The Scientific Journey Behind Ozempic (with Lotte Bjerre Knudsen, Novo Nordisk's Chief Scientific Advisor)

Transcript: (disclaimer: may contain unintentionally confusing, inaccurate and/or amusing transcription errors)

Ben: Hello, Acquired listeners. After David and I finished the Novo Nordisk episode, we thought it really would be cool to meet Lotte Bjerre Knudsen and talk with her about the science. We cold emailed her and she responded that she had just finished listening to the episode, and she was about to email us. She said she'd be happy to chat.

In this episode, we talk not about the business side of Novo Nordisk, but zoom in on the science that we didn't really do as much in the episode. She takes us back to the moment where she first started the research over 30 years ago, and the process of identifying the molecule, improving it, and ultimately launching the drug to the world. Now, on to our interview.

Today we are joined by Lotte Bjerre Knudsen, the Chief Scientific Advisor of Novo Nordisk. For those of you who listen to our Novo Nordisk episode, you will recognize her name as the person who led the initial team that investigated GLP-1 starting way back in the 90s, eventually creating Liraglutide, what led to Semaglutide, or what we know today as Ozempic, Wegovy, or Rybelsus. Are we pronouncing Semaglutide, Liraglutide? How do you pronounce it at Novo Nordisk, Lotte?

Lotte: I think you're doing pretty good. I've heard many versions over the years depending on where in the world you are. Some people say Semaglutide, some people say Semaglutide, and you're also doing pretty well with the trade names. Good job.

Ben: Doing our best.

David: Before we get into all the science, which we want to cover with you in-depth, we wanted to start first though with your personal journey. How did you come to join Novo Nordisk? I guess first it was Novozymes that you first started at right out of undergrad.

Lotte: Thank you for taking me down memory lane and you did really nice research. I enjoyed listening to that episode. Denmark is a small country. I'm born and raised here. Somehow during university years, I got my eyes set on this company, I really wanted to work there, and then I just looked for various ways to join the company, actually. The first job I applied for I actually didn't get.

Then I set my eyes on joining the enzyme research division as you also picked up on. When I eventually got in, I actually never applied for a job because I did my thesis and then they offered me a job.

Ben: When you did apply, you got rejected, and then you ended up working for the company without applying.

Lotte: Yeah, but that was before I joined university, actually. I have a degree also as a laboratory technician before I went to university, and it was there that I applied for a job that I didn't get. I'm thinking in hindsight, they probably thought I would skip to university and not keep the job as a laboratory technician, which was probably true.

I started out there working. Back then Novozymes had a collaboration with Procter Gamble, so we were making enzymes for laundry detergents. It was super exciting. I always had my mindset that I wanted to do product-related research and never had a strong interest in being an academic researcher. For me, it was exciting to make a product.

David: You certainly ended up doing that. To my mind, enzymes are completely different from diabetes research and what ultimately GLP-1. Is it common to switch between those two fields?

Lotte: I wasn't the only one. It's not common, of course. I graduated from the Technical University of Denmark. We're a small country, but still Denmark's Caltech or MIT. I'm trained in biotechnology, and that means I could go several ways. I was in a small group when I started in Novozymes where many of us actually came from the Technical University, but our boss at that time, the head of the group, was also a medical doctor.

When Novo at the time, or Novo Nordisk, wanted to look more into finding new medicines for diabetes and especially type 2 diabetes, they actually put him in charge. Then the whole group that he had in the enzyme division was put over in the diabetes part of the company to bring a little bit of an outside perspective on the other research groups that were there. I'm sure it was a little bit unusual, but it was by design. They did want someone to come in and try to look at things differently.

Ben: Just for listeners, so that they understand the clear difference between these two things, the enzymes that you were working on as a part of this collaboration with Procter & Gamble, it was to do stuff like change the features of the detergent, to lift more fibers away from it, to make your clothes appear brighter. That's why David and I are so wrapped around this idea you went from that to diabetes and weight loss interaction of molecules within the human body.

Lotte: Back then there was a lot of focus in the laundry detergent business on making natural products, so there are actually quite a lot of enzymes in laundry detergents. The new thing that we did back then was to find the cellulase that chews off little pieces of cotton on your colored clothes making it look brighter.

I think today, I'm not fully up to date on the market stats, but I think actually those products are going down a little bit because people don't want to wait for the results. For that, you have to keep washing your clothes in order to get good results based on this natural method. Today, actually, unfortunately, I think there is more chemistry going into the detergents because people want immediate results.

We also tried to make another one that would bleach in the solution so you would be able to mix white and red clothes. We never succeeded with that one, but I did blow up a refrigerator trying to get that chemistry going. It was not super popular because it actually had butyric acid in there. If you just know a little bit of chemistry, that smells like rotten eggs. That was what the whole building smelled like.

David: Wow.

Lotte: That was the end of my research in the enzyme division.

