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

27:28You can make formal collaborations. And 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 or also the larger companies or academic groups. Then there's just a research contract on how we're doing things together, which then obviously also mean sharing the IP. 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 to discuss what this problem and also pursuing different avenues.

28:14You 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. Of course, you watch what the competition does. And then here, 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.

28:59We had the space pretty much to ourselves for quite some time, which you could also see that if you wouldn't look at the patents. We have a lot of IP on that technology from that time. What would you consider is the platform that has taken you and N. N. of an artist from Samaglutai to Beyond? Is it the fatty acid? Yeah, it's the fatty acid technology that I would call a platform technology today. That was what we started working within the 19s. And no one was doing. Obviously, the principle, you explained it well in the episode, on Norvodorus, right, that the fatty acids actually bind to Alpumin.

29:41And Alpumin is this big molecule that we have in the blood. That is a transporter of lots of things that need to be transported around in the body. It's a natural principle that these fatty acids, which we eat, we get them in with the food, right? That they are poorly soluble in blood. So they bind to Alpumin and then they get transported around. So we kind of piggyback on this nature's principle of the fat that can bind to the Alpumin. 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.

30:29I see. And so when you're referring to platform, it's we know how to make this fatty acid bind well to Alpumin 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. Yeah, that's what we say in Farmer. We call it a platform technology when we come up with a new principle for making a medicine. All right, listeners, we want to thank a new friend of the show, plaid. The name is likely very familiar to you after our recent ACQ2 episode. Odds are you've used plaid before without even maybe realizing it. If you've ever linked your bank account to apps like Robinhood, Venmo or Chime, you're one of the millions of people like one in every two Americans who've already used plaid.

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32:31Yeah, maybe this is a good time to ask the question, how does Lira Glutide and now 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 you know, it doesn't have the science background. In diabetes, where the disease is that you have your blood sugar is too high. Their GLP1 works by increasing the levels of insulin, which then gets the glucose down.

33:21At the same time, it also lowers the level of glucagon, which is kind of the opposite to insulin. And that means that there are two mechanisms that play at the same time, at both lead to a lowering of blood glucose. That'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.

34:03That means that there are actually three mechanisms that play for how GLP1 works when to treat diabetes. So, and then what we were emailing about was the obesity effect, or the anti -obesity effect. The effect that helps people lose weight, whether it is in patients with diabetes or in people with obesity or in your other diseases. Then the way that these GLP1 agents work is that they help people to eat less. You simply consume less calories when you are on this medicine. And I think we have a really good understanding on, for example, going from lyracletide to semacletide, where you get approximately twice as much weight loss.

34:47You also have approximately twice as much reduction in energy intake. So with lyragutide, it's like 15 % of reduction in energy intake. Then it's about 30 % with semacletide. So that is how it works when you look at it from the patient side of point of view. But then you can of course go 12 further into that mechanism as I was just doing in diabetes with insulin, glucose, 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 know, you can you can separate, you know, which receptors are in the in the lower part, the peripheral part of the body or which are in the brain.

35:35And 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 you'll be one works in the brain. And 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, how you may be dislike food. And that's what they mean when they say, you know, we don't know what work, we don't know exactly which part of the brain and how much for that part of the brain, how much for another part of the brain.

36:09But we do know that the majority of it is in the brain. And then from the 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 the better kind of control of eating. And we've investigated that in people, right? Where they are asked to rate how well do you feel that you can control how much you eat? And you can even see that it looks like it actually works well again, savory food, which is for example burgers and things like that. And then we also know in people with obesity that that's how it works.

36:50So I would say, you know, we know how it works. But of course, there's always detail, you know, I could go on and explain you stuff about what happens in the brain for the next 30 minutes if you have time. Well, 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 GLP1 has such a short half -life, is natural GLP1 present in the brain in, you know, less or less quantities than Lyric Lutide or somaglutide is because there's obviously a much longer half -life. Does that mean it gets into the brain more than natural GLP1 does?

37:25Yeah, so that's actually a really, really clever question. There is not that much difference in how much GLP1 there is in a person with disease versus a person not with disease. That was a kind of in your question also on whether there's a difference. So what we're doing with GLP1 is, it's not like with insulin. We know we type one diabetes. You don't have insulin. If you don't get insulin, you die, right? It's not like that with GLP1. GLP1 is part of this pulse pran gel. After you eat, there's a lot of different hormones and neuromotulators that are at work to make sure that you process the food.

38:05GLP1 is one of those, but it's not super important in its own. And maybe that's actually a good thing in this context. Maybe that's actually why it has been kind of allowed to say, you know, 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 kind of counter regulation to it so that it actually, maybe it would work for a week, but it wouldn't continue to work. So that's one part of it.

