S2, E11: Drug Repurposing - Opening Treatments
About this Episode
Sanath Ramesh was determined to track down the resources needed to repurpose a drug for his son Raghav's ultra-rare disease. This determination led him to apply his experiences and empower the rare disease community with his collaborative platform, the OpenTreatments Foundation. Find out how his repurposed drug platform is now giving hope to other rare disease patients.
Gina Mullane (00:04):
Hello, welcome to another episode of Vital Science. Today, we conclude our three-part series on drug repurposing. We began this discussion with an inspiring story from Dr. David Fajgenbaum, who shared his perspectives as a patient clinician and researcher in his quest to cure his own Castleman disease. Dr. Fajgenbaum's experience really demonstrated the tangible and immediate effect drug repurposing can have on a person's life. However, it also shed some light on the challenges and roadblocks that may be faced along the way. As we learned, the journey that gets scientists from an existing therapeutic to a new indication, in a safe and effective manner, is rarely a straight line.
Navigating us through the turns in episode two were Charles Rivers' own Ian Waddell, chief scientific officer, and Vad Lazari, director of integrated biology. Together with Barbara Killian, senior product manager and discovery, Ian and Vad explained that while there is no exact roadmap for drug repurposing, the process is getting more efficient. Tools like machine learning and artificial intelligence have helped scientists to more efficiently identify the hidden potential of existing therapies, often shaving valuable years of the drug development timeline. I can't think of a better way to round out this discussion than by sharing the story of Sanath Ramesh, founder and CEO of OpenTreatments.
Although you won't be able to tell it from listening to him, as his knowledge and eloquence on the topic is impeccable, Sanath stands apart from our previous guests. A long-time software engineer, he began his drug re-purposing journey with no professional experience in medicine or drug development. But when his son was born with a rare and debilitating genetic condition, Sanath took it upon himself to investigate unconventional treatment options, conduct his own extensive literature review and personally connect with scientists in the field, including those here at Charles River.
His inspiring transformation into a self-made drug hunter led him to found OpenTreatments, a collaborative platform for fellow families and patient organizations investigating rare disease therapies. Barbara Killian joins the conversation again, along with Dr. David Fischer, executive science director at Charles River, to help illustrate just how powerful it can be when patients like the Ramesh family and CRLs like Charles River come together in partnership. I'm eager to share this story with you, so I'll go ahead and turn it over to Chris.
Welcome to episode three in our series on drug repurposing. Back again is Barbara Killian from Charles River's discovery team. Welcome back, Barbara.
Barbara Killian (02:48):
Thanks, Chris. Looking forward to our next story.
And also joining us is Dr. David Fischer, executive science director at Charles River and Sanath Ramesh, founder and CEO of OpenTreatments. Welcome to you, both. David, you were a guest of Vital Science early this year, but can you reintroduce yourself to our audience?
David Fischer (03:08):
Absolutely. Thank you, Chris. Yeah, so I work at the discovery part of the Charles River organization, and we work with clients to design and execute their drug discovery programs, and some of them really do start from scratch, and this is across different therapeutic areas, and also nowadays with a variety of different drug modalities from small molecules to cell therapies.
And Sanath, I'm really honored to have you as our guest here. Your OpenTreatment platform has been described by science as a roadmap for drug development that will supercharge patients, allowing them to act like their own small biotech. But before we dive into details of that platform, can we go back to the beginning and how this journey started? I understand it began the day your son Raghav was born?
Sanath Ramesh (03:58):
Yes. Thanks for having me in the show. It's a real honor for me to be talking to you all here. My journey started when my son was born, but it was not until his first birthday that we actually got his diagnosis and a name for all of his challenges. When he was born, right away we noticed he had significant abnormalities. He did not have the energy to move his hands or legs like other babies do. He did not take anything by mouth, and so he had to be fed through a tube going through his nose. And for the next year, we struggled with Raghav not reaching any of his developmental milestones. We saw him struggle to even lift his head up. And in fact, it took us even several months, and even today he doesn't, he cannot live this head up on his own.