David: It just tickles us because we love things that just seem so unlikely. The whole Novo Nordisk story is so unlikely and yet you're now the 15th largest company in the world. Speaking of unpopular avenues of research that you were involved in, take us back to when you did move over to the diabetes division and pursued GLP-1 research in the 90s. To our understanding, to say it was unpopular in the research community was an understatement at the time. How did you latch onto it and what gave you the confidence to keep pursuing it?

Lotte: It's fun to think back on now and the company was so small back then compared to what it is now. Everyone knew each other. Today, there are so many people. I have no idea who they are, but back then I knew everyone. There was a lot of great academic research.

When science gets successful, it's always the story of the many people over many years. If you gave me half an hour, I could mention so many names and what everyone did. But to try and make it a little bit condensed, there are some people in academia. You mentioned Dan Drucker, for example, when you did the Novo Nordisk podcast. There's also Jen Juul Holst, the professor here in Copenhagen. They did some of the foundational work to find and identify GLP-1.

People had been speaking about a substance like that actually for more than 100 years, knowing that there was something that's being produced in the intestine that would be able to have an effect to increase insulin and then lower blood glucose. But it wasn't until 1984 that it was identified.

There were primarily two groups that were involved in that. Obviously, we had one of those groups here in Copenhagen, so very close to where we are. We started talking to them in the very early 90s. There was also a really great group in Germany led by Michael Nauck who were doing some of the early clinical studies. Because this was a natural substance, you could actually put it into people and look at what happened. In short-term studies, you're allowed to do that.

We knew that there was a good effect on diabetes, and then we just try to figure out how we could make a drug based on this. Pretty early it was also discovered that GLP-1 is very short-acting so you'd either have to carry around an infusion pump, or you'd have to have multiple injections. We also tried to make small molecules early on.

Now, you're on the West Coast. We collaborated with a company in La Jolla, San Diego, and I was there quite a lot also in the 90s. We're trying to make tablet-based small molecules back then, and they were just not drug-like enough. It had to happen to be these injectable drugs. We just pursued multiple things.

Then you're asking how I got into it? In the beginning I was just the lab rat. I was the young scientist on the team. I modernized a lot of our assays. Back then we'd go from single tubes to these plates where you could do 84, 96, or 384 assays at a single time. Back then that was big, right now it's even larger and robots, but that's what I was doing in the beginning, and I was screening all of these compounds. It's industry.

A lot of things happened. My boss back then was actually leading the work. When I came back from maternity leave in 1994, everyone I worked with was gone. There were a lot of things happening and new people coming in. Most of the group I was in actually went back to the enzyme division. But I didn't want to leave because I got excited about GLP-1, but then I was the only one left.

Then I was asked by the new head of research, [...] Thompson to take up the torch for leading the GLP-1 project. He said to me you figure it out. You know about this, you figure it out.

Ben: A few threads to pull on there. One, I just want to clarify something. The initial research that you were doing was to take natural GLP-1 and inject it into humans?

Lotte: No, what I mentioned there was that there were people in the academic sector. I mentioned Michael Nauck in Germany who did these studies. Back then it was a slow offline world. Nothing got put on the Internet. I did this back then when either you met someone and they told you about what they did or you waited until it got published in a journal and you went to a physical library to read the article.

We were closely connected to Jen Jul Holst here in Copenhagen. He was closely connected to the group in Germany and [...]. We had this knowledge that GLP-1 was actually a really good idea for patients with diabetes. Then we tried to figure out because we knew that unfortunately then the native peptide is not a good drug. Then our job was to try and figure out how we can actually make a product that is convenient for the patients.

We went through several different rounds. We actually had two, maybe you could even say three projects that failed before the one that ended up being successful with Liraglutide.

Ben: Were you binding different fatty acids to GLP-1 molecules? What did the failures look like before you got to the success?

Lotte: I really liked in the episode that you actually understood the fatty acid binding principle.

David: We tried.

Lotte: I think that was pretty well done. That was what ended up working. The other thing that didn't work was to try and make what is called a sustained release formulation where you make a classical formulation and you add some things to the liquid and then when you inject that it stays on the injection side for a longer time. That was a very common approach and we could get it to work, but unfortunately, it also gave a severe skin reaction. So that didn't work.

Then we tried other ways of protecting the peptide, but that wasn't enough in order to make it last to become a convenient product. It was about a year of work and what we managed was to change the duration of action from two minutes to five minutes. That didn't work either because it turns out not only is GLP-1 being chewed down by metabolic enzymes, but it's also being filtered by the kidneys really rapidly so that didn't work either.

Then we started to look into this fatty acid isolation concept which other people were working on at the time also with insulin. When I was told you figure it out, I was sitting fairly alone at that point in time and thinking what can I do? We also thought about DPP-4 inhibitors.

I don't know if you came across that class of medicines also in your research. They give a small increase in GLP-1, so you can get glucose lowering. But eventually, it was found out you don't get weight loss with that.

I didn't choose that because I didn't have so much access to small molecule chemists at the time, so I chose the fatty acid acetylation idea actually because I thought I can actually do that. I know how to do that. I can lead that program. That was my choice for moving ahead.

