664. Are Thousands of Medical Cures Hiding in Plain Sight?

There is a horrible infectious disease that you have probably never heard of.

It's called balamuthia.

“It's basically your brain eating amoeba.”

They don't really know how it's transmitted probably through some sort of soil exposure. It causes encephalitis, which is swelling in parts of the brain. It can kill you in relatively short order. It's extremely rare and so there's been very little study of it. That is Heather Stone.

She is a health science policy analyst in the Food and Drug Administration. The FDA has not approved any treatments for balamuthia, but that doesn't necessarily mean there aren't any treatments. Three or four years ago, a clinician in San Francisco at University of California, treated the first patient with a drug called nitoxelene, which had been approved in Europe

for 50 years for urinary tract infections. One preclinical study had shown off the chart and mebasidal activity that nobody had ever known about. You might not think that a UTI drug could treat a brain eating amoeba, but biochemistry can surprise you.

A couple of years later, I got a call from a mother of a young girl who had been infected with balamuthia and was not expected to survive. And she was desperately trying to get a hold of nitoxelene. I was able to help get what's called an emergency ID and an investigational new drug application because the drug is not approved in the US, but it's approved in Europe.

“You have to get special permission from the FDA to use the drug.”

They sent the drug and Elena had a pretty remarkable recovery. Now, I mean, it's not a miracle cure. There have been other patients who have received the treatment who have not survived. But for a disease that had a 90% fatality rate to have two patients survive, like that, was pretty remarkable.

There are 18,000 known human diseases, but only about a quarter of them have an FDA-approved treatment. So, is the story of balamuthia, a story that could be replicated? How many more things are there that we could potentially uncover to save lives today? Because these drugs are already at the pharmacy. They're already manufactured, they're already available.

Today, on Freakonomics Radio, the economics of repurposed drugs with a special guest host, Steve Levitt, my Freakonomics friend and co-author, who is a professor emeritus at the University of Chicago, and that episode starts now. This is Freakonomics Radio, the podcast that explores the hidden side of everything, with your guest host, Steve Levitt.

Hi, I'm Steve Levitt, and I'd like you to meet a doctor with an unusual life story. My name is David Faganbaum, and I'm co-founder and president of every care, and also a physician scientist at the University of Pennsylvania. David Faganbaum grew up in North Carolina. His parents were from Trinidad, and his father was a surgeon.

But he didn't always think that medicine would be his chosen path.

When I was about eight or nine years old, I decided I wanted to become a division one college quarterback. For the next nine or ten years, that's literally all I thought about. My walls were covered with poster boards with how fast I could run, how far I could throw a football, and I was just completely 100% laser focused on this dream of being a college quarterback.

“And it turned out, I mean, you took the team to the state finals two years in a row, right?”

That's right. Yes, but you didn't finish the story, and we didn't win either time. And then you're seeing your year, you broke your collarbone. And it looked like the end, right? That's right. Yeah, it was the first pretty much senior year. My dad's a orthopedic surgeon. I got a concussion on the play, and my dad came down to the sidelines and he put his hand under my shoulder pads, and he felt my collarbone.

And he said, David, you're never going to play football again. And I was like, wait, what?

Actually, he operated on my shoulder. And I was back on the field about five weeks later, and ended up being okay. My senior year, you're not very good. I never really played the same again after I broke my collarbone. You get recruited to play quarterback at Georgetown. But almost as soon as you get to Georgetown, your mom is diagnosed with brain cancer and turned her life upside down. That's right. It broke me to my core. Probably the most difficult

known my life was hearing my dad tell me that my mom had brain cancer. She was amazing. She was the most incredible person. And it shattered my belief in what was fair and right in the world. It also immediately shattered my focus on football. The moment that I learned my mom had brain cancer, and I started seeing what she was going through and started seeing these doctors who were trying to save her life. I just said, I've got to do this. This is what I have to spend my

it's got to go towards helping to take care of patients like my mom. So you had didn't plan

“I being a doctor until your mom got sick. Is that right? That's right. I was very interested”

in sports and eating well nutrition health, but not necessarily medicine. Once I saw my mom's illness. And then once I learned that there were these horrible diseases out there like brain cancer where there are no treatments. I just said, well, I got to spend my life trying to find them. So you did go to med school and then you all but died from a rare disease. Could you tell me about that? I was on an OB joy on rotation and over the course of just a couple of weeks I went from

being in really top shape and really healthy to being critically ill. It started out first as feeling more tired than I ever felt before during med school. We're usually all pretty tired because

things are so busy, but it was a tiredness that I'd never felt before. And I noticed in large lymphaments

in my neck and I started getting horrible abdominal pain. I took a medical school exam and then I went down the hall from my med school's aim to the emergency department and asked for them to do blood work for me. And they told me that my liver, my kidneys and my bone marrow were all shutting down and that they'd have to hospitalize me right away. Once I was hospitalized, I was transferred to the intensive care unit, again, over a hundred pounds of fluid, needed daily transfusions to

keep me alive and I actually had a redinal hemorrhage that made me temporarily blind on my left eye. So it was really, really bad, really, really quick and we had no idea what it was. It turned out to be a rare disease, something called castlement disease. At this time, there were no

“drugs approved for treating castmen. Did the medical profession just not really understand this disease?”