And so on his first birthday, we got Raghav's diagnosis. We got to know that he has an ultra, ultra rare genetic disease due to a mutation in a gene called GPX4. When we got his diagnosis, the doctors told us there is no treatment, no cure, nothing that could be done about this disease, and so they sent us home to just love Raghav like we ever could and hope and pray for the best. So when we came back home, we said, "Well, we just cannot sit here idle." We know from the literature that kids born with this condition passed away a few weeks or months after birth.
So we knew Raghav was already in over time, and we did not want to delay that any further. And so right away, we got started in our journey towards finding a treatment for Raghav. We read through the scientific literature, understood the disease and the gene a little bit more, and then started reaching out to a lot of resources in the scientific community. And these are academic professors, these are drug development companies, and these are, including folks like Charles River, and many of them that we reached out to get our drug development journey started.
I can't even imagine what you went through and then the willpower to just turn 180 and start this journey and looking for those answers. So, Sanath, how did you come to direct contact with David from Charles River then?
Yeah, and I think it was through another connection at Charles River. I had reached out to Dr. Lauren Black a couple of months after my son's diagnosis, and she was the one that introduced us to David and asked us to talk about possible options of drug repurposing. At that stage, I had no idea what I had to be doing, because all of this was new to me. I did not even know what a gene meant. So I had to Google everything and look read Wikipedia to get up to speed on all these terminologies. And David and I had been speaking since then for a variety of projects. It started with a drug repurposing activity that we were hoping to get started in 2019, and at that point, there were many prerequisites that had to be done to get the repurposing study started.
We first needed a cell line, we first needed an assay on the cell line, and then we could go do a repurposing and also, we needed money for it. And so I said, "Well, I just cannot wait six to nine months for all of these to be ready," and so I doubled down on the scientific literature, read through a lot of papers and identified 36 drugs that I could potentially repurpose for my son's condition. And in just about three or four weeks after his diagnosis, we got him started on a cocktail of four drugs that he has been on since then. And so David and I have been working on projects subsequent to that.
Sanath, I'm so amazed when I talk to families like yours, that you mentioned how little you knew about genomics when it started. But just hearing you talk about cell lines and all you need to start a direct development program, I'm just so impressed by, as Chris said, what you had to do and how quickly you did that.
Sanath's initiative to learn about Raghav's condition and treatment options is commendable, as information regarding rare diseases can be scarce. For rare disease families, finding resources can often feel like looking for a needle in a haystack. A rare disease is defined as a condition that affects fewer than 200,000 people in the United States. However, the total number of Americans living with a rare disease is estimated at between 25 and 30 million, or one in 10 of our population.
Among these conditions lies a subcategory of ultra-rare disease. It is the proposal. The disease is considered to be ultra rare. It has been proposed that a disease is considered to be ultra rare if it affects one patient per 50,000 people, or fewer than 20 patients in a population of one million. For those patients in particular, therapies may not yet be available due to resources and long development timelines. Let's hear more about Sanath and how drug repurposing can prove useful in treating rare and ultra-rare diseases.
So David, what is the first piece of advice you give to families when they connect with you?
So yeah, my first question really is that genetic diagnosis, if that's been made, what is the gene that is mutated? What is the mutation or mutations if both alleles are affected? But it also, is indeed a starting points, a journey towards finding a potential treatments for that indication. So, yeah, yeah, I can't emphasize how important that genetic diagnosis can be. Now very often the second question that I ask is, have you collected any cells of the patient? Like skin fibroblasts, something relatively simple. Because if we figure out that we need to help with a repurposing screen, you need cells, patient cells.
And we heard that from David Fajgenbaum. He says the reason he's alive today is because he had done exactly that, taken his own cell samples. So David, this screen that you're doing right now is with Raghav's own cells.
That is correct. Yep, his skin cells.
As we've heard in our previous episodes, there's many paths to drug development. When Sanath shared the details of Raghav's condition to you, what made you consider a repurposing screen?
So clearly the strategy that Sanath has taken to look in literature as potential off-label drugs that could alleviate some of the symptoms, that this is one very powerful way to discover new uses for drugs, and thereby repurpose them for novel indication. There are a number of other strategies that you can use, and some of them take a little bit longer. And the one that we're running right now is really due to one that is probably the broader strategies by screening every single molecule that is on the markets, or that has been in clinical trials. And perhaps, it just hasn't progressed yet, or it didn't work in that particular indication, and screen those in cell culture, on Raghav's cells, looking toward the cellular phenotype that we've observed in those cells that is different from a control cell line.
