Hard Drugs

Saloni Dattani: New weight loss drugs called GLP-1s, which include Ozempic and Mounjaro, have transformed treatment for two diseases: obesity and diabetes. They reduce high blood sugar levels, slow down the stomach's emptying of food, and suppress appetite, which causes weight loss.

Jacob Trefethen: New research suggests they also help with other conditions, including heart disease, kidney disease, sleep apnea, and potentially even Alzheimer's, and clinical trials are underway to test these too.

Saloni Dattani: But these aren't the only drugs with multiple effects. Although aspirin has been used for more than a century, it was established in the 1980s that it could help treat cardiovascular disease as well. The same is true for colchicine, an ancient gout medicine that was recently found to help treat heart disease. There's omalizumab, originally an asthma drug that, it turns out, helps treat food allergies.

Jacob Trefethen: In this episode, we're going to talk about the multiple effects of GLP-1 drugs and the broader idea of repurposing: when you take a drug that's used for one condition and find it works for other diseases too. What if many more drugs like these are hiding in plain sight? How do we get more of them?

Saloni Dattani: Welcome to Hard Drugs, a cool, awesome new podcast by Saloni Dattani, that's me, and Jacob Trefethen.

Jacob Trefethen: I don't know if we're new anymore, Saloni.

Saloni Dattani: Oh, that's true.

Jacob Trefethen: But it's awesome still.

Saloni Dattani: It's been our first birthday. We started our podcast a year ago.

Jacob Trefethen: That's right. That's right. Did you do anything to celebrate?

Saloni Dattani: No, I only realized a few days after.

Jacob Trefethen: That's a classic anniversary right there, you know? We both missed it.

Saloni Dattani: Okay, so I want to start this episode by doing a little bit of trivia. There are a lot of drugs that have multiple effects, multiple uses, and I wonder how much you know about them.

Jacob Trefethen: Hmm. I'm ready. I think I'm going to, well, we'll see. You hit me and then I'll tell you how well I'll do.

Saloni Dattani: I'm going to start with an easy one.

Jacob Trefethen: Oh gosh.

Saloni Dattani: I think you'll get this one. I hope. Okay. In the early 1990s, researchers at Pfizer tested a new heart drug for angina. It turned out it did very little for chest pain, but male volunteers in the study were strangely reluctant to return their leftover pills. What was it? What did it eventually become used for medically?

Jacob Trefethen: I think I'm going to get this one. I think it's Viagra.

Saloni Dattani: Ding, ding, ding! You're right. It's Viagra.

Jacob Trefethen: Yes. This one is a famous repurposing story that I've heard before. Yes. Viagra or Sildenafil, or I forget what the, what's the name for Viagra?

Saloni Dattani: Yep. Sildenafil.

Jacob Trefethen: Sildenafil, sildenafil, yes. Some surprising side effects found in the clinical trial.

Saloni Dattani: So what's the other condition that it's used for?

Jacob Trefethen: You mean now or in the 90s?

Saloni Dattani: Yeah, like medically.

Jacob Trefethen: Oh, I see.

Saloni Dattani: I guess that's also medically.

Jacob Trefethen: In my memories, it's something to do with the heart and blood vessels, but I actually can't remember.

Saloni Dattani: Yeah. That's right. It's hypertension, so pulmonary hypertension. It reduces the blood pressure.

Jacob Trefethen: Very good. Did the original thing it was tested for, is it used for that?

Saloni Dattani: I think the original use was angina as well, which is also related to blood pressure, but it basically acts on certain enzymes that are much more common in the lungs and the penis than in the heart or near the heart. So that's how it works. Okay. You got that one. I have another, this one's harder, maybe. I didn't know this until recently. So have you heard of thalidomide?

Jacob Trefethen: I have heard of thalidomide.

Saloni Dattani: Thalidomide is an infamous drug because it was originally sold for morning sickness in Europe and many other countries. Later on, it turned out that it actually caused birth defects as well. It's one of the worst medical scandals and led to the FDA changing its oversight on safety for new drugs. But it turns out that's actually also a treatment for another disease. It's used as a standard treatment for another disease today. Do you know which one?

Jacob Trefethen: This rings a bell... Oh, gosh. What is it used for? Um. Oh, God, I'm embarrassed. I can't remember. I remember it is used, and I can't remember what's for.

Saloni Dattani: Maybe take a random guess.

Jacob Trefethen: Okay, random guess. Thalidomide might be used for... hair loss.

Saloni Dattani: That's a good guess. It's not hair loss though. It's multiple myeloma, which is a blood cancer.

Jacob Trefethen: A little bit more serious than hair loss. The reason I should have done better test-taking skills there is the fact that thalidomide can have quite severe side effects related to the fact it's only used for a severe disease.

Saloni Dattani: Yeah.

Jacob Trefethen: That was what we would say pretty bad guessing from a trivia participant.

Saloni Dattani: It's also used in some cases to treat leprosy.

Jacob Trefethen: Oh, okay.

Saloni Dattani: Which I didn't know either. But the way that it works is it tags a cancer-causing protein for destruction. That tagging and causing destruction thing is also what happens in limb development in babies. That's how it causes birth defects as well.

All right. Third one. This one is not a single answer, but you can give as many answers as you can. It's about Botox. Botox paralyzes muscles and it was originally discovered as a toxin, but in small and precise quantities, it can be used medically or cosmetically, for example, in reducing frown lines and wrinkles. It's actually approved for around a dozen medical conditions in the US, and over 30 worldwide. How many of those medical conditions that Botox is used for, can you name?

Jacob Trefethen: Okay. Over a dozen?

Saloni Dattani: Around a dozen.

Jacob Trefethen: Over 30 worldwide. Okay. I think it's frown lines between the eyebrows, number one. Frown lines on the side of your eyes, number two. I think little sort of cheeks sometimes we'll be going for. We're already at three. Oh, there's left side of the face, right side of the face. We're actually at six.

Saloni Dattani: Oh, yeah.

Jacob Trefethen: The remaining six approvals, I'm not sure. Do you want to give me some?

Saloni Dattani: Frown lines on your arms, frown lines behind your ears. Okay, no, let me name them. I think you had the right idea-

Jacob Trefethen: That's VERY generous.

Saloni Dattani: -that it was kind of about muscular paralysis. But it's not about frown lines. It's used to treat crossed eyes, strabismus, and eyelid spasm, neck muscle spasm, also for preventing chronic migraine and severe underarm sweating.

Jacob Trefethen: Oh, I know that one. Yeah, I know someone.

Saloni Dattani: You knew that one? Then to treat overactive bladders and urine leakage that's caused by neurological conditions, then also spasticity of the legs and arms. It kind of makes sense, they're just different reasons that you would want to paralyze muscles.

Jacob Trefethen: Right. Luckily for us, we...

Saloni Dattani: You don't have any wrinkles yet?

Jacob Trefethen: Thank you. I was waiting. My armpits so far are, doing just fine.

Saloni Dattani: Not sweating that much.

Jacob Trefethen: Well, how do you rate that? I do think that men sweat more.

Saloni Dattani: There's probably a way to, I don't know, collect the sweat and see how much volume of sweat.

Jacob Trefethen: Good point. Good point. Yeah. I think the thing that matters is, is it enough sweat that someone can see it on my shirt? So that's actually, it's a binary.

Saloni Dattani: Right. Right. That makes sense.

Jacob Trefethen: And as soon as that happens... We're going into general anesthetic.

Saloni Dattani: I don't actually know if people use anesthetic to- before they use Botox. I thought it was just still injection or something. I have no idea, obviously.

Jacob Trefethen: Obviously. You're making so many YouTube watchers jealous right now.

Saloni Dattani: You're welcome.

Jacob Trefethen: They're like zooming in on our faces. They're like, oh shit.

Saloni Dattani: 'Wow, they really don't have wrinkles.' Last question. Out of all the small molecule drugs that the FDA has approved, roughly what proportion of them have an approval for a second medical use? How many, what proportion have been repurposed?

Jacob Trefethen: That's a really fun question, although I think those are two different questions because you don't need an approval for a second use. A doctor can prescribe off-label if they think it might help you even without approval. So let's just break down the question.

Saloni Dattani: I just mean the ones that are approved for a second use.

Jacob Trefethen: Totally. I'm breaking it down in my own head. So there's small molecules. There's different types of drugs and therapeutics. Small molecules are, in my head, more likely to go all around the body and have effects in places you might not expect.

Saloni Dattani: Right. These aren't hormones or peptides. They're not vaccines or antibodies. They're small chemicals.

Jacob Trefethen: Yeah. That's going to increase the number here. I would say the off-label use of small molecules is probably quite a large percentage, I would guess, have doctors who at least have once prescribed it off what it was approved for.

Then in terms of how many approved for a second condition or disease, I bet that it's going to be less than 50%, would be my guess. Because to get that approval, you often have to generate an evidence package and, are you really going to have an effect size large enough on a new condition? I bet it'll be less than 50. Then will it be more than 10%? Yeah, I bet it will be, because these drugs go everywhere. But I bet it's going to be between 10 and 50, so I'm going to say 20%.

Saloni Dattani: I think that was a great reasoning process. You're pretty close. It's about a third.

Jacob Trefethen: Wow. That's cool.

Saloni Dattani: Yeah. Which is quite a lot.

Jacob Trefethen: Yeah.

Saloni Dattani: This is out of drugs approved between 1997 and 2020.

Jacob Trefethen: Okay.

Saloni Dattani: Yeah. About 32% have a new use approved.

Jacob Trefethen: Okay. Wow. If we run the clock for another couple decades, some of the ones in that batch will get more uses approved probably.

Saloni Dattani: Probably, yeah. Isn't that cool?

Jacob Trefethen: That is cool.

Saloni Dattani: It's not that uncommon for drugs to have multiple uses.

Jacob Trefethen: I think I did pretty poorly in that trivia.

Saloni Dattani: How many did you get? You got the Viagra one.

Jacob Trefethen: I got the Viagra one.

Saloni Dattani: You sort of got what it was used for.

Jacob Trefethen: Yeah, I got the gist. The thalidomide one, I recalled that it was used for something and didn't even get close. Then the Botox one I got, I pretty much nailed that one. Okay, so maybe one for four. That's about the same amount as drugs get repurposed.

Saloni Dattani: Very good. All right. So the most famous current drug that is being repurposed or actually has already been repurposed, I think, are GLP-1s, and so these are weight loss drugs that act on a receptor called the GLP-1 receptor. They include Ozempic and Mounjaro and a bunch of other ones that are kind of in the pipeline right now.

They're used currently for treating both diabetes and overweight or obesity. But it seems like they might work for other conditions as well. They already have benefits for kidney disease, heart disease, sleep apnea - among people who have diabetes or obesity. But it's possible that they also have benefits for people without diabetes or obesity. So I wonder if you can guess how that's possible.

Jacob Trefethen: Yeah, how it's possible there's multiple effects, basically? Yeah, I think in general, if you're creating a drug that intervenes in some way in a process that happens in multiple parts of the body or a process that is pretty general purpose, then you might find that you're having effects down the line that aren't the primary thing you were aiming at. I think that's probably the core of the answer here. Is that fair?

Saloni Dattani: I think that's right. There are a lot of drugs that are called 'promiscuous'. They can act on multiple different receptors in the body, especially if they're small molecule drugs, because they're so small, they can get to lots of places that bigger drugs can't. Yeah, they have lots of effects.

But also sometimes, different diseases share the same pathway, like lots of viral infections use similar viral enzymes, or lots of allergies have kind of some similar pathway. So drugs that work for some of them could work for multiple.

Then there's also this idea that the benefit is sort of downstream. You're treating obesity and because you're treating obesity, it also has benefits for, let's say, heart disease or something else. Then I think there's a last example with a lot of mood disorders or mental health conditions where the conditions are often treated in similar ways. Antidepressants, many of them are also approved to be used for treating anxiety, for example, that might be because somehow biologically they're related. So yeah, there are lots of different ways that you can do that. With GLP-1s, they're not a small molecule drug. They're peptides.

Jacob Trefethen: Well, that's pretty close to small molecules as far as I'm-. They're pretty small and they're a molecule.

Saloni Dattani: Yeah, right. They're a big molecule.

Jacob Trefethen: They're not that-

Saloni Dattani: They're a medium molecule.

Jacob Trefethen: Yeah, medium. I'll take medium. I'll take medium. But the reason I'm harping on this is because presumably the fact that they're a peptide, not a big antibody or something like that, means that they distribute to more tissues around the body. Is that true?

Saloni Dattani: I think that's true. Also their receptors are found all around the body. There are GLP-1 receptors in the pancreas, which release insulin and reduce glucose. Then there are GLP-1 receptors in the brain in the hypothalamus, which suppress appetite. Then there are GLP-1 receptors in the stomach, which slow down how quickly the stomach empties food into the intestines. And there's also GLP-1 receptors in the heart and blood vessels, and probably in a bunch of other organs as well. So lots of different effects that you can have with this one type of peptide.

Yeah I think what's interesting about GLP-1s is that a lot of people now have heard of them as weight loss drugs, but they were first used for diabetes, and they still are used for diabetes. That is pretty long, like the first GLP-1 drug, that was approved in 2005, which is pretty long ago. We have a lot of data on this and we know that it can be used for these two conditions and it's pretty effective for them and safe.

Jacob Trefethen: I actually think the first GLP-1 drug was approved thousands of years ago. I've been using that stuff naturally. It just created in my body. You got any of that?

