The Scientific Journey Behind Ozempic (with Lotte Bjerre Knudsen, Novo Nordisk's Chief Scientific Advisor) 01:00:35

helloacquiredlistners after David， i finish the Nobel nor disk episode we thought huh it really would be cooled to meet lottabeer canuteson and talk with her about the science so we call the email der and she responded that she had just finished the episode and she was about to email us she said she be happy to chat so on this episode we talk not about the business side of nova nor desk but zooman on the science that we didnt really do as much in the episode she takes us back to the moment where she first started the research over thirty years ago and the process of identifying the molecule improving it and ultimately launchingthedrug to the world so now on to our interview today we are joined by lata beer canudes in the chief scientific adviser of nova nordesk and for those of you， who listen to our novel norsk episode you will recognize her name as the person who led the initial team that investigated GLP one starting way back in the nines eventually creating lyria gluetide what led to semclutide or what we know today has osampack we go v or ribelsis are we pronouncing a glue tide lyria gluetide how do you pronounce it and overnordisclata i think youre doing pretty good ive heard many versions over the years you know depend on where in the world you are some people say seam a glue tide some people say symactive tide and youre also doing pretty well with the trade names good job doing our best before we get into all the science？

which we want to cover with you in depth we wanna to start firstthough with your personal journey how did you come to join nova norkedanicus？

first？

it was novosimes that you first started out right out of undergrad yeah thank you for taking me down memory lay and you get really nice research i enjoyed listening to that episode so denbarg is a small country im born and raised here and somehow during university years i got my eye set on this company i really wanted to work there and then i just look for various ways to join the company actually， and the first job i applied for actually didnt get and then i set my eyes on joining the inside research division as you also picked up on so when i eventually got a and i actually never applied for a job because i did my thesis and then they often be a job so when you did apply？

you got rejected and then you edit up working for the company without apply yeah！

but that was before a join university actually you know i had i have a degree also as a laboratory， a technician before i went to university and it was there that i applied for a job that i didnt get im thinking in high side they probably thought i would skip to university not keep the job as a lavatory technician， which was probably true right， so i started out there working with back then nova simes had a collaboration with procturing gamble， so we were making in science for launtery detergency it was super exciting i always had my mind set on that i wanted to do product related research and never had a strong interest in the being an academic research for me， it was exciting to make a product wow！

well， you certainly ended up doing that to my mind and sives are completely different than diabetes research and and what ultimately GLP once is that common the switch between those two fields or i actually wasnt the only one its not common of course you know i graduated from the technical university of of Denmark so we are small country but still you know then marks caltech or mit right？

im trained in in biotechnology and that means you know i could go several ways but i was in a small group when i started in nova times that by many of us actually came from the technigroup， but i was at that time the head of the group he was actually also a medical doctor so when Novo at the time or nova knowledge is quite wanted to look more into finding new medicines for for diabetes and especially type to diabetes they actually put him in charge and then the kind of the whole group that he had in the end time division voice put over in the diabetas part of the company to bring a little bit of an outside in perspective on the other research groups that were there im sure it was a bill bit unusual！

but it was by design you know they did want someone to come in and try to look at things differently and 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 practicing gamble it was to do stuff like change the features of the detergentto lift more fibers away from it to make your close appear brighter like thats why David and i are so wrapped around this idea of you went from that to you know diabetes in a waitloss interaction of molecules within the human body yeah！

you know back then there was a lot of focus in the laundry deterchen business on making kind of natural product so there are actually quite a lot of in science in laundry deterssions the new thing that we did back then was to find this cellulease that choose off little pieces of kotlin on your color close right making it look writer i think today you know im not fully up to date on the market dance but i think actually those kind of products are going a little bit down because people dont want to wait for the results you know for that you have to keep washing your clothes in order to get the the good results based on this natural method so today on actually unfortunately， i think there are more category going into the deterssions because people want immediate results we also try to make another one that would bleach in the solution so you would be able to mix white and red close we never succeeded with that one， but i just blow up over featurate trying to get that chemistry going and it was not too popular because i actually had beturing acid in there and if you just know a little bit of chemistry that kind of smells like roadnix， so uh that was about the whole building smell wow！