And this is in the DSA, that was already mentioned, that phenotypic difference between Raghav's cells and control cells. And we trying to find any drug that restores that phenotype as much as possible back to the control cell levels. But that's not the only strategy that you can look at. So we're testing about 5,500 individual molecules. So it's at least a large set of compounds, something you will never be able to test in an animal model, if there would be an animal model. So this is clearly where cell culture and those miniaturized assays at 384-well format, for instance, really come into play.
Drug repurposing is only a piece of this drug development plan. What other strategies are being used?
Yeah. That's a very good question, Barbara. And I think what Sanath is doing is keeping all options open at the moment. And clearly, gene therapy could potentially be a treatment. Because in Raghav, a gene is missing, GPX4. So replacing that gene through a gene therapy vector, of course, would then attack the disease that is at the root of its cause, which is the lack of a gene. Of course, to develop a gene therapy products, it takes quite a bit of time. I think the timelines have definitely gone shorter over the years. So because these symptoms, of course, warrants a more expedient treatment, a drug repurposing screen, hopefully, can give us potential treatments while the gene therapy project is on its way.
So Sanath, that's the original goal to address the symptoms now and hopefully slope some progression as you wait for this gene therapy to be developed.
That is precisely true. We wanted to get a treatment today that's slowing things down, hopefully, and a treatment tomorrow that would be more long-term.
Gene therapy is a promising treatment method for rare disease patients. As more than 80% of rare diseases have a known monogenic or single-gene cause. But this area of treatment is still finding its footing in drug development. While the scientific community has identified about 7,000 rare diseases, only five percent have approved treatments. The most active area of gene therapy research for children has been for genetic disorders, like cystic fibrosis. As Sanath mentioned, gene therapy can offer rare disease patients hope as it has the potential to actually cure the condition by addressing its underlying genetic defects.
Another upside is that successful gene therapy may require only a single dose, rather than requiring a lifetime of ongoing treatment. However, these therapies can take years to develop as emerging gene therapies work their way through the pipeline. Identifying repurposing existing drugs can offer relief to patients like Raghav. Let's hear from Sanath and Dr. Fischer on what the screening process looks like.
So we've also learned through this series that drugs that are approved for one indication may not be used as they were originally designed at another indication. So, with a patient that has this complex of a disease, I can imagine it'd be necessary to look at other side effects, off-target effects, of this drug so it doesn't have any negative impacts.
Yeah. And I think that it's sometimes forgotten, but it's a very important aspect of, as I said, drug repurposing screen, because you test every compound as equals. You may indeed identify that some supplements that you thought could be beneficial, actually aggravated the phenotype, may thinks at least in that cell culture assay worse. And so, yeah, it tells you both potential drugs that could be tried if they're, of course, fit for purpose, but also perhaps drugs or supplements that should be avoided.
This is where some clinical expertise also comes in. So once we identify some drugs through these screens, the next step is actually even a longer step, and it's something that I'm actually going through for a couple of other drugs that we had identified through literature search. And that step involves a clinician making sure the drug is safe to be given to this condition, determining the dose in which the drug can be given. And even if the drug is FDA approved, the formulation that it's currently available in a pharmacy might not work for my son.
For example, there's a drug that is available as a 120 milligram capsule. My son cannot even swallow saliva today, let alone swelling a capsule, right? We have to reformulate that into a solution, and then our challenge is doing that. We probably will have to start with a pretty low dose of the drug and escalate it over time to make sure to find the maximum tolerated dose for him. And that might also not be possible right away if the drug formulation is not available at low doses. And so, there are a lot of steps that we would do in parallel, in the clinic, to ensure the drug is safe and tolerated. And that's again a longer process after we get through the screen.
Sanath, can you describe what it was like to suddenly become a member of a drug development team?
Sanath Ramesh (18:12):
I'd like to say it was awesome, but there's always the other part of me, which feels like an imposter, right? And I am an imposter here, because I'm in this journey that I did not want to be in, but I'm here out of compulsion. It feels awesome that I'm a part of the team, understanding the signs and being able to make the decisions and calls. But at the same time, every single day, I get reinforced that I know nothing in this industry, that I know very little. And so I'm always in the quest of trying to talk to more people that are smarter, that are more intelligent, that'll give me a different mental model on how to think about all of these possibilities. And in addition to that, I'm always on the quest to bring more people into my team, so we augment our perspectives with more experience.
