RARE Daily

Translating Urgency into Science

February 17, 2023

The National Institutes of Health in November named Joni Rutter Director of the National Center for Advancing Translational Sciences. Rutter had served as acting director since April 2021. She succeeded Chris Austin, the first permanent director of NCATS, who stepped down after ten years on the job. NCATS is charged with developing technologies and approaches to accelerate the process of moving new treatments from the lab to the patient. As part of its work, it has several program and initiatives that are focused specifically on rare diseases. We spoke to Rutter about NCATS’ priorities under her leadership, the challenges of translational science, and where she sees the biggest opportunities for accelerating the discovery and development of therapies for rare diseases.



Daniel Levine: Joni, thanks for joining us.

Joni Rutter: Danny, thanks for inviting me. It’s a pleasure to talk with you.

Daniel Levine: We’re going to talk about your role as director of the National Center for Advancing Translational Sciences, the challenges of translating scientific discoveries into therapies that benefit patients, and what the biggest opportunities for speeding the process are. We’ve been living in a time of enormous scientific innovation, but the pace of drug development hasn’t changed significantly. Why is that?

Joni Rutter: Yeah, it’s a good question. The short answer is because it’s very hard. and I don’t mean to be sort of flippant about that, but it is a very difficult process. Why is it so hard? I can talk a little bit more about that. But I also want to talk about some of the successes, because we’ve all experienced the pandemic over the past three years now, which is kind of hard, unbelievable to say, but in that three years we did see some really unprecedented times in terms of vaccine and therapeutic development and it’s been done at record pace. The basic science work that has been done over the last decades, for example, has really set the stage for some of these processes to move much faster. And I think a case in point, for example, is the COVID vaccine development, which from the time we received the sequence of SARS COVID-2 to the time we received a vaccine in arms—that was less than a year. And that’s a pretty incredible timeframe for that to happen and really unprecedented. And we can say the same about therapeutics for COVID as well. Those are starting to come out. The monoclonal antibodies, of course, we’ve seen happen early on to try to address the pandemic, and those have had mixed responses because of the ever-changing nature of the virus. Now we’re seeing antivirals being much more mainstream too. And I think that kind of activity will continue to develop. But what about other areas like in rare diseases and in other diseases too. How about drug development there? I think the pace of drug development, when we think about the pace, it’s kind of about how do we count the number of diseases and how do we count the number of medications for those diseases? And I think that’s part and parcel of sort of understanding what that rate is, to really understanding, too, that we’re seeing what the advent of genomics technology, for example, for rare diseases, we’re seeing more and more rare diseases come onto the scene. In fact, it’s about three to six new rare diseases per week at the rate we’re going, or about 200 new rare diseases per year. And so, that denominator of the number of diseases that we have is also increasing. And so the number of treatments may seem to be keeping pace with the number of diseases that are being defined now as well. And I think soon enough that curve will start to change where we will see more treatments at the table for a variety of different diseases. And a real reason behind that too, I think now, is because a lot of the technologies and tools that I mentioned before, over the last decades of the basic science that’s gone into development of new approaches for therapeutics, we’re seeing new approaches for the different kinds of modalities of therapeutics to be delivered. So, we often think of small molecules or pills when we think of therapeutics, but we’re also now seeing things like gene therapy and gene editing, and we’re hearing more about those kinds of modalities of how we can deliver treatments. Those are still in their early phases, but I think the promise of those kinds of therapeutics is gaining traction, and we’re seeing more and more successes. So I do anticipate that even though the pace has seemed to not really change, there’s been a lot of activity where we’re going to start to see that change coming in the decade ahead.

Daniel Levine: Well, if you think about the new approvals that the FDA makes in any given year, in a good year we’ll have 50 new drugs approved. Where’s the rate limiting step in drug development and drug approvals? Is it our regulatory capacity? Is it the clinical challenges? Is it the underlying scientific understanding of the diseases we’re seeking to address?

Joni Rutter: Yeah, it’s probably a little bit of all of the above and these are challenges that we’re going to continue to face. But I think that when it comes to thinking about the diseases that we’re trying to impact with therapeutics, the diseases are quite complex. The biology—it’s almost as if the low hanging fruit, if you will, has been all picked. And now we’re getting into the more complex biology that we’re trying to tackle now. And I think that that’s part of it. So, understanding the biology and the different ways of developing compounds for those therapeutics, and also understanding our limitations in terms of the compounds that we have available and access to that we can know about and actually start to screen for their effectiveness and safety in different kinds of disease states. So, I think all of those are at play. And of course, we have heard and seen reports that talk about the numbers of IND packages, for example, that are being submitted to the FDA. So, I think all of those things are growing and it is going to be difficult to keep up with the pace of those activities. And anything that we can do more to support our colleagues at the FDA to better streamline those—our understanding of what it takes to develop the science underneath those IND regulatory packages—how can we streamline those more? How can we make platform-based approaches that become more familiar to them? Those are the kinds of activities that NCATS is trying to work on.

