This month we're talking with Dan Skovronsky, President of Lilly Research Laboratories and Chief Scientific Officer for Eli Lilly and Company. He walks us through his career that has taken him from the pharmaceutical startup world to his current position at Eli Lilly. He gives us a peek into the drug discovery and development process specifically focused on Alzheimer's detection and research.
The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease.
Dr. Aaron Carroll: Hi, welcome back to the Healthcare Triage Podcast. This Healthcare Triage Podcast, and all podcasts, are sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care. IU School of Medicine is leading Indiana University's first Grand Challenge the Precision Health Initiative with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma, and prevent type 2 diabetes and Alzheimer's disease.
Today we're going to be talking about Alzheimer's disease, specifically drug development. I'm super excited today because our guest is Dan Skovronsky, President of Lilly Research Laboratories and Chief Scientific Officer for Eli Lilly and Company. I've known Dan for years. We actually went to medical school together at the University of Pennsylvania School of Medicine. Did you graduate with us in 1998 or was it later?
Dr. Daniel Skovronsky: Well, it took me a little bit longer because I stayed on to get a PhD as well. I was there for seven years ago.
Dr. Aaron Carroll: Very good. Well, let's start with that. I'd love to talk about how you got to this position, given that we both started in the same place, which was at University of Pennsylvania in 1994. When I took off in 1998, what were you doing?
Dr. Daniel Skovronsky: I was working towards my PhD, working in neuroscience on basic mechanisms of Alzheimer's disease.
Dr. Aaron Carroll: Then what did you do after getting your PhD in MD?
Dr. Daniel Skovronsky: I continued my training through a residency and surgical pathology, and then I went on to fellowship training in neuro pathology.
Dr. Aaron Carroll: Where was that?
Dr. Daniel Skovronsky: That was all at the University of Pennsylvania.
Dr. Aaron Carroll: Oh, great. Okay. Then you finished in what year?
Dr. Daniel Skovronsky: All of that training took me about to ... it must have been 2005, I think. Then at that point, I took a different path. Instead of continuing in the academic research path in which I had been working for many, many years at that point, I took an entrepreneurship path and took one of the projects I had been working on even as a graduate student, and started a company around it.
Dr. Aaron Carroll: How do you do that?
Dr. Daniel Skovronsky: Well, at the time, I actually didn't know the answer to that question. Now I do, which was probably helpful, because it's a difficult thing to do, particularly so, even more than today. Back then I think it was a bit more unusual for someone from academia to go out and start a company. At the time, I quickly identify there's three big things you need to have a company. One is you need the technology, and in this case, of course, the technology which I'd been working on, was co-inventor of, had all been invented at the university. It belong not me and the other vendors, but to the university. It's how things work.
You have to get that. But of course, you go to the university and say, "Hey, we want to license it," and they say, "Well, great, we license technologies to teams. So show us the people who's your team, and you need money. So show us the money to devote [inaudible 00:02:54]." Of course, I didn't have those other two things. Then I went said, "Okay, well, maybe I could go hire some people," and started talking to experienced drug developers and see if I could put a team together. Of course, they said, "Well, it sounds like an interesting idea. But you don't actually have the technology, and you don't have any money."
Then I said, "Okay, let me try the money side," and you go out and talk to venture capitalists so you want to invest in this technology, and what do they say? We need a team and we need to get the technology. The first year or so was trying to get those three things together, and how do you assemble those resources, the people, the technology, the dollars, so you can get started? Eventually, I had some traction there. Put together a team which grew to be over 100 people, and over time worked on this idea that we had in academia.
Dr. Aaron Carroll: I'm somewhat [inaudible 00:03:47] I don't even know what muscle to flex. How do you even start? Was this you thought that you could do this, or did you have some other people that were with you that were like, "We could do this?" Or how does that happen?
Dr. Daniel Skovronsky: It was mostly me, actually. I had friends who had different experiences, some who had more on the business side than I did. I mainly asked them for free advice, which they gave me. Then just started reading on the internet and making phone calls and driving around in my car to meet people.
Dr. Aaron Carroll: How much venture capitalists did it take to get something like that started?
Dr. Daniel Skovronsky: Well, to get started, it varies. In my case, it was a million dollars that made me think that it was going to be real, which just shows how little I knew at the time. Because now I know a million dollars isn't actually very much for this kind of endeavor. But at the time, I remember that day very, very well where, after intense work and negotiation, I closed on a million dollar financing and I kept calling my bank, which was just my neighborhood bank, because again that's what I knew and they were open on Sundays and that's what I needed. I kept calling my bank and saying, "Is my money there?" The teller said, "Okay, I now see a new balance in your accountant." She's like, "It's 110,000." She's like, "Oh, no, it's a million."