That's exactly right. Castleman's is a rare disease and it causes your immune system to attack your vital organs and shut them down and it's deadly unless you can get under control. The way that one of my doctors described it is we're going to literally try the kitchen sink. We're going to give you seven chemotherapys all at once at the highest possible dose because we don't know what's going wrong, but we think if we just give you sort of the nuclear option, then we'll stop

whatever is going wrong. Fortunately, it worked. We all hear about chemotherapy and how bad they make you feel. I actually felt better with every dose of chemotherapy, which just sort of gets across just how sick I was. So you had a little bit of respite. You decided if the medical

profession didn't know what to do with you, you would figure it out yourself, right? Basically,

right around then I was started on an experimental drug and it was the only drug. It still was the only drug to ever undergo a large clinical trial like that for castlements. I was really hopeful that drug was going to work. I mean, this is the answered prayer that we didn't get for my mom. So I went back to med school after being on medical leave for about a year. Then when I relapsed about a year later, now this is May of 2012. And my doctors explained to me that we were out of

options, but I realized that I couldn't just sort of wait and hope that some research or somewhere would find a drug for me. I realized that if I wanted any chances to survive, I would have to really turn my hope into action and start trying to find a drug that could save me. But there just was really only one way to save my life. And that would be to use an existing medicine in a new way because the finance is just don't add up to create a new drug from scratch. It costs

between one and two billion dollars and it takes 10 to 15 years to create a new drug. So that

wasn't an option for me. I didn't have the time where the money what I thought was possible was maybe I could find an old drug for another disease that could save me. And then that was really inspired by the fact that none of those chemotherapies were made for castlements. I'm sitting there thinking okay you're telling me that there's no more treatments for my disease, but you just gave me seven treatments for another disease and it worked. So how do we know that there isn't an eighth

drug out there that might actually help me? And that became my real obsession. Could I find a drug that's made for another disease that could treat my castlements and save my life? What was even your approach to trying to sort this out? The history of medicine had failed to do it. It doesn't seem very likely that you this one guy was going to make it happen. It was very unlikely. The way I was thinking about it was that I'm going to go out swinging. There's a website called PubMed where you can

“find all the published literature and I found that there were 2,000 papers that had the key word”

castlements somewhere either in the paper or linked to it in some way. And so I emailed everyone of those authors and there's 5 to 10 authors per paper so I probably sent like I don't know 10 to 15,000 emails. What I found is that obviously a very small fraction of them are actually studying castlements or interested. But 27 of them showed up to a meeting that I held in December of 2012 at the American Society of Humanity. That was a big moment. I remember I couldn't sleep

the night before I felt like the Super Bowl. I'm getting together these leading experts for castlements and we're going to learn what do we know and what do we need to know to better understand and treat this disease. So for me that was really step one as let's build this community. The second parallel approach was let me start looking at related diseases and what we know about castlements

could be on the short list for when I relapsed again. And then the third thing that I did.

“So I started collecting my own blood samples. I started storing my blood every few weeks in”

the freezer and it wasn't my home freezer. It was the freezer in the lab. But the idea was that if and when I relapsed I would want those blood samples to show me what was happening in my immune system. So if I could possibly survive that relapse then I could go back to those samples and see if I could pick up what happened when I was relapsing. And then you did relapse and then I relapsed and I had my fifth deadly flare and there's one person I haven't mentioned who played such an

important role and everything. That's my girlfriend the time Caitlyn. I had that fifth relapse shortly after we became engaged to get married. That fifth flare was really, really, really

tough emotionally. For a lot of reasons one I was dying but also just heartbroken that I wasn't

able to have this family with Caitlyn. But I was given the same seven chemotherapys and they somehow worked again like just sort of just scraped by and I remember waking up and just having this smile like, oh my gosh, I got another chance. And the moment that I started to wake up my sister, Gina was on my left side of my girlfriend, Caitlyn was on my right and my sister Lisa was at the foot of the bed and I remember waking up and seeing them and saying, gee, I need you to call you

and see and get a lymph node that's there sent a Philadelphia Caitlyn. I need you to go downstairs