Daniel Levine: Let’s take a step back. For listeners not familiar with NCATS, can you explain what it’s charged with doing and how it works?

Joni Rutter: Sure. Thanks for asking that question because it’s an important piece of what we do. And I’m guessing that your listeners probably know a little bit about the NIH in general, but the NCATS piece of the NIH—we’re one of the 27 different institutes and centers within the NIH and the NIH in general is very well known. It’s the world premier organization for doing basic science and foundational science. And NCATS is a little bit different in this regard because what we do within the NIH ecosystem is we want to take those basic findings and advance those into translational science and try to move those through the pipeline to more clinical application or real world application. And so, NCATS is advancing translational science by addressing the long-standing bottlenecks in pushing those findings through that translational pipeline so that new treatments can reach people faster. Our whole mantra is to turn basic science observations into health solutions. And we do that by essentially developing cross-cutting ideas and collaborations and partnerships because we work within an ecosystem. So, we don’t do anything alone. We need to work within our ecosystem with industry partners, with other agency partners, with researchers, with patients and patient advocates, for example. And developing those partnerships to really get a big picture of what’s going on in the problems that we’re trying to address is very critical. So, thinking about those stakeholders and engaging patients in that process is critically important. Our other main driver is developing robust platforms and technologies that can help us be more predictive in understanding the science that we do. So, I mentioned one of the bottlenecks in the drug development pipeline, actually maybe I haven’t mentioned it yet, but a key bottleneck is the predictability of a particular compound and how it might act in humans in terms of safety and efficacy. And it turns out that for any given compound, it takes an average of 10 to 15 years to get that through that translational science process. It takes about $2.6 billion to do so, and it has a high failure rate. It’s over 90 percent failure rate for any given compound to make it through that process. So, the more we can develop platform technologies that can get us to understand a better way of getting predictability for how those compounds will be in humans, the better off we will be. That’s one of the big drivers across what we’re trying to do in helping that process. And in doing so, we take a lot of risks to remove those scientific and operational barriers. We want to take those risks off the table so that other researchers and scientists, across the nation, can learn from the risks that we take and hopefully apply those across what they’re doing in this area as well. And in that way, we think that we can bring more treatments to all people more quickly. And when I talk about treatments to all people, I should also just add that we’re not talking about making sure that we want to overmedicate people, but what we really want to do when we’re talking about all people, is address the idea that we want to make sure that the science that we support in drug development is accessible to all different kinds of racial and ethnic groups and populations. And that’s a really critical thing that we can add to the table as well. So when I talk about bringing more treatments to all people more quickly, that’s really what I’m talking about.

Daniel Levine: You stepped in as acting director of NCATS when Chris Austin stepped down in April 2021. You were named director in November of, forgive me, 2022 you were named director, right?

Joni Rutter: That’s right.

Daniel Levine: I have it wrong in my notes. What’s different under your leadership? And congratulations on being named director.

Joni Rutter: Thank you. I appreciate that. We’re still in early days, but I think the key difference here is that, in a way we’re all experiencing, and that is the experience of the COVID pandemic. What that has brought, I think, is a new lens on these ideas of how can we bring urgency to the many diseases that we face every day and learn from that urgency that we felt during COVID. That’s a key area for us. And one of my goals is to really bring that urgency to addressing how we can apply the lessons learned from COVID to all of these other diseases. For example, some of the lessons that we’ve learned from COVID are to really strengthen our ability to look at clinical data in understanding health and disease. And so, we had a large activity around electronic health records. Another example of that is that we really helped coordinate multi-site trials for COVID-19 clinical trials and the infrastructure that’s needed for that, largely through the CTSA program that NCATS supports, has really been game changing and an opportunity for us to continue to leverage those kinds of activities moving forward for other diseases. So, those are just a few things, but the experience and the environment that we are in now with what we have built and learned from the Covid pandemic is something that we have to apply moving forward. And as we’re starting to, we’re still very much in the pandemic. [As] we start to apply the findings, we’ll have a little bit more bandwidth to do so.