wow that was the end of my research in the end time division it just tickles us because you know we love things that just seem so unlikely i mean the hold of our doordisk story is so unlikely and yet so evenyounow the fifteenth largest company in the world speakingof unpopular avenues of research that you were involved in take us back to when you did move over to the diabetes division and pursuing GLP 1 research in the 九十 to our understanding to say it was unpopular in the research community was like a an understatement at the time how did you latch on to it and what give you the confidence to keep pursuing it is fun to think back on now ide and the company was so small back then compared to what it is now everyone knew each other today there are so many people like i i have no idea who they are but back then i knew everyone so there was a lot of great academic research and you know when science get successful is always the story of the many people over many years you know if you gave me half an hour。

i could mention so many names and what everyone did but to try and make it as a little bit content right， then there s some people in academia， you mentioned then tracker for example， when you did the novel office podcast， theres also yentio holes， the professor here in coping dated some of the foundational work to find an identified JLP one people had been speaking about a substance like that actually for more than a hundredyears knowing that there was something that being produced in the intestine that would be able to have an effect to increase insulin and then a lower block Google， but it wasnt until that it was identified and there was these primarytwo groups that were involved in that obvia see we had one of those groups here in coping so very close to where we are so we started talking to them in the very early 九十 there was also a really great group in Germany lit by Michael and out who doing some of the early clinical studies because this was a natural substance you could actually put it into people is like i look at what happened in in short term studies you allowed to do that so we knew that there was a good effect on diabetes and then we just try to figure out how could we make a druck based on this because pretty early it was also discovered as you know chilp one is very short acting so you die they have to carry around and infusion pump， or you have to have multiple injections we also try to make small molecules early on now youre on the west coast we collaborated with a company in the Lajoia， San Diego for and i was there quite a lot also， in the nines were trying to make template base small molecules back then and they were just not druck like enough so it kind of had to be these injectable drugs we just pursued multiple things and you know the youre asking how did i get into it well， in the beginning you know i was just the lab right right i was the young scientist on the team i modernized a lot of our asse so back then we go from single shopes to these kind of plates where you could do and not eighty four or nine six or three hundred and eighty four as a is at a single time you know back then that was big right now its its even larger and robots but thats what i was doing in the beginning and i was screening all of these compounds with industry right and a lot of things happened you know my boss back down was actually leading the work when i came back from maternity leave in 994 everyone i work but was gone there was a lot of things happening a new people coming in most of the group i was then actually went back to the end time division， but i didnt wanna leave because i i kind of got excited about Chile p one but then i would see only one left and then i was asked by the the new head of research mask role score Thompson to take up the torch for leading the jilp one project you said to me you know， you figure it out you you know about this！

you figure it out OK， so 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 ones and inject it into humans no other i what i mentioned there was that there were people in the academic sector。

i mentioned Michael， now in Germany， who did these kind of studies back then it was a slow offline world i nothing got put on the internet i did expect then when i does you met someone and they told you about what they did or you waited until i got published in a journal and you went to a physical library to read the article so we were closely connected to Yentio hall， Sean Cobemac， and he was closely connected to the group in Germany in Michael log so we had this knowledge that chill p one was actually a really good idea in patience with Diabetas， and then we try to figure out you know， because we knew that unfortunately， then the native peptide is not a good job， so then our job was to try and figure out how can we actually make a product that is convenient for the patience and we went to several different rounds we actually had to maybe you could even say tree projects that failed before the one that ended up being successful with live active and were you binding different fatty acids to glp one molecules what what did the failures look like before you get to the success i really like in the episode that you cover that you actually understand the fad yesterday binding principle， i think that was pretty well done right that was what ended up working the other things it didnwork was to try and make what is call they sustained release formulation where you you make a classical formulation and you add some things to the liquid and then when you inject that you know it stays on the objection side for a longer time that was a very common approach and you know we could get it to work but unfortunately， it also gave a severe skin reaction so that didnt work then we try other ways of protecting the peptide， but that wasnt enough in order to make it last to become a convenient product it was about a year or work and what we managed was to change the duration of action from like two minute to five minutes so so that didnwork out there because it turns out， not only is jillp one being chewed down by metabolic and times， but its also being filtered by the kidneys really rapidly so that didnwork other and then we started to look into this fatty asset isolation concept， which there were other people working on at the time like also with insulin when i was told you know， you figure it out i was sitting fairly alone at that point of time and think you know what can i do we also thought about dvp for inhibitors i dont know if you came across that class of of medicines also， in your research， they give a small increase in jilib one and so you can get blue cos loring but eventually it was found out you know you dont get the way loss with that i didnt choose that because i didnt have so much access to small molecule chemist at the time so i chose the fad yes， i desolation idea actually！