Dr. Aaron Carroll: Wow.
Dr. Daniel Skovronsky: 100. Then I was like, "Okay, now I've made it." Of course, we went on to raise nearly, must have been 60 or $70 million to develop this product. That was just the very beginning.
Dr. Aaron Carroll: Right. Okay, so that was about what year?
Dr. Daniel Skovronsky: 2005.
Dr. Aaron Carroll: Now you have a company, now you want to develop drugs, what do you do next?
Dr. Daniel Skovronsky: When I started my company, we were working ... We haven't said yet what we're doing, which is we're working in Alzheimer's disease. Our goal there was to develop a drug that could be an imaging agent to see the plaques in the brain of Alzheimer's disease and help detect the disease and diagnose the disease. The first thing we needed was chemistry, because we had to design, create a molecule. I hired some chemists, and the first chemist I hired, I said, "Okay, our first job is to build a laboratory so we can make molecules."
He and I went around and bought equipment. Initially, we even went to companies that were going bankrupt and selling all their used laboratory equipment. We'd show up there in my truck, and literally with a bank check, because it was a cash type of transaction, and we said, "Okay, we want that machine and that machine that one," and load them up and take them back to the lab and see if we can get them working or not. We spent some time building a lab and and then hiring more chemists and getting to work.
Dr. Aaron Carroll: Okay. Then how do you actually make a ... I mean, I'm sure there's multiple steps here, but part of what I'm trying to ... How do you then ... What do you do? I mean, now you've got a laboratory, so you want to make this ... We'll call it drug. It doesn't sound like a drug. It sounds like it's-
Dr. Daniel Skovronsky: It's a drug. Yeah.
Dr. Aaron Carroll: Okay. But it's for diagnosis-
Dr. Daniel Skovronsky: Yes.
Dr. Aaron Carroll: Purposes. You now have all these people, what do you do?
Dr. Daniel Skovronsky: We started making molecules, making chemicals that have the properties that we were looking for, and then testing them in different assays in the laboratory and trying to get closer and closer to a molecule with the ideal properties. The goal of that stage of research is to get something good enough that you can eventually test it in people and see if it works.
Dr. Aaron Carroll: Is it first in ... Would you start with cells or animals? Or where did you start?
Dr. Daniel Skovronsky: Some of the initial screens were what we call in vitro screen, so just in a test tube, using different chemicals and extract to test them. Then another stage of screening was using human tissue from people who had died with Alzheimer's and donated their brains to research, and then we were able to see, "Okay, if this is supposed to detect amyloid plaques in living people, can it at least see it on post mortem or-"
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: "... tissue from people who had died?" That was another level of screen. Then you can go to animal models, like mice, and say, "Okay, well, it needs to get into the brain." When we inject it into the blood, does it travel into the brain and get in there? Those are the types of experiments that ultimately can lead up to human testing.
Dr. Aaron Carroll: This came from your work as a graduate student, you were saying?
Dr. Daniel Skovronsky: Yeah, I'd actually started this project at the tail end of my graduate training, of my training as PhD, and then I continued to work on it through some of my postdoctoral training.
Dr. Aaron Carroll: How did you even come up with the molecule to begin with? I mean, where did it come from?
Dr. Daniel Skovronsky: Yeah. My background is I'm a neuro pathologist, and in neuro pathology, one of the things that we have relied on for almost 100 years is histopathological stains that are essentially dyes that came from the textile industry that people discovered could stain different kinds of tissues in different ways. One of those stains that you might remember from medical school was called Congo red.
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: [crosstalk 00:08:54] an attractive name there that the textile industry gave it to make it seem more attractive. Congo red binds, it turns out, to amyloid plaques, and it was just empirically discovered by histopathologist many, many years ago. The idea that we had was to take that dye, which must have some affinity for these plaques, and start modifying it and see if we can make it thousands of times better at doing it. In fact, there was another dye also called thioflavin, that had the same kind of property, very different chemical structure. We're working on that as well. One of the breakthroughs came when we saw that structurally we could have elements of each of the two molecules combined, and that was one of our breakthroughs that then led to the ultimate compounds that we developed.
Dr. Aaron Carroll: Is it you're just synthesizing compounds trying to get them to fold the way you want?