Saloni Dattani: That is true. I have that too. We all naturally have GLP-1 as a hormone in the body to reduce our appetite and reduce blood sugar levels. But the versions that are used in drugs are much longer lasting. This is what is really interesting because the GLP-1s that are used in drugs were originally discovered in a type of lizard called a Gila monster. It's spelt G-I-L-A, but it's pronounced 'Heela'. There's no G sound.

Jacob Trefethen: No G sound? Wow.

Saloni Dattani: There's no G sound.

Jacob Trefethen: Gila monster.

Saloni Dattani: I have been pronouncing this wrong for the last two years.

Jacob Trefethen: It's better than saying GAILA monster.

Saloni Dattani: That's true.

Jacob Trefethen: Actually, two wrongs make a right. Maybe GAILA monster is better.

Saloni Dattani: I guess there's no G sound because it's Spanish. It's found in the southwestern parts of the U.S.

Jacob Trefethen: So do you call them Hee-L-Ps?

Saloni Dattani: No.

Jacob Trefethen: You're taking your latest HeeLP-1 agonist.

Saloni Dattani: Have you ever seen this lizard before? This Gila monster?

Jacob Trefethen: I think I have seen one picture from maybe a scientific article, but I have not met one in real life, yes.

Saloni Dattani: Me neither, which is kind of a shame because it's really cute.

Jacob Trefethen: Is it time for a Hard Drugs expedition?

Saloni Dattani: What, to Mexico?

Jacob Trefethen: Yes, we have to meet one.

Saloni Dattani: I want to meet one. It's quite deadly though.

Jacob Trefethen: Oh.

Saloni Dattani: We'll come to that soon.

Jacob Trefethen: Oh.. kay. Deadly to diabetes too?

Saloni Dattani: Yes.

Jacob Trefethen: Good. That's the goal.

Jacob Trefethen: Just remind me, so the way that this was discovered is that a patient with diabetes got bitten by a Gila monster and there were surprising effects!

Saloni Dattani: No, but that would have been a great story. Yes, but they're found in the southwest parts of the U.S. and North Mexico, and they're about two feet long, or one to two feet long. Pretty big for a lizard. Actually, one of the largest lizards in North America, apparently, or maybe the largest.

Jacob Trefethen: It goes with the name monster, fair enough.

Saloni Dattani: That's true. They really do look really cute. Like if you're listening, I would highly recommend googling them and looking at these cute lizard pictures.

Jacob Trefethen: Okay. But didn't you just tell me they're deadly?

Saloni Dattani: Yes. Just forget about that part.

Jacob Trefethen: Got it. Okay, great.

Saloni Dattani: I have a few more trivia questions for you. They're more just like, fun facts, but some of them are fake. You have to guess which facts are true.

Jacob Trefethen: I'll try and redeem myself. Hit me.

Saloni Dattani: All right. Number one, Gila monsters can detach and regrow their tail when threatened by a predator.

Jacob Trefethen: When a predator is threatening... their tail? Why would that help them? They could run faster?

Saloni Dattani: Yeah, yeah. They could run away.

Jacob Trefethen: Hmm. Let me think. I mean, that's random. I don't know that it would speed you up that much when they start losing balance or something. I feel like that's so random that has to be true. I'm going to say true.

Saloni Dattani: Well, it's actually false.

Jacob Trefethen: No!

Saloni Dattani: That's true of some other lizards, but not Gila monsters. They actually do that. They're just like, you're trying to bite my tail. Well, guess what? I've just dropped it.

Jacob Trefethen: Honestly, the predator probably likes that too. Tasty tail.

Saloni Dattani: That makes sense. But I think they're probably quite disappointed. Wait, what? Your tail just dropped off!

Jacob Trefethen: It is kind of like an ultimate gag. It's like Arrested Development with the guy with the arm that is trying to teach them a lesson.

Saloni Dattani: I watched this so long ago that I don't remember.

Jacob Trefethen: George Sr. hires his friend who has a detachable arm to teach his children lessons because the arm comes off.

Saloni Dattani: Wow. I would love that.

Jacob Trefethen: Yeah.

Saloni Dattani: Okay. Here's the second fact. I think I gave this away a little bit. Okay.

Jacob Trefethen: Finally one I'll get right.

Saloni Dattani: The Gila monster is sluggish in nature so it is not generally dangerous and very rarely poses a real threat to humans.

Jacob Trefethen: Okay. I think this might be a little of column A, a little of column B. I think it is dangerous to humans because of maybe venom would be my guess. But maybe that is compatible with it being sluggish. I sort of do think of it as sluggish. I think maybe... Yeah, I'm going to go with sluggish, but deadly.

Saloni Dattani: You just have a stereotype in your mind that it's like, oh my God, it's so slow.

Jacob Trefethen: Yeah, basically. I definitely think of it as lounging. Do you know what I mean? It's not like one of those geckos. We're talking a monster. It's lounging. It's baking in the sun. That's the kind of energy.

Saloni Dattani: You are exactly right.

Jacob Trefethen: Oh, finally.

Saloni Dattani: It is a very slow lizard. Its top speed is about one and a half miles per hour.

Jacob Trefethen: You're kidding. That can't be-

Saloni Dattani: Can you imagine being that slow?

Jacob Trefethen: That is really embarrassing for the Gila monster. Wow, I kind of feel... I really changed my perspective on the Gila. That's also... Who measured that?

Saloni Dattani: They were in a little race. They were like, oh, wow.

Jacob Trefethen: I guess you would put some prey in front of it that it wants and then see how fast it could go after.

Saloni Dattani: Maybe they've just been videotaping it for a really long time and seeing how fast it usually goes. But you were right, so its venom is very poisonous, its bite is excruciating. But they just don't encounter humans that much, so they're not very...

Jacob Trefethen: Who are they mainly biting then?

Saloni Dattani: I guess its food, usually it eats small animals like mice.

Jacob Trefethen: Right.

Saloni Dattani: And little birds, I guess.

Jacob Trefethen: It's kind of interesting because I feel like it's kind of like Tom and Jerry, but if Tom couldn't run. It's surprising, but anyway, okay.

Saloni Dattani: Okay. Next one. The Gila monster has very muscular jaws that produce a firm, tenacious bite with the venom dripping into the wound as the lizard chews.

Jacob Trefethen: Oh my God. And so is that true or false, basically?

Saloni Dattani: Yeah.

Jacob Trefethen: Okay. I think that's true.

Saloni Dattani: That is true. Pretty terrifying.

Jacob Trefethen: Oh God.

Saloni Dattani: That is the exact description that I found in a paper.

Jacob Trefethen: Okay. Delightful.

Saloni Dattani: Sounds quite horrible. Okay, last one. Gila monsters spend most of their life underground and can survive eating only a few meals per year. True or false?

Jacob Trefethen: That is going to be true because that and that's really going to be related to, I think that's going to be related to Hee-LP.

Saloni Dattani: Yes, it is. It is true. They stay underground most of the year. They come up overground only during the spring, usually. And they can survive eating only a few meals per year. They're really good at fasting. I was wondering if you could only eat three meals per year, what would those three meals be?

Jacob Trefethen: I have a sort of tradition I've lapsed that I, a few years ago, very much valued, which was having pancakes the night before Thanksgiving. I'd probably keep that one then. Okay. I've got two left. You have to really be eating the most calorie dense thing... No, I guess I'm taking that too seriously. We're going to die in this example.

Saloni Dattani: Oh no!

Jacob Trefethen: No, no, no. Two more. Maybe, well, I have always been a sucker for cornbread. I would have a meal that was very cornbread forward. Right.

Saloni Dattani: Pancakes, cornbread.

Jacob Trefethen: Yeah. Everything's yellow. That's the theme.

Saloni Dattani: Potato?

Jacob Trefethen: No, the third would be a delicious salad, actually, Saloni. Oh. You got a problem with that?

Saloni Dattani: I find this hard to believe.

Jacob Trefethen: What's your answer then?

Saloni Dattani: Potatoes. Potatoes and potatoes.

Jacob Trefethen: All three? Oh, no. I didn't know that about you.

Saloni Dattani: I heard that potatoes contain all the nutrients that you need.

Jacob Trefethen: That's right. That's why I make sure to avoid other foods.

Saloni Dattani: What's interesting about the Gila monster is that they also, they eat very large meals. They eat just like entire quail eggs at once and stuff, and they store fat in their tails.

Jacob Trefethen: Oh, their non-detachable tails.

Saloni Dattani: Yes. If they were detachable, they actually would be yum for predators to eat.

Jacob Trefethen: Okay.

Saloni Dattani: Separately, I wonder if you've ever wondered how venoms work. It's not that common for lizards to be venomous and Gila monsters are venomous. I hadn't really thought about what makes venom actually deadly to people.

Jacob Trefethen: Yes, I, um... I have looked into this a bit in my previous day job, and there's a multitude of ways they can, is what I remember. But messing with your blood is a classic sort of vector of destruction. But is there a more... Do you have a list of destruction methods?

Saloni Dattani: What makes venom venomous? The answer is you can either use your venom to destroy red blood cells, or wreck clotting mechanisms so you cause lots of internal bleeding. The one that I had thought about was like being a nerve agent, disrupting nerve signaling, causing paralysis.

Jacob Trefethen: Yeah, yeah, yeah, definitely.

Saloni Dattani: Then some venoms digest cell membranes and connective tissue, and that spreads the rest of the venom even further.

Jacob Trefethen: Wonderful... So if anyone wants to lose weight, then...

Saloni Dattani: Let's talk about medicines instead.

Jacob Trefethen: GLP-1s, how does this relate to GLP-1s, Saloni?

Saloni Dattani: Yeah, how does this relate to GLP-1s? What are GLP-1s? They are a type of gut hormone that is released when you eat, naturally. They're a type of gut hormone called an incretin, and those hormones tell the pancreas to release insulin. In the 1980s, people found a natural incretin, which they called GLP-1.

But what's sad about natural GLP-1 is that it has a really short half-life. It only lasts about two minutes in the body. That's not very useful medically. The reason for that is that it just gets destroyed by enzymes and removed by the kidneys. So scientists were looking at this two minute long hormone and they thought maybe there's a better version of this that we could make that we could use as a treatment for diabetes. If you can stimulate insulin production, you can treat diabetes.

There were a bunch of scientists who were trying to study that, but also trying to study this Gila monster, the lizard, for other reasons. The story here, I feel like, is kind of different from what I had heard about this. I feel like I had heard several times that GLP-1s were discovered accidentally. People were studying this lizard and then somehow it produced this hormone that was really helpful and was a source of GLP-1 drugs. But when I looked into it, it turned out that it wasn't very accidental at all.

Jacob Trefethen: Oh, as in the Gila monsters were planning this the whole time?

Saloni Dattani: Yes, that's exactly what I meant.

Jacob Trefethen: I knew it!

Saloni Dattani: The Gila monsters were actually- the scientists took off their masks and it turned out...

Jacob Trefethen: That is, it actually does all make sense now. The scientists were- The way they found out was they were walking at 1.5 miles an hour. Oh, sorry, sprinting.

Saloni Dattani: The other scientists were like, why are they so slow? There must be something special about them.

Jacob Trefethen: If it's not accidental discovery, so what happened?

Saloni Dattani: There were two scientists studying these lizards for different reasons. One scientist was an endocrinologist who was interested in the venom and the fact that if people were bitten by this venomous lizard, the Gila monster, they often developed this extreme pancreatic reaction to it. It somehow stimulated the pancreas so maybe it's involved in doing something to pancreatic hormones.

Then there was another scientist called John Eng who was studying peptide hormones in animals. He had already studied a beaded lizard's venom and found a hormone that resembled human GLP-1. Then he turned to study the venom of another lizard, Gila monster, to find out whether it had a hormone like that too. That's why they were studying the venom of this lizard, the Gila monster.

Jacob Trefethen: So are you telling me the venom is circulating through its veins and keeping it skinny?

Saloni Dattani: Yeah, that's a good point. I don't know why this hormone is in its venom. That part is surprising.

Jacob Trefethen: Yeah.

Saloni Dattani: Okay. Maybe venom is just a mix of random stuff.

Jacob Trefethen: Yeah. Yeah. Maybe. Okay. Interesting. Were they collaborating or were they working at cross purposes?

Saloni Dattani: Yeah. They were working together. Okay, so they were interested in this lizard for these two different reasons and decided to look at what was in the Gila monster's venom and they found a bunch of peptides, and one of them turned out to be really similar to GLP-1, the natural gut hormone. It was called Exendin-4. Sounds like a villain from a cartoon I would have watched when I was five years old.

Jacob Trefethen: Did they get to name it that villain or was it already named?

Saloni Dattani: I think they named it.

Jacob Trefethen: Maybe they were watching the same cartoons as you.

Saloni Dattani: Probably. They found this other hormone that was similar to GLP-1 in the Gila monster's venom. It also switched on the same GLP-1 receptor, so this was all in 1992. But what was even more cool about this version of the hormone in the Gila monster was that unlike natural GLP-1s in humans, which only last a few minutes, this hormone lasts hours. That makes it much more useful as a drug. The reason for that is just it contains a slightly different amino acid at the place where the enzyme was breaking down natural GLP-1, so it doesn't get degraded as much.

Jacob Trefethen: But overall, they look pretty similar?

Saloni Dattani: Yeah.

Jacob Trefethen: Yeah. Okay.

Saloni Dattani: I guess what also I found kind of interesting was how long it took between when they discovered this Exendin-4, this Gila monster GLP-1, and how long it took from that to developing it into a drug. It was first approved for diabetes in 2005, which is really like 13 years later, which seemed pretty long to me. Apparently John Eng, who discovered it, patented it pretty quickly and presented his findings to a bunch of pharma companies but some people just thought the idea was too weird and they just didn't see like a commercial use for it.