Ben: On the episode, we drew this parallel or we tried to take away this idea that it was because of all the work done over decades at Novo Nordisk on the insulin side of the house to figure out how to do longer lasting insulins that made you feel comfortable like oh, I know how to do this fatty acid binding for GLP-1. Is that the right way to think about it? If Novo Nordisk hadn't had that expertise with insulin would you have felt comfortable taking this approach?

Lotte: That's, of course, really difficult to say. Of course, I was at a place where there was some experience, but it was completely unproven and it turned out to work differently on insulin as compared to GLP-1. It was a component that other people were working on, but the two groups worked completely separate. Then you were saying is there something around the decades of work of insulin? Yeah, maybe something.

As an example, I decided that I wanted to focus on things that were very close to the native human GLP-1 form, and the reason for that was because of the learning with the animal insulin. You can get a patient's own immune system to react towards those animal insulins. It's not really dangerous, but then it means that the medicine works less well. That experience I took from decades of work on insulin and say I'm going to try and see if we could avoid that.

I was saying, I'm going to go with these fatty acids and I'm going to try and see if we can keep it as close to native human GLP-1 as possible. There were other people who were pursuing other ways, like you spoke about the [...] molecules as well and the Gila monster, the very dangerous Gila monster.

David: A lot of people wrote into us and said it's actually pronounced Gila monster, not Gila.

Lotte: Oh yeah, that's probably true. It is Spanish. Everyone in the science field calls it the Gila monster.

David: Oh good. All right, vindicated. How close were you to that work, though? We were just laughing as we were telling that episode. We're like, you can't make this up, a lizard!

Lotte: It was a small world, so of course we knew about it, but we had this strategic intent from the beginning that we wanted to make something that could last for 24 hours with just one injection. Once weekly wasn't really a thing. It came a little bit later. But we wanted to say, this had to be simple. This is not insulin. It has to be much simpler, so we didn't want to work with exenatide because it wasn't really possible.

Then you'd have to do two tricks. First of all, you have that it's somewhat longer-acting than GLP-1, but it's not enough. It's like 30 minutes instead of two minutes so you'd have to apply another principle on top of that. That could be the sustained release that I mentioned earlier, where you add something to the formulation and then it sticks on the injection side. But then I had the learning that that can give either skin reaction or antibodies, so I didn't want to work on that.

Ben: The idea was that you just wanted to figure out one magic trick, not have to figure out two that would work together?

Lotte: Yeah.

David: Is it correct to say that during the (at least) initial development process, the target market was type 2 diabetics who were not yet insulin-dependent.

Lotte: That's the next level of the conversation that could be really interesting because actually for us, the target market was also obesity from the beginning. Of course, it's impossible to be on top of everything that's being written, but for us it was obesity all the way from the beginning.

Then that comes back to now before I mentioned there are these people in academia that were showing that GLP-1 would be beneficial in diabetes, but then there were actually other groups, also academic groups, that pursued the angle of obesity early on. One of them, for example, was Stephen Bloom in London, who actually got knighted for his contributions to science over the years, I think.

There was also another research group here in Copenhagen, Ole Metz, who was also pursuing this angle, very different methodologies they were using. Then again, I was close to one of them here in Copenhagen, so the work that he did actually inspired me to say I was in a pharma setting where I saw some people were working on type 2 diabetes and as you're saying it could be before insulin, trying to maybe compete with tablets, metformin, and sulfonylureas.

But then I had other colleagues who were pursuing obesity, and I was thinking why can't I have both? The GLP-1 idea actually can be used to both treat diabetes as well as obesity too. Completely separate mechanisms.

The way GLP-1 works in diabetes is that it increases insulin, but it also lowers another hormone called glucagon, so it actually has two mechanisms in one. Then what's also built into it is this safety switch where you don't really get the low hypoglycemia that you can get with insulin. That's a separate mechanism in diabetes. Most of that occurs around the pancreas and the liver, just to get the peripheral organs in there.

But then with the weight loss effect, that's happening in the brain. The brain is the main organ for anything related to how we eat. There can be some effects of the peripheral nervous system also, but it is mainly the brain. That's a completely separate effect of GLP 1. I just thought, why can I not say we can go after two indications at the same time.

Ben: This was as early as the early mid-90s, this was the thinking?

Lotte: Yes, it was.

Ben: I think this is important to underscore for listeners. This is extremely different from the widely held belief in most media right now that is about Ozempic. What you commonly read is that they were seeking a diabetes drug and oh my god, in this most recent study they stumbled upon this idea that it's amazing for weight loss. You're saying, no, from the very beginning, we thought that this could do both.

Lotte: Yeah, it is a common misunderstanding. I think that maybe a little bit comes also for the lizard story. It's just not true. We were the only company for 20 years that pursued obesity. The weight loss that was seen with Exenatide and also with some of the other early agents were never going to be enough to obtain an approval for the treatment of obesity.