Dr. Daniel Skovronsky: Yeah.
Dr. Aaron Carroll: I mean, is it all the way back to organic chemistry?
Dr. Daniel Skovronsky: It's organic chemistry. You have chemists adding. Well, what happens if we add oxygen in this position or nitrogen in this position? Over time, and this is still this is how we do drug discovery, even a company like Eli Lilly, is you start to develop an understanding, and we call it a structure activity relationship, or SAR, which is, okay, if I modify the molecule in certain parts, in certain directions, the left side becomes bigger, for example, then that seems to work better, bind better.
If the right side becomes smaller, that works less well. Of course, there's many, many different properties. That's a gross oversimplification. But the chemistry team combined with the biologists who are testing these molecules start to develop that kind of an understanding, and then they can make rational decisions about how to modify the compound. Of course, we're always trying to change, optimize for many different things at once. One is, how tightly does it bind your target? But that's not enough. You also need to make sure that it gets into the target organs. So in this case, does it get into the brain?
Sometimes those things will be conflicting. When you make a compound that works better binding, it doesn't work as well getting the brain. Another thing might be metabolism. Your body has all kinds of ways of metabolizing or chopping up foreign molecules, make sure it doesn't get chopped up too quickly or in a bad way. Optimizing for safety. It has to be something that is safe. Often in drug discovery, we're looking for things that can be taken orally, and those properties are often very unique and different. The job of the medicinal chemist is to make modifications that can simultaneously optimize for all of these properties. Once we have something good enough, we go into human testing.
Dr. Aaron Carroll: Okay. You've got now to the point where you feel like you've got something. You've been testing it, you think it binds. How do you know you're ready for human testing?
Dr. Daniel Skovronsky: Yeah. You set criteria at the beginning of any campaign and say, "Okay, if I get a molecule that hits these criteria, a certain level of affinity, brain entry, et cetera, we'll go on and test it in humans." We had one, and on it went. One wrinkle here is that the first module we tested didn't work very well in humans, and so it was a bit of back to the drawing board.
Dr. Aaron Carroll: How do you even do the human testing? I mean, you can't obviously just [inaudible 00:12:00] put a shingle and say, "We want to give you a pill or a shot." How do you actually get that done?
Dr. Daniel Skovronsky: Yeah. Drug companies, big companies and small companies, although we say we do human testing, of course, what we really do is collaborate generally with academic physicians, as well as private physicians, who see patients, who do the testing on our behalf. In this case, it was ... Typically, in early drug testing, it's very specialized, so there are specialized physicians who can do that kind of testing and they have all of the safety precautions and the apparatus set up to be able to do it.
In our case, it also required brain imaging, so it was a very complicated thing to do. We worked with academic centers that could do that kind of brain imaging, and they found patients and injected the compound for the first time, which is nerve wracking because you don't want to hurt anyone of course, and we're very, very happy that we never did. But testing a new drug in a patient always carries some risk. Then look at the brain scan and see if it works or not.
Dr. Aaron Carroll: Right. Okay, so you did it originally and it did not work?
Dr. Daniel Skovronsky: That's right.
Dr. Aaron Carroll: What do you do next?
Dr. Daniel Skovronsky: We had a strategy to test multiple compounds, nearly in parallel. We had a number that were going to come forward, almost regardless of what the first one did. We knew that we would take a few attempts to optimize. Eventually, we had a few that looked pretty good, and we picked the best one and took it through longer stage testing and ultimately became a drug.
Dr. Aaron Carroll: What do you do next?
Dr. Daniel Skovronsky: Yeah. The next big goal is to get a medicine approved by the FDA, and there's global regulators around the world that work like the FDA does in the United States. At that point, there was lots of discussions with the FDA. Well, how should we demonstrate that this really works? Because we're trying to diagnose Alzheimer's disease. Image is something in the brain and Alzheimer's disease that hasn't been seen before. One thing you could do is just say, "Okay, I'm going to image 10, 20 people who have a clinical diagnosis of Alzheimer's, and 10 to 20 people who don't and show you there's a difference."
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: Of course, we did that. That's early testing. What you see is that most of the people who have Alzheimer's show that they had a brain full of plaque, but some of them didn't. Our view was those are people that the clinician is making mistake, they don't actually have Alzheimer's. That's why we want to develop a new test-
Dr. Aaron Carroll: Absolutely.