Jacob Trefethen: People.

Saloni Dattani: 'What do you mean it's too weird? It's just a lizard!'

Jacob Trefethen: He's walking around with his vial like, 'There's nothing weird about this!'

Saloni Dattani: Yeah, but that changed in San Francisco, which is where you are, at the 1996 American Diabetes Association conference, where scientists from a biotech company called Amylin Pharmaceuticals-

Jacob Trefethen: Yes, Amylin!

Saloni Dattani: were interested in this and they decided to license his patent. Then they turned it into a drug. The drug is called Exenatide. It's a synthetic version. They're not actually extracting it from the lizard each time. That was the first GLP-1 drug that was approved.

Jacob Trefethen: That's great. I'm glad we got our first one. But exenatide is not what we all talk about now, so...

Saloni Dattani: Maybe we should be talking about it.

Jacob Trefethen: Maybe we should be talking about it. Exenatide in the armpits. That sounds like it was a great beginning, but how does it relate to other GLP-1s? What's the story?

Saloni Dattani: Yeah, the other GLP-1 drugs are basically modifications of that first one. After Exenatide, the first GLP-1 drug was developed, scientists at Novo Nordisk tried to tweak it and they turned it into a longer lasting drug called liraglutide.

The way that is tweaked is basically it has like a fatty acid chain attached to the molecule, to the peptide, and that means that it can bind to albumin in the blood. Albumin is a protein in the blood that just carries around lots of different things. It's basically like a little bus that's going around your body and it's like, hey, get on the bus and then the little hormones get on the bus and then eventually they get off the bus. Liraglutide can last a day versus exenatide, which could last hours. This was another advance.

Then after that, there was semaglutide, which was modified even more to last about a week. It just had a stronger fatty acid chain that grips onto the albumin more tightly.

Jacob Trefethen: We basically have this original insight starting in 1992 from the Gila monsters. Then that insight is built on to its first pharmacological point in '96 and onwards, and then we're iterating, iterating, iterating off of this idea.

Saloni Dattani: Yes, exactly. You've probably heard of tirzepatide and retatrutide as well.

Jacob Trefethen: I have. Yes, retatrutide, yes.

Saloni Dattani: Retatrutide. What's so interesting about these is that now it's not just that they act on the GLP-1 receptor, they actually act on multiple receptors. Tirzepatide, which is by Eli Lilly, or it's called Mounjaro, that acts on both GLP-1 receptors and GIP receptors. Then there's retatrutide, which acts on GLP-1s, GIP and glucagon.

Jacob Trefethen: Boom, boom, boom, triple!

Saloni Dattani: The way that it does that is all of these receptors are evolutionarily related to each other and they look kind of similar. So you can design, you can just slightly tweak a drug so that it fits into multiple receptors and not just one.

Jacob Trefethen: It's sort of fascinating to think about that because this is one molecule doing three things. It's kind of like, why, why, why not have three molecules? If you ask a drug developer, a medicinal chemist, I think the answer you'll get is, well, you can control better the dosing. You kind of want one. But it's all over your body and randomly interacting with all sorts of things all over it. You're making this statistical bet of how much you will interact with the three different things.

Saloni Dattani: Yeah, I think there's like another layer of that though, because even GLP-1 receptors, on their own, they're present in multiple parts of the body. Sometimes it helps to have a really specific drug that only attaches to one thing. Sometimes it's better if they act on multiple things - then they could have multiple benefits.

Jacob Trefethen: Now, I live in San Francisco and I was recently at a conference where a British person was, I was talking to a British person who was visiting about science and he immediately, well, he from context got that despite the fact I grew up in England, I now live in San Francisco. So he said, oh, probably you have to leave soon so you can go buy your peptides on a street corner.

I thought, that's a bit rude. He's telling me that I have to go buy peptides on a street corner. Then I thought, this man, he's stereotyping San Franciscans. Then I sort of ran through my head and I thought, well, I do have a lot of friends who have bought peptides if not on a street corner, then from an apartment.

The most common one that I have seen is retatrutide. This is not approved yet, but it's going through the process of the FDA. But the data looks so strong that to the San Franciscan mind, you want to be getting illegal imported versions of it as soon as you possibly can, stirring them up in your fridge and then jamming yourself. Yeah, around here it's actually called Rita. People don't even say retatrutide.

Saloni Dattani: Rita like Rita Hayworth.

Jacob Trefethen: Yes, exactly.

Saloni Dattani: Just like her.

Jacob Trefethen: Just like her.

Saloni Dattani: I find it also, yeah, I find it interesting, the new GLP-1 drugs, they're more effective partly through working on multiple receptors. They act on more receptors than the previous ones did, and they're more effective probably because of that.

Jacob Trefethen: What fourth and fifth receptor would you add?

Saloni Dattani: Oh, I don't- I think I would stop there. Honestly, that's enough.

Jacob Trefethen: At some point, it gets so effective. It's like, the serious point is that all of these things come with trade-offs. If you're hitting more things, that might dial up your efficacy depending on what you're trying to measure. But also it adds risk. You're hitting things you might not want to or that have some function that is beneficial or keeping your body normal. Most things in the body happen for a reason. There is a genuine trade-off. You might not want to add a fifth or a sixth. I do find it funny that we now kind of have GLP-1 and then it feels like GLP-2, GLP-3. It feels like GLP-3. We've got to get to 5.5.

Saloni Dattani: I think I remember reading that one of the most common reasons that people dropped out of the clinical trial for it was that they lost too much weight.

Jacob Trefethen: Totally. Yeah.

Saloni Dattani: Yeah. It's pretty high. Retatrutide in its phase three trial caused a 28% reduction in body weight. It's huge.

Jacob Trefethen: It's absolutely crazy. That is crazy. And that happened over the course of one day.

Saloni Dattani: What? No, it didn't. It's more like a year and a half.

Jacob Trefethen: I don't even think I tricked you with that one, I think.

Saloni Dattani: I'm very used to this because when I was growing up, my brother used to just make up things and he'd say things that sounded plausible. It wouldn't be like in the context of like, oh, do you believe or whatever. You would just say things that were false. He'd be like, ha, you believed that!

Jacob Trefethen: It's a trick with no upside.

Saloni Dattani: That's why I've turned into a really skeptical person now. I just don't believe anyone at all.

Jacob Trefethen: Aww. No, that's not true. You believe.

Saloni Dattani: That's true. I thought you were right about the tapeworm being called a tapeworm because it was sticky underneath.

Jacob Trefethen: I now have to read to the audience, totally unrelatedly, the most Saloni text I've ever read.

Saloni Dattani: Oh, what was it?

Jacob Trefethen: About what you can believe and what you can't believe. Let me pull it up. Someone on the internet posted a chart and we're in a group chat together with some people who read charts and look at charts. Someone asked, "any takes on this?" Basically on this chart, how would you evaluate it?

Saloni responded, "I find it so odd for someone to tweet out something like that without even looking up the data quality notes." I don't know that anyone else would find that odd. "I just can't imagine someone tweeting something without reading the appendix first!"

Saloni Dattani: I realized just after posting that, I was like, wait a second, I'm probably the only person who does that.

Jacob Trefethen: "I just find it so odd."

Saloni Dattani: It's very annoying when people do that.

Jacob Trefethen: No, I am with you. Anyway, so-

Saloni Dattani: Thank you. GLP-1s. We know that they're useful for weight loss. Retatrutide, the latest one, causes a 28% reduction. That compares to semaglutide, the first one, which was about 15% weight loss. Tirzepatide, which was about 21% at the top dose. These are getting a lot more. This is crazy. I do think that it's non-linear and that eventually we won't be able to just keep increasing how much weight loss you can achieve with new drugs.

Jacob Trefethen: I hope so. Some of the weight is your organs, some of the weight is your nose, your teeth. Yeah. It's worth saying this is... It's not like, once you go off the drugs, you, most people start gaining weight again. It's not like a permanent in your body forever kind of thing. But yeah, these graphs are really quite, quite something. It's only 18 months. It's not very long time.

Saloni Dattani: It's much larger than I, I think that what's interesting to me is that I remember in maybe 2021 or so, I was trying to find someone to write an article for us at Works in Progress about weight loss drugs. I remembered learning in my undergrad that there were a lot of failures in the 1970s, 80s, 90s, people trying to develop obesity medications and a lot of them were really toxic. Or they just caused weight loss in a really unpleasant way.

I was interested in like, what's the state of that research now? Are there new drugs that are in the pipeline today? I asked this nutrition researcher called Stephan Guyenet to write an article about that for us. He wrote one on the future of weight loss, basically these GLP-1 drugs that hadn't been, that hadn't reached the finish line at that point, but it was so interesting even then to just see like how much happened in the meantime.

There was this period of maybe two decades where it seemed like a lot of pharma companies were pretty afraid to touch obesity as a potential area. Now it's the biggest or one of the biggest areas for new pharmaceutical drugs.

Jacob Trefethen: Yeah. How much can change.

Saloni Dattani: So much can change. I also, I think that. Yeah. People often don't know that these are also treatments for diabetes. I wonder if you know how they work at doing that.

Jacob Trefethen: I think of them originally for diabetes, or at least type 2. I believe they lower your blood sugar levels. But more specifically, let's see...

Saloni Dattani: Yeah. I think you've kind of got it, but there's an additional piece of evidence there that they don't just reduce blood sugar level on the whole, but they reduce blood sugar level when the blood sugar levels are high.

Jacob Trefethen: Yeah, yeah, yes. Right. Right.

Saloni Dattani: It's like a glucose dependent effect. What's good about that is that a lot of previous diabetes drugs just generally reduced blood sugar levels. If you are on a high dose, then you could suffer from hypoglycemia, you could have really low blood sugar levels and that would be bad. But this doesn't happen with GLP-1 drugs. They only reduce blood sugar levels when they're high.

Jacob Trefethen: Although you have to watch out for it, right? But it's not a big problem, it seems.

Saloni Dattani: Right. Also, unlike some other diabetes drugs, they cause weight loss instead of weight gain. There were a bunch of other diabetes drugs that did that, which is probably not great because a lot of people with diabetes are also overweight or obese. This is helpful because it tackles both things. I wonder if you know how- they've also been used to prevent the development of diabetes, so in people who have pre-diabetes but don't have actual full-blown diabetes yet, how much it reduces that progression?

Jacob Trefethen: Hmm. I wonder how you measure that because prediabetes is set at a debatable binary cutoff point. Do you measure it against a continuous variable?

Saloni Dattani: This is, so both of them are measured in part based on HbA1c, which is a measure of how much sugar is attached to your hemoglobin. At a certain threshold, you can be considered having pre-diabetes. Then if it's above that level, it's considered diabetes. The question is, if you are in this range where you have pre-diabetes, how much does it reduce your chances of eventually developing diabetes?

Jacob Trefethen: Yeah. I don't know the number, but my impression is a lot. I think it's a very effective way on it.

Saloni Dattani: It is very effective. There is a trial recently called the SURMOUNT-1 trial where they gave tirzepatide, that's Mounjaro, to people with obesity and prediabetes. They had a 94% reduction in the progression to type 2 diabetes.

Jacob Trefethen: Wow. Over what period? I'm trying to make sense.

Saloni Dattani: Over three years.

Jacob Trefethen: Okay. Basically over a three-year period, if you have prediabetes, there's some chance you'll progress. For people on the drug, it was like basically no chance you'll progress.

Saloni Dattani: Right. It was like 18% or so chance of progressing in the next three years if you were on a placebo.

Jacob Trefethen: Got it.

Saloni Dattani: But if you're on tirzepatide, it's like 2%.

Jacob Trefethen: Oh, wow. That is amazing. Wow. That's awesome.

Saloni Dattani: We talked about how GLP-1 drugs are used for diabetes and obesity, but they're also being studied for lots of other diseases, like kidney disease, cardiovascular disease, sleep apnea, and also diseases like Alzheimer's and Parkinson's. Most of those trials are being studied in people who are already diabetic or obese and the trials are looking at whether it also improves those other conditions that they have.

With the two exceptions of the two brain diseases, brain conditions. So in the Parkinson's and Alzheimer's trials, GLP-1s were tested in people without diabetes or obesity. But so far those trials have found null results. They haven't been demonstrated to be effective.

I think there's like an ongoing debate around, does it have all of these multiple benefits because it's actually effective for those conditions? Or is it just because it's reducing weight and improving blood sugar levels, which usually have all of these other negative consequences? So if you reduce weight, you're going to reduce your kidney disease or heart disease as well. I think that's still an active debate. I wonder what you think. Would you guess that if GLP-1 drugs were tested in people who are not diabetic, who are not obese, would they still have those benefits as well?

Jacob Trefethen: Ooh, depends on the benefits, depends on the people is my scapegoat answer. My guess is that there's stuff going on that will benefit people who are not diabetic and not overweight. Yes, yes. Now, it was disappointing to see the Alzheimer's result that came back null. I think that could still go both ways though. That trial enrolled people who already had essentially-

Saloni Dattani: Early onset.

Jacob Trefethen: Yeah. Not early onset, but early Alzheimer's, I believe. You can tell me if I'm right. I think it was.

Saloni Dattani: No, you're right. Early stage Alzheimer's.

Jacob Trefethen: Early stage. Yeah.

Saloni Dattani: So it didn't slow that down.