“the basement, start getting medical records sent them to fill me like I think I'm going to make it”

out of here. Like I got another shot at this and sure enough I was able to get back to Philadelphia and I just went straight to lab. Was it the blood in the freezer that ended up being the key that put this puzzle together? It was the blood in the freezer and that it actually was that lymph node that was in North Carolina that was also really important. So the blood in the freezer I thought those blood samples and did something called serum proteomics where we measured a thousand

different proteins in my blood and looked for a signature. What are the things that were elevated in my blood? They can maybe give me a sense for what my immune system was doing and why those things were elevated and I got a strong signature for something called the M tour pathway. So M tour is really important for your immune cells to become activated and to fight off things. It's sort of like a communication line in the immune system. We're almost like an alarm system. What I found was that

it looked like it was turned on and to overdrive like it was massively on. I didn't have a way to confirm it in my blood but that lymph node that had my girlfriend get sent to Philadelphia. That lymph node I was able to do an experiment to confirm that the M tour path I was turned into overdrive. So now I had two sort of orthogonal or disparate data points that were pointing to the same thing. That was enough for me to take that data to my doctorate and I age, present the data to him

and say you know what do you think and really the question of what do you think about actually giving me an M tour inhibitor because when M tour is turned on like it is your immune system's out of control of their M tour inhibitors that were made for organ transplant rejection decades earlier and they were FDA approved. They never been used for castlements but they were already on the market so I thought maybe I could try an M tour inhibitor. So when you made this

M tour discovery, this was a new knowledge. This is something that nobody in the medical domain had ever noticed before. That's right. It was a novel discovery and it ended up being the discovery that would be needed to link the drug serolimus to castlement disease and say my life. Serolimus is also known as rap a micein. That's right. And rap a micein has an interesting history. It was discovered in the soil on Easter Island, right? That's right. You want to tell

the story because it's actually such an amazing example of how drug discovery doesn't always

perceive linearly. We would all like to think that medicine and medical research is more linear.

“It's more systematic but boy is it random at times and I think this is a great example of it.”

There was a researcher at Y of pharmaceuticals who was going around various specific islands and digging up soil samples and he believed that maybe there would be antifuncles in the soil basically to help keep the local organisms fungus free. And so he had this hypothesis. He collected all these soil samples. One of those samples he collected on the island of a rap in Nui which is why he called it rap a micein and it turned out that rap miceins are pretty lousy antifuncle. But it

is very good, exquisitely good at inhibiting M-tore. In fact, it's so good at inhibiting this complex that the complex got named after the drug. M-tore actually stands for mammalian target of rap a micein. Like this thing in our body is inhibited so well by this drug rap a micein that we named the thing after the drug. I've also heard a story that because rap a micein was not very good antifuncle when they were shutting down some plant, they were just going to throw it all out.

And the researcher actually smuggled it out and put it in his freezer. It is own freezer. No, you're right. I actually, I'm sort of getting goosebumps thinking about that because yes, he believed in the drug and you're right. The company said throw it out and he said no and he put

and he said can I study this in the new boss and share. I'm just thinking about the chain of things

“that had to happen in those decades before, you know, I'm here in Philadelphia looking”

under the microscope at my lymph node and thinking, I want to try serolimus. Well, if any one of these things don't line up, there is no rap a micein, there is no serolimus and I'd make it discovery, but there's no drug for it and I would have died 11 and a half years ago. Has the drug had the same effect on others that are afflicted with castlament? Well, the next three

patients we treated first a patient in Brazil and then a patient in New Zealand and then a patient

here in Philadelphia, all three of them responded incredibly well. And the midst of relapses when they were doing very poorly, they responded incredibly well. The third patient, the one here in Philadelphia, was a young boy named Joey. He was about 13 or 14 years old at the time. He was very, very sick. And it meant so much for me to actually be able to see him getting better day to AC as blood work improving because with the other patients I heard about it, but they were in

“other parts of the world. With Joey, we would come in multiple times a day to see him and to actually”

see him getting better on it, it meant everything. So now we're four for four basically, me and these three patients, that or I said, we did it. We took down castlament this intractable, horrible deadly disease. It's done. Unfortunately, the fifth patient we tried it on it didn't work in. What we now know is that it works in somewhere around 20 to 25 percent of patients, which is something to both celebrate, but also, hey, we got a lot more work to

do. And this initial success that you had with yourself and others was the inspiration for you launching an organization called EveryCure. Can you tell me about the approach that EveryCure is taking to this problem? From the moment that that drug serial I'm asserted saving my life, I just haven't made a list of things about how many more drugs are out there. They could

treat more patients in need. I'm not supposed to be here. Sarah Lymeus was never made for

“castlements. And who knows if it ever would have been discovered for castlements. So the question”

became, well, how many more things are out there that we could potentially uncover to save lives today? Because these drugs are already at the pharmacy. They're already manufactured. They're already available. My lab at Penn, and I joined the faculty shortly after discovering that drug to save me, so I've been on faculty for about 10 and a half years. And my lab started doing this more and more frequently trying to study immune cells from patients with hyperinflammatory diseases.