38:45Then you also ask, natural GLP1 get into the brain. Those studies are really difficult to do because it's gone so quickly, right? But I would just argue that since we know that the target for how GLP1 works, we call that a receptor that those are in the brain, then there has to be some GLP1 that gets to the brain. There's also some local production of GLP1 in the hind brain. And back of the head with a really spinal cord comes up, there's a lot of nerves coming up towards the brain. And there's also some GLP1 being produced there. Fascinating. So, 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, it's effect weight loss happens in the brain.

39:38Yes. I think also some of the confusion on the mechanism also comes from the way these things are regulated. So, 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 right? Journalism is a diabetes medication. So, we write about how it works with diabetes. That's how the FDA does it. Then with DOB, study medication, there you speak about how it works on the weight loss. And then I think that leads to the confusion, you know, that, oh, since there isn't a description on how it works on weight loss in people with diabetes, it's adds to the confusion, maybe that it just could be just a side effect.

40:29You also said something there that I want to follow up on, which is that the reason people lose weight is that they eat fewer calories. 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? From a pharmacological point of you with the medicine, there's definitely a clear correlation, you know, with lyracletide to semacletide, double the weight loss, double the energy intake reduction.

41:11So, I think that's a really clear correlation. I think what you're going at is also, you know, 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 to, like, if you go on a starvation diet, it's probably not going to work very well because your body will protect you, right? So, 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 than the pharmacology. So, I think probably both sides have their points, right?

41:58Right. 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 sort of body mass. Yeah, and it's always important if you want to lose weight that you exercise. And 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.

42:46There 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 Lira Glutide to Semaglutide, the goal was to increase the half -life. So you go from a daily injection to a once weekly injection. And one of the things you observed is the weight loss was twice as effective, or the energy consumption was reduced by twice as much and people trying to lose weight. Was that surprising to you? Yes, that was a little bit of a surprise. Yes, and I'll take you back to that time. So first we had Lira Glutide and then we started to think about, could we actually make an even longer acting version so that it would be even simpler for patients.

43:34And 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 GILP1 also started to grow. There were many more people that started working on it. So I also have some more phenomenal chemistry colleagues that started working. So the actual chemistry invention of the Semaglutide was carried out by some of my colleagues. There's going to be a whole bunch of dating names, but yes, Palau and Thomas Cruz and Pao Blok. They were the one who did the chemistry on Semaglutide. And the thinking just was, we have to make it stick harder to Alpeman so that it stays on Alpeman for a longer time.

44:18So they engineered the fatty acids to actually bind harder to this Alpeman molecule so that when it was in the body, it would stay longer on Alpeman. So when you look at how long Lira Glutide large, then it's 12 hours, whereas with Semaglutide it lasts for 160 hours. That was the intent. And in order to do that, I think they probably looked at about 4 ,000 different molecules and then ended up choosing the one that was Semaglutide. And compared to Lira Glutide, it's a little less sticky. A fatty acid, you cannot understand that it's fat, it's sticky, right? But with Semaglutide, they engineered some more less stickiness into it.

45:03But the point was to make it long acting. But 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. So it's the idea that it's potentially penetrating deeper, since it's sticking around longer. Yeah. It's not as such penetrating into the brain, but it kind of has access to some of the outer parts of the brain. And Semaglutide does that a little bit better because of the way that the chemistry was done differently.

45:44It was a surprise that it was that much better. Is it an interesting line of thinking then if we found a way to make the GLP ones 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 sort of 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. Yeah. Yeah. I think there's definitely a lot of thinking right now on what else could you do to make it easier for the patients?

46:23I think if we just take a side step 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 has to be taken once every six months. So I think the whole field is going towards trying to and make it even easier to take the medicines and that will also increase adherence to therapy. Right? Because we all live lives, right? People forget to take their medication, right? So 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 and you can also get a better adherence and and less impact on people's lives that they have to remember.

47:14You said that the team of chemists who were leading smagletide development looked at 4 ,000 different molecules. That sounds like a titanic task to me. How do you do that? Yeah. That's the fun part. I did ask one of the reasons why I still love being a farmer after 35 years because it's a lot of teamwork. So there are different experts in the teams and everyone's doing their bits and 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 say, you know, this worked here, this worked here, this worked not here.

47:59So it kind of goes in small cycles or that's what it did back then. Of course, these days we also have AI, right? So some things are being completely transformed in the way that we're doing things. But back then, you know, it was, you know, so maybe you make 200 compounds and then you test them in various different systems and then you you discuss, you know, what worked. And when you say test, it's it's like looking at them under a microscope to see how the molecules are bound together. It's not a microscope, right? It's more that just to look at that they're different chemical methods to see that they're pure that you don't have a lot of different things or you have one molecule in there primarily.