Dr. Daniel Skovronsky: ... as the diagnosis isn't so good. When we took older patients who don't have a diagnosis of Alzheimer's and image them again, you can image 20 of them, a few of them looked like they did have and we would say, "Okay, well, those are patients who are likely to go on to get Alzheimer's disease, and maybe the physician has noticed the changes in their cognition yet." Anytime you're developing a new diagnostic test like that, that's supposed to be better than anything else that's out there, what do you compare yourself to show that you're actually right?
We call that a truth standard. What is your true standard? Lots of discussions with the FDA on that, culminating in what's called an advisory committee where the FDA calls a panel of its top advisors, and we present our ideas. At that meeting, we presented an idea that we would do something no one had done before, which is image people's brains and see whether they had the plaques or not, and then follow the people over time until they died. These would be people who've agreed in advance to donate their brains to research and then we would look at their brain under the microscope and see was the test right?
The gold standard would be the neuro pathology at autopsy. That was a difficult idea and a difficult trial to conduct. So we went to hospices and to researchers who are studying Alzheimer's disease, and said, "We're looking for people who have perhaps cognitive decline, or maybe not. We need both kinds. But also have another reason why they might be near the end of life. So do they have cancer, heart disease, or lung disease?" We were able to find people like that, which was really meaningful that these individuals said, "I know I'm in the end of my life, but I want to do something to help science and health research."
Some of them had family members with Alzheimer's, some had Alzheimer's themselves, and their family members said, "This is what my wife would want in her final days, to be able to give something back to research." Really touching and meaningful contribution from people who sent me, at the end of the study, photos of their loved ones and poems they had written and articles and newspapers that they had contributed. Everybody I think wants to help out on Alzheimer's disease. So we were able to conduct this study and show that it was successful, and then bring that data back to the FDA and say here, "Look, it really works out well."
Then ultimately, got it FDA approved, and it's now available. It has been for several years. Unfortunately, it's not covered by most insurance payments, which has been a deep disappointment for me and for many people with Alzheimer's. Really just because it's expensive to do a test like this. It involves a very specialized scanner and radioactive drug and physician to read it. Means it's been out of reach for most people, which is too bad.
Dr. Aaron Carroll: Yeah. What do you do even at this step?
Dr. Daniel Skovronsky: Yeah. We were lucky to contract with national companies that can make the radioactive drug for us, the imaging agent. We have been able to make it available for people around the country. But, again, that facility needs to get paid, and the doctor who administers it and the doctor who owns the scanner or the hospital that owns the scanner and the physician that reads the scan. That's been a barrier. We worked over the years with Medicare, because that's the primary care for elderly patients. Worked with Medicare and we're gratified to get some progress with something called coverage with evidence development, where they paid for it for people who were involved in research. Thousands and thousands, more than 10,000 people have gotten access to it through that, which is something but still out of bounds for most people.
Dr. Aaron Carroll: What is their rationale? How do they make the decision about whether to cover it or not?
Dr. Daniel Skovronsky: These are tough decisions, and there are people whose job it is to decide whether or not certain medical technologies and procedures are paid for by insurance or not. In this case, I think the basis of their decision was, we don't really know that whether diagnosing Alzheimer's disease early or more accurately will result in changes in care and changes in outcomes for patients.
Dr. Aaron Carroll: That's interesting. So if tomorrow we came up with a drug that they said, "Well, if you get this early, it would prevent Alzheimer's," then all of a sudden that might be a very different calculation, it sounds like.
Dr. Daniel Skovronsky: Of course. Yes, yes. That's always been the end goal here, is while it's very important to detect Alzheimer's as early as possible, this is one of the things that neurologists spend a lot of time doing because they can offer counseling to patients and they can offer different therapies to patients. None of them are a cure, but it can have important impacts on people. When it's not Alzheimer's, that's important to know too. But ultimately, our goal is to say, "How can we help develop a drug that can really meaningfully stop or meaningfully slow down the progression of the disease?"
Dr. Aaron Carroll: But it would still sound like the drug that we've been talking about most of this competition is super important for research because how else would you pick up the patients who are potentially at high risk for [crosstalk 00:19:59]
Dr. Daniel Skovronsky: Yes. Yeah. While it's been deeply disappointing that it hasn't been available to patients, for me it's been extremely gratifying that just about every modern Alzheimer's clinical research trial uses this to find the right patients to treat, or one of the related technology. There are two others who came out after ours.
Dr. Aaron Carroll: [inaudible 00:20:15] Okay, so you've done that?