Jacob Trefethen: It didn't slow that down, but that's- the inclusion of one of the inclusion conditions to be in that trial was that you already had confirmed amyloid in the brain, or something that would signal you probably have amyloid in the brain. So I think there's almost a separate question of, the average age of people in that trial is probably 71 or something.

If you gave people- if people were on GLP-1s preventively much earlier, before amyloid and tau had accumulated or got that far into accumulating, could you have a preventive effect? I'm actually sort of hopeful, and my read is that the jury is still out there and there may be some benefit on Alzheimer's that's earlier prevention. But yeah, the data... It's pretty clear from that trial that the hope of something that as soon as you get a diagnosis, you go on that then helps, it's not going to be as magical as that.

Saloni Dattani: Yeah, that's a shame. I hope you're right that it is effective for that. I feel like when I read about these for the first time, I thought, well, some types of dementias are actually caused by cardiovascular problems, like vascular dementia. I sort of thought, maybe they'll find a benefit in this trial, if not for any other reason, for that reason. But I think people with Alzheimer's also having vascular dementia is not that common, but also it seems like it didn't help in that sense. Or maybe it wasn't powered enough to find that.

Jacob Trefethen: Right, yup.

Saloni Dattani: Yeah, I think with the other conditions like kidney disease, cardiovascular disease, at least with cardiovascular disease, my guess would be probably it does help with that in part because GLP-1 receptors are also found on blood vessels and they reduce blood pressure slightly. But also I think with lots of these conditions, it's not really like a binary of overweight or obesity or not. Right? Like it's continuous. I'm sure that, okay, if it helps a lot for people who are obese, it probably helps as well for people who are not to a lesser extent.

Jacob Trefethen: Yep. Then, there's, of course, as with everything in biology, you go to the other extreme and you can harm people. If you're prone to anorexia, if you're, if you have low body mass, there's ways you, but these, these things can do harm too.

Saloni Dattani: Right. I was interested in this as well because I was thinking, okay, so we have now really effective drugs that help with weight loss. What about drugs that help with weight gain? Because there are some conditions where maybe someone who has chemotherapy or something and has lost a lot of weight because of that, are there any drugs in the pipeline that help them gain weight... aside from marijuana?

Jacob Trefethen: Oh, yes. Good point. Marijuana. The pathway there goes via Taco Bell, actually, at the end. No, if you are severely malnourished, then you can get prescribed Plumpy Nut or other forms of ready-to-use therapeutic food. Therapeutic food in the sense of they are treated as medicines in some sense. Yes, there at the very least is high fat, high protein food that you do get prescribed if you're severely malnourished. Probably not the answer you're looking for, you probably want something more biochemical than that.

Saloni Dattani: Yeah. There are apparently a bunch of drugs in the pipeline right now that are for weight gain. There's an antibody treatment called ponsegromab, which seems to help with weight gain, but it's in phase three trials right now. I haven't tried it.

Jacob Trefethen: You're making me run through the list in my head now. There's other appetite suppressant, stimulants have often been weight loss drugs either off-label. Are there things that off-label everyone knows you gain weight if you eat? Yeah, there are a bunch of those probably.

Saloni Dattani: That's right. Aren't there antipsychotic drugs that make people gain weight?

Jacob Trefethen: Yep.

Saloni Dattani: Huh, interesting. Might try one. I'm kidding. But I guess the last thing to say about GLP-1 drugs is that this is not the end. There are a lot more in the pipeline. There are new drugs being developed that don't just cause complete weight loss through both fat and muscle, but there are new drugs that are muscle-preserving, weight loss reduction drugs. There are also different types of actual dosing or different durations of these drugs. There are people developing patches like a needle patch that you put on your arm and that slowly gets released into your body.

There's also, recently, there's a small molecule drug version of a GLP-1 agonist. I wonder if you know, or remember, what that's called? It has a really funny name.

Jacob Trefethen: Oh, oh, do you mean the, the oral one? Wait.

Saloni Dattani: Yeah. Yeah.

Jacob Trefethen: Okay. Gosh, yeah, what is that?

Saloni Dattani: It's a pill. It's a small molecule. It activates GLP-1 receptors.

Jacob Trefethen: Gosh, I can't remember. I can't remember. What's it called?

Saloni Dattani: It's called orforglipron.

Jacob Trefethen: Yeah, they really have run out of names for Pokémon these days, reaching the bottom of the barrel.

Saloni Dattani: I usually imagine a cat typing on the keyboard and that's how these drugs are named. That's the end of that. GLP-1 drugs have two uses already, diabetes and obesity. They're being tested for a bunch of other uses as well.

They were originally developed by finding GLP-1 peptides in Gila monster, a type of lizard, in their venom. That hormone was much longer lasting than the natural GLP-1 that we have in our body. By tweaking that hormone, scientists made sure that it lasted longer, even longer, in the body for days or weeks. That has led us to the drugs that we have today.

Jacob Trefethen: It's an amazing story. I wish it could have happened quicker, as is often the case with some of the stories on our episodes, but not so bad. These drugs will go on to prevent millions of people from earlier death. Even aside from the health gains that a lot of people are going to see, there's... these are really big population-wide effects at this point. It's kind of wild to have something that is so new that will be so impactful.

Saloni Dattani: That reminds me that with some of these drugs, they've also been tested for how much they reduce mortality rates overall. The first, well, the second GLP-1 drug, liraglutide, the FDA said with any new weight loss drug, it has to be tested for how safe it is for cardiovascular disease as well. They did trials to find out how effective, how safe it was. They actually found that it reduced heart attacks in that population and it reduced mortality rates on the whole by about 12% in people with obesity, which is actually quite large. Like that's, roughly, that's roughly the effect of, statins in reducing mortality rates as well. And that was for the earlier GLP-1 drug so I'm guessing these new ones have a slightly larger effect.

Saloni Dattani: Okay so GLP-1 drugs are a type of drug that have multiple effect. I'm going to raise a potentially controversial or surprising opinion, which is that what if there are lots of other drugs that can do things like this too?

Jacob Trefethen: Dun-dun-DUN! I don't think it's possible.

Saloni Dattani: You don't think it's possible.

Jacob Trefethen: No, I'm joking. What's my real answer? I sort of am a bit of a conspiracy theorist on this. Often the most powerful drugs are doing something that's quite important. Yes, I think that sometimes-

Saloni Dattani: Yes, that seems circular, though.

Jacob Trefethen: Let me rephrase it. Some of the most important functions in the body are sort of these pathways that have many different downstream effects. If you're targeting an important node, for sure there might be repurposed things that could happen. The thing is that most people are mostly healthy most of the time. You don't want to be messing with those important panels.

The GLP one story is so shocking because it's like, wait, hold on, we could have just done that the whole time? Like if we'd evolved different GLP? That's crazy. Because usually if you're hitting a channel like that, there's something bad happening somewhere else. This has been a big problem in Alzheimer's, for example. The genes and proteins that are involved in the development of Alzheimer's, there's more and more knowledge about them every decade. A lot of the problem is happening in the brain, but those genes and proteins are doing things all over the body. So if you try and give someone a drug that is going to interfere with them, you may end up causing issues. This happened with BACE1 inhibitors. This happened with gamma secretase.

Saloni Dattani: What's a BACE1 inhibitor?

Jacob Trefethen: B-A-C-E-1. It's just a class of drugs that people have tried for Alzheimer's. The off-target effects really get you. This kind of principle, if you go to something really important and it will have lots of effects is good and bad, but true.

Saloni Dattani: Right. I wonder if you remember, so we talked at the start of the episode about some examples of drugs that have multiple uses, but how many other ones can you name?

Jacob Trefethen: Oh, okay. That's a fun prompt. Let's see. So there's... maybe I'll try and get to three and then stop. Well, there are things that you would use in different contexts for different patients. I don't know if that counts. Like low dose aspirin for different, if you are pregnant and meet certain conditions can be useful, but that's not the main way you would think about aspirin. Or, lithium is one that we are looking into right now, actually, for Alzheimer's, again. Is there an effect of lithium orotate on Alzheimer's? Not on, lithium is often used for others.

Saloni Dattani: It's usually bipolar, right?

Jacob Trefethen: Yes. Lithium carbonate is used for bipolar. Let's see, what's the third fun one? How about, oh, BCG. This one always blows my mind.

Saloni Dattani: Is it actually used for those yet? I think it's still unclear.

Jacob Trefethen: For what? BCG is used for bladder cancer.

Saloni Dattani: Really? I didn't know that.

Jacob Trefethen: Yeah, yeah, yeah. BCG is-

Saloni Dattani: The vaccine.

Jacob Trefethen: -covered in previous episodes and you should, listeners should go back and listen to every single one in case it pops up. It is a sort of wondrous vaccine from 1921 that is still used, it's that good, against TB. It is producing some sort of non-specific immune response in that it's not just helping with TB, it's helping with other stuff too. One of the things that it's now used for is bladder cancer. People have tried it out for a bunch of different stuff too, due to this kind of non-specific effect. Do you ever want to just jack up your immune system to achieve some other goal? Yeah, BCG is a fave.

Saloni Dattani: Nice. I was thinking of SGLT2 inhibitors.

Jacob Trefethen: Nerd! Loser!

Saloni Dattani: Sorry, yeah, these are kind of similar...

Jacob Trefethen: Wait, listeners, do you not think about SGLT2 inhibitors?

Saloni Dattani: I think about them every day. I think this is the original, wow, does this just work for everything? Where they were originally developed for diabetes, but it turned out later on that they also could treat heart failure and chronic kidney disease and maybe some other conditions as well. Then you mentioned aspirin, a painkiller, but also use sometimes in pregnancy and also is a heart disease drug. That was only found out, I think, in the 1980s. Have you heard of colchicine?

Jacob Trefethen: Colchicine rings a bell, but what is it?

Saloni Dattani: It's a gout medicine. I think in the last 15 years or so, it turned out to be pretty effective against heart disease as well. Then there's minoxidil. Have you heard of that?

Jacob Trefethen: Any man my age has heard of that, Saloni.

Saloni Dattani: That was originally an antihypertension drug, but it later turned out to be somewhat effective as a topical treatment for baldness. Why I remembered it this year was that there was a phase three trial this year with a different formulation of minoxidil, which is longer lasting and that led to hair regrowth that was much more than the previous version. I think the previous version was like, you would have to apply it every day or something. Whereas this one, it's a pill.

Jacob Trefethen: Yep. I, you know, just talking to friends, of course, the issue with applying it every day is like, oh God, so do I do it before a shower, after a shower? It's kind of annoying. You can't, there's a pill version, finasteride. But that goes all over the body and has all sorts of off-target effects. It's much, nicer if you can just do it topically. But it's also more of a hassle.

Saloni Dattani: Yep. Then there's omalizumab that I mentioned at the start. That was originally developed as an asthma drug. But more recently, it's shown to be effective for various food allergies. Peanut, milk, yeah, various food allergies. Then you brought up Viagra, Sildenafil.

Jacob Trefethen: I didn't bring that up! You brought that up!

Saloni Dattani: Sorry. You answered that to my first question.

Jacob Trefethen: Now, Viagra, I do expect, if I had to make a prediction, we will get another usage of Viagra. People actually talk about Viagra in the context of Alzheimer's too. There's not, to my knowledge, been a big trial of it.

Saloni Dattani: Interesting. That seems like something, we probably have enough people taking it now that we could find out.

Jacob Trefethen: That's a good point. Look back at that data.

Saloni Dattani: Then there's, yeah, a lot of antidepressants are also used for other conditions like anxiety. Then sometimes there's a kind of related phenomenon where something is tested for one thing and then it turns out to be useful for something else.

If you've heard of KarXT or xanomeline-trospium, that is a new schizophrenia drug that was approved, I think maybe one or two years ago. It was originally tested as a dementia drug, but in those trials, I think in the 1990s, they found that it reduced hallucinations in those patients and then thought, oh, maybe we could use this as a schizophrenia drug. But the problem was that the drug had multiple effects. One was in the brain reducing hallucinations, but the other was that it caused really severe nausea and vomiting, and that's because it also attached to receptors in the gut. So I think researchers tweaked it and added trospium to it, which prevents it from binding to those other receptors in the gut; it's basically tweaked to become more specific so it only reaches the brain.

Jacob Trefethen: Which is a good sort of lens to apply here as well, where repurposing is not always you have one drug used for three diseases. Sometimes you get insight from the development of a drug for one disease that leads you to keep going and keep tweaking for a different disease. From a drug developer's point of view, maybe the more common exciting story, I'm not actually sure, but that certainly is a common thing that is a bit different. You still got to do some chemistry after you get the initial.

Saloni Dattani: Right. You might tweak, you might change the way that it's given so that it has more effects in one organ than another, or you might attach something else to it so that it can't get into certain places that cause side effects.

Jacob Trefethen: From the point of view of a philanthropic funder, this is often something that sounds like a detail that can be quite important because there's the magical hope is that you could fund a trial for a drug that already exists against a new indication and then it works. Then you don't have to go through all of the original testing again, because you already have these big safety data from the first usage! That is really amazing from a point of view of health benefit without having to spend as much money. And that can happen.

The issue is often you're finding these insights that you actually then do want to go back a little bit to the drawing board and make some edits to the chemistry. Once you do that, you then have to sort of re-enter as if you're a new drug to some degree. So that can get you back into more traditional pharma land and that can cost a lot more money.

Saloni Dattani: Right. I guess what's also interesting is that we've talked about a bunch of different types of drugs that have these multiple effects. Small molecule drugs, which are so small and they can get everywhere, they often have effects in different places. But also some peptides, like GLP-1s, have multiple effects, and also some antibodies have unexpected effects as well. I recently saw this study a few months ago where they tested all the approved antibody drugs and found that about a third of them had an off-target effect as well. Then there are gene therapies, which I guess that's less likely because those are so focused on a specific gene.