So Sanath, how did that experience become the motivation for the OpenTreatments platform?
The experience that I gathered initially through the drug development process that I embarked on, mostly around small molecules, were very helpful in helping me find the right people and the expertise to get a gene therapy treatment started for my son. But as I was going through this process, I realized I could spend the $5 million to build a gene therapy for my son, although I did not have the money for it, I could raise that. But even if I did that, with just nine patients worldwide, no company is going to take this treatment forward to the clinic. And that means that kids born with this condition five years from now, 10 years from now, are not going to have this treatment available to them, and that hurts.
So I started looking at what other foundations were doing to solve this problem and other problems that they're facing, and I observed consistent patterns. All of the foundations are operating just like how I do, just making shit up on the way, right? And these foundations have to learn a lot of things very quickly, act like they know a lot, but they actually don't, and along the way, make a lot of mistakes. And the foundations that have gotten the treatment in the clinic, or close to getting a treatment in the clinic, have told me that they spent a lot of money just redoing some of the experiments because they made mistakes along the way that could have been avoided with the right expertise. And so I started OpenTreatments out of the necessity to help me and help other patient foundations build a robust gene therapy program.
And through the OpenTreatments foundation, we hope to de-centralize drug development and bring more patients and patient foundations into the drug development space by giving them the right tools so they can develop a treatment without making a lot of these mistakes. We have the roadmap for gene therapy development that we built with David Fischer and several other groups that is available through OpenTreatments. I'm also putting together a team of experts that could go and help these patient foundations answer their questions, help them make scientific decisions and regulatory decisions along the way. And this is again a starting point for me to understand how best to bring in more people into drug development.
Can you describe a little bit more about how OpenTreatment works?
So right now, there is a software platform, wherein a patient foundation would go and sign up, and they would answer a few questions to determine whether the gene therapy is a good fit for their disease or not. And if it is, then they will be presented with a roadmap from getting started to building the right disease models, to getting the proof of concept for the gene therapy up and running, all the way through manufacturing. And the roadmap, obviously, is just a genetic roadmap that a lot of people could adapt. And so the first step for them to do is to do a gap analysis, working with us to look at what has been done so far in their disease, in their foundation, and identify where they should invest their money in to take them to the clinic.
And based on the gap analysis, we update the roadmap and present it back in the software platform for the foundations. The software platform also provides a project management interface with giving them an estimate of cost and the time it would take for them to build their therapies, build each step of the therapies in fact, and this helps them to keep their cost and time under check. The platform also allows you to reach out to different service providers, including contract research organizations or individual scientific consultants that you might need to work with in order to advance your program.
David, you've guided many clients through their drug development programs. From a direct developers point of view, how did you give Sanath guidance as he developed this open treatment platform?
Of course, every client is different, but what we clearly wanted to do here, and this was a team effort, so it wasn't just me working with Sanath, but there were others that were consulting on this whole process. It really designed something that wouldn't create a billion-dollar drug, but rather something fit for purpose for ultra-rare indications. So where you have very small number of patients, and also where it's the most economical program. We really wanted to design something that was building on the technologies that are now tried and tested and approved.
Sanath and David, we've been discussing repurposing previously approved drugs to speed up the drug development, but it sounds as though you are also repurposing the drug development process itself.
Absolutely. Because a number of gene therapy programs have progressed from preclinical studies through clinical studies, and some of them have now been approved. We can clearly learn from that. And hopefully, by sticking it as close as possible to that whole process, understanding what tests you need to do at which stage, how to manufacture the drug product, both for research purposes, but of course also, finally, as a clinical product.
I think that understanding that whole process, that is what we've tried to put into the roadmap. Yeah, thereby you repurpose the process of developing these drug therapies. We do think that this is not the final product. I think as we all progress through scientific developments, we, as a community, we learn and we optimize. So hopefully, those optimizations can feed back into the roadmap and make it quicker, easier, more effective, and with a higher chance of success over time.