because i thought i can actually do that i know how to do that so i i can lead that program so that was my choice for moving ahead and on the episode we drew this parallel we try to take away this this idea that it was because of all the work done over decades at nova nordesk on the insolentside of the house to figure out how to do longer lasting insolence that made you feel comfortable oh， i know how to do this fatty acid binding 4 GLP ones is that the right way to think about it like if nover nortis hadnt had that expertise with insulin would you have felt comfortable taking this approach yeah thats of course really difficult to say of course！

i was at a place where there was some experience but you know it was completely on proven and it turned out to work really differently on insulin as compared to jilup one it was a component you know that there were other people working it but the two groups were completely， separate and then you were saying it always for something around the decades or work of entler and yeah maybe something right because i send the example you know， i decided that i wanted to focus on things i were very close to the native human jilp one form and the reason for that was because of the learning with the animal instance you know that you can get patience all immune system to kind of react to watch those animal instance its not really dangerous but then it means that the medicine works less well like that experience i took from the decades of work on excellent and say you know im gonna try and see if we could avoid that so im Gonna go with these fates and im Gonna try and see if we can keep it as close to native human Jill pi one as possible there were other people pursuing other ways like you spoke about the extension molecules as well and the Gila Monster the very dangerous a lot of people road into us and said its actually pronounced a helimonster not oh yeah thats probably true it is Spanish yeah yeah everyone in the in the science field calls at the gin oh good alright vindicated how close were you to that workthough you know。

we were just laughing as we were telling that episoi were like you cant make this up a lizard 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 twenty four hours with just one injection once weekly wasnt really a thing it came a little bit later right， but we wanted to say this had to be simple this is not an excellent it has to be much much simpler so we didnt want to work with exannoted because it wasnt really possible then you have to do two tricks right because first of all you have that its somewhat longer acting than till p one， but its not enough right its like thirty minutes instead of two minutes so you have to to apply another principle on top of that， and it could be kind of the sustain believes that i mentioned earlier you at something to the formulation and then the sticks on the injection side but then i had the learning that that can give i the skin reaction or antibodies so i didnt want to work on that so the idea was that you just wanted to figure out one magic trick not have to figure out two that would work together yeah？

yeah is it correct to say that during the least that initial development process， the target market was type to diabetics who were not yet insulin dependent thats a next level of the conversation that could be really interesting because actually for us。

the target market was also obesity from the beginning right of course， its impossible to be on top on everything thats being written right， but but for us you know it was obesity all the way from the beginning and then that comes back to now before i mentioned you know there are these people in academia that were showing that tilpy one would be beneficial in diabees， but then there were actually， other groups also academic groups that pursued the angle of obesity early on and one of them for example， was Steven Bloom in London， who actually got nighted for his contributions to uh science over the years i think and there was also another research group here in coping ollermets who was also pusuing this ankle very different methodologies they were using， but then again i was close to one of them here in coping so so the work that he did actually inspired me to say you know i was in a in a pharma setting where i saw people some people were working on on type to diabetes right and as you saying you know could be a before instance with templates and mid formance often all your but then i had other colleages who were pursuing obesity and i was thinking you know why cant i have both the JLP one idea actually can be used to both street diabetes as well as obesity to completely separate mechanisms why the way jillp one works in diabetas is said it it increases insulin， but it also lowers another hormone called so it actually has two mechanisms in one and then whats also built into it is a safety switch where you dont really get the low high book like semia that you can get with instance so thats a separate mechanism and diabetas most of that occurs around the pang creas and the liver just to get the powerful organs in there， but then with the way loss effect thats happening in the brain you know， the brain is the main organ for anything related to how we eat it can be some effects of the powerful nervous system also， but it is mainly the brain and and so， thats a complete disperate effect of glop one you know i just thought why can i not say we can go after two indications at the same time and this was as early as the sort early mid 九十 this was the thing yes！

he was i think this is important to underscore for listeners this is extremely different than the widely held belief in most media right now that is about osampact what you commonly read is they were seeking a diabetes， drug and oh！