Jacob Trefethen: But genes do multiple things sometimes.

Saloni Dattani: That's true. That's true. We've talked about ones where there is pretty good evidence so far that they can be used for different conditions. But what about some speculative possibilities about drugs that are used today that could be used for other conditions, and we don't really know yet? Do you have any that come to mind?

Jacob Trefethen: Yeah. Oh, well, I hate to hop on one theme of Alzheimer's, but the shingles vaccine and Alzheimer's.

Saloni Dattani: That is one. I'm pretty skeptical of that..

Jacob Trefethen: You're skeptical?

Saloni Dattani: But why don't you make your case first?

Jacob Trefethen: Okay, I'll make my case. There have now been four, I believe, independent, quite interesting natural experiments or observational studies that point in the same direction, that show that when the shingles vaccine got rolled out to different people who are older to prevent shingles. It looks like it may have also prevented the probability you progress into develop Alzheimer's or dementia.

The first or the most sort of striking study of these four as far as I've seen is in Wales, there was a introduction of the shingles vaccine, where if you were born in 1933, I believe, the cutoff date was September 2nd, if I remember. If you were born before that, you were not eligible. If you were born after that, you were eligible. You have this really clean cutoff date where you can then see what happened to the people on either side of that, what an economist would call a regression discontinuity. The answer is that in that population, the people who did get the shingles vaccine were, after seven years, had a drop in relative risk of Alzheimer's or dementia of 20%.

That is not as high quality evidence as a randomized controlled trial, which is what you would usually do for developing a new drug that went through clinical trials. However, it's pretty suggestive. It's- I've had friends who skeptical friends trying to poke holes in it, and I've heard different holes trying to be poked, but you usually have a rejoinder. It's the kind of observation I've been saying, like, oh, maybe there's something here. Then the fact that this has popped up in other countries as well, in other studies, is pretty interesting.

Now, the thing that I think is not known yet, so there hasn't been a randomized controlled trial testing this yet, and there's various questions that are one level detailed down, but that are very important. Question number one, in the trial, in the observational setting I just mentioned in Wales, the vaccine in question was the live attenuated herpes zoster vaccine. Now, there's another vaccine that is now used in the US, for example, called Shingrix, which is the trade name, which is a subunit vaccine with an adjuvant made by GSK.

Saloni Dattani: Right. So both of these are shingles vaccines, and the studies that showed this benefit were using the old one.

Jacob Trefethen: That's right. Well, one of them was. There's that one that also trying to look at, well, hold on a second, with the modern shingles vaccine that was designed to be better for preventing shingles, is it also better for preventing Alzheimer's? Is it the same? Is there any difference?

I've actually heard different opinions from different scientists on that. The evidence is not strong enough to give a good answer on that. Some people actually think it is, it's going to be worse than the original live attenuated vaccine. Because of the way your immune system responds to live attenuated vaccines differently than sub-unit vaccines. Some people think it will be better. That's a question.

Then another question is, okay, well, what's actually going on here? Is it about shingles? Like reducing the amount you get shingles is the channel that reduces the amount you get Alzheimer's. It's probably not. There's probably something else going on about, just at that age, jacking up your immune system to clear out a bunch of stuff. That is-

Saloni Dattani: So it's not, you're saying it's not shingles necessarily that's contributing to dementia.

Jacob Trefethen: Not necessarily. People are debating this now. They're trying to chase down what is the mechanism of if there is a real effect here, why is there a real effect here? Could you get that effect from simply an adjuvant that boosts your immune system rather than a specific vaccine.

Saloni Dattani: I guess I want to get the shingles vaccine, but if I could just prevent it with just an adjuvant, then that's really easy.

Jacob Trefethen: If I recall from a previous episode, you have trauma related to the chickenpox vaccine.

Saloni Dattani: Oh, that's true.

Jacob Trefethen: You weren't allowed to get it.

Saloni Dattani: It really depresses me that in most, I think in every country or maybe most countries, you can't get a shingles vaccine unless you're above a certain age, and that age is like 50 or 65 or something, even though lots of people younger than that get shingles.

Jacob Trefethen: Yeah. Some countries recommend it 65 plus. The US is now recommended at 50 plus. Imagine if there is a preventive effect against Alzheimer's and we're just YOLO-ing it, and it's like, what the hell? Yes, that is a fascination of mine, and I am still reading up on it. But why are you skeptical?

Saloni Dattani: Why am I skeptical? I think, so there are multiple reasons that I'm skeptical. One is that, okay, it seems like there are many vaccines that are links to a lower risk of dementia. Not just shingles, but flu and DTP and various others as well. I have to say, when I see something, when I see results like that, I'm like, what if they're all just confounded? What if it's healthier people tend to get these vaccines and they have a lower chance of developing dementia? That doesn't really apply to the study that you mentioned, of course.

But I have other reasons for skepticism there. One is the specific way that these studies were done is, as you mentioned, they're looking at a particular birth date where, after that birth date, people were offered the vaccine and people before that birth date weren't. Even though these are somewhat large studies, when you're doing that comparison, the thing that matters most is how much that drop is just before and after that cutoff. The number of people who are just above or below that birth date in that year, it's not that big. So the results that I've seen, they seem to be kind of marginally significant. I am sort of skeptical that they'll hold up in larger samples. I think there's an ongoing study with a larger population of the whole of England, instead of Wales, where they didn't find any discontinuity. So I'm thinking there's probably something going on there.

But I think that just in general, when you look at these kind of cutoff studies, you often have to ask, what if something else changed there as well at that same time? That it was not just getting eligible for that vaccine, but also maybe that was the start of the school year and maybe grandparents with little grandchildren have a higher risk of getting shingles or something, I don't know, whatever, something like that. There's like little nigglings in my mind that make me think, I don't know if this will hold up. I would say I'm pretty unconfident that it will hold up, but I would say probably about 20 to 25% chance where I think maybe it will actually prove to be true and that seems high enough to warrant more attention. But I'm pretty skeptical.

Jacob Trefethen: I would take the bet against that. I think it's higher chance than that. I'm curious how you think about the evidence from other countries. You mentioned the England evidence that's kind of ongoing. I should know more than I do about it. But what about the Australians? What about all these other countries?

Saloni Dattani: As far as I've seen, they've also been just marginally significant. When I look at that, it's a bit... When you tweak certain things in your statistical analysis, you can get things that are marginally significant. There's a really cool blogpost by a friend of mine on the Uncanny mountain of P-values. Basically, if the literature is full of results that are barely statistically significant, or just under the threshold, that's a warning sign that the effects might not hold up.

Jacob Trefethen: Do you think that there is a real effect, but it's so small that it won't be detected? Or you think there's not even a real effect?

Saloni Dattani: I guess this depends on, how small of an effect can we detect? My guess is that it'll be too small to matter.

Jacob Trefethen: Got it. Okay.

Saloni Dattani: But I hope that I'm wrong. Anyway, shingles vaccines are just good. Shingles is terrible. It's painful. Take it anyway!

Jacob Trefethen: Okay, so let's just step backwards and could there be more drug repurposing than there is? Is this a panacea, Saloni? What do you think?

Saloni Dattani: What do I think? I do think with many of the examples that we've talked about, we only found out that they could be used for something else pretty late. With aspirin, for example, that's been used for over a century, but people only really established that it could be used for cardiovascular disease in the 1980s. Then there's dexamethasone during COVID - that was originally a steroid, and it took public funding to run a trial to find out that it was useful for COVID as well. There's another one I read about recently called moxidectin.

Jacob Trefethen: Yes, moxidectin, yeah.

Saloni Dattani: Right, which was originally developed as a, I think, deworming drug for animals, is that right? It was a veterinary drug in the 1980s. People thought, oh, maybe we should try this out for worm infections in humans as well. But there was just not really a market for that because people who are most affected by that live in poverty, they're children in poverty in Africa and south Asia, for example. So there wasn't really interest in funding the trials for it and actually proving out that it works and getting it to market, until a nonprofit did that in the 2010s and more recently. Their trial showed that it could cure 70% of whipworm infections in kids in Tanzania.

My view is, okay, there are a bunch of examples where it took really long to figure out that these drugs that were already there were gonna be effective for something else. That suggests to me that there must be other drugs right now that are gonna take a long time to be found effective for something else. So that's my optimist take on that.

Jacob Trefethen: Okay, let me be pessimistic then. If a drug had a really useful use, you usually spot it because people taking it will experience that side effect. Everything else is minor in comparison.

Saloni Dattani: What if they don't have the other disease though? What if they're like quite different things and there isn't that much overlap?

Jacob Trefethen: Hmm... You got me. The more public health benefit you want, the more it has to be a common disease. But you are, it is true, unfortunate. Wow, I didn't manage to stay skeptical for very long, did I? It's true that you can often, there are many diseases out there and you won't have collected evidence for the utility against most. That's true.

Saloni Dattani: I guess one reason that, when I first heard about this topic, I was pretty skeptical and I was like, isn't pharma already doing this? Aren't they already testing for whether their drugs work for multiple conditions? Because if they did, then, you know, that's a larger market. That's more money. Why wouldn't this be happening?

I also, I know that pharma companies individually have hundreds of thousands of compounds in their libraries and often they will just mass screen all of them against the diseases that they're interested in. And so, aren't they just doing this already? How can there be more that we haven't found?

Jacob Trefethen: What I would say to that is that presupposes we understand these diseases and we usually don't. You can't actually do a screen that tells you the truth because diseases are very complex and manifest in ways that are not just about cellular receptors, you know. Often you discover these things that you wouldn't expect just in virtue of complexity of the body. So that one, yeah, I think screening can't be the whole story.

Saloni Dattani: It also sort of made me think that often when pharma companies are testing these hundreds or thousands of drugs, they often start with a disease, or they start with a target, and they're like, which of the many drugs we have work against that target? I think it's less common that they have all the drug compounds and they're like, which of the hundreds of different diseases do these work against? Because that's like way too many combinations as well.

Jacob Trefethen: Yes, the combinatorics. Then, in addition, the amount of money that you can make off of different drugs for different diseases varies by orders of magnitude. If you're a company that's trying to make sure it doesn't go bust, then you won't be putting the same amount of energy behind leprosy as you would be behind cardiovascular disease.

Saloni Dattani: One other reason that I am a little bit skeptical, or was a little bit skeptical, was lots of attempts at repurposing drugs have failed. For example, metformin, there was a lot of hype around that.

Jacob Trefethen: There's still hope on that!

Saloni Dattani: Oh there is? There was a lot of hope that it would be a cancer drug as well. There were a lot of academic trials on this. The same is true for, I think, vitamin D in various different conditions as a treatment. Most of, I think so far, the conclusion is that they don't work for those.

But one of the interesting things about that was that the evidence for this before the trials were done were observational studies. Some of these observational studies were affected by various biases. One of these biases is called immortal time bias. Have you heard of that?

Jacob Trefethen: I'm pretty biased myself as a immortal demigod. Yes. But what about you?

Saloni Dattani: I had, well, I had heard about this for a long time and I was like, what does that, why is it called that? I feel like hardly anyone had given me an explanation of this that made sense. It was like really complicated and people would explain it with these diagrams that were very difficult to read.

But the basic idea is that you have, you're looking at like, let's say hospital data or something, and you're comparing people who have taken a drug to people who haven't. You look at, while they're on the drug, what are their chances of developing the disease versus people who are not on the drug?

What a lot of these studies would often do is that they count the time that people are not on the drug, or before they start the drug, in the control group, and they take the time that they spend on the drug in the treated group. But that creates a problem. You've like already lived up to a certain age before you get to the treatment group, which means you've sort of lived longer by definition. The only way that you could be prescribed that is if you've lived a certain amount of time.

This affected a lot of the studies that were claiming there were benefits of metformin for cancer. That is called immortal time bias, because when you start getting on the treatment group, it's like you've been immortal until that point, and that's the only reason you've been included in the study. You can't have died.

Jacob Trefethen: Right, right. Yeah, that's a sneaky one.

Saloni Dattani: There's also another bias that's often called confounding by selection, which is that the people who get prescribed a certain drug are different in some systematic way from the people who don't. So in a randomized trial, you're randomly deciding to put some people on the placebo versus some people on the treatment. But that's not true in the real world. People who get certain drugs might have a more advanced stage of the disease. Or with vaccines, often it's healthier, more educated people who will get vaccines as adults. Or for certain vaccines, like the rabies vaccine, it's often people in certain occupations, like they're vets or something else, that get the vaccine. They're systematically different, which might mean that they're healthier in some way.

Jacob Trefethen: Anything observational is more stressful. It is true. I have to admit that.

Saloni Dattani: Yeah. Yeah. I think there's just, there's a lot of uncertainty and many or maybe most repurposing efforts will fail. I think this is why randomized controlled trials are so helpful. But I wouldn't lose faith in the whole idea. Most clinical trials also fail, but some of them work. You shouldn't assume that because many or most of them will fail that they're not worth trying.

Jacob Trefethen: Let me give another pitch that there might be a goldmine out there and see what you think. One issue from a pharma company's point of view on repurposed drugs is that if a drug has been approved for one use, then it's sort of like an immortal time bias for drug patent length. It's quite likely the patent has expired by the time you have suggestive evidence for second use. If I'm a company, why would I pony up $75 million to confirm an effect that then anyone legally can sell that drug? Because I don't have a patent anymore. So what do you say to that? Doesn't that imply there's all of this low hanging fruit because companies aren't paying for these trials? Why would they? We got to pay for them as taxpayers!