Somehow these fatty acid acetylated compounds actually do a little bit better on weight loss. We saw that. I guess we were also a little bit lucky. There's some luck to everything that we didn't know, of course, going in with this fatty acid acetylation technology that would work or actually work even a little bit better for obesity than some of the other methods. But we did have a strategic intent to go after obesity early on.

We've been alone in that for the longest time in keeping up with the medical community experts out there. We've just been going at it for 20 years. It's only within maybe a little bit more than five years that we see other companies going in and now everyone's in there. Back then it was only us. There was a lot of interest in obesity also in pharma, but they all wanted to make small molecules that would deeply penetrate the brain.

There were some made, but then there were side effects. There was also a hormone, I don't know if you stumbled upon a hormone called leptin that is produced by the fat tissue, that was another idea that is approved today for lipodystrophy.

Ben: Do I have it right that leptin is the most common signal to your brain of hunger? Hey, I'm hungry is the leptin production.

Lotte: Yeah, it's a signal that comes from the periphery that then signals to the brain. There are other signals in the brain that also have really strong hunger signals. But that never worked in general obesity. I can still remember exactly the year where the data were released, I think it was in 1998 or something, and everyone was at the American Diabetes Meeting in Chicago excited about these results, and then it just didn't work.

Leptin is also a larger molecule that would have to be given by injection, but it just didn't work in general obesity. Then there were these other small molecules that didn't have safety problems associated with them, so that meant that the entire field of obesity and big pharma died out for some time.

David: We spent a long time in the episode painting a picture of stigma in the pharma industry in the late 90s and early 2000s around weight loss drugs and that whole category in that it was something that the industry just didn't want to touch. Was that accurate?

Lotte: Yeah, I think it's a good way of phrasing it. One side of it is the scientific side. There were numerous attempts made both on this injectable treatment, potentially with leptin and then there were all these small molecule attempts. You went back to the snake oil as well in your episode. There have just been so many attempts where medicines were put forward for obesity that weren't safe or they didn't work.

I think the whole pharma industry gave up and they simply didn't want to touch it anymore. Then I think there was probably also this: is it important to treat obesity or should we rather focus on cardiovascular disease and diabetes and some of the other diseases that have more comorbidities maybe or when you look at it are more acutely serious?

David: I guess there's the whole moral issue. The belief that many people have for a long time is like oh, people should exercise more and eat less.

Lotte: Yeah, I certainly heard that a lot. But for all of those years, we continued to work with many obesity specialists all over the world who were desperate for help for their patients, and it only became worse and worse and worse in all of these years where we were working on this.

David: As we did the research, the great irony is that as that belief became stronger, the problem just got worse, as you say.

Lotte: Yeah.

Ben: Were you sitting in that 1998 meeting where that was the kickoff of everyone losing interest in funding and investing in obesity drugs? Were you sitting there thinking, no, but I have it, I have the answer, or do you feel like that wasn't clear yet?

Lotte: I always thought I had the answer because I kept on having good data. I was well connected in the academic setting, even though it was small. I think you said earlier that it was not a very popular field and that's certainly true. We were always in the smallest room at the back end of the conference center.

But it was then because the community was small, people were well-connected, knew each other, and supported each other. I always knew that the data was there, so I just kept on. I can be very, very, very patient. I can also be impatient with myself on things, but when I see that there's a plan and we just need to keep working, I can be extremely patient.

But it took time. We had to say, okay, it's actually a big task to get these GLP-1 approved for the treatment of diabetes. We also had to take it slower on the obesity studies. It was running behind the diabetes program because things take time. It takes time to actually do these things. There are a lot of studies you have to do and some of these studies we're doing are with 10,000 people, with 17,000 people, and follow-up for 5 years sometimes.

Ben: It's amazing. You keep talking about the academic community. It's a small group of people who all know each other. Where are the bounds where you can share information versus where you tend not to?

I could imagine two university researchers who are not affiliated with companies at all sharing early data before they publish it. But I could also imagine two researchers who are employed by competing companies not sharing any early research. What is the level of communication between various types of researchers in the field?

Lotte: By the time you choose to publish things, of course you share, you go to conferences, you share a lot, you stand next to some of your competitors with the poster and there are some things you can talk about, even though you might also have to protect the IP. But there are limitations, of course. When you're in that period where you are developing the intellectual property rights, of course, you cannot share any of that. Of course, there is an element of competition between the industry groups.

But then there are things you can bond over and maybe discuss the biology when there are problems to be solved. I think we have actually also worked together sometimes on some things. Probably some people think that you're unfriendly with each other. That's not the case at all, but everyone in the industry respects that there are times when you can't share because you're working on the IP.

You can make formal collaborations. Today, when I look at how we're working today, we have so many collaborations where we call it co-creation times when we work. Even with other biotechs, also the larger companies or academic groups. There's just a research contract on how we are doing things together, which then obviously also means sharing the IP.