Dr. Daniel Skovronsky: Yes.
Dr. Aaron Carroll: What did you do next?
Dr. Daniel Skovronsky: Yeah. That pathway led me to Eli Lilly. In 2010, I sold my company to Eli Lilly, a leader in Alzheimer's disease research, who shared our vision for what we could do in Alzheimer's disease and saw the value of this for patients but also for research, and I became part of this company. Then over the years, from then till today, I've had different roles inside the company learning and leading different parts of our research organization, and then for a few years leading the drug development organization. Research is how we discover drugs, development is how we test them in patients. Now I have the privilege of leading research and development being the head of R&D at Lilly.
Dr. Aaron Carroll: I can wrap my head around the story of how you got to your drug, or the one we've been talking about where we know that the stains work, can we manipulate the stain and make work, but is that the story for most drugs? I mean, how do you come up with the drug?
Dr. Daniel Skovronsky: Yeah. That's right. There's a couple different ways to find new medicines, but you often have to think about what's reasonable starting point, And sometimes it's something that's out there in the literature that's not very good but gives you an initial handle on where to start. Another way we can do it, which is a lot more sophisticated than anything I had available back then, is we can actually determine the structure of the target. If you have a particular protein, and mostly we're trying to drug protein so that we can talk about other ideas in a minute, you can do what's called crystallize it, which then allows you to determine the structure.
So you're seeing the structure of the molecule, almost at an atomic level, so you can really understand the shape of it. the drug is supposed to fit into a particular groove on the molecule, And you can actually see the groove. Then using sophisticated computer software and simulation as well as know how for medicinal chemists. You can say, "Okay, I can design a molecule with this particular shape and pattern of charge that could fit into that groove very tightly." We call that structural-enabled drug discovery, where we actually know the structure that we're working on. It's not just trial and error in the dark, and that represents a great deal of what we do.
Dr. Aaron Carroll: Now that I understand that, why does it fail? Why can't you just nail it?
Dr. Daniel Skovronsky: Yeah, there's a couple of reasons why. Actually, unfortunately, there's many, many reasons why drug discovery fail. It's been said that developing a drug is not rocket science. It's actually much, much harder.
Dr. Aaron Carroll: Great.
Dr. Daniel Skovronsky: In most of our attempts to fly, fail. But hopefully we learn from each one. If we have a target that we want to make a drug to, actually, most of the time, not always, given enough time and money and we'll have large teams of chemists working on things for many years, we can find a molecule that can impact it. That's because we choose our targets carefully, and-
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: ... there are some targets that we just know are undruggable. We don't know how to make a molecule, and so we just avoid those. But the ones we go after, we generally have an idea of how we're going to be able to make a molecule, and given enough time, we can make a molecule that can hit it. But it turns out that many of these won't be safe and will fail because of safety that even in preclinical models, we'll see, well, yes, it inhibits the protein X that you're going for, but also Y and Z which are dangerous.
Or sometimes we'll get all the way to human testing, and we'll discover that there are some safety abnormality which we hopefully and usually thankfully detect very early that a particular enzyme in the patient might go up that is an indicator that if we kept at this, it could cause long term harm and we stopped. Sometimes it just turns out that our understanding of the biology that we know that hitting protein X might be a good idea to stop a disease, but we were wrong about that, and actually, it's really an important target for normal bodily function or it's not an important target for the disease. The biology lets us down a lot.
Those are the two basic paradigms, is sometimes you've got a great drug that perfectly and cleanly hits the target you want, but the biology was wrong that that target isn't great to hit. Sometimes you have a great target, but you can't make a drug that cleanly hits it because the chemistry is too challenging. It's not cleanly druggable. Of course, the beautiful targets are the ones that have both really great biology that we totally ... at least we think we totally understand that hitting this will have a beneficial effect, and they're clearly druggable.
We know how to make a drug against that. Those are the golden targets, they go fast. Anytime someone has an idea, you can imagine most of the pharma companies that will jump on that, and the first one or two will have a medicine, the rest of us will step back because we don't need six drugs against a given target.
Dr. Aaron Carroll: What are you trying to do with most of the targets? Are you trying to block them? Are you trying to make them go faster? Are you trying to break them? What are you trying to do?
Dr. Daniel Skovronsky: Mostly, we're good at turning things off. We look for targets that are overactive so that we can turn them down. The other thing that we sometimes can do is supplement the activity of a target. But that's, as you can imagine, a little harder to make something work better than nature engineered it. It's often easier to make it work less. We're often in the inhibitor game. But sometimes we can do activators. I talked a lot about chemistry and small molecules, we call them because they're relatively small compared to proteins, which are big molecules.