my god this most recent study they stumble upon this idea that itamazing for waitloss and youre saying no from the very beginning we thought that this could do both yeah yeah it is a common misunderstanding i think that may be a little bit comes also for that the list story is just not true and we were the only company for twenty years that pursued obesity the way loss that was seen with exenotide and also with some of the other early agents were never gonna be enough in order to uh obtain an approval for the treatment of obesity somehow these fatty acid esolate that uh compounts actually do a little bit better on the way loss so we saw that i guess we were also a little bit lucky you know it theres some block to everything right that we didnt know of course， going in with this fatty as a desolation technology that that would work well for all actually work even a little bit better for obesity that some of the other methods， but we did have a strategic intent to go after obesity early on and we been alone in that for the longest time in keeping up with the medical community experts out there we have just been going at it for twenty years its only would end the last to five may be close to uh yeah， a little bit more than five years that we see of the companies going in and now everyones in there right but back then it was only ass there was a lot of interest in obesity also in pharma， but they all wanted to make small molecules that would deep penetrate the brain there were some made， but then there were side effect there was also a horm i dont feel stumble the point a horde more name lepton uh that is produced by the fat tissue that was another idea that is approved today for light and do i have it right that leptin is the most common signal to your brain of hunger hey！

im hungry is the leptin production yeah！

its a signal that comes from the priorfree that then signals to the brain there are other signals in the brain that also， have a really strong hunger signals but that never work in the general object you know， i said i can still remember exactly the year where for the data were or released i think it was in nineteen， ninety eight or something and everyone was at the American diabe this meeting at Chicago exciting about these results and then it just didnt work lept in this also， a large or molecule that would have to be given by injection， but it just didnt work in general ability， and then there were these other small molecules， and then had safety problems associated with them so that meant the entire field of obesity and big farm died out for some time we spend a long time in the episode。

painting a picture of a stigma in the pharma industry in the late ninesonearly， two thousands around waitlost drugs and and that whole category and that it was something that the industry just didnt want a touch was that accurate yeah！

i think its a good way of phrasing it you know there was one side of a is a scientific side there was numerous attempts made both on this injectable a treatment potentially with leftin and and there were all these small molecules attempts you went back to the snake oil as well right and your episode right there are just been so many attempts where medicines were put forward for obesity what that wert safe， right or or they didnwork so i think the whole pharma industry gave up and they simply didnt want to touch it anymore i did i think there was probably also， this is it important to treat obesity， or should we rather focus on cardiovascal idycies and diabetes and and other， some of the other， some of the other diseases that have more comabilities maybe or is when you look at the cukly or more serious acute serious i guess there is the whole sort of moral issue the belief that many people have for a longtime of like oh！

this is just people should exercise more any less right yeah！

certainly heard that a lot but for all of those years， you know we continue to work with many of we should especially st although with the world who were desperate for help for their uh patience and it only became worse and worse and worse in all of these years where we were working on this as we did the research kind of the crediary that as that believe became stronger！

the problem just got worse as you say yeah！

yeah and so were you sitting in that ninety nine meeting where that was sort of the kick off of everyone losing interest in funding in investing in obesity drugs were you sitting there thinking no but i have it i have the answer or do you feel like that that wasnt clear yet i always thought i had the answer because i kept on having good Jade of i was well connected in the academic setting you know even though it was small i think you said earlier that it was not a very popular field and that certainly true we were always in the smallest room at the back end of the conference center， but it was stand because the community was all people were well connected and new each other and supported each other， so i always knew that the data were there， so i just kept on you know i can be very very very patient i can also be impatient with myself on a new thing but when i see that there is a plan and we just need to keep working i can be extremely patient， but it took time right， we had to say OK， its actually a big task to to get these Jill if you want to prove for the treatment of diabetas， so 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 kind of things there is a lot of studies you have to do and some of these studies were doing our ten thousand people uh with seventeen thousand people and follow up for five years sometimes amazing you keep talking about the academy community is a small group of people who all new each other where the boundswhere you can share information versus where you tend not to that could imagine two university researchers were not affiliated with companies at all sharingearly data before theyre publishing it。

but i could also imagine two researchers who are employed by competing companies not sharing any earlyresearch what is the level of communication between various types of researchers in the field but the time you choose to publish things right of course。