Ben: I have to imagine, too, when it's a space that everyone else has written off, there's a little bit more camaraderie among the researchers, even if you're at competitive companies. I imagine you knew for a long time that there were folks at Eli Lilly who were also just as obsessed with this problem and also pursuing different avenues, and you couldn't know exactly what they were working on, but there had to be some amount of, hey, we both have a belief that there's a future here.

Lotte: Of course, you watch what the competition does. In this case, for the first 10 years or something, maybe even close to 15 years, no one believed in this methodology that we pursued, which today I would call it a platform technology because everyone's using it. When you look at scientific papers, there are thousands of papers that use this methodology, and we developed that.

But no one was interested for 15 years. They left us alone. They must have been thinking this is not going to work. We had the space pretty much to ourselves for quite some time, which you could also see if you went and looked at the patents. We have a lot of IP on that technology from that time.

David: What would you consider is the platform that has taken you and Novo Nordisk from Liraglutide to Semiglutide to beyond? Is it fatty acid?

Lotte: Yeah, it's the fatty acid technology that I would call a platform technology today. That was what we started working with in the 90s. The principle—you explained it well in the episode on Novo Nordisk—is that the fatty acids actually bind to albumin, and albumin is this big molecule that we have in the blood that is a transporter of lots of things that need to be transported in the body. It's a natural principle that these fatty acids, which we eat, we get them in with the food, that they are poorly soluble in blood so they bind to albumin and then they get transported around.

We piggyback on nature's principle of the fat that can bind to the albumin, but to actually make medicines out of that that could then eventually last for a week. That was an idea that we came up with and that we worked on for many years to prove both that it worked and also that it was safe.

Ben: I see. When you're referring to platform, we know how to make this fatty acid bind well to albumin to circulate in the bloodstream for a week. Therefore, we can plug other things into that fatty acid too to be carried around and be long-lasting.

Lotte: Yeah, that's what we say in pharma. We call it a platform technology when we come up with a new principle for making a medicine.

Ben: Maybe this is a good time to ask the question. How does Liraglutide and now Semaglutide work from the moment it is injected to all of the things that it does in the body? We had been emailing. You pointed out that I had a line on the episode which was we don't exactly know why it works, we know that it works. You said no, of course we know why it works. I would love to dive into that, knowing that our audience is primarily a smart, technical, business-savvy, logical audience, but doesn't have a science background.

Lotte: In diabetes, where the disease is that you have, your blood sugar is too high. There, GLP-1 works by increasing the levels of insulin, which then gets the glucose down.

At the same time, it also lowers the level of glucagon, which is the opposite to insulin, and that means that there are two mechanisms at play at the same time that both lead to a lowering of blood glucose. There's also safety built into that because the mechanism stops working when glucose is normalized, so you can't really get too much of it.

It also has an effect on your intestine, so that food is absorbed slower, which then helps to not get too much excursions in blood glucose after you eat. Of course, when you eat, your blood sugar will go up, but then it will eventually go down again. That means that there are actually three mechanisms that play into how GLP-1 works when treating diabetes.

What we were emailing about was the anti-obesity effect, the effect that helps people lose weight, whether it is in patients with diabetes or people with obesity or any other diseases. The way that these GLP-1 agents work is that they help people to eat less. You simply consume less calories when you are on this medicine.

I think we have a really good understanding on, for example, going from Liraglutide to Semaglutide where you get approximately twice as much weight loss, you also have approximately twice as much reduction in energy intake. With Liraglutide, it's like 15% reduction in energy intake, then it's about 30% with Semaglutide. That is how it works when you look at it from the patient point of view.

You can of course dwell further into that mechanism as I was just doing in diabetes with insulin, glucagon and gastric emptying, and then you can say, okay, which organ does it work on? And here it really is the brain, but of course you have to go to and accept some animal studies in order to understand the mechanism further, because in animals, you can separate which receptors are in the lower part, the peripheral part of the body, or which are in the brain, and then you can make animal studies to show that it's happening in the brain.

When people are saying we don't know how it works, then they refer to the animal studies because there are actually so many places that GLP-1 works in the brain. It has effects both on hunger systems, on satiety systems, but also on the reward system, which is like how you want food, how you like food, and how you maybe dislike food. That's what they mean when they say we don't know where to work. We don't know exactly which part of the brain and how much for that part of the brain and how much for another part of the brain. But we do know that the majority of it is in the brain.

Then from a patient point of view or the people with obesity, then we just know that it's because they eat less calories when they're on this medicine. They also have better control of eating and we've investigated that in people where they are asked to rate how well do you feel that you can control how much you eat? You can even see that it looks like it actually works well against savory food, which is, for example, burgers and things like that. We also know in people with obesity that that's how it works.

I would say we know how it works, but of course there are always details. I could go on and explain stuff about what happens in the brain for the next 30 minutes if you have time.

David: Actually, one thing I was curious on that. I may have even said on the episode, but I wasn't qualified enough to know for sure. Because natural GLP-1 has such a short half life, is natural GLP-1 present in the brain in less or less quantities than Liraglutide or Semaglutide, is because those obviously have a much longer half-life? Does that mean it gets into the brain more than natural GLP-1 does?