Sanath, anything to add to that?
I think the big key point to underscore when it comes to repurposing is standing on the shoulders of giants, right? We have to get to a point in drug development, in general, not just in gene therapy, but also in small molecules areas, or any of the technologies where we are reusing what has been done before and not going after inventing something new for the sake of it. While there is a lot of opportunity for commercial upside, when you go invent something new, there is still a lot of opportunity when you repurpose something by taking it to the clinic. And so, the act of repurposing drug development process is just one attempt to understand how much of what we already know is applicable and something that can be scaled to a lot of people.
With OpenTreatments, Sanath has found a way to impart his knowledge and empower the rare disease community to not only understand the drug development process, but to help drive it. Through this online, users receive a roadmap to help them work through the gene therapy pipeline, from planning and design all the way through the manufacturing and clinical trials. It also connects users with service providers and members of the research community, so they don't need to walk this journey alone. Let's hear more from Sanath about his inspiration for OpenTreatments and his advice for other rare disease families.
Sanath, what really struck me about your story was, as you said in the beginning, how much did you really know about genomics or even about this ultra-rare disease? But you were able to use some of your other talents, your engineering talents, to support your son. So what advice would you give other families that feel frustrated? We know many rare families feel that they don't know how to help, but you uniquely used your talents to help your son.
I think the bottom line is that we need to create networks, and these could be networks of engineers, networks of scientists, networks of parents and families that all work towards one purpose. And so regardless of the skillsets you have, you probably have already been building networks in your own ways. For example, if you run a grocery store at your local town, you probably have a network of friends that also run grocery stores, right? Everybody has in their life built networks of some sort or the other. If all of us can come together and help build a network towards a common purpose of building a treatment, I think that would be fantastic.
And so as a pattern, if you have the capability to read the signs, understand that, get into drug development, well, awesome. You should do that, but in addition to that, you should also be constantly thinking about, how can we get a bunch of people together that have the right skillsets, that complement each other towards a common purpose? And how do we instill that common purpose in them so they keep continuing to work on it? And then, how do we raise the funds necessary for this network to keep making progress towards treatment? And if you work backwards from that perspective, I think there is an opportunity for almost every one of us to contribute to drug development.
Yeah, it's all about making those connections. And David, you obviously have drug development talents, and you've dedicated your talents to so many drug development programs that I've watched over the years. But in this case, I know most of your time at this project was volunteer. I thought maybe you could take this opportunity here to tell our listeners about how you use Charles River's one-day program towards this project?
Absolutely, yeah. So Charles River is very committed to investing in the communities in which we work and live. And as part of that commitment, every Charles River employee can spend a certain percentage of their time to volunteer in their community. And that can be gardening in the local council, or it can be painting something, like a community center, or it can also be something scientific, if that fits. And a very good example is the contribution that a lot of our medicinal chemists have given over the course of a couple of years now to medicines for kids initiative. This is a not-for-profit that wants to develop a treatment for pediatric brain cancer.
And this is open science. So our medicinal chemists design molecules, they are tested and everything is published online so that you can seek further input from the community. And this is all done through volunteer time. So in the same spirit, I've, of course, volunteer time last year to help Sanath build this platform. And actually, Charles River is committed to further support the OpenTreatments platform by volunteering yet more time to those individual families, foundations, that come through the platform. Because we feel that you still need scientific input at different stages to look at some of the details involved in discovering these therapies and testing them.
You mentioned that M4K is an open-science platform. For those who may not be familiar with open science, it means the research is open access, public information, available to other researchers and the general public. With the name of OpenTreatments, does that mean this is open access as well, that the research will be shared?
That's correct. We really share all of our learnings publicly, and we have open-sourced the entire software platform. So you can basically look at the source code as a software platform, on GitHub, in a project called RareCamp, R-A-R-E-C-A-M-P. And we'll continue to share sharing on all of our learnings that's coming out of it. We might likely not share the scientific advancements that each of the foundations do, and it is really dependent on the foundation's interest to share that or not, and that is not something that we force them to do. But everything that we do as a part of OpenTreatments is hundred percent open and publicly accessible. And it's one of the reasons why we call it OpenTreatments is the first place.
And Sanath, when you look to the future, what do you see for OpenTreatments?