Saloni Dattani: I think you're right. I think, well, the counter argument to this is that a lot of the companies still do trials before the patent expires. So maybe they've- if they're taking so long to start running a trial, maybe that's because there weren't these other uses at all.

Jacob Trefethen: It takes a while to accumulate off-label data. I don't know. I think, the aspirin case, it was literally decades and decades, right? I don't know.

Saloni Dattani: No, you're right.

Jacob Trefethen: Now, what I will say is I just have to give a shout out to one of the best trials of all time. Any guess what I'm about to... which trial that is?

Saloni Dattani: I don't know. What are you thinking of?

Jacob Trefethen: What do you mean you don't know, Saloni.

Saloni Dattani: RECOVERY?

Jacob Trefethen: Yes! RECOVERY! Yes! Okay, so let's say you find yourself in 2020, which I do not recommend.

Saloni Dattani: For many reasons.

Jacob Trefethen: For many reasons. There's an issue you face, which is an incoming global pandemic. If you want to develop a drug against COVID from scratch, it's going to take a while because it just came out of nowhere. It's a great time to see whether there's a repurposed drug that could work. However, most of these drugs are off patent, because they have been around for decades. Time is of the essence. So what do you do? If you are Martin Landray and collaborators and Peter Horby, I believe, at the University of Oxford, and if you are the UKRI and MRC, the two funding agencies in the UK government, and then later, if you're the Wellcome Trust and the Flu Lab, what you can do is fund a trial that has many arms.

You have people who are like, 'Hydroxychloroquine is gonna prevent COVID!' Great, chuck it in the arm. We're gonna test. We're gonna have some people on a control group. Okay. 'What about, dexamethasone?' 'No, that's very dangerous. You don't want to be giving people a steroid.' Let's try it out. Chuck it in the arm. They had all these different arms. Then by June, 2020, which is months before vaccines, they had managed to find that hydroxychloroquine didn't work. Some other things didn't work. Dexamethasone did work.

And then within the day, they had, well, they had to confirm that it wasn't spurious. They like really double checked the data before that press release went out. Then they, within the day, the NHS system in the UK absolutely flipped and said, okay, if anyone comes in, gets hospitalized with COVID. Now we know what we can give them, it's going to reduce their chance of death. It's a stunning result. People have tried to model out how many lives that saved. The most prominent modeling, which I haven't gone deep to vet myself, but suggests that within 12 months that saved a million lives around the world. Oh my goodness. Just unbelievable. You could not have known ahead of time. People were saying all these different stuff. People were making all these different predictions. And they got the data. Oh my gosh.

Saloni Dattani: People have so many hypotheses and it's hard to know which ones are actually going to work. There are probably some good reasons to believe all of them might have worked. It's so useful to actually run the trials and figure out which ones they are. The wonder of repurposing. Save millions of lives.

Jacob Trefethen: Completely. I think that when you look at, okay, how can we repeat that for different areas? My suspicion is that you're just not going to have many areas where you're getting a 90% reduction from a repurposed drug. Then maybe you will have some areas where you're getting a 20, 30% reduction. Okay, you've got to be kind of looking for these population-wide things. That sort of changes the catchment area a little bit. It makes you want to go cardiovascular. It makes you want to go maybe Alzheimer's. But I'm not so sure it will be. Yeah, I guess I hold out less hope for 90% reductions.

Saloni Dattani: I think that brings me to another reason for optimism, which is that some diseases just don't have a large enough commercial market that companies would even be willing to try to test them for them. Like they're not interested in repurposing something for a tropical disease where there isn't that much money in developing those drugs anyway, or diseases like addiction or something like that, where people who have them aren't able to pay for them. That makes me think there are a bunch of diseases like this where we don't really have the incentives for pharma companies to test them, even if they are on patent.

Jacob Trefethen: Yup.

Saloni Dattani: I think the other one, we mentioned a few vaccines, but I think this also applies to vaccines especially because once they're universally recommended and you test them out for a different thing, you're not going to get a larger market from doing that. You've already put it on the market. It's already recommended to everyone. You're not really going to get much more of a benefit from doing that.

Jacob Trefethen: I disagree on that one. I think GSK has a massive incentive to test Shingrix against Alzheimer's because the Shingrix vaccine, it's not exactly your top priority for everyone. Something like a third of people who are eligible actually get it. It's a painful vaccine, massive adjuvant jab. A lot of people don't go back for their second dose. If it were known that you could reduce your chance of Alzheimer's by 20%, I think that would go to, they probably double their sales, so that's, I think they have a big incentive personally.

Saloni Dattani: I guess, yeah, I agree with that, but I think vaccines tend to have a lower price than other drugs, and so that would make it hard for them to- and I don't think that they would be able to raise the price that much.

Jacob Trefethen: Yeah, interesting, yeah.

Saloni Dattani: I think the last reason is that I think, even though there is this economic incentive to testing drugs for new conditions, that incentive is going to kind of run out once the patent expires and generics enter. Because like you said, if you've tested it for some new condition, you've like spent the millions or tens of millions of dollars on these clinical trials, and it turns out, okay, it's useful for something else, well people can just get the generic version anyway, and they're much cheaper. What's the point of doing that?

Jacob Trefethen: Yeah.

Saloni Dattani: There's a really interesting paper that basically looks at drugs that spend longer in clinical trials and therefore, when they finally get to market, they have a shorter patent life remaining. Those drugs tend to be repurposed less. That suggests that there are economic incentives that can run out. If you look at the kind of repurposing efforts over time, after the patent is issued or after the drug is approved for the first thing, it kind of slowly declines over time. Companies are trying, once the drug is approved, to test it out for lots of different things. Then when it reaches the end of the patent period, they're like, ah, well, the generics are just going to undercut us.

But there is this, there's a little bit of like a back and forth here because I think that, often when people hear about this, they're like, well, don't pharma companies do all these sneaky things to lengthen their patent lengths anyway? Can't they just get around this by doing that instead? I think that's sort of true, but there's a limit to how true that is.

Jacob Trefethen: Only so much you can, you can finagle.

Saloni Dattani: Have you heard of some of these sneaky tactics?

Jacob Trefethen: Let me invent some. Here's what I would do. Okay.

Saloni Dattani: What, you're the pharma company?

Jacob Trefethen: Yes. I would, if I think, oh, hold on a second, there might be a off-target effect here that's beneficial instead of harmful. Okay, here's what we do. We go back and change the molecule by the minimal amount to generate a new molecule according to the US Patent Office. We generate new data on that molecule and we submit a new patent. We say, we just invented a new drug. Then we want it to have not changed that much, because the effect might disappear. Do people do that?

Saloni Dattani: That's true. People do that, but can't the generics just use the original version and say, hey, well.

Jacob Trefethen: Damn, wow. I'm so stupid. I'm such a bad- That was crazy. I completely missed that. Okay, let me think. Yeah, you have to then actually, well, that's pretty cool. The system's aligned with benefit pretty nicely because you have to then make it a better drug.

Saloni Dattani: Yeah, right.

Jacob Trefethen: I guess, yeah. Okay, here's my new scheme. I make it so that it is demonstrably slightly better. Then the way that drugs work, you get a winner-takes-all effect where no one wants a slightly worse drug, you know? Everyone wants something that's slightly better. That takes 100% of market share regardless of price. How does that, how's that?

Saloni Dattani: Is that true? I feel like if I, if the brand name drug was like 5% more effective, but the generic drug is... 10 times cheaper or whatever.

Jacob Trefethen: But consumers don't pay. The health system pays. You might get negotiated by the NHS on that. You won't get negotiated in the US though. I'm exaggerating. In some cases, you will.

Saloni Dattani: I was going to say that there's this thing that generic companies can do. Let me sort of take a step back and explain how this works. Let's say I'm the brand name drug company and I have developed drug for this thing, this one condition, diabetes, and then I've also tested it for weight loss. I would put both of those things on the label, but the diabetes thing came first.

A generic company, let's say that's you, you could decide, I'm just going to say that this is used for diabetes on the label and not also for weight loss. But doctors know that it's the same molecule and it can be used for weight loss as well. So they can just prescribe the generic drug for weight loss.

Jacob Trefethen: But your point being that patent protection, it doesn't really follow an indication, it follows a molecule.

Saloni Dattani: It follows an indication, but... you have to, the brand, the company that has the brand name drug has to prove that the generic company actively is trying to prescribe, get it prescribed for that second use and that's quite hard to prove. You get undercut by the generic company.

Jacob Trefethen: Right. You're not going to confirm that effect necessarily with a trial.

Saloni Dattani: Yeah. The patent extension or whatever is only helpful if the generics haven't got in.

Jacob Trefethen: Got it, yes.

Saloni Dattani: There's another thing you can do as the original brand name company, which is that you can switch patients to a different version of the drug. You can say, oh, you know what, instead of this twice-daily drug, you should take the once-daily drug instead, or once-daily version instead. If you do that, then those people can't get the generic drug instead of your brand name drug, if they're prescribed it. At pharmacies, they can automatically prescribe you a generic drug if it's the same dosage and stuff, but they can't if it's slightly different.

Jacob Trefethen: That's really interesting, yeah. That makes sense.

Saloni Dattani: Okay, so there are all these things, there are all these economic incentives that can affect whether generic repurposing happens. My conclusion is that there are probably a lot of repurposing efforts that aren't happening.

That's probably especially true for drugs that are already off-patent and that are generics. It's probably true for things where people can already get these things very cheaply and they've existed for a long time, like vitamins and supplements.

Also for diseases like tropical diseases or diseases of poverty where the market and the incentive for a pharma company to run these clinical trials to try to do repurposing isn't really there. And also for diseases where the clinical trials take a really long time, because if they take a long time, then you have a shorter time still on patent and you have less time to recoup that investment.

Finally, I think it's probably also not happening as much as it could for vaccines. My guess is that the reason for that is that companies are trying to, generally when you're developing vaccines and they're used universally by children, by like 80 or 90% of children, and they're healthy children otherwise, you kind of want to limit how many off-target effects, how many side effects there are. So you're trying to make them as specific and precise as you can, and because of that, you're just looking for toxicity.

Jacob Trefethen: Right. I would add in the optimism column from this episode for me is it's just so nice that for repurposed drugs, you have an existing large safety dataset. The existing safety data is just such a boon. If you can find these now, I will give my pessimistic take from this episode is that I don't think you'll get many miracle drugs in the sense of I don't think you'll have these massive cures and reductions. I think you're going to be improving various markers similar to the weight loss drugs by meaningful amounts, maybe you'll be reducing your risk of heart attacks by 10 or 20% with something or reducing your risk of Alzheimer's if we get a repurposed drug for Alzheimer's. But I don't think we'll get an Alzheimer's cure this way.

Saloni Dattani: Aww.

Jacob Trefethen: Sorry. You don't even think the shingles vaccine works!

Saloni Dattani: Well, I don't think the shingles vaccine works for dementia.

Jacob Trefethen: We have to come back in five years and see who is right about that.

Saloni Dattani: We definitely should.

Jacob Trefethen: Okay, so we've learned about repurposing drugs and I wanted to check with you right now. If I, instead of injecting Mounjaro in my thigh, injected it somewhere else, would different effects happen? If I injected it in my scalp, would it be a baldness drug? What do you think?

Saloni Dattani: Wow. This is hard. I know that-

Jacob Trefethen: I don't think it's hard.

Saloni Dattani: You're trying to lose weight somewhere else?

Jacob Trefethen: No, no, no, no. I'm trying to have a different effect that I want. But because it's a magical drug, you can have any effect depending where you inject it.

Saloni Dattani: Ooh. Hmm. You know what I would like?

Jacob Trefethen: What?

Saloni Dattani: More hands.

Jacob Trefethen: You want an increase of 50% in hands?

Saloni Dattani: Yeah. You could do so many more things with them. You know what that would make really easy? Juggling!

Jacob Trefethen: How frequently do you find yourself juggling?

Saloni Dattani: Never. I'm so bad at it.

Jacob Trefethen: You don't have more hands.

Saloni Dattani: Exactly. It's because I don't have more hands.

Jacob Trefethen: Also there's complementarities, because if you had more hands, you could inject more Mounjaro quicker. You could get the benefits of other drugs too.

Saloni Dattani: This is what I'm missing out on. What about you? What's your answer?

Jacob Trefethen: If you had more hands, would you also want more feet?

Saloni Dattani: No. What do you do with feet? You just walk and run. They're not that useful. You're not picking up stuff with them.

Jacob Trefethen: I think if you had four feet... Now I'm just thinking, would I have four legs?

Saloni Dattani: I'd be a centaur.

Jacob Trefethen: Maybe if I had... Here's what I want. Instead of two flat feet, lame, pathetic, I want two curved, kind of like...

Saloni Dattani: Oh, wow. Like a rocking...

Jacob Trefethen: Yeah, yeah. Exactly. Then walking would be kind of fun. I actually got taught how to walk once. You're meant to land on the...

Saloni Dattani: You didn't know- sorry, you got taught how to walk? What is the context of this?

Jacob Trefethen: Like in the sense of by a gay person, like how do you, how do you walk in a way that's like chic?

Saloni Dattani: What?

Jacob Trefethen: You, I can't even remember now. Wait, let me just practice. You go, yeah, yeah. You have to, you have to do the weight right at the heel and the ball of the foot, but I can't do it without doing it live. I can't explain it. You wouldn't get it!