Daniel Levine: You mentioned the work in COVID, how translatable is that to rare disease? And with regards to the electronic health records, which can be a big boon to finding rare disease patients and understanding these conditions, how much of an issue is the lack of similar data from one electronic health record to the next?

Joni Rutter: Yeah, that’s a very important observation. So, the big lesson that we learned, but also this is one of those areas of risk that we took on to try to take a big barrier off the table for future development, and that is that electronic health record development. Through a process or a program called the National COVID Collaborative, we’ve been able to assemble over 17 million electronic health records for researchers to analyze, to understand what causes risk, what are risk factors, what are protective factors in people with COVID-19, and even really opening up some avenues of research for the same kinds of questions related to long COVID, what are medications that might be working and what aren’t working? These are important questions for how we can use those electronic health records for other activities as well. One of the things that has been highlighted with electronic health record research and the clinical data that we’ve received over the course of the pandemic, that’s been quite robust. But when we talk about rare diseases, it’s actually quite difficult to identify individuals with a rare disease in the electronic health record system. So, I should take a step back because, within the electronic health record, the program that we did for the N3C or National COVID Cohort Collaborative, the key issue there was making it comparable from one clinical hospital to another clinical hospital. The data that we received from multiple different clinical hospitals are not necessarily overlapping. And so what we took great care in doing is to bring those data in and make them interoperable so that we were comparing apples to apples and not apples to oranges. So, we took that interoperability off the table. We have solved that problem, and I think that’s a really big contribution to this kind of research moving forward. But when it comes to electronic health records with rare diseases, that actually isn’t the main problem. The main problem for rare diseases is that they’re very difficult to find in electronic health records because the codes just don’t exist as robustly as they do for other diseases within those electronic health records. So, it makes it very difficult to identify. So, I think one thing that we’d like to do is based on the learnings of how valuable the clinical information has been to do research on and learn from so that we can develop new hypotheses and ideas for helping address certain diseases, we can think about what we need to do a little bit differently for rare diseases. Are there other kinds of terms that we need to be thinking about that aren’t the typical terms that classify diseases, but they might be other terms that are used in electronic health records that we can identify? Those are the kinds of activities that we’re thinking about now. How can we really leverage the information within an electronic health record without disease classifications to identify those rare disease patients? And that’s a big area of research right now that we’re very interested in pursuing.

Daniel Levine: One of the things NCATS did during the COVID outbreak was support a repurposing strategy for finding existing therapies that could benefit people with the disease. Repurposing is often stated as a viable strategy to quickly finding a therapy for a rare disease. What’s NCATS doing in that area?

Joni Rutter: Yeah, it’s a great point. Repurposing has been a critical activity for us during the COVID pandemic. And we have recognized, of course, that even prior to the pandemic, we have initiatives that support drug repurposing. One thing that I’ll just focus on for this conversation is that at NCATS, we have an incredibly large collection—over a hundred thousand compounds—that we have within our NCATS laboratories that we can do screening on. And a small percentage, not insignificant, but about 3000 of those compounds are compounds that are FDA approved or they’re approved in other countries by an equivalent of FDA in other countries. So, these are compounds that have a lot of information that we know already about their safety and that’s an incredible piece to know for going into a regulatory process or IND filing for new investigational drugs. And we can cut that time in half because we are already using compounds that have been FDA approved, then we really need to focus on showing that efficacy piece and the safety is already relatively known so we can cut the time it takes, I mentioned 10 to 15 years, we can cut that down by anywhere from 50 to 80 percent. So, the value of doing repurposing is incredibly promising, but it’s not always that straightforward because some compounds perhaps might still have IP rights. Some compounds might be in the generic phase, but they aren’t necessarily being manufactured or the company no longer exists that develops them. So, it’s not always going to be straightforward. It’s not without some problems. But I think getting to the point of being able to screen this large number of compounds and do high throughput screening in a very strict way to really understand how these compounds are working, in particular biological assays, becomes an incredibly important process for us to evaluate these compounds and their role in a variety of different kinds of diseases, including rare diseases. So that’s a big program that we run here at NCATS.

Daniel Levine: In the past we’ve featured your colleague PJ Brooks on this podcast to discuss the Platform Vector Gene Therapy pilot project, and the Bespoke Gene Therapy Consortium. These represent platform approaches to accelerating the development of gene therapies, the idea that you can compress the preclinical timeline for developing a gene therapy by using the same vector and data package, and just swapping out the genetic fragment used for a particular disease. Has progress been made there?