Sanath Ramesh (32:25):
I see a couple of lot of different directions here. If I take a step back from the tactical stuff that we are doing, and look at our mission, our mission is to enable treatments for every single patient across the country or across the world, irrespective of their geography and reality. In a mission this broad essentially needs a lot more perspectives and a lot more investments, and a lot of other angles that we would go into. And so in the short-term future, I see ourselves expanding to antisense therapies as well, and potentially get into drug repurposing as well, because there've been a lot of demand in those two spaces from patient foundations.
In the long run, I see ourselves discovering and publishing new models of drug development. These could be innovative funding models that patient foundations could take and move forward. These could be innovative business models that companies could pursue to tackle these market-failure diseases, like the ones that my son has, which is nine patients worldwide. And this could also be innovative technologies, like quantum computing, that we can leverage to solve some of these challenges.
While I don't hope to solve any of these challenges myself, the hope is that we can bring in the right people, have them talk about it, and then publish it for the benefit of the rest of the community. And so, in addition to the software platform, tactically helping foundations build treatments, we will also be thinking ahead as a thought leader in the space about how this industry should progress in the future.
And David, as a drug developer, how do you see platforms such as OpenTreatments impacting drug development, especially for rare families?
Yeah, I think what is clearly a benefit is that there is now an entry points for families, and you don't then need to contacts lots of different companies, talk to a lot of different researchers. This is a starting point, and it helps families also define the next steps. What do you need to know? What do you need to resource? And I think this is really enabling, because there are so many families out there that have a child with a rare condition. So to be able to help them at scale, I think is very important.
So each of our guest speakers in this repurposing series has emphasized the power of collaboration as a key to factor in success. So Sanath and David, your collaboration is really an inspiring example of that.
Thank you for having me here. And it's a pleasure to be always working with you all, because you have the patient's interest in mind. And especially working with David has been just an incredible pleasure. I can't wait to see how our journey shapes up in the next couple of years, but I'm sure it's going to be awesome.
Yeah. I really look forward to seeing the results from the repurposing screen.
Well, I want to thank David and Sanath for sharing their drug repurposing collaboration today. Truly inspiring project, and I really think it'll potentially speed up the drug development process and, more importantly, provide hope for many other families. We will all be following your journey and we wish the best of health for Raghav. This concludes our series on drug repurposing. And I want to thank Barbara so much for joining us for the series.
Well, Chris, it was a pleasure, and to hear the experiences of patients such as our first guest, David Fajgenbaum, and today's guest, a parent, like Sanath. And then, all my colleagues, the drug hunters, Ian, Vad and now David. Really motivates me to connect more patients with researchers, and I encourage those that are listening to contact us through our show page.
Throughout the series, we've had the opportunity to examine drug repurposing from several vantage points, clinician-patient, scientist, and advocate. And what we've learned is that while drug repurposing brings opportunities to get treatment into patient's hands faster, it is by no means a silver-bullet solution. The process of identifying existing therapies with a potential to treat a different condition is not always easy. As Dr. Fajgenbaum emphasized in our kickoff episode, connecting with the necessary experts is essential.
And as our own Charles River scientists, Ian and Vad, explained in episode two, it is through the use of new technologies, such as artificial intelligence and machine learning, that drug hunters are able to unlock secondary uses for existing therapies. Historically, these experts and technologies have not always been readily available to rare disease patients, but through Sanath's tenacity and determination, he was able to track down the resources he needed to repurpose a drug for his son's ultra-rare disease. And now, it is the same passion that has led him to convey his knowledge and empower the rare disease community with his collaborative platform, OpenTreatments.
Our guest speakers were all change agents in their drug repurposing journeys. Each bring a unique skillset to the table, be it at the bedside, behind the bench or from the other side of the computer screen, we've seen that with a spirit of partnership and willingness to pool our collective expertise, we can go further together. We hope you enjoyed all three episodes. If you missed any, we encourage you to catch up by visiting, criver.com/vital science. We'd also love to hear from you. Share your feedback and story ideas with us by emailing [email protected] Until next time, thanks for listening.
Hosted by: Chris Garcia
Narrated by: Gina Mullane and Chris Garcia
Special thanks to: Sanath Ramesh and David Fischer
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