you share you go to conferences to share a lot you stand next to some of your competitors with the poster and there are something you can talk about even though you might also have to protect the ip but there are limitations right of course， because when you are in that that period， where you are developing the uh intellectual property right of course， you can not share any of that so of course， there is an element of 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 work together sometimes on some things probably， some people think that you are unfriendly with each other thats not the case uh at all right， but everyone in the industry respects that there are times when you cant share because youre working on the ip you can make formal collaborations and you know today when i look at how we working today， we have so many collaborations where is you know？

we call it co creation plans when we work even with other biotex or also all the large companies or academic groups or then there is just a a research contract on how we are doing things together？

which then obviously also mean sharing uh the IP i have to imagine to when its a space that everyone else has written off theres a little bit more camera among the researchers even if youre at competitive companies， i imagine you knew for a long time that there were focused 依赖 Lily who were also just of success with this problem in also pursuing different avenues and you couldnt know exactly what they were working on but there had to be some amount of hey， we both have a belief that theres a future here of course。

you watch what the competition does and then you know here in this case you know for the for the first ten years or something may be even close to fifteen years no one believed in this methodology that we pursued which today i would call it a platform technology because everyone to using it when you look at scientific papers you know there are thousands of papers that uses methodology and we develop that but no one was interested for fifteen years they left us alone they they must have been thinking you know this is not gonna work we have the space pretty much to ourselves for quite some time which you know you could also see that if you wand and look that the patterns and we have a lot of ip on that technology from that time what would you consider is the platform that is taken you an end of our Doris from lirglutid semiglutid to be on is it the fatty acid yeah， its the fatty as to technology that i would call the platform technology today you know that was what we started working within the nineteings and no one was doing obviously the the principle you know you explained it well， in the episode on nover noise right that the the faddies is actually bind to albumen and albumen this is big molecule that we have in the blood that is a transporter of a lot of things that need to be transported around in the body its a natural principle that these fades its， which we eat we get them in with the food right that they are pulling soluble in blood so they bind to alpimen and then they get transported around so we kind of picky back on this natures principle of the fat that combined to the alphamen 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 at it worked。

and also that it was safe i see and so when you referring to platform its we know how to make this fatty acid bind well to albumen to circulate in the bloodstream for a week therefore， we can plug other things into that fatty acid two to be carried around and belong lasting yeah！

yeah， thats what we save in pharmo we call that a platform technology when when we come up with a new principle for making a medicine well listeners。

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savi logical audience but you know doesnt have the science background in diabethis where the disease is that you have your blood sugar is too high there g o p one a works by increasing the levels of insulin， which then gets the clucles down at the same time it also the words the level of Luca gone this is kind of the opposite to excellent， and that means there are two mechanisms that play at the same time at both lead to a lowwaring of blood glucos thats also safety building to that because the mechanism stops working when glucos is normalized， so you cant really get too much of it， it also has an effect on your intestend， so that food is absolutely， which then helps to not get too much excurtions in blood new cos after you eat of course， when you eat， you have a your blood sugar will go up， but then they will eventually go down again that means they are actually tree mechanisms at play for how jlp one works went to treat die beas so， and then what we were emailing about was was the eubeacity effect or the antiobesity effect the effect that helps people lose wait whether it is in patience with diabetes or in people with obesity or in your other diseases than the way that that these jeal p one agent work is 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 liberty to some acrotide where you get a proxmated choice as much way loss you also have a proxmated choice as much reduction in energy intake so with there are good tide its like fifteen percent of reduction in entity intake then its about thirty percent would seem a food side so that that is how it works when you look at it from the patien side of uh point of you were， but then you can of course go twelve further into that mechanism as i was just doing in die beatus with insulin a Google gone and gastergampting， and then you can say OK which organ does it work on in here it really is the brain but of course you have to go to and accept some animal studies in orders to understand the mechanism further because in animals you know， you can， you can separate you know， which factors are in the in the lower part， the powerful part of the body， or and which are in the brain， and then you can make animal sort is to show that its happening in the brain when people are saying we dont know how it works， then they refer to the animal studies because there are actually so many places that chill p one works in the brain， and it has effect both on hunger systems， on societysystems， but also on the reward system which is like how you want food， how you like food， how you may be dislike food and thats what they mean when they say you know， we dont know what work， we dont know exactly， which part of the brain and how much for that part of the brain how much for another part of the brain but we do know that the majority of it is in the brain and then from the patien point of view the people with obesity then we just know that it because they eat less calories when they are on this medicine， they also have the better kind of control of eating， and we investigated that uh in people why where they are us to wait how well do you feel that you can control how much you eat and you can even see that it？