And we actually had discovered in total, including Sarah Lymeus for me, a total of 14 drugs for disease they weren't intended for. And we saved well over a thousand lives with drugs that weren't made for their disease. So we're so proud of that. About three years ago, we started thinking about, well, we're doing really well for these few rare diseases that we're working on. But what about all the other diseases out there? We said, what if we could really scale

what we're doing in my lab by looking across all drugs and all diseases? And we could actually quantify how likely every drug is to treat every disease. And all 4,000 drugs against all 18,000 diseases. And AI could actually focus us in on the best matches across all of the possibilities. Could you walk me through the clues that would lead your algorithm to focus on a particular drug

disease combo? We utilized what are called biomedical knowledge graphs, but you're basically

if you try to create a map of every single biomedical concept. So every drug disease, gene, protein that you've ever heard of, putting that all onto one giant map, and then annotating the relationships between every single one of them. GOP ones, treat diabetes. We can do that a thousand of times to the models, pick up what's an example of a good treatment in this graph. And what are the patterns of connections between a drug and a disease where that drug actually works for that

disease? And then give us a score from zero to one if the model finds a pattern that looks likely that that drug will work for that disease. M-tore is elevated in castle and disease. We discover that serolimus inhibits M-tore, therefore serolimus can inhibit M-tore and treat castle and disease. It's basically looking for those sorts of connections across everything. And if it finds something that looks really good, it gives it something close to a .99 and it finds something

that doesn't look like a connection. Let's say a tonal fungus drug and pancreatic cancer, it's going to give it like a .001. And then we humans, we can go to the very top and say, what's AI telling us is a .9999? That's where we start. When you say start, you really mean start because the hard work actually probably begins where the .99 ends. Oh, absolutely. Our platform is a low-hanging fruit finder. It's pointing us to these .99s. And then our medical team, which are

M-d's PhDs and M-d PhDs, they actually look at the .99. This drug for that disease. Why is it that Lydicane might be a treatment for breast cancer? Lydicane is the numbing medicine you get if you

injecting Lydicane around breast tumors before surgical excision. There was a large clinical

“trial done of 1,600 patients that were randomized to have this numbing medicine injected around”

the tumor and the other half didn't. The patients who were randomly assigned at the injection around their tumor had a 29% reduction in mortality. This is startling because a 20% reduction in mortality is a huge mortality improvement. It's also startling because Lydicane is already used in nearly every surgical procedure. It's used at the side of the incision. So that way when you wake up from your surgery, you have less pain when you wake up. So it's

already a substance that's being used during the surgery. What's being proposed here is to use that exact same substance, but just put it around the tumor, eat to 10 minutes before surgery, and you have the potential to reduce mortality in a really significant way. This study was done. It was published in a great medical journal, the journal clinical oncology. And no one's doing it. And the reason no one's injecting this is probably a fewfold. One is that it's only one clinical

trial. So maybe we need to do another trial. Maybe we need to wait another five or seven years to learn more about it. Another part of it is that there is no company that makes Lydicane in a branded fashion. There's 10 plus different companies that make generic Lydicane, and they all make it for pennies and injection, and they all share fractions of this market. So there's no entity that's financially incentivized to do more studies with Lydicane,

or to make sure that every patient who is breast cancer asked their doctor to have Lydicane injected around their tumor beforehand. Now we're getting into more familiar territory for me incentives. What's frustrating when it comes to finding new uses for all drugs is that the science is so much easier. But the economic incentives are almost totally absent. Here's how a faking bomb describes it. Once you're dealing with FTA proof drugs, you already know

how it works in the body, because it's been proven. You already know that it's safe enough to be approved for one thing, and you actually also already know that they can do something in the body that can be clinically meaningful for a particular condition, which means that it's more likely that it can also do something clinically meaningful for another condition. So you've taken it from all of this uncertainty, which is many unknowns about every molecule, and of course 90 plus percent

of drugs that are started in development will never make it to approval. So now you're dealing

with just the things that they work and they hit something in the body, they're safe when they do that. They can have a clinically meaningful benefit. Oh, and by the way, they're already at your CVS, and for 80 percent of these, they're generic, which means they're also cheap. So you add all

“this things up, and that's what we work with, and you might say to yourself, well, why aren't people”

repurposing drugs? It costs about 1 percent of the cost to develop a new drug, to repurpose a drug, and find a new useful for an old drug. Of course, the economic reason is that though it's much, much less expensive to do it, there is zero financial upside, even though it's going to help a lot of patients, no one's going to make any money off of it. There's this broken economic system. I just think that there's something here that's totally outside of my realm of understanding,

and my work, it would be so great if some really smart economists could spend some time thinking about this and anything about ways to solve it. As a matter of fact, some smart economists already have, we'll hear from one of them after the break. I'm Steve Levitt, hosting Freakonomics Radio today, and we'll be right back. We've been talking about the potential benefits of repurposing existing drugs for new diseases.