Lotte: That's actually a really clever question. There is not that much difference in how much GLP-1 there is in a person with a disease versus a person not with a disease. That was in your question also on whether there's a difference. What we're doing with GLP-1 is, it's not like with insulin. We know with type 1 diabetes, you don't have insulin. If you don't get insulin, you die.

It's not like that with GLP-1. GLP-1 is part of this postprandial. After you eat, there are a lot of different hormones and neuromodulators that are at work to make sure that you process the food. GLP-1 is one of those, but it's not super important on its own. Maybe that's a good thing in this context.

Maybe that's actually why it has been allowed to say here's a substance that in nature only works for two minutes, but it's actually okay to make a pharmacology out of it where you give high amounts for an extended duration of time. And that actually can work because it's not super important. If it was super important, there'd be some counter regulation to it so that maybe it would work for a week, but it wouldn't continue to work. That's one part of it.

Then you also asked, does natural GLP-1 get into the brain? Those studies are really difficult to do because it's gone so quickly, but I would just argue that since we know that the target for how GLP-1 works, we call that a receptor, that those are in the brain. Then there has to be some GLP-1 that gets to the brain.

There's also some local production of GLP-1 in the hindbrain and the back of the head where the spinal cord comes up. There are a lot of nerves coming up towards the brain, and there's also some GLP-1 being produced there.

Ben: It's fascinating. Am I hearing it right that the majority of the effect on type 2 diabetes happens in the periphery, but the majority of the effect for its effect on weight loss happens in the brain?

Lotte: Yes. I think also some of the confusion on the mechanism also comes from the way these things are regulated. You take your medicine, you read the package insert, and then if you have the diabetes medication, you won't see a description on how it works to regulate weight, because that's the way it's done. This is a diabetes medication, so we write about how it works with diabetes. That's how the FDA does it.

Then with the obesity medication, there you speak about how it works on weight loss. I think that leads to the confusion that since there isn't a description on how it works on weight loss in people with diabetes, it adds to the confusion that maybe it just could be just a side effect.

Ben: You also said something there that I want to follow-up on, which is that the reason people lose weight is that…

Lotte: They eat fewer calories.

Ben: Correct. They consume less energy. I think there's been a debate in the weight loss community for, I don't know, 20 years of is calories in minus calories out a reasonable way to figure out how many calories are retained by the body in the form of fat, muscle, whatever mass. Do you have an opinion on that?

Lotte: From a pharmacological point of view, with the medicine, there's definitely a clear correlation with Liraglutide to Semaglutide double the weight loss, double the energy intake reduction. I think that's a really clear correlation. I think what you're going at is also how does your metabolism trick you when you start eating less than your energy expenditure, your metabolism also goes down.

That's why sometimes it can be really hard. If you go on a starvation diet, it's probably not going to work very well because your body will protect you. Also, the energy expenditure system shuts down so that you actually won't lose as much weight as you think in that way. But that's a little bit different from pharmacology. I think both sides probably have their points.

Ben: It's the idea that, well sure, if I eat 500 calories less and my energy expenditure stays exactly the same, well then I'm going to be losing 500 calories worth of mass in order to make up the difference.

However, it's unlikely that my energy expenditure is going to stay exactly the same if I'm eating dramatically less because the body has many mechanisms to make it so that I don't expend as much energy to keep me alive or to keep me static at that body mass.

Lotte: Yeah, and it's always important if you want to lose weight that you exercise. That's also what you can see with the description of the medicines, that it's highly advisable that you should exercise at the same time as you try to lose weight in order to keep up your metabolism.

Ben: There was another point in the episode where I think David and I might have glossed over something, and I wanted to hear it directly from you. Going from Liraglutide to Semaglutide, the goal was to increase the half-life, so you go from a once daily injection to a once weekly injection. One of the things you observed is the weight loss was twice as effective, or the energy consumption was reduced by twice as much in people trying to lose weight. Was that surprising to you?

Lotte: Yes, that was a little bit of a surprise. Now taking you back to that time. First we had Liraglutide, and then we started to think about whether we could actually make an even longer acting version so that it would be even simpler for a patient?

Now I also have to mention a few other people because at that point in time, you could say the guerrilla army that was interested in GLP-1 also started to grow. There were many more people that started working on it. I also have some more phenomenal chemistry colleagues that started working.

The actual chemistry invention of the Semaglutide was carried out by some of my colleagues, these will be a bunch of names, Jesper Lau and Thomas Kruse [...], they were the ones who did the chemistry on Semaglutide. The thinking just was we have to make it stick harder to albumin so it stays on albumin for a longer time. They engineered the fatty acids to actually bind harder to this albumin molecule so that when it was in the body, it would stay longer on albumin.