it looks like it it actually works well again save very food， which is for example， burgers and i think like that and that we also know in people with obesity that thats how would work so i would say you know we know how it works but of course， theres always detailed you know i could go on and explain you stuff about what happens in the brain for the next thirty better if you have time well？

actually what the gameserious on that i may be even said on the episode but i wasnqualified enough to know for sure because natural GLP one has such a short halflife is natural GLP one present in the brain in either less or less quantities than learning lutide or sum aglutide is because theres obviously of a much longer half life does that mean it gets into the brain more than natural glp one does yeah。

so thats actually a really really clever question there is not that much difference in how much chill p one there is in a person with disease versus a person not foot disease that was a kind of in your question also on whether there is a difference so what we doing with chilp you want is its not like but insulin we know we type one diab this you dont have insulin if you donget， insulin you die right its not like that with jilp one jilepy one is is part of this post you after you eat theres a lot of different horoads and neural motulators that are at work to make sure that to process the food and Jill p one is one of those， but its its not super important in its own， and maybe thats actually a good thing in this context， maybe thats actually why it has been kind of allowed to say you know heres a substance that a nature only works for two minutes， but is actually OK to make a a farm， a quality out of it where you give high amounts for an extended duration of time， and that actually can work because its not super important if it was super important that be some kind account regulation to it， so that it actually maybe it would work for a week， but it wouldncontinue to work so that thats one part of it then you also asked you know does natural gop one get into the brain those studies are really difficult to do because its gone so quickly right， but i i would just argue that since we know that the target for how jelp one works we call that of a sector that those are in the brain then then there has to be some jlp one that get to the brain there is also some local production of jlp one in the hind brain and the back of the head with a very spinal cord comes up there is a lot of nerves coming up to watch the brain and theres also， some tlp one being produced there fascinating so if i hearing it。

right that the majority of the effect on type to diabetes happens in the periphery， but the majority of the effect for its effect on waitloss happens in the brain yes！

huh， i think also some of the confusion on the mechanism also comes from the way these things are i regulated i also， we you take your medicine， you read， the package entered， and if you have the the diabetes medication， you wont see a description on how it works to regulate wait because thats the way its its done right， only this is the diabetas medication so we write about how it works with diabetes thats how the fda does set then video be certain medication there you speak about how it it works on on the wait loss right and then that i think that leads to the confusion you know that oh since there isn the description on how it works on wait loss in people with diabetes as to the confusion maybe that its just could be just a side effect you also said something there that i want to follow up on which is that the reason people lose wait is that they eat fewer calories correct that they assume less energy i think there is been a debate in the waitlost community of for i dont know twenty 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 from a cological point of view with the medicine there is definitely a clear correlation you know wait liberty energy intake reduction so i think thats a really clear correlation i think what youre going at is also you know how does your metabolism trick you when you start eating less than your energy expenditure your metapless also goes down so thats why sometimes it can be really hard to like if you go on a starvation diet， its probably not gonna work very well because your body will protect you right， so you also the energy expenditor system shots down， so that you actually want lose as much way does you think in that way but thats a little bit different than the pharmacology so i think probably both sides have their points right its the idea that will sure if i eat 5 hundred calories less and my energy expenditure stays exactly the same well。

then im gottl be losing 5 hundred calories worth of mass in order to make up the difference however， its unlikely that by energy expenditure is going to stay exactly the same if im eating dramatically less， because the body has many mechanisms to make it， so that i dont expand as much energy to to keep me alive， or or or to keep me static at that sort of bodymess yeah！

edits always important if you want to lose weight that you exercise and thats also what you can see with the description of the medicines that is highly advisable that you should exercise at the same time as you try to lose weight in order to keep up your metabolism there is another point in the episode where i think David and i might have lost over something and i wanted to hear it directly from you going from learning tide to summit the goal was to increase the halflife so you go from a once daily injection。

to a once weekly injection and one of the things you observed is the waitloss was twice as effective or the energy consumption was reduced by twice as much and in people trying to lose wait was that surprising to you yes！