Saloni Dattani: Okay... sorry.

Jacob Trefethen: Anyway, point being, it's a bit like a rocking horse. I think you could walk better if you had a rocking horse.

Saloni Dattani: This is a very strange choice of off-target side effect you want.

Jacob Trefethen: Okay, fine, fine, fine.

Saloni Dattani: You want to turn into a rocking horse.

Jacob Trefethen: Let's see, what else do I want? Maybe it would be nice if... If you had the thing that would just give you massive muscles, would you do it? I guess we do have that. It's called a steroid.

Saloni Dattani: I think, yes. Well, not massive, but bigger. No, I don't take steroids.

Jacob Trefethen: I just entrapped you. I'm actually a police person.

Saloni Dattani: Oh, no. The other thing that made me think of was, I would love to be taller than I am. I'm very small.

Jacob Trefethen: They have that too, growth hormone.

Saloni Dattani: It's too late for me to take that, isn't it? I think it's when you're growing up.

Jacob Trefethen: It's true. It's true.

Saloni Dattani: I used to stretch more. When I was a teenager, I was like, maybe if I stretch more, I'll get taller.

Jacob Trefethen: That's so depressing. You were like, do they still have any of the torture racks that they used?

Saloni Dattani: Not that extreme. I don't know. I just thought it was, I was like, maybe this is one of those things that's like a 'use it or lose it' situation. The more you stretch, the more your body is like, oh, she needs to be taller than she is.

Jacob Trefethen: It can sense. Yeah. I guess I'm trying to think, would I want a tail? I don't know if I need a tail.

Saloni Dattani: What about a tail that can drop off and regenerate itself?

Jacob Trefethen: Definitely better than a tail. Why not have the optionality, if you're going to have a tail? Yeah. I think if I had a tail, I'd want it to be really long.

Saloni Dattani: To do what with?

Jacob Trefethen: Just to curl around my legs.

Saloni Dattani: Like Rapunzel.

Jacob Trefethen: You know how Italian people will gesture with their hands? I want to gesture with my tail.

Saloni Dattani: I was thinking of Rapunzel. You could let down your tail and someone could climb up.

Jacob Trefethen: I live on a first floor.

Saloni Dattani: Yeah, that's not very useful.

Jacob Trefethen: People are always trying to climb in. Anyway.

Saloni Dattani: She uses her hair for martial arts and stuff.

Jacob Trefethen: Which presumably hurts.

Saloni Dattani: As a weapon. Yeah.

Saloni Dattani: So I guess our conclusion is there are probably a lot of repurposing efforts that aren't happening for various reasons. According to economists, the value of that or the missing amount of innovation that's not happening is pretty large. The estimate is around 100 to 400 billion dollars per year in social value that's not happening because of all of these misaligned incentives. So this seems like a really important problem to solve. What's helpful, as you mentioned, is that these are drugs that are already approved for something, so we already have lots of data on them and it wouldn't be that hard to test them out for new conditions as well.

Jacob Trefethen: With that in mind, what are some of the- not the scientific things that can help with drug development, but some of the economic or regulatory or, related to patents policy? What are some things that we could do that would improve the system here?

Saloni Dattani: I think there's probably a lot of things that we could do. I guess the basic idea maybe that I should re-describe is that in general, when pharma companies do more repurposing, or they're testing their drugs for more conditions, they have a larger population of patients that the drug can be prescribed for, so there's a larger market. There is an economic incentive to some degree to test drugs for new conditions. But that incentive is kind of time limited because once the drug goes off patent, and generics can enter the market, they can get outcompeted by those generic manufacturers and it becomes no longer worth it to run trials and expand the uses.

I think this is more of a problem for small molecule drugs, because it's really easy for generics to develop their own version of the small molecule drug in general. It's easier to develop small molecule drugs and cheaper, and they can get into the market pretty quickly. It's harder for biological drugs like antibodies and vaccines. That's for two reasons. One is that those drugs tend to have twelve years of exclusivity once the drug gets approved, rather than five. But also it's just harder to develop those, you need a lot of technical know-how, it's more expensive for generic manufacturers to develop them.

Based on that, how do we get more repurposing, more of the ideas? I guess the obvious one, which is probably, which I think is often pretty unpopular, is just extending the length of the patents. But right now, you don't extend your patent length for a new use. You get more exclusivity on the market. It's slightly different. The U.S. Patent Office gives you a standard length of 20 years after you file for a patent. A company develops a drug, maybe immediately after they develop it, they file a patent for it, they get the patent. For 20 years, they have the exclusive rights on producing that thing.

Then once it gets approved at any point during that 20 years, the FDA then gives them an additional five years where they're the only people that can sell the drug for that condition. The idea would be either you could extend the length of the patent so it's more than 20 years, or you could extend the exclusivity period that the FDA gives you after the first use is approved.

If you get another use approved, then you get another three years of exclusivity for that new use. But that's only helpful if it's before generics become available on the market. I think the downside is higher prices for longer, but the upside is there's more of an incentive to test new uses for these drugs at all. And we find out about new uses of drugs that we wouldn't have known about before. Does that make sense?

Jacob Trefethen: Yeah, maybe. This stuff is complicated though because you have more of an incentive for one company, that's true, but you do incur more deadweight loss because you have a monopoly for a longer period. Yeah, I'm not sure I have a clean intuition that will point me in the right direction. My intuition could take me in either one.

Saloni Dattani: Can I give you a weird example? It's actually, it's not the same. It's not what we're talking about, but it's kind of related.

Colchicine, the gout medicine, it's an ancient gout remedy. I think it was probably properly developed as a medicine in the 19th century for treating gout. For drugs that are developed so long ago, before the FDA even existed, before drug regulation existed, and that were already on the market, they weren't approved and the generics weren't approved either. They just were there already- they're sort of approved to be used because of that ancientness.

At some point, I think the FDA developed this pathway where they wanted to get companies to test whether these drugs were actually effective, and if they were effective for different uses as well. What they said was that, if you do test these existing grandfathered-in drugs for some other condition, then you will get exclusivity to sell them. There was this company called URL Pharma, which tested colchicine, I think for gout or maybe it was for cardiovascular disease. They found that it was effective. The trial succeeded. The FDA was like, okay, cool, now you get exclusivity. They actually cleared out and like shut down all of the unapproved competitors. This became the only one on the market and they raised the price massively and everyone got really mad. Understandably.

Jacob Trefethen: Wow. Extending patent length. That's maybe a pretty big one, kind of blunt. Are there other options?

Saloni Dattani: What do you think?

Jacob Trefethen: There's the classic, you know, two approaches to the economy as supply and demand, Saloni.

Saloni Dattani: Oh, really? What?

Jacob Trefethen: Yeah. When you put that in funding terms, you sometimes get into push and pull, where push funding is-

Saloni Dattani: What I'm getting really confused with, with doors.

Jacob Trefethen: Yes, yes. Imagine a door that could go both ways, sort of like an operating theater. No, the push means sort of grant funding investment. There's money coming from some financial entity into some operating entity to run trials or to do something or other. Then pull funding is on the demand side. You're saying, okay, because you're not going to get a big payout because of all this generic entry, we have some other way of paying out.

Saloni Dattani: It's like, if you develop the thing, we'll pay you.

Jacob Trefethen: Exactly.

Saloni Dattani: Whereas the push funding is like, we'll pay you to try to develop it.

Jacob Trefethen: Exactly. Yeah. I would look at both sides of this. I would say, if there's a market failure in the sense of there's not a private incentive for companies to generate this knowledge about whether a drug works well, number one, you can make grants. To those companies, to other entities to generate the knowledge. That's push funding.

Number two, you could create prizes or payoffs of some form out the other end, where you say, okay, it's not that you're going to be able to charge a ton for this drug because there'll be generic entry, but whoever can generate the knowledge gets a big payout. Here's a hundred million dollar prize! Those are the two things that come to mind. What do you think?

Saloni Dattani: I really like those ideas. I think that maybe they're useful in different situations. With a prize, you're giving a prize for someone who can successfully test that a drug succeeds. Why would you do that? Why not just pay the company, or why don't you just run the trial yourself? I think often the prize is more helpful when you're not sure what the succeeding drug or vaccine or whatever will be.

You're like, you guys try it out and you guys fund the trials. If you made the right bets, you'll succeed and you'll get this prize at the end. I think maybe what's difficult about a prize is actually deciding how much the prize should be. Like, what if it is really obvious and you just didn't know that and you might as well have just funded the trial?

Jacob Trefethen: That said, one of the nice things is you only have to pay out if it's successful, depending on how you design the prize.

Saloni Dattani: What if the prize is too small, though?

Jacob Trefethen: That's true. Then you have dangled something that hasn't had any effect, but it's better than paying for a bad outcome, which happens all the time in grantmaking.

Saloni Dattani: That's true. I guess with the prize, the other thing is that, especially if the thing is already a generic drug, you have a prize for showing that it works, and then immediately the generic drugs can be used for a very low price. I think the other side is, maybe you have examples of this where you were pretty confident that certain things might work so why not just fund those research groups themselves, instead of having a prize or something at the end?

Jacob Trefethen: Laying my cards on the table, my biases are often in that direction. That's because I am a grant maker though in my day job where, people say, but how are you going to pick winners? What if you don't know? I'm like, well, how bad do you think I am? Come on.

No, I basically think that people often, economists often have an instinct of: you don't know anything, you have to let the market decide; if there isn't a market that works, you have to create a market. That's a healthy instinct in some cases.

Then people like me think they know things. I'm kind of like, well, yeah, but actually I'm pretty sure we should fund this one and this one and it might actually go pretty well. So yeah, there's a healthy tension between the two.

I think you want to be looking, the cases where the pull funding and prizes appeal more to me are when you have some reason to think that there is knowledge and data that's dispersed throughout different firms and the economy broadly, that you're like, oh yeah, I definitely don't know. In some cases, I can point to those better than others. I'm sure that there is internal data on how different drugs get used that I've never seen that will be useful for some companies making a decision about whether to go after this prize or not in some circumstances. So there, I'm not omniscient.

Saloni Dattani: That makes sense. I guess there's also, even with the pull funding, you have to have some people to decide that it's worth the investment and to do the push funding. You have the prize at the end, but you need the companies, or the researchers, to decide that they think that their own candidate has good enough chances that they'll fund the trials to get to that finish line at all.

Jacob Trefethen: Indeed, which means that the prize has to be much larger than it costs to run a trial because there's some probability they'll fail.

Saloni Dattani: Have you heard of CASPR?

Jacob Trefethen: I have heard of CASPR. Do you mean the addiction thing?

Saloni Dattani: The ghost.

Jacob Trefethen: I hear him right now. Ah!

Saloni Dattani: They're the Center for Addiction Science Policy and Research, CASPR, and they've proposed a program that is trying to help do repurposing for off-patent drugs and supplements. Their idea is that there should be a program that is led by the NIH that funds and runs many trials for off-patent drugs, peptides and supplements, to see whether they work for other conditions. That is an exact example of one of these push funding uses, where you're paying directly for the trials. And also the RECOVERY trial was actually-

Jacob Trefethen: Exactly. The RECOVERY trial was some of the best push funding we've ever seen. Genuinely, if you run the numbers there, my goodness, that costs maybe $20 million. That's over a million lives. That's just shocking. But you don't get many trials that are as urgent as that, in the sense of we have no treatment for this new thing.

Saloni Dattani: I think that one was also maybe cheaper than usual because it ran through the NHS, the UK's public health system, where people were already in hospital for COVID and it was just an extra additional one or two page form that they had to sign to be participating in this trial. They'd randomly get assigned to one of the many drugs that was in the trial. It wasn't very much of an additional cost. It wasn't like running a separate trial in these different academic centers or hospitals. It was already people who were already getting treated for stuff.

Jacob Trefethen: Yep. Yeah. If you were, if you as a listener happened to be in the RECOVERY trial, you are a complete fucking legend. That is so epic. Thank you for doing that. That applies to all of our listeners who've been in trials. I know a bunch of you have. It's so cool. It's like, it's a great, it's just a wonderful thing to do for other people. I am glad that some of our listeners are so, kind as to give to the rest of humanity.

Saloni Dattani: Right. Have you, I think maybe in a previous episode, you also mentioned EveBio, which is kind of working on this as well, from a scientific perspective.

Jacob Trefethen: That is right. Full disclosure, I am such a fan of EveBio that at the OpenAI Foundation, we just gave them some money to do more stuff.

Saloni Dattani: Oh, cool.

Jacob Trefethen: But yeah, they're amazing.

Saloni Dattani: Tell us, tell me more about them.

Jacob Trefethen: They're a repurposing outfit in some sense, although we actually funded them to do something a little different. But they're taking in their original mission of all FDA-approved molecules and running that against running them all against a set of receptors on cells and seeing what happens, and generating a dataset that they then just drop into the public domain as soon as it gets created. That can give you more insights into can you repurpose any of these drugs for some effect you might not have thought.

Saloni Dattani: I found this really interesting, but I also, I think when I heard about it, I was like, aren't pharma companies doing this already? They have these huge drug libraries, aren't they already testing them for other effects?

What I found out was that, that's true to some degree, but I think what pharma companies are usually doing is trying to test their drug compounds against specific off-target receptors, or whatever, that are listed as being important for safety or toxicity. They're not testing them against all- or more receptors than that. Also, as I mentioned before, they're often, you start with a specific disease that you're interested in and you're testing the drug compounds to see how they affect the receptors involved in that disease. You're not doing like a much larger thing where you're testing lots of drug compounds against lots of targets or lots of diseases. Whereas this is trying to create that matrix.