But we can also sometimes more and more use what we call biologics, which are now ... they're not made by chemists, but they're made by cells. We can engineer cells to be our laboratory to make new medicines, and often those will be proteins themselves or a specific type of protein called an antibody, which is what your body uses to fight off infection. We can actually create antibodies that can turn off and in some cases turn on signaling pathways in your cells, and then that becomes the medicine, is antibody itself.
Dr. Aaron Carroll: This is almost overwhelming. How do you figure out what thing to do for what disease, or is it just all throwing over the kitchen sink and everything, or is it more thoughtful?
Dr. Daniel Skovronsky: Yeah, it has to be more thoughtful because it takes so long and it's so expensive. We as a company spend between five and $6 billion a year in research and development to discover new drugs.
Dr. Aaron Carroll: So where's that money spent? Is that on equipment, labs, people?
Dr. Daniel Skovronsky: It's mostly on the clinical testing. It costs a lot to run these trials, which involve thousands and thousands of people volunteering to participate in research all over the world. But for that investment, we and other companies that are our size, we hope if we're wildly successful, our goal is to deliver two new medicines every year. Five or $6 billion in, two medicines out. That's what it costs. Of course, it's also time delimited. The money might be spent many, many years before you have the medicine. So you also have to think about the idea that a dollar 10 years ago is much more valuable than-
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: ... having a dollar today. That's the business we're in, so we have to make careful decisions because failures in drug development, particularly in late drug development, are extremely expensive, which means we have less money for the next project. We spend a lot of money and time trying to understand biology of disease. One way of doing that is genetics and understanding, okay, people with a change in certain gene might be more predisposed to certain disease. That's an important clue. We'll also do things like system's biology, which would be to study specimens from patients with the disease.
So maybe we're studying at patient with Crohn's or ulcerative colitis, inflammatory bowel disease, and take a little biopsy from their intestine and look at all of the things that are dysregulated and say, "Okay, all of these things, it's like traffic is flowing in a different direction in this city, and how can we reverse the flow of traffic?" Instead of understanding disease as a single abnormality, it's a system, a pattern of things, look for the nodes that can reverse from disease to healthy tissue. That's another way that we approach thing. Then we're careful observers of clinical data. As we test our molecules in patients, we always learn and see what's impacted and how we go in a new direction from there.
Dr. Aaron Carroll: How do you decide whether a biologic is the answer versus small molecule versus something else?
Dr. Daniel Skovronsky: Biologics is mostly antibodies. These are really big. The great opportunity is that because we can use a biologic process to make them, the specificity is exquisitely high. What that means is that if you have a protein target, and we develop an antibody to it, the antibody most likely will bind just that protein target and nothing else. It's very, very clean. The downside is because these are big, they don't get inside of cells, so they can only hit targets that are on the outside. If we say see something on the cell surface, that's a very good target for an antibody. But most of the action, most of the proteins in your cell are on the inside, and for those we can't use biologics, so we focus on small molecules.
Dr. Aaron Carroll: Even when we go to small molecules, I mean, given that there are so many cells and then so many molecules and so many cells, how's it possible that we give a drug it can affect enough molecules all over the body that it works?
Dr. Daniel Skovronsky: Yeah. It is somewhat magical to think about this, right? One of the ways that this happens is it's driven by very high affinity. Although this analogy doesn't work perfectly, we talk about a lock and a key, that this is a key that fits a particular lock. But now you have to imagine a room full of doors-
Dr. Aaron Carroll: Right, right. [crosstalk 00:30:37]
Dr. Daniel Skovronsky: ... and one lock that's floating around, and it's literally just floating around being bounced around by random forces that eventually fits into the lock and turns it. When it fits, it better stick there and stick really tightly so that it doesn't have to find it again, because most of the time, it's not going to find its lock.
Dr. Aaron Carroll: I mean, when you get down to that level, it amazes me any drug works at all. I mean, just how does it get to all the sediment, all the molecules [crosstalk 00:31:01]
Dr. Daniel Skovronsky: Well, people have to take the medicine for it to work, and often that's why you take it every day, and we have to keep the blood levels such certain concentration of this molecule so it can find all of its targets. The problem isn't often that the target is too rare, it's actually the other way around. If the target is too frequent, if there's lots and lots of that keyhole, that particular lock, then you're going to need a lot more keys and then you start overwhelming the system with that. We think about that as well.