that was a little bit of a surprise yes， and now taking you back to that time so first， we had larklties and then we started to think about you know could we actually make a i even longer acting version so that it would be even simpler for the patience and there and now i also have to mention a few other people because at that point in time you could say you know the gorilla army that was interested in chelp one also started to grow there were many more people that started working on it so i also have some more phenomenal chemistry collekes that started working so the actual chemistry invention of a similar good side was carried out by some of my colleagues gonna be a whole bunch of dadis names but yes for law and Thomas crews and power block they were the one to get the chemistry on Simon cue side and the thinking just was you know we have to make it stick harder to a alpiement so that it it it stays on alpimen for a longer time so with they engineered the fatty assets to actually bind hard to this alpimen molecule so that when it was in the body， it was stay longer on alpimen so when you look at how long oracletide large， then its twelve hours whereas with seam， a good tide in last or hundred and sixty hours， and that was the intent and in order to do that i think they probably look that about four thousand different molecules and then ended up choosing the one of us i and compared to we accide its a little less sticky you know， a fatty acid you can not discan that its fat its sticky right， but with some acotide they engineered some more less stickiness into it， but the point was to make it long acting but it turns out that when you doing that chains at the same time， you also get more wade loss and its likely that its because of the stickiness so you actually get a little bit more to go to some the areas of the brain that are important for the for the way loss so its the the idea that its potentially penetrating deeper since it sticking around longer！

longer yeah！

its not as such penetrating into the brain。

but it kind of has access to some of the outer parts of the brain and symeclide does that a a little bit better because of the way that the chemistry was done differently it 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 through a year that humans could all be better at regulating all of these things all the time be a waitloss or cravings or addiction or any of these things that that 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 definitely a lot of thinking right now on what else could you do to make it easier for the patience？

i think if we just take a side step to another area that i think its some uh areas of cardiovascular disease where you wanna regulate lippits down？

there are some medicines now that uh that only has to be taken once every six months so i think the whole field is going to words trying to 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 is a lot of interest both from patience as well as from the from a sutical industry to try and find ways where you can actually both get a better treatment and you can also get a better adherence and unless impact on peoples lives that they have to remember you said that the team of chemists who were leading smacklifile development。

looked at 4000 different molecules thatsounds like a Titanic task to me like how do you？

how do you do that yeah thats the fun part and it has one of the reasons why i still love being a farmer after 35 years because its a lot of teamwork， so there are different experts and the teams and everyones doing there bits and some people are doing the chemistry， some people are making purifying the molecules， some people are testing them in different asjs and then everyone comes together and say you know this work， tier this work， tier this work not here so it kind of goes in small cycles or thats what it did back then of course， these days we also have ai write so somethingsa are being completely transformed and the way that we doing things but back then you know it was you know so maybe you make two hundred compounds and then you test them in various different systems and then you you discuss you know what work and when you say test its its like looking at them under a microscope to see how the molecules are bound together its not the microscope right its more that just to look at that there different chemical methods to see that there pure that you dont 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 you know does it actually activate the system that it suppose to activate you back to some of those asks i modernized when i first first started in the company taking them from single tube ases to then testing 9 十啊 6 at a time or something so a biological asse you would also look at maybe are they stable if you put them into a glass and look at the solution， not does it look clear， could be something like that also， there is not much to do when there are microscope for these kind of test cycles so then you do you maybe you look too hundred to say what work， what didnwork then you do another two hundred and you go on like that until you actually have your predefined criterior or satisfied with the molecules in my head when you said 4000 its like OK well！

well， create 4000 test 2 then well see， which one bound together in the way that we want them to and last the longest but it sountickets are much more chemical biological process almost like a funnel of OK， wetry twenty very different approaches and then these two or three showed pretty interesting signs so well， take just those three and then well vary that again with a new set of twenty based on those two or three yeah！

yeah！

and of course， today you know the use of various types of ai is is changing that right， so you can be smarter im sure that back then sometimes there is some some molecules we didnt have to make because we werent clever enough， we always had 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 actually have to make few a molecules yeah！

im 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 its in everything we do today why did using chat tivity for everyday work？

right its looking for patterns trying to use machine learning to improve the understanding of a pattern that maybe you cant really see it well enough its not just statistically significant than you apply machine learning you can see the pattern better super cool its 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 knowledge leadership basically took the position that theres no business for us in waitloss and yet you and your team were doing what would become the most important work within that same company for the way 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 in your team to get this thing to market when there were opposing forces even within the same company yes！