Joni Rutter: Oh, yes. Thank you. You articulated gene therapy very well, I appreciate that. The idea is swapping out the genetic fragment for a particular disease. And the Bespoke Gene Therapy Consortium is another activity that you mentioned along with the Platform Vector Gene Therapy pilot project. Both of those projects are really seeking to do these kinds of activities. And for the Bespoke Gene Therapy Consortium, it is now a year in the making. And it will be going on for the next couple of years. It’s still in early days, but we’ve issued requests for proposals to do research on identifying ways in which we can generate these adeno associated viruses in a way that we can streamline the manufacturing of those viral capsids. So, when we talk about swap, using the same vector and swapping out the genetic fragment, developing that vector becomes something that we can streamline or make a platform out of. And that’s the approach that we’re working on with both PGT and the Bespoke Gene Therapy Consortium. So, we’re starting now to see research on developing these vectors and manufacturing these vectors in a more streamlined way. We’re just starting those processes and evaluations. We’re also thinking about how we can enhance the genetic fragment that’s used for particular disease. How can we make sure that we’re enhancing, that that fragment gets taken up by the viral vector that we’re using. Sometimes we end up with empty capsids, for example, when we’re trying to insert that genetic fragment. So, we want to reduce the empty capsids and enhance it or increase the capsids that have that genetic fragment. And hopefully if we can do that, we can actually even reduce the dosage required for gene therapies when those ultimately get delivered. Of course, that it has huge ramifications for thinking about dosing and safety and efficacy. So, those are important considerations to keep in mind. We’re just starting those scientific programs now to support those activities and do research. And we’re also asking the community for their insights and ideas on what kinds of disease candidates we can use for clinical trials. What are disease candidates that are really an unmet need. There’s no one else working on it, and there’s a patient population that would be available for perhaps trying a clinical trial for these kinds of approaches. So, we’re starting to narrow down that process to identify those disease candidates, and I hope that within the next five to six months, we should have a much better picture of where we stand on all of those fronts moving forward. So, the first year has really been about organizing a very large consortium of industry organizations, government agencies, and our foundation of NIH partners to pull this together. And now, I think, I’m starting to move into the scientific phase, and that’s an exciting feature. So, I hope that we’ll see more in terms of what these manufactured viral vectors will look like in developing platforms to support that for testing those vectors. And again, I think more to come in the next five to six months on those activities.

Daniel Levine: The FDA’s Peter Marks, director of the Center for Biologics Evaluation and Research, has been an active partner in these programs. How much of a translational barrier exists in the regulations, and do you find the agency open to creating pathways more appropriate for small patient populations, particularly in the case of ultra-rare diseases?

Joni Rutter: Oh, absolutely. In fact, the Bespoke Gene Therapy Consortium that I mentioned before, NCATS co-leads that with the FDA and an industry partner at Pfizer. And so, having FDA and sitting with them at the helm of this program in complete partnership is really a testament to that idea that there are barriers that exist, but creating those pathways is a high priority because the FDA sits on these committees to help us understand how can we use regulatory science to help us really understand what those barriers are and how to tackle them. And this becomes incredibly important with those with rare diseases that have an unmet need, because we’re talking about the challenge of N-of-1 and of small and of 10-20 people who might have a particular rare disease where this kind of approach could be very helpful. So, as we’re thinking about developing a platform that could support the therapeutic development, we also need to develop the regulatory infrastructure to support how we can examine those smaller trials and tackle the issues and the barriers they’re in, and think about different kinds of approaches there too. How do we think about new ideas such as tissue chip programs that might be useful for clinical trials in rare diseases? And expanding our understanding of looking at that predictive toxicology and predictive efficacy in human-based psychophysiological systems, like those tissue chips that I mentioned. And those are some activities that I think that we can start to really bring to bear on these kinds of translational barriers that exist on the regulatory side. But having the FDA at the table on all of these types of questions is incredibly important, and I think it does really show that this is a priority for all of us because this is an ecosystem that needs to work together.

Daniel Levine: There’s been a lot of excitement about the potential for AI to transform drug discovery. Is NCATS doing any work around AI and how do you think it might change drug discovery and development in rare diseases, if at all?

