Zealand Pharma A/S (ZEAL) Earnings Call Transcript & Summary

I think we're ready to begin. So I wanted to welcome everyone, and thank you for joining us today here in London and to everyone who is also joining us online. I am Anna Krassowska. I'm Head of Investor Relations and Communications at Zealand Pharma, and we are very excited to be here today to discuss the future of obesity management. How we believe the mechanisms that we are pursuing and in particular, the peptides that we are developing may shape the future treatment of obesity. So please be aware, therefore, that we will be making forward-looking statements today that carry risks and uncertainties, and actual results may differ from these forward-looking statements. So for the agenda today, we will start by framing the global obesity pandemic that we are facing today, and then this will be followed by 3 presentations that cover the scientific mechanisms and the clinical potential of the candidates in our pipeline. So first, we'll start with our 2 wholly owned candidates, our GLP-1, GLP