When you look at how long Liraglutide lasts, then it's 12 hours, whereas with Semaglutide, it lasts 160 hours. That was the intent. In order to do that, I think they probably looked at about 4000 different molecules and then ended up choosing the one that was Semaglutide.

Compared to Liraglutide, it's a little less sticky, a fatty acid, you can understand that it's fat, it's sticky. But with Semaglutide, they engineered some more less stickiness into it. The point was to make it long acting.

It turns out that when you're doing that change, at the same time, you also get more weight loss and it's likely that it's because of the stickiness, so you actually get a little bit more to go to some areas of the brain that are important for the weight loss.

Ben: It’s the idea that it's potentially penetrating deeper since it's sticking around longer.

Lotte: Yeah. It's not as such penetrating into the brain, but it has access to some of the outer parts of the brain. Semaglutide does that a little bit better because of the way that the chemistry was done differently. It was a surprise that it was that much better.

Ben: Is it an interesting line of thinking then if we found a way to make the GLP-1s bind in a way that lasted a month or a year, that humans could all be better at regulating all of these things all the time, be it weight loss or cravings or addiction or any of these things. That feels like the next step of, oh wait, if we can make these things stick around longer, maybe they can go to even more places in the brain.

Lotte: I think there's definitely a lot of thinking right now on what else could you do to make it easier for the patients. I think if we just take a sidestep to another area that I think in some areas of cardiovascular disease where you want to regulate lipids down, there are some medicines now that only have to be taken once every six months.

I think the whole field is going towards trying to make it even easier to take the medicines and that will also increase adherence to therapy because we all live lives. People forget to take their medication. I think there's a lot of interest both from patients as well as from the pharmaceutical industry to try and find ways where you can actually both get a better treatment, you can also get a better adherence, and less impact on people's lives that they have to remember.

David: You said that the team of chemists who were leading semaglutide development looked at 4000 different molecules. That sounds like a titanic task to me. How do you do that?

Lotte: That's the fun part, and that's one of the reasons why I still love being at pharma after 35 years, because it's a lot of teamwork. There are different experts in the teams and everyone's doing their bits. Some people are doing the chemistry, some people are making, purifying the molecules, some people are testing them in different assays, and then everyone comes together and says this worked here, this worked here, this worked not here. So it goes in small cycles or that's what it did back then, of course.

These days we also have AI, so some things are being completely transformed in the way that we're doing things, but back then maybe you make 200 compounds, then you test them in various different systems, and then you discuss what works.

Ben: When you say test, it's like looking at them under a microscope to see how the molecules are bound together?

Lotte: It's not a microscope. It's more of just to look that there are different chemical methods to see that they are pure, that you don't have a lot of different things, so you have one molecule in there primarily. Then you have a biological test system where you look at does it actually activate the system that it's supposed to activate?

Back to some of those assays I modernized when I first started in the company, taking them from single tube assays to then testing 96 at a time or something like a biological assay. You would also look at maybe are they stable? If you put them into a glass and look at the solution, does it look clear? It could be something like that also. There's not much to do under a microscope for these test cycles.

Then maybe you look at 200 to say what worked, what didn't work, then you do another 200 and you go on like that until you actually have your predefined criteria or are satisfied with the molecules.

Ben: In my head, when you said 4000, it's like, okay, we'll create 4000 test tubes and we'll see which ones are bound together in the way that we want them to and last the longest. But it sounds like it's a much more chemical, biological process, almost like a funnel of okay, we'll try 20 very different approaches and then these two or three showed pretty interesting signs so we'll take just those three and then we'll vary that again with a new set of 20 based on those two or three.

Lotte: Yeah, and then of course today, the use of various types of AI is changing that, so you can be smarter. I'm sure that back then, sometimes there were some molecules that we didn't have to make because we weren't clever enough. We're always looking at the patterns. Whereas today, there are steps that can be eliminated because we can use AI to see what is the pattern and then actually have to make fewer molecules.

Ben: I'm curious, is the AI generating new ideas? Or is it in simulating the chemical reaction.

Lotte: Maybe seeing the patterns in the data?

Ben: Oh, I see. In the analysis afterwards, too.

Lotte: It's in everything we do today. It's using ChatGPT for everyday work. It's looking for patterns, trying to use machine learning to improve the understanding of a pattern that maybe you can't really see it well enough. It's not statistically significant and if you apply machine learning, you can see the pattern better.

David: Super cool.

Lotte: It's in everything that we do, I would say.

Ben: Well, one other area, when we were in our research and on the episode, we talked about this crazy moment in time where previous Novo Nordisk leadership basically took the position that there's no business for us in weight loss. Yet you and your team were doing what would become the most important work within that same company for the weight loss indication.

Can you give us a little bit of what it felt like and the work you had to ultimately do for you and your team to get this thing to market when there were opposing forces, even within the same company?

Lotte: That I'm super happy to talk about. It didn't feel that uncomfortable because I think it maybe gets displayed a little bit in the wrong way because here gives me the chance to talk about the Scandinavian work culture, which is another reason for why I'm super happy to be in this company after 35 years, because it's actually welcomed to challenge the authorities or the leadership.

