses efficiently and effectively? And I've been partnering with the Chan Zuckerberg Initiative for the last couple of years to create a system and tools to facilitate collaborative research in the rare disease space.
And then, the third area that I focus on is around drug repurposing, and I've talked about trying to create systems and pathways for drug repurposing. Right now, we're actually also collaborating with the Chan Zuckerberg Initiative on a project related to drug repurposing, but also a collaboration with the FDA, and with a group called the CURE Drug Repurposing Collaboratory. Collaboratory is a word that we made up. It combines collaboration and laboratory. So, it's the CURE Drug Repurposing Collaboratory, and it's all about figuring out, how do we create the environment so that drug repurposing happens more quickly and effectively?
So, that's really kind of where I spread my time, is between those three buckets, and of course, COVID kind of hits all three of them in a way. I mean, I mentioned earlier that it feels strange talking about anything positive coming from COVID, because gosh, this has just been so negative in every way. But I do thing that there's the possibility that there could be some positives.
One of the things I talk about in my book, that I think is an important lesson that's stuck with me for many, many years is this concept of creating silver linings. In tough times, all of us, from the time we were kids, are encouraged to find silver linings during tough times like COVID. But actually, my mom taught me that we shouldn't just look for silver linings; we should look to create silver linings.
And so, the point here is that, with COVID, we have the potential for there to be a silver lining around better drug repurposing. There's the potential for there to be a silver lining around maybe better, open access to data and papers moving forward. Maybe even a silver lining around improved collaboration, because it's been pretty amazing to see the way that labs and research groups have collaborated since COVID emerged.
But at the same time, none of these things are going to happen unless people take action to make them happen. Just because drug repurposing has been successful for COVID doesn't mean it's going to be successful for any other condition, unless we take the steps to do that. So, I think that we have the potential to create some silver linings from COVID, but they're not going to happen unless we actually do the work.
Yeah, let's hope that some of these changes stick with drug development after COVID.
David Fajgenbaum (39:04):
Drug repurposing in the context of COVID has been in the news, as the global research community has sought effective treatments for a disease we know little about. This is perhaps an effective parallel to highlight what's possible, and emphasize the work we still need to do for other challenging diseases. I admit, I was surprised to hear that over 400 existing therapies have been used to treat COVID symptoms, but that number obviously reflects what we can accomplish when we come together and find solutions.
One of the themes David emphasizes in his book is collaboration. Since diagnosis, he has forged connections with mentors, colleagues, classmates and friends to create systems that foster knowledge sharing and empower advances in medicine. In this final segment, we'll hear a bit about the organizations he's built, and what he hopes will be his legacy.
So, Barbara, you've listened to David's story, you've read his book. What lessons have you learned from all of this?
David's story really underscores for me that previous efforts can not only provide us with new scientific discoveries, but he's also given us new platforms we can use for drug development to bring therapies to patients even sooner. But the real takeaway for me is how similar the diseases we've talked about today were. As David said, we often divide research into buckets. Is it a neuroscience disease? A cancer? An infectious disease? An immuno disease? David has shown us that we can learn so much about looking outside of those categories. As they say, we don't know what we don't know. Are there more approved drugs out there that could be used for a disease that it wasn't originally developed for? Currently, 95% of rare diseases have no treatment. Just imagine the possibilities.
I love that. I'm so glad that that's come through so clearly, because I mean, you can tell that the thing that keeps me up at night is the realization that the drug that's saving my life was sitting at my neighborhood CVS for years while I was in and out of the ICU and I nearly died five times. And so, the question I ask over and over again is, how many more drugs are there out there, that are already FDA-approved for something, that could actually be lifesaving for another condition, we just don't know about it yet?
And so, that's why I'm so focused on this Collaboratory that I mentioned, and also, here in COVID as an example, obviously a major public health threat, to figure out what drugs are out there that could be lifesaving, and let's make sure we move them forward as quickly as possible. And I might throw in a few other lessons that I hope were also apparent from our conversation, but also from checking out Chasing My Cure.
I think the first one is something that we've talked about a bit, and that is turning hope into action. Chris, you asked such a great question about, you're hoping for progress for this condition, but what can you do about it? And I think that all of us hope and pray and wish and want lots of things in live, but oftentimes, we stop once we've finished hoping and finished praying and finished wishing. That's kind of the end of it.
But I think that progress only happens when we reflect on what we're hoping for and wishing for, then we go do something about it, and we go take action. As I said earlier, whether it's finding an advocacy organization and getting involved, or donating a sample to research. Whatever it may be, taking action, I think, is so critical.
We also talked about the idea of creating silver linings. Whether it's something that is as awful as COVID, or something else in live, finding a way to create something positive out of it, I think, is really, really important.
And then, the last one is really just an emphasis on that first comment around basically this idea of repurposing. The short phrase that I use to describe it is, it's kind of like teaching old dogs new tricks. And you know, most people will tell you, you can't teach old dogs new tricks, and in fact, when it comes to drug repurposing, it's actually really hard to get these old drugs and use them in new ways. It's actually hard to teach these old dogs new tricks.
And so, I think we've go to turn our hope into action, we've got to create some silver linings here, and we've really got to do the work that we can to make sure that drug repurposing happens as quickly as it can.
Yeah, I think the biggest lesson I've learned from the podcast, from the book, is that hope into action. And I think, back to your book, just the thought that there could be a cure for whatever rare disease someone has two blocks down the street at CVS or Walgreens.
Exactly, and we have to do everything in our power to figure out whether that's the case or not, because there are a lot of rare diseases where, unfortunately, every drug that's ever been approved is not going to be effective. So, there's not a single drug. But then, there are other diseases, like Castleman's disease, where there may be drugs just waiting. I mean, COVID is a great example, where when the pandemic emerged, there were drugs just waiting to be found, that literally now have saved thousands and thousands of lives.
So, most drugs are going to fall somewhere on that spectrum between nothing currently available can be helpful, to oh my gosh, there are dozens of drugs that could be helpful, we just have to find them. In my opinion, we've got to do all the work we can to figure out where on that spectrum every disease falls, because I think it's a real tragedy if a patient dies from a disease where there was a solution that was, as you said, just within a couple of miles of them at their neighborhood pharmacy.
As mentioned, you'll also find out where you can get a copy of David's book, Chasing My Cure: My Race to Turn Hope Into Action. This is an excellent read if you're interested in learning more about Castleman's disease, current approaches to research, and the systems that David hopes will serve as a foundation for faster progress on the critical path to a cure.
We've also included additional resources on high-throughput screening, repurposing libraries, and bioinformatics for those interested in understanding how these tools work in the quest to find new applications for existing drugs. Be sure to check those out at criver.com/vitalscience.
As we learned today, strategic drug repurposing has unlimited potential to accelerate the drug development process, especially for those who feel the clock is ticking. Join us for our next episode, when we take a closer look at drug repurposing from the perspective of drug hunters, scientists who are dedicated to screening thousands of drugs already available on pharmacy shelves in hopes of finding a hit for a patient in need.
Until next time, thanks for listening.
- Chasing My Cure
- Repurposing Compound Libraries
- High-Throughput Screening
- Artificial Intelligence for Drug Discovery
- Center for Cytokine Storm Treatment and Laboratory
- Corona Project
- Castleman Disease Collaborative Network
- CURE Drug Repurposing Collaboratory
Hosted by: Gina Mullane
Narrated by: Chris Garcia
Special thanks to: Dr. David Fajgenbaum
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