48:38Then you have a biological test system where you look at, you know, does it actually activate the system that it's supposed to activate? You act 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. So 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 kind of test cycles. So then you do, you maybe you look at 200 to say what work, what didn't work, then you do another 200 and you'd go on like that until you actually have your predefined criteria or satisfied with the molecules.

49:27In my head when you said 4000, it's like, okay, well, we'll create 4000 test tubes and we'll see which one bound together in the way that we want them to and lasted 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. Yeah. Yeah. And then of course today, you know, the use of various types of AI is changing that, right? So you can be smarter.

50:01I'm sure that back then sometimes there were some some molecules that we didn't have to make because we weren't clever enough always at 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 and then actually have to make fewer molecules. Yeah, I'm curious is the AI in generating new ideas or is it in simulating the chemical reaction? Maybe seeing the patterns in the data? Oh, I see. In the analysis afterwards too. It's in everything we do today, right? It's using chat TVT for everyday work, right? 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.

50:48It's not statistically significant and you apply machine learning. You can see the pattern better. Super cool. It's in everything that we do, I would say. Well, one other area when we were in our research and on the episode, we talked about this crazy moment in time where previous Nova Nordic leadership basically took the position that there's no business for us in weight loss. And 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 how you 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?

51:32Yes, that I'm super happy to talk about. It didn't feel that uncomfortable because I think it's also it gets maybe 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. And it's true that Lars, this was the other last right, our previous CEO. Not everyone is called Lars and Denmark, but there are a few. He said that he didn't believe that obesity was an area that would become important.

52:13But at the same time, he did support his chief science officer to say, you know, I think that this is an area we should pursue. So even though he said that he didn't personally think that this was important, he still trusted the people that he had put in charge of leading the research area. So it was it was never of course it did mean that you say, oh, okay, we got to work extra hard on on this. It wasn't uncomfortable in some way. And actually, he also made fun of it himself later saying, you know, I tried to shut this down three times, but I was I was never successful, right? So I think he he's even on on tape himself.

52:57I don't know if you checked those videos that the No One All This Foundation did on the discovery of JLP one. I think is one of those episodes where he says that this is what it's like to work here. And I think why there's 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. You know, I've done that many times and I'm I'm still here. And ultimately, it sounds like the data is the data. The work you're doing is science. And so if the experiments yield data that it meets the goals of the company, I mean, then you're going to pursue it.

53:33Yeah. 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. Well, 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 7 ,000 equivalently impactful careers in the world, which there are not. It's closer to one in a 500 million career or something like that. You know, 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.

54:13What 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? Well, 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. You know, I was in that team that worked with Jill P1. The others left. I was the only one that wanted to stay and the previous programs failed. I said, you know, I can actually do that. So it kind of became my baby project, a baby back then, right? That I, you know, this is mine. I'm going to make it work.

55:00So another thing that also worked for me was that, you know, the that some people were not supportive or there was a little bit of, it wasn't a popular topic. That actually motivated me. And, you know, the more people that said to me, you know, 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's certainly also worse supportive people in the company. To me, it only mentioned, or 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.

55:40So that's the one thing that kind of stands out for me after all of these, there's also another thing that I often think about, you know, I often get asked, you know, how could you do it and how could you continue to work for such a long time, what you advice to other people? And, you know, then I want to say that if you want to work on something that's really kind of novel ahead of the time, then you also have to accept that you have to keep on convincing people. And that it takes time, so then you've 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.

56:23Is 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 sort of piggyback it on something else that has enough sort of political support first. Like 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. That could be a point, right? But then you could also say, you know, what if there hadn't been these disappointments in the obesity farmer area, then maybe it could have been successful in that way.

57:07So you could definitely say now that I think what has happened is a fact, you know, that what has happened is that with these CHILP1 -based medicines, you know, 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 kind of a point in time where then it can kind of explode from there with the knowledge, right? But I think it's certainly probably has played into the way that it worked out for CHILP1, that it was just this really, really slow going process.

57:51But then a lot of good data kept on coming out. And I know we haven't even talked about the fact that these medicines also save people's lives, right? That there's a better effect on the cardiovascular system. So that's another thing, right? It's the slow study work over many, many years. And 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 kind of really made things happen is because it's very relatable to the individual person, right? You don't feel so much if your blood glucose is better.

58:37You 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, right? And actually, I heard that from quite a lot of people that, you know, if you just feel that you're hungry all the time and you feel you just can't stop eating, you know, then it becomes very relatable to the individual person that this is really helping me in my daily life. So 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.

59:21Makes a lot of sense. And 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. Well, I think this is a good place to leave it unless you have any other parting words for us. Yeah, I think we've been around some really good topics, right? I think so. All right, well, thank you so much and listeners. We'll see you next time. We'll see you next time.