That's not a new idea. Here's the Dartmouth economist, Chris Snyder. A famous case is aspirin. In the late 1800s, it was developed and used as a pain reliever. It was discovered later in the 1900s that my goodness, when people took aspirin, they didn't

suffer from their second heart attack. Studies showed that it reduces the chance of a second heart

attack by 25%. Snyder and I were in grad school together at MIT. MIT ran out of space for

“students. I think we had a bulge in the admits. They cleared out a windowless supply closet and they”

threw both of us in there. Which for me was a great opportunity to be locked with Steve Levitt for a year in an office. So you've done all sorts of great things over your career, but I would say that your latest efforts as one of the directors of the University of Chicago market shaping accelerator or MSA for short, this feels to me like it might be a legacy of a thing that you tell your grandkids about. Could you explain what MSA is trying to do? Sure,

it involves faculty, co-directors at the University of Chicago, that's Michael Kramer,

is moved to in Washington DC. We decided that it was going to be easier to influence policy in Washington, DC than Chicago, and then there's me up at Dartmouth. We got funding from Schmidt Futures and Citadel Foundation, and they were interested in these areas of public health, pandemic prevention, and climate, big existential social issues. And the question is, how do we solve those? Maybe without having to break the bank one way to do it is through innovation and saying, "How can

you spend a dollar of public funds to get a hundred dollars of social benefit?" They're different ways to come out the problem if you're a funder. One is you can try to find the most promising inventors and just encourage them along, provide them with grant funding and push them through from the beginning of the process. The market shipping and seller is not against that for a funding. We probably think there's too little of that anyway, but what we think is that there's an alternative,

and that is to work at the other side of the pipeline. To do that, they use a mechanism that Rachel Glennister and Michael Kramer developed about 20 years ago called an advanced market commitment. It works like Kickstarter. Governments or foundations commit to buying a product that doesn't exist yet. That means companies can invest in creating new treatments, knowing there's a buyer waiting at the other end. You dangle market incentives in the right parties who are going to

actually have the best ideas. Well, in a sense, self-organized, just as markets often do, and bring themselves to the pipeline to try to get that reward at the end. You can think of the push funding as a payment for attempt, and poll funding is in a sense payment for success. In 2004, Glennister and Kramer proposed an advanced market commitment to stimulate research on vaccines in poor countries. Snyder joined the team, and they got to test their academic theory out in

reality a few years later to try to develop a more affordable, normal cockle vaccine, which prevents pneumonia, meningitis, and sepsis. The pneumococle vaccine advanced market commitment was picked up by the Gates Foundation, and they organized finance ministries from five different countries, and this global alliance for vaccines and immunizations comes to be called

Gavi. It was part of the administration of it, and it turned out to be a $1.5 billion fund.

“And how many companies tried to go after this $1.5 billion in payouts that we're sitting there?”

There were two. There was Wyeth that was then bought by Pfizer that had the existing vaccine, and GSK was developing one that had even more strains that would have qualified under this program. Then the CIRM Institute of India came in, probably halfway through the program, and actually the prices did come down with the entry of CIRM Institute. They came down quite a bit. And have you tried to estimate in the end the return on investment to this advanced market commitment?

The second generation pneumococcus vaccine has been credited over that period of time with saving 700,000 lives of children under five. It really hits any mark you want for cost effectiveness.

Prevener was the first generation vaccine that was sold in high-income countries.

This is the next generation that was going to conjugate more strains into that vaccine. This sits close to home. My own son Andrew died of pneumococcus meningitis just like a year to before Prevener got approved, and Prevener would have been just the thing that probably

“would have saved his life. I think about that when we talk about the pneumococcus vaccine.”

Yeah. So this was a big success, I think. Almost anyone would look at say, "Hey, this worked exactly as we hope maybe even better." But this was launched in 2009 and as far as I know, there weren't any other big market commitments like this done until COVID. Is that true? And what do you think that seeing the success here didn't spur government to let time to this more quickly? I think that is true. There were some other limited programs. I worked on one for

multi-drug resistant TB, but it's on the order of several million dollars, not in the billions.