Joni Rutter: Yes. absolutely. Artificial intelligence, machine learning, these are certainly activities that NCATS has been involved with, and I think there’s huge potential here. We’ve heard a lot about the idea of computer assisted design of developing compounds and how we can actually see it, we can draw a compound and see how it interacts perhaps with the target, and is the pocket of where the compound interacts with the target appropriate? What’s causing something to not interact as well and how can we then use that information to go back to the medicinal chemistry side and start to develop compounds that address the nature of how those compounds interact with targets and artificial intelligence is a critical feature of how we can look at those kinds of characteristics. I think, in terms of artificial intelligence, the not just the idea of developing compounds, like I just mentioned, is important, but also thinking about if we can start to develop a cadre of those compounds that might be in IND enabling studies moving forward, if we can identify those toxicities early and understand what compounds might have certain features that contribute to those toxicities, that kind of algorithm development for machine learning could then be used to identify compounds early on that say, oh, this compound has a moiety on it, or a feature included in that compound that’s been seen in toxicity studies. So, that would be something that you really look at moving that compound forward. And I think the same could be said for efficacy as well, so that this idea of combining sort of that computer assisted design approach with the idea of developing algorithms that can identify particular features of compounds to understand compounds that might be more toxic, or compounds that might be more efficacious in certain situations. Those are areas where I think AI could really be very helpful. We’re still kind of in the early phases of that in really testing that through, but certainly the potential is there and we’re very excited about that.

Daniel Levine: We’ve talked a bit about the translational challenges of drug development, but as you think about NCATS, where do you think the biggest opportunity for it is with regards to making positive impact on that?

Joni Rutter: You know, I think we’ve talked about some of these, for example, the gene therapy kinds of approaches and I should expand that even to gene targeted therapies, which include gene therapy activities through viral vectors, but it’s also inclusive of gene editing approaches that we’re seeing more of as well, antisense oligonucleotides that can be used for the later science of DNA moving to RNA and proteins. Antisense oligonucleotides are more important for those—that side of the molecule. So, I think there’s huge potential there. I think another area a big opportunity is thinking about how we can move the tissue chip program into the next phase of development. So, we have spent the last decade really identifying ways in developing tissues on a chip for lung, well, actually for all organs, for lung, for heart, for kidney, for brain, et cetera. And we’ve been able to really show the power and the promise of that kind of a use of tissue chips for drug development. And I think that’s an exciting time where we can really put those through the paces over the next decade and really understand how we can get that into the regulatory space. And I think that will be a big help for rare diseases, but also just the regulatory science of the IND packages that can be put forward for drug development. So, the tissue chip program, I think, needs to continue to make advances in that way. And we’re starting to do programs like that. We now have organs on a chip where we have multiple tissues on one chip so that we can look at perhaps what’s happening in the heart, what’s happening in the lung, what’s happening in the liver all at the same time, and from the same types of cells with the same backgrounds. That’s really critical, I think, in advance of what’s happened over the last couple of years. And moving forward, we can start to see how, for example, if you’re a patient, there might be a day where we can take blood from you as a patient and create a tissue chip that would be helpful for understanding if you have to be in a clinical trial to test the medication that’s being used in that clinical trial, first on a tissue chip made from your own cells. So that’s kind of the wave of the future that we’re trying to think about, and I think there’s big opportunity there, including those other areas on gene therapies too.

Daniel Levine: World Rare Disease Day will take place February 28th. NIH and NCATS will be holding a conference that day to recognize it. It will also be streamed live. You’ll be delivering opening remarks. What can people expect at the event?

Joni Rutter: Maybe I’m biased, but it’s the event that I really look forward to every year, because what people can expect from this event is it it’s not your typical workshop, not your typical meeting. It is full of rare disease resources and highlighting particular programs that are happening across the nation—programs that NCATS supports, programs that others support. And a lot of our partners are at the table giving presentations on their latest and greatest activities and resources that they have. So, these are coming across the nation, but also across the NIH and the NIH resources and partners that we have here, for example, for resources for clinical trials, resources for researchers out there doing rare disease research, resources for patients who are interested in learning more about rare diseases. And what we’ll hear too at the Rare Disease Day at the NIH is what I really appreciate a lot—hearing from the patients themselves. And so we’ll hear lots of rare disease stories from people with a rare disease, the important role of advocacy, and industry and how we can collaborate and partner together. And I think that comes across really well when we hear from the patient stories about their experience, their lived experience, and how we can learn from that moving forward. I hope that all of your listeners are able to join on February 28th. And if you need any information on that you can Google Rare Disease Day at the NIH, or there’s a link to it, which is ncats.nih.gov/news/events/rdd for Rare Disease Day.

Daniel Levine: Joni Rutter, director of the National Center for Advancing Translational Sciences. Joni, thanks as always for your time.

Joni Rutter: Thank you so much. I really appreciate it.

This transcript has been edited for clarity and readability.


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