that im super happy to talk about it didnt feel that uncomfortable but cause i think its also it gets maybe displayed a little bit in the wrong way because there gives me the change to talk about the Scandinavian work culture， which is another reason for why im super happy to be in this company after thirty five years， because its actually welcomed to challenge the authorities or the leadership， and its true that large uh this was the other last right， our previous ceo are not everyone is called Mars and then mark， but there are OK he said that he didnt believe that obesity was an area that would become important but 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 didnt personally think that this was important he still trusted are the people that he had put in charts of leading the research area so it was it was never of course， it did me and say oh OK， we got a work extra hard on this it wasn uncomfortable in some way and actually， he also made fun of it himself later saying you know i try to shut this down tree times but i was i was never successful right， so i think he is even on the on tape himself where i dont know if you checked those videos that the no notice foundation did on the discovery of joke you want i think as one of those episodes where he says that this is what its like to work here and i think why uh theres actually quite a lot of people who choose to stay in the company if you really want to make a difference and you dont mind speaking up its absolutely welcome to speak up you know ive done that many times and im im still here and ultimately it sounds like the data is the data the workyoudoing is science and so if the experiments yield data that it meets the goals of the company。

i mean youve gonna pursue it yeah yeah of course。

there also has to be a commercial angle， so its 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 thirty five years， i was thinking before the episode of making the comment youhad a one and a million career but i think that would undersell what has happened because that would mean that there are seven equivalely impactful careers in the world， which there are not its closer to one and a 5 hundred million career something like that you know when youre laying in bed at night， youlooking at the sealink and youre like what a wild journey this has been what are the things along the way there are some of your biggest takeways 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 chilp one， the others left i was the holy 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 of baby back then right that i you know this is mine im gonna make it work so i know the thing that also work for me was that you know the that some people were not supported or there was a little bit of it wasnpopular 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 have had quite a few of those over the years i still have the data i still talk to people who were maybe outside of the company or other people in the company because they are certain also were supported people in the company to me it only mansion all im going to show them that uh we are gonna do this uh and we are gonna solve all the problems and eventually get moving so that to one thing that kind of stands out for me after all of these you theres also i know the thing that i that i often think about you know i 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 i want to say that if you want to work on something that really kind of novel ahead of the time then you also have to accept that you have to keep on convincing people and at it it takes time right！

so then you gotta be comfortable in that you should listen to the critic but you should not let yourself be stopped by it if if you still believe that its a good idea is there something else to that if you believe in something in the way that you believed in the waitloss indication and you believe that it needs decades of room to come to freeition that you might need to sort of piggy back it on on something else that has enough sort of political support first， like i could imagine if this only had the effect for waitloss and you werentableto pursue bringing it to market for type to 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 hadnt been these disappointments in the obcity farm area than maybe maybe， it could have been successful in that way so you could definitely say now that i think what has happened is a fact you know that what has happened is that with these chillpy one base medicines you know its just been decades of the additional positive data， more positive data， more positive data i think there is actually some research that says that by the time that about fifteen percent of the population nose about something then that s kind of a appointed time where then it can kind of explode from there with the knowledge right， but i think its it certainly probably has played into the way that it worked out for jlp， one that it was just is really really slow going process but then a lot of good data kept on coming out and now we havent even talked about the uh the fact that that did these medicines also save peoples lies right that there is a better effect on the cardiovascular system so thats another thing right its the slow steady work over many many years and and suddenly there was this extra ordinary moment where more people realized uh oh， my god this this could really help me i think that the reason why it was the effect on wake loss that has kind of really made things happen is because its very latable to the individual person right you dont feel so much if your blood glucos is better you dont feel so much if you have less risk of getting a cardiovascular attack or a stroke， but you feel that youre hungry every day i dont actually， i heard that from quite a lot of people that you know if you， if you just feel that you are hungry all the time and you feel you just cant stop eating you know that it becomes very latable to the individual person that this is really helping me in my daily life so so in that way i think it makes sense that it is the effect on on hunger and society that really has worked to uh tractually get more attention to the fact that this can actually help uh a lot of people makes 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 a lot a i think this is a as good a place to leave it unless you have any other parting words for us no i think weve been around some really a good topics right i think so all right will thank you so much and listeners will see you next time well？

see you next time。