If you think about say innovations that are going to help develop in countries, I think that after the global financial crisis, all the countries in high-income areas were cutting back their aid budgets. So I think that's part of it. And then, you know, we had COVID hit and then we're thinking, "How do we get out of that pandemic?" So government has made huge advanced commitments to firms developing COVID vaccines. And at least to an outside or like me,

the COVID vaccine development felt like a stunning success. Incredibly fast times from idea to ramping up manufacturing to a global scale. Is the true story as good as it appears and

“you give a lot of the credit to these advanced market commitments? I think the story is miraculous,”

really. When COVID hit, Michael Cramer got some calls, because people are wondering,

Michael Cramer's brainchild was a pneumococcal advanced market commitment. And who's named do we know? Well, Michael Cramer won the Nobel Prize in Economics. So he was getting a lot of calls from all over the world to say, "What do we do? How much should we invest?" And certainly policy makers had the intuition, like this is a big problem. We should invest a lot of money. We said over and over again, or a paper after paper and made call after call, like, "Yes,

you can't spend enough money on developing these vaccines. You're losing trillions of dollars every

“month in morbidity, illness, death and closure of your economies and schools." So you should”

invest billions to save trillions. Obviously, with Operation Warp Speed, there was push funding. Basically, all the companies, except for Pfizer, their facilities being scaled up, and R&D costs, they were all covered by the government, and also these poll commitments to buy the vaccine, even though they hadn't been approved yet, were being signed. So they're doing both, and, not either, that seems sensible to me, and such an emergency. So when you launched the market

shaping accelerator in 2023, I'm curious, you had this powerful tool. You knew it could work.

Did you have a whole long list of applications where you already knew you wanted to apply it? Or was it more you were searching for ideas to try to figure out where to go next? So to announce ourselves, we took $2 million of our startup funding, and we put it toward, it's kind of a meta idea, but let's use poll funding to try to poll fund the best ideas for planning back to us. We used the money to provide prizes and milestone payments for the best ideas

for neglected areas that might benefit most from these market shaping interventions. We got about a hundred and ninety submissions from all across the world from some really serious players, which we went down to three finalists, and one of the finalists is this program for generic repurposing. It was actually an idea submitted by a lawyer named Sava Credemalites, and it's kind of blows in my mind. There's a lawyer out there who proposed this idea, which is now working its way

towards having, if we're lucky, a trillion dollar impact. That doesn't actually happen in research. Do you agree? A lay person had an idea that is turning into something that is really really gonna matter. It's not a great message about a concept that I push all the time, which is that nobody's got a monopoly on ideas, even people like Michael Cramer who have great ideas, don't have that many great ideas and finding a way to let regular people express these ideas

is a powerful, powerful, very democratizing force, which is really great to see.

It's part of the idea of market shaping in a way that we don't necessarily have all of the answer

“is, okay, so repurposing generic drugs. What's the problem here that needs to be solved?”

There are plenty of incentives to develop the initial drug. We have a patent system. You have to sell these blockbuster drugs to patients and insurance companies and pharmacies, and you can make billions of dollars. In the inventor of that branded drug, they have incentives to find other uses if that expands their market. The trouble is that that's true for branded drugs, but not for generic drugs. Once a drug goes off patent, essentially any incentive to come up with

new uses and to do the clinical trials, those incentives drop off a cliff. What's interesting about that is we have laws that are trying to incentivize people to do it. So if you come up with a brand new use for an existing pharmaceutical compound, you can get a patent that covers that use. The problem in practice is that it's completely uninforcible because let's just say Viagre turned out to be a great drug for fighting cancer, which it isn't. But let's say it was a $500 billion market.

The problem is when a doctorates a prescription, they don't write a prescription and says,

this is a prescription for Viagre for cancer. They say this is a prescription for Viagre, and when they fill it, they'll just fill it with the generic drug, not with the drug that's covered

“by the patent. And the only way to enforce it would be to do lawsuits one after another against”

every doctor, which of course would be a terrible publicity and impossibly difficult to do. It's not that people don't realize and haven't written laws to try to help it. It's just that the laws we've gotten place have not worked empirically at all. Yeah, you can get patent on new uses for drugs and new uses for generic. The trouble is, as you say, you can't monetize it. So the market shaping accelerator, well, along with researchers

from the Duke Markolus Institute for Health Policy, has spent the past three years developing

into new uses for generic drugs. We think this would cost roughly $1 billion,

per successful opportunity. That's Siren Chathak. He's a senior policy analyst who works with Schneider at the market shaping accelerator. Here's some Chathak describes their pull funding proposal. First, a funder, like Medicare, Medicaid, or the NIH, would promise a reward if companies successfully discover and proven they use. So this reward would be based on impact. For example, whoever the funder is could say, we've assessed that every year that someone uses this drug,

it saves Medicare $2,000. So now we have this drug that's successfully been repurposed and a impact metric per patient. Next, the manufacturers would sell the drug for the new use and then each year the funder, say Medicare, would measure the adoption of that drug for the new use and they would pay the company based on the impact. Let's say $50,000 patients take it that year and as we said, the estimated savings are $2,000 per patient, then this would imply savings of

$100 million. And so they would pay the company some percentage of that. So as long as the promise

of that payment is enough to justify running the clinical trials, companies will make the investments and run them in the first place. Will this ever happen? We've had promising conversations, no commitments yet. HHS Health and Human Services has made this a priority on a higher level. There was a health and human services strategy report that was released in September and it had, I don't remember exactly, but maybe 30 priority areas and drug repurposing was one of those

“areas. And here again is the Dartmouth economist, Chris Snyder. I think there's a chance here.”