It's true that Lars, this was the other Lars, our previous CEO, not everyone is called Lars in Denmark, but there are a few. He said that he didn't believe that obesity was an area that would become important. But at the same time, he did support his Chief Science Officer to say I think that this is an area we should pursue. Even though he said that he didn't personally think that this was important, he still trusted other people that he had put in charge of leading the research area.

Of course, it did mean that you say oh, okay, we got to work extra hard on this. It wasn't uncomfortable in some way. Actually, he also made fun of it himself later saying I tried to shut this down three times, but I was never successful. I think he's even on tape himself. I don't know if you checked those videos that the Novo Nordisk Foundation did on the discovery of GLP-1.

I think he has one of those episodes where he says that this is what it's like to work here and (I think) why there are actually quite a lot of people who choose to stay in the company. If you really want to make a difference and you don't mind speaking up, it's absolutely welcome to speak up. I've done that many times and I'm still here.

Ben: Ultimately, it sounds like the data is the data. The work you're doing is science. If the experiments yield data that meets the goals of the company, then you're going to pursue it.

Lotte: Yeah. Of course, there also has to be a commercial angle, so it's not always that even though the science works out that the business models work out, but we do follow the data.

Ben: As you reflect back on the last 35 years, I was thinking before the episode of making the comment, you've had a one-in-a-million career, but I think that would undersell what has happened because that would mean that there are 7000 equivalently impactful careers in the world, which there are not. It's closer to a one-in-a-500-million career or something like that.

When you're laying in bed at night and you're looking at the ceiling and you're like what a wild journey this has been, what are the things along the way that are some of your biggest takeaways of why you were able to create something with such profound impact?

Lotte: I think the most important thing is that I was lucky to be the right person at the right time at the right place. There was certainly some luck in it. I was in that team that worked with GLP-1. The others left. I was the only one that wanted to stay and the previous programs failed. I said I can actually do that. It became my baby project, a baby back then that I was like this is mine. I'm going to make it work.

Another thing that also worked for me was that some people were not supportive. It wasn't a popular topic that actually motivated me. The more people that said to me this is a bad idea, stop working on it. I've had quite a few of those over the years. I still had the data. I still talk to people who were maybe outside of the company or other people in the company, because there certainly also were supportive people in the company.

To me, it only meant I'm going to show them that we are going to do this and we are going to solve all the problems and eventually get moving. That's the one thing that stands out for me after all of these years.

There's also another thing that I often think about. I often get asked how could you do it and how could you continue to work for such a long time? What's your advice to other people? Then I want to say that if you want to work on something that's really novel ahead of the time, then you also have to accept that you have to keep on convincing people and that it takes time. Then you got to be comfortable in that. You should listen to the critique, but you should not let yourself be stopped by it if you still believe that it's a good idea.

Ben: Is there something else, too, that if you believe in something in the way that you believed in the weight loss indication, and you believe that it needs decades of room to come to fruition, that you might need to piggyback it on something else that has enough political support first. I could imagine if this only had the effect for weight loss and you weren't able to pursue bringing it to market for type 2 diabetes that it may never have made it.

Lotte: That could be a point, but then you could also say what if there hadn't been these disappointments in the obesity pharma area, then maybe it could have been successful in that way. You could definitely say now that I think what has happened, it's a fact, with these GLP-1 based medicines that it's just been decades of additional positive data, more positive data, more positive data.

I think there's actually some research that says that by the time that about 15% of the population knows about something, then that's a point in time where then it can explode from there with the knowledge. But I think it certainly probably has played into the way that it worked out for GLP-1, that it was just this really, really slow-going process, but then a lot of good data kept on coming out.

I know we haven't even talked about the fact that these medicines also save people's lives, that there's a better effect on the cardiovascular system. That's another thing. It's slow, steady work over many, many years. Then suddenly there was this extraordinary moment where more people realized oh my God, this could really help me.

I think that the reason why it was the effect on weight loss that has made things happen is because it's very relatable to the individual person. You don't feel so much if your blood glucose is better. You don't feel so much if you have less risk of getting a cardiovascular attack or a stroke, but you feel that you're hungry every day.

Actually, I heard from quite a lot of people that if you just feel that you're hungry all the time and you feel you just can't stop eating, then it becomes very relatable to the individual person that this is really helping me in my daily life.

In that way, I think it makes sense that it is the effect on hunger and satiety that really has worked to actually get more attention to the fact that this can actually help a lot of people.

Ben: It makes a lot of sense. Not only can you feel it, but you can see it. You can see it quickly when you look in the mirror. You can see it quickly when you look on a scale and other people say nice things to you. It has this unbelievable reinforcing effect.

Lotte, I think this is a good place to leave it unless you have any other parting words for us.

Lotte: No, I think we've been around some really good topics.

Ben: I think so. All right. Well, thank you so much, and listeners, we'll see you next time.

David: We'll see you next time.