Dr. Aaron Carroll: Your job today is, I would say ... I mean, you tell me if I'm wrong, I'd imagine much more overseeing a lot of research going on.
Dr. Daniel Skovronsky: Yes.
Dr. Aaron Carroll: What do you do now?
Dr. Daniel Skovronsky: At Lilly, we work across a couple different therapeutic areas. Of course, diabetes is our longest standing and largest therapeutic area. Diabetes includes the complications of diabetes, like heart disease and kidney disease and liver disease called NASH. Altogether, of course, that's still the biggest killer in society, heart disease, and then complications of diabetes is important cause of illness. That's one area. Oncology, all the different cancers is another area that we work in. Immunology, which is diseases where your own immune system attacks your body for various reasons and causes disease like psoriasis, rheumatoid arthritis, inflammatory bowel disease that I mentioned before, these are all examples of immune diseases.
Then in our science we continue to work on neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, as well as the area of pain. In fact, pain is the number one reason people go to see the doctor. Something doesn't feel right and it hurts, and so we work in headache like migraine. We recently launched a drug for migraine as well as chronic pain, like back pain and osteoarthritis pain. It's an area that pharma didn't pay much attention to for many years, and then recently has become much, much more important.
Dr. Aaron Carroll: Is it organized by disease? Is it organized by symptom? Is it organized by the types of drugs that get developed? The cure's with the biologics [crosstalk 00:33:10]
Dr. Daniel Skovronsky: Yeah.
Dr. Aaron Carroll: How do you organize all that?
Dr. Daniel Skovronsky: You can imagine a matrix or a grid, and across the top, you could write the different disease areas and then those could be the columns, and then the rows could be that therapeutic modality. We'll have scientists who are focused on a particular technology, and other scientists who are focused on a particular pathway of biology or particular disease. So perhaps the person working on psoriasis, who's really interested in the biology of psoriasis and in particular, one pathway, we'll then find a person who's really good at making biologics because they'll think, "Oh, we need a biologic for this target," and then that starts to form a team around a particular target. You need all kinds of expertise. I've greatly simplified it to say-
Dr. Aaron Carroll: Of course, yes.
Dr. Daniel Skovronsky: ... just those two but-
Dr. Aaron Carroll: I mean, you might not have the exact number, but how many people are working in labs?
Dr. Daniel Skovronsky: Yeah. Well, we have over 6,000 people working in research and development at Lilly and on all my different teams, and of course on any individual project is much smaller. But that's-
Dr. Aaron Carroll: I guess I'm trying to think how many people are in labs trying to develop? We talked about there's ... I can't remember the two words you used. I think it was drug development, and then drug-
Dr. Daniel Skovronsky: Discovery.
Dr. Aaron Carroll: Discovery? Okay. How does it get divided?
Dr. Daniel Skovronsky: Yeah, so I don't think I have the exact numbers for discovery-
Dr. Aaron Carroll: Sure.
Dr. Daniel Skovronsky: ... and development. But it's probably around four fifths of our resources are in drug development. If you said, "Okay, in a given year, if we spend about $5 billion, three and a half to four of it is going to be on drug development, and one or one to two will be on drugs discovery.
Dr. Aaron Carroll: That blows me away because it feels like we should be able to do that more efficiently. There's just got to be a better way to do the testing. Because it would seem that the hard part, maybe I'm just naive again, would be they come up with the actual drug, and then there should be some kind of machine there. I mean, less physical machine, but some kind of organizational machine to do the test. Dr. Daniel Skovronsky: I agree with you. Drug development seems more straightforward, and yet it's such a major investment in time and money.
We can certainly get better than. There's lots of ideas and lots of investment to try and make things better. But right now, a clinical trial starts with going out and finding hundreds of investigators who are interested in a particular research project, explaining the protocol to them and getting all the ethical consents to start the research, and then they go out, start looking for patients, and they start with zero. Then they ask them, "Do you want to participate in this trial?" And so forth. We spend half the time in drug development, something like that, just looking for patients to participate in our research. That's a major focus. How can we start a clinical trial with a list of people who already want to participate? Because they're known, they're out there. If you start an Alzheimer's patient trial, of course there's so many people who have symptoms of Alzheimer's and would love to participate in research. Why can't we start with a list of those people?