We'll work with whatever agencies want to work with us to iron out the wrinkles in the program

and to start specifying what the program looks like. We are definitely trying to hit a home run here.

We would want this to be a really broad and systematic solution for drug repurposing. Maybe I'm wrong about this, but I don't think small necessarily means easier. Governments have time constraints and many government officials want to have a lot of impact. So we're hoping that's the case with this. That, in my opinion, is a fantastic recovery idea for how the U.S. government couldn't incentivize drug repurposing. And one big advantage of it is

that it doesn't cost a government of penny unless it works. Coming up after the break, we'll hear about what it's like working on drug repurposing for inside the government. Generally, the phrase that's thrown around is it's not considered sexy enough.

“So I think that's a fundamental problem.”

We heard how some economists think the U.S. government should encourage farmer companies to make groundbreaking discoveries of new curious from existing drugs. But even when those discoveries are made, getting them actually adopted by doctors is its own challenge. On average, it takes 17 years for a new medical advancement to be adopted. That again is Heather Stone from the FDA. We heard from her at the beginning of this episode.

And that's probably a promising estimate for many repurposed drugs where there's no commercial incentive, and so there's no real marketing around them. Stone has been thinking about and working on drug repurposing for practically her whole life. My mom was an infectious disease doc, Ben. I often saw her face patients with diseases that did not have any approved treatments. At that time, you phoned up your mentor, your colleague, and asked them what they had tried

“or how they would approach it. That was how information was disseminated. I remember the”

inordinate amounts of time that we're spent trying to find solutions to help these patients. And then I myself, we joke that I'm like the repurposing test cases. I have benefited enormously from repurposed drugs with my own health issues. I'd love to hear that story. Let's see where to begin. I have a chronic pain condition, probably fibromyalgia, but it's kind of a diagnosis of exclusion. It began in high school and by

the time I was in college, I could barely get out of bed and actually almost dropped out of college because of the pain and fatigue. Eventually a drug called Lyrica, which had been approved for diabetic neuropathy, patients started reporting that those who also had fibromyalgia noticed really large improvements in their fibromyalgia symptoms when they were taking it for diabetic neuropathy. So I was put on that drug and that has been a treatment that I've been on now for

So you have been instrumental in creating something called cure ID. Could you just describe

“what cure ID is? -Cure ID is a treatment registry. It operates as a website and a mobile”

application that allows patients, caregivers and clinicians to all share their treatment experiences with repurposed drugs and then to explore with others, have tried. It makes the data all openly available to everyone to see. -Let's say I go to cure ID and I type in toxoplasmosis. -What will I see? -You would see all of the cases where clinicians or patients or their caregivers have submitted their treatment experiences with the drugs that they have tried

for toxoplasmosis. They will be able to see whether those drugs were effective or not in individual

patients and then as a whole or whether they were not effective or had side effects that

perhaps led them not to be used. And then you can go each layer down to see the full details

“that were submitted for each patient about their treatment experience. -And what is the scale?”

-Now of cure ID. How many entries are there in the database? -There are about 700 clinicians of medications and about 600 to 650 patients of many cases or caregivers of many cases. There are approximately 5,000 cases that we've extracted from the published literature and then there are 115,000 cases that we have extracted from electronic medical records, but those are specific to acute COVID-19. -So if you think about it from maybe a skeptics perspective,

what you're asking for with your ID is you're asking practitioners to do something that

is going to help someone else but doesn't really have any career benefit. It's an act of good will on the part of the clinician or the patient who enters the data. So if you would talk to a economist you'd say well wouldn't be that surprising that it would be hard to get doctors to report outcomes. Did it surprise you though when you launched your ID just how hard it was to get people to make entries? -It didn't. It didn't. You're absolutely right. There is an incentive problem

and it's something we've worked very hard to try to figure out what is in it for the clinicians and also part of why we pivoted to patients and caregivers, sharing their experiences. I think the answer to what is in it is that it creates sort of a virtuous cycle where they then get information that is important to them in the treatment of their patients by reading what others have