Jacob Trefethen: It's really cool. You might- there's lots of additional things you can do, lots of edits you can make, but what a cool start. That group in particular just is so into open data. You can just go on their website and you can start clicking around.

Saloni Dattani: Ooh. I read something else about them, which is that they're a time-limited single-mission non-profit. Is that right?

Jacob Trefethen: They're a Focused Research Organization. Yeah, they were originally founded with the idea of let's do this in five and a half years.

Saloni Dattani: Oh, wow. And then once that happens, they were planning to shut down, but maybe they aren't anymore.

Jacob Trefethen: We'll see. They're so good that they might accidentally stick around. But yeah, we'll see. I don't know. You'll have to ask Elaine, the CEO. She gets to decide.

Saloni Dattani: Oh, cool. Maybe they would just shut down that project and do something else. That's very cool.

Okay, so let's do a quick summary of the different ideas we talked about for trying to get more repurposing. The first one we mentioned was, extending the patent term. I think probably this is pretty effective, especially for drugs where there is a large commercial market for producing new drugs for that use, but it takes a long time to run clinical trials for it that eats away the patent. Probably just, well, it doesn't work at all for drugs where the generic is already on the market because the generic can just undercut them immediately. It probably doesn't work very well for tropical diseases or rare diseases or diseases of poverty and addiction and things like that, where customers are too poor to pay for them.

Jacob Trefethen: What about reimbursement for off-label uses?

Saloni Dattani: What is that?

Jacob Trefethen: What I've heard is certainly in a US context that a lot of what happens in terms of how you make revenue as a company, a drug company, is about reimbursement codes. Does that play a role here?

Saloni Dattani: It does, yes. So helping people track what off-label uses a drug is being prescribed for as well, that could help you collect more data, which might suggest to you that this drug could be effective for something else as well. Then you might then run the trials for it. But also it can result in different pricing depending on which diseases they're prescribed for. That would give more of an incentive, I think, for companies to test these new uses.

Jacob Trefethen: We also talked about prizes and push funding with public or philanthropic funding. With prizes, you can dangle a carrot at the end of a stick for different it's large enough that different companies that suspect that a drug they're working on, which could be repurposed, even if it's off patent, end up paying for trials to confirm that. Then with push funding, you can directly pay for trials with different options, different drugs, that might be beneficial, but haven't been confirmed or tested yet.

Saloni Dattani: You know, whenever I hear the carrot on a stick idea, I'm always like, who is actually incentivised by this? You know what I mean? Like the metaphor. Who likes carrots enough that dangling it on a stick is actually going to get something to happen?

Jacob Trefethen: Yeah. I think it is either a donkey or Bugs Bunny, I think are the two main sort of actors involved in this incentive scheme.

Saloni Dattani: Yeah. I wonder where that metaphor came from. I always...

Jacob Trefethen: I think it's mules. Oh, it's mules. Because it's carrot or stick. Unfortunately, I think the stick is hitting a mule.

Saloni Dattani: I thought it was a carrot on a stick. Like a fishing rod. Like a fishing rod with a carrot on the end.

Jacob Trefethen: That's also how I visualize it. It's like the stick is sort of over the back of the head of this poor mule. Then it's sort of dangling carrot. Then so it's walking forward like, I'm going to get the carrot, I'm going to get the carrot.

Saloni Dattani: This is so sad.

Jacob Trefethen: It's really sad. Some people don't like to talk about.

Saloni Dattani: Wait, so the carrot doesn't get eaten at the end. It's just making them move forward?

Jacob Trefethen: I think they...

Saloni Dattani: That's really depressing.

Jacob Trefethen: It's really depressing. I believe in full emancipation for mules.

Saloni Dattani: Me too. You can just use robots or tractors for stuff, no?

Jacob Trefethen: Robots don't even eat carrots.

Saloni Dattani: No, I mean for the things that you need the mule to do. You were just thinking of dangling a carrot in front of a tractor?

Jacob Trefethen: I'm now just thinking about the humanoid robots and yeah, you just dangle reward. All you have to dangle is a one instead of a zero.

Saloni Dattani: I mean, I do like carrots, but I wouldn't...

Jacob Trefethen: I wouldn't go out of my way.

Saloni Dattani: Yeah. I wouldn't continue to follow this carrot once I realized that I wasn't getting any closer to it.

We are now at the end of the episode. Let's do a little summary and some takeaways that we had from all of this chat about GLP-1 drugs, all the other cool drugs that have been approved for multiple things, how it's possible that things can be used for multiple conditions, and how we can get more of this repurposing done.

Jacob Trefethen: Let's do it. Let's start with GLP-1s. What did you think?

Saloni Dattani: I think GLP-1s are much more interesting than I realized. It's not just weight loss, but they have multiple effects. They reduce blood sugar levels, which helps with diabetes. They suppress appetite and slow stomach emptying, which helps with weight loss, but also causes nausea and vomiting. They slightly reduce blood pressure as well, which might help with cardiovascular diseases. It seems like they might be effective for other diseases too. I think that research is still ongoing.

But what's amazing about this is that there are actually many drugs like this. Around a third of all FDA-approved drugs are approved for second use. That's much more than I would have thought. There are some other cool examples that we talked about, like SGLT2 inhibitors, and aspirin and colchicine, things like that have turned out to be effective for something quite important that we wouldn't have predicted at the start.

The other thing that really stuck with me in this episode was Gila monsters, the lizard. They're so cool. They're so cute. I wouldn't have expected them to look so cute. They're so slow, which is so funny to me that their top speed is one and a half miles per hour. That's hilarious. Most importantly for us, beyond the cuteness, they helped us find cool new drug compounds that we could tweak and use for various important health conditions. I think it's kind of a shame how venomous they are but I think they're just a very cool type of lizard that more people should know about.

When I started doing research for this episode, I had this vague idea that it was some kind of accidental discovery. It turned out that actually there were important reasons to suspect that something interesting was happening in their venom, that included their effects on the pancreas, and also the fact that they had very long-lasting fasts and they only ate a few meals per year and could control their blood sugar levels despite that.

Jacob Trefethen: I also left this episode a fan of the Gila monster. The fact that even in the deadliest venom, we can find the most wonderful benefits for humanity. There's got to be a lesson there, which we can leave to the listener.

Saloni Dattani: That's very moving.

Jacob Trefethen: It's very moving, slow moving, 1.5 miles an hour. I think that overall stepping- taking the GLP-1 example and then going further to repurposed drugs in general, I left this episode, I would say the pessimism I have is on effect sizes of repurposed drugs. I'm not sure many will turn out to be, stunning radical cures for a second indication. But I left this episode more optimistic about repurposed drugs in general. The fact that for drugs that already have been approved for one thing, you have an existing safety dataset that's large. The fact that we can point to these economic reasons why companies themselves, wouldn't be incentivized to pay for confirmatory studies for second indications, and all of that because of competition from generics and how patents work. I think that I am sort of cautiously optimistic there's low hanging fruit for these beneficial second, third use cases for some drugs.

Saloni Dattani: I also, I think I started out as a skeptic. I sort of thought, well, observational studies are pretty misleading and lots of repurposing efforts are going to fail. Aren't pharma companies already doing this internally anyway? But I think in doing research on this, I realized actually there are lots of economic reasons why there aren't the incentives that there could be for doing more repurposing. That's, as you said, the competition from generics, but also I think some diseases just not being commercially worthwhile to study.

I'm more optimistic about effect sizes, I think, than you are. I think sometimes we'll have what look like moderate effect sizes, but there's such a large patient population for them that they'll be really beneficial. That seems to be true for the aspirin with cardiovascular disease, with colchicine for heart disease, for SGLT2 inhibitors, and for GLP-1s. But to be fair, those were tested commercially, aside from aspirin and colchicine. I think sometimes it'll turn out that the secondary use is actually pretty big. With GLP-1 drugs, for example, the weight loss was the second use and those have a massive effect size.

Jacob Trefethen: Fair enough. Another thing I took away from this episode is just there are a lot of drugs out there already. Sounds basic to say, but there are thousands or over a thousand FDA approved medicines mostly from the last hundred years and we're still finding out ways they work, and all the different things they do in the body, at different doses, for different people facing different problems or diseases.

Saloni Dattani: Yeah, it's pretty cool.

Jacob Trefethen: It's a bit punk that we don't even know yet.

Saloni Dattani: I think that's maybe especially true for the rare conditions or the tropical diseases where just someone hasn't tried them out or hasn't tested them. There must be lots of things that we just haven't found out about yet. What was your favorite repurposed drug that you heard about today?

Jacob Trefethen: I think my favorite is the potential repurposed drug of the shingles vaccine. Maybe it turns out that it reduces your risk of developing Alzheimer's. So I'm excited about that. But even better, if that ends up being true, I'm excited about me being right and you being wrong.

Saloni Dattani: I really hope you're right.

Jacob Trefethen: Well you being 75% wrong because you think there's a 25% chance that I'm right.

Saloni Dattani: Right. No, I really hope you're right. I wish I could go out and get a shingles vaccine right now, but I am not old enough to. It's one of those things where, when you're a kid and you're like, oh my God, I wish I was old enough to do whatever. Right now I'm like, oh God, I wish I was 50 years old so I could get the shingles vaccine.

Jacob Trefethen: Wow. For me, it was when I was 11. All I wanted to do, we stayed in a hotel once and I, well, probably more than once, but roughly once. They had a gym and I couldn't go in alone unless I was 18. I was like, one day I'll be old enough and I'm going to go into this gym. I had to go back to Ohio and then I can go into that gym.

Saloni Dattani: I didn't know that there were age restrictions on gyms.

Jacob Trefethen: Yeah, I hate to give you such horrifying news this late in an episode.

Saloni Dattani: The other thing that I took away was I didn't realize how important this was as an issue. I didn't realize how large this social value of repurposing drugs could be. The estimates that I described, they were conservative estimates that put it at hundreds of billions of dollars in social value per year allowing for more repurposing to happen and under a hypothetical where patent terms were longer.

If you think about, okay, you extend patent terms to get more repurposing, that's still only going to get you repurposing for diseases that are worth the commercial market. I think that's still a conservative estimate. It doesn't include very much like drugs that could be repurposed for tropical diseases, for example. Getting more repurposing could be really valuable. I think we're missing out on knowing which other conditions many existing drugs might work for. And people need to go and find that out.

Jacob Trefethen: Yeah. One of the things in this episode that I think will stick with me is how much that problem is not scientific, but is about policy, economics, patents, and all of that. Just discussing, okay, how can reimbursement change? When should people run prizes for repurposed drugs? When should you, as a government or philanthropy, use push funding to fund off-patent trials and get more repurposing to happen? I think there's a lot more activity that could happen in those different areas that would be really beneficial.

Saloni Dattani: I think also what I learned from reading for this episode was just, there are lots of these things already happening. Like there are incentives to some degree for repurposing your drug. You get an extra few years of drug exclusivity and stuff like that. Like, people have tried a bunch of these things already, but we could be doing a lot more of them. What was your favorite idea to get more repurposing to happen?

Jacob Trefethen: I think my favorite one is, honestly, my favorite one is modeling more trials like the RECOVERY trial. You know, have a platform trial, a shared control group, you can make it adaptive as you go. And have lots of off-patent drugs, but companies can chuck in their on-patent drugs too if they want and test things against each other. That is my most exciting takeaway from this episode.

Saloni Dattani: I'm going to disagree with that. I'm going to say prizes, I think, are better.

Jacob Trefethen: Prizes are better than the RECOVERY trial? The best trial of all time?

Saloni Dattani: Maybe not, actually. I think one reason a prize is better is that you don't have to, as a funder, you don't have to pick which drugs you think will succeed. Hopefully someone else has some better idea. But also, you could just get other companies to work on funding the trials themselves. You don't have to pay for that. You can just pay for a prize, which is higher than the cost of one trial, but lower than the cost of funding all the trials. So why not?

Jacob Trefethen: Okay, I'll meet you in the middle and say, let's do both.

Saloni Dattani: I guess you do need someone to do both in the end. I guess the other upside of that is that if the drug already exists and it's already on the market and maybe generics are already there, once you've given the prize for it, everyone can use it already.

Jacob Trefethen: True, true.

Saloni Dattani: The last thing that I found interesting was EvE Bio. I thought it was just really cool to have, one, this idea of initiative that is focused on one thing and then will planning to wind down after they finish that one project. But also just scientifically, this idea of testing out lots of combinations of drugs versus targets that haven't been tested before and then publishing that as an open database that lots of researchers, academics, and pharma companies can use in the future. I think we need a lot more public goods like that and it's just a really cool example of one.

Jacob Trefethen: Okay, we've left this episode with a lot to do. I feel like we both have to get back to work, Saloni.

Saloni Dattani: We should get back to trying out some of these repurposed uses for ourselves.

Jacob Trefethen: You and me volunteering for the sake of science. Each day we can do a different drug and measure what happens to each other.

Saloni Dattani: That's how a randomized trial works.

Jacob Trefethen: I think so. It's a shame about immortality bias or whatever you told me about because otherwise I could give all the data we need.

Saloni Dattani: All right. Thank you for listening. I hope you enjoyed this episode. If you did, please rate us on Spotify or Apple. We occasionally get comments on Apple podcasts, but we don't have that many, so if you could add a comment, that would be really helpful to us.

Jacob Trefethen: Yes. Thank you very much. We would really appreciate that. Feel free to take this episode, chop it up, repurpose it for your own use too. Goodbye!

Saloni Dattani: Bye!