Dr. Aaron Carroll: Now clearly, Lilly does a fair amount of partnering with academic institutions. I mean-
Dr. Daniel Skovronsky: Yes.
Dr. Aaron Carroll: [crosstalk 00:36:21] table, Lilly's in Indianapolis, we're sitting here in Indianapolis, I work in Indianapolis. IU School of Medicine, it's in Indianapolis. I mean, I see connections all the time. Do most of those happen on the discovery phase or most of those connections on the development phase, or is it both?
Dr. Daniel Skovronsky: It's both. I don't think we could proceed in drug development without collaborations with academic institutions at all, because that's where many patients are seen in academic hospitals and academic institutions have a long history of doing clinical research. On the discovery side, there's certain things that academic institutions are more focused on and certain things that pharmaceutical companies are more focused on.
For example, the idea of how do we identify a new target and understand its biology? A lot of that happens in academia, some of it happens in pharma. The question of how to make a drug that hits that target and changes its activity, that mostly happens in pharma, sometimes a little bit in academia. We have collaborations with academic institutions around the world, including IU here in Indiana, but it's the partnership I think that creates great ideas.
Dr. Aaron Carroll: Besides small ... We mentioned small molecules, we mentioned biologics. Is there anything else that's new and big that you're excited about?
Dr. Daniel Skovronsky: Yes, there is. There are new modalities of making drugs. Most of the drugs, nearly all the medicines that are available to patients, they are either a small molecule or biologic, generally an antibody or protein or peptide. But now for the first time we have new ways of making medicines that actually involve using DNA and RNA, particularly, which are the genetic material that our cells use. We're particularly interested now in RNA-based therapeutics, and probably most people know that DNA is the genetic code and it sits in the nucleus of the cell and determines the fate of the cell.
But all of the action happens in the cytoplasm, in the main body of the cell. That's where the proteins are made and function. How does the cell get the signal out of the nucleus and tell the cell what to do? It uses a short piece of nucleic acid called RNA, a particular kind of RNA called messenger RNA because it carries the message from the nucleus in the DNA to the cytoplasm.
Now we've learned how to turn off, and in some cases turn on, particular messages and then change what the cell is doing. So turn on and turn off gene transcription and translation in some cases, and ultimately impact the cell. That's exciting, and opens up whole new classes of things that might formerly had been undruggable that we can now impact.
Dr. Aaron Carroll: Can you give me an example? What something that would be been druggable then now you think might have some promise?
Dr. Daniel Skovronsky: Yeah, there's different challenges to this technology. Of course, there's advantages I just talked about, which is now you can turn on and off any particular genes. One of the challenges is directing it to the right tissue. A lot of times, these for various reasons get directed to organs like the liver, and so you can turn on and off genes in the liver, but many diseases are outside. So we're trying to work on getting it outside of the liver. But initially, we've seen a lot of progress on some of the rare genetic diseases where you know it's a particular gene that's gone awry.
It might only be one in 100,000 or one in a million people who have this gene that's gone awry, but they've got a mutation and now you can specifically turn it on or turn it off. We're trying to apply that same idea to larger diseases, because we're focused on helping as many people as possible. But diseases like cardiovascular disease, and then a particular disease of the liver called NASH are important targets that we're working on with this technology. We're also interested though in how to get this into the brain. There, there are diseases like Alzheimer's and Parkinson's, where we know that there are particular genes that get turned on that are mutated, that can cause the disease in some small groups of patients.
In the greater population, those same genes seem to be important to disease if we could just turn them off, and so that's what we're trying to do in diseases like Alzheimer's and Parkinson's, and these are things that we otherwise wouldn't be able to get to with a biologic or small molecule. That's why we're using RNA technologies. A lot of promise, it's still very early. There's just a handful of examples of RNA drugs now that have been approved by the FDA, and other related technology is actually modifying the DNA, and that's called gene therapy. You can put a new gene in or you can perhaps, although this hasn't yet been ... There are no drugs like this yet, but you could perhaps modify a gene and change a gene in a person from a bad one to a good one if you know the mutation. That's an exciting new area of research as well.
Dr. Aaron Carroll: Well, this has been fascinating. To be honest with you, I have about a million more questions, and there's a lot more I could ask. Unfortunately, it seems to happen almost every episode. I'd love to have you back at the time in the future. We can talk more about this because there's just tons of other questions about how [inaudible 00:41:36] But thank you so much for being on the show. It's been it's been absolutely fascinating.
Dr. Daniel Skovronsky: Thank you, Aaron. It's been fun.