“tried. As was sort of any social media platform you have to get the ball rolling and it's been”

difficult to do that. The feedback that we had received was very positive. People thought this was a brilliant idea and that they thought that there was an enormous need for this kind of platform. They certainly recognized that people would potentially be resistant to taking the time to share their experiences. There might have other reasons for not wanting to share them but I don't think we recognized just how difficult it would be. -As I listen to you talk I can't help but think about

how different your approach to saving lives via cur idea. How different it is versus business usual at the FDA where drug approvals require the carrying out of costly time-consuming randomized experiments to prove the safety and efficacy of the drug therapies. I suspect for that reason alone. Probably other reasons too, you likely faced a lot of resistance within the FDA as you work to getting cur idea launched. Is that a fair statement? -Yes, it's been challenging to

persuade people of the utility of the platform and to acknowledge its limitations. We don't think that a drug should be approved based on the data and cur idea. That's not its intent and it's not designed to do that. What it's designed to do is to generate hypotheses that can then be studied in more robust clinical trials or observational studies. We can't tell from these cases alone for sure whether a drug is helping or not. -The idea of pull funding, so the idea is if a firm

went in and got FDA approval for a new indication for a drug that the way they'd be compensated would be after the fact by going and looking in the data and saying how much good is this drug doing in this new setting and the obvious people to make that decision would be the people who run Medicare and Medicaid because they're the ones who are spending the money they can see that patient outcomes. That strikes me as a really radical idea of a very different way of doing business.

I love the idea, but I worry that public entities would just look at that and say no way, that's

It's not clear to me that we have a way of effectively making those kinds of assessments.

“I mean, maybe CMS does. It's outside of my scope of expertise. I think the general premise”

of pull incentives is something that has worked in other similar areas. And so, from that sense, it's not a totally radical approach, but some of the details of the implementation are different enough that it's hard to know whether it would be possible. -I know you probably don't know the numbers of the top you have, but just guessing what your medical research dollars are currently going into drug repurposing and just in your own opinion, what will be the right

share? -If I had to guess, I would say a fraction of one percent. Like incredibly small. What is the

appropriate fraction? Maybe 10 percent? I mean, I really don't know. It depends on the value

that you can gain for society from it. Obviously, there is enormous value that is gained from the development of novel treatments and from understanding of basic biology. But I think that there is a lot of unrecognized value in identifying existing drugs that could be treatments for diseases that have really large morbidity and mortality. It's very difficult for repurposing research to compete with novel drug discovery, for example. Generally, the phrase that's thrown around

“is that it's not considered sexy enough, right? So I think that's a fundamental problem.”

There is one person who's trying to make drug repurposing research sexy, David Faganbaum. His organization every cure has already raised some serious dollars from the federal government and also from foundations and philanthropists, including Ted Zodatius Project, John Arnold,

and Mark Zuckerberg. We've now raised over $100 million, which is just transformative to

build a direct towards drug repurposing when you consider that this has really been so neglected over the years, but also typically a cost between $1 and $2 billion to make one drug. So $100 million is much less than a cost to make even one drug, but we're able to go a long way with that, because the drugs are already approved, they're already available, and with the $100 million that we've raised, we anticipate being able to treat 15 to 25 debilitating conditions in

the next five years. So you've raised a bunch of money and hopes for what you're doing in our sky high. Do you ever wake up in the middle of the night and worry about the fact that maybe it's just not going to work that well? Then the end, it'll be disappointment. I probably should wake up and worry about that, but when I actually worry about all the time, or just the people that are waiting for our drugs, that there's a drug that could help them, and there's someone suffering

right now, and we haven't found it yet. I walked past the CVS when I was coming here today, and I thought to myself, what drugs are in there on that pharmacy shelf, and who is suffering right now in Philadelphia, let alone anywhere else in the world that can benefit from one of those medicines that's not on that medicine. I'm fortunate enough to have been one of the lucky ones that got on one of these medicines that wasn't made for me, and I'm here. So I sure as hell better

“spend the rest of my life looking for more of these things for more people. I think back to that final”

promise I made to my mom that I was going to become a doctor to discover drugs in her memory, and maybe if I got really lucky, I could develop one drug for one disease, and that would just be

a pinnacle moment in my career. Never in my wildest dreams could I have imagined that my own

personal experience would open my eyes up to the simplest, highest ROI lowest cost way to help people in a way that hadn't been done before. The worry for me isn't will we meet expectations. The worry is just 100% that person that's waiting for that drug that we haven't found yet, and how can I engineer our system and our program so that we find that drug in time for that person so they don't suffer and they don't have to. That again was David Faganbaum in conversation

with Steve Levitt. Thanks to both of them as well as Heather Stone, Chris Snyder, and Sarah Chuthik. You'll be hearing more episodes down the road with Levitt as host, meanwhile coming up next time on the show. I see an educational system that immediately rewards you for everything. A great job. There's no way to tell a kid well this wasn't really good work, but I know you can do better and why don't you work on this, bring it to me tomorrow, and all of a sudden you have

a good one. It's a philosophy behind education and make the children happy instead of making them

like it. We will hear from the filmmaker, writer, and self-styled philosopher Werner Herzog.

“That's next time on the show until then, take care of yourself, and if you can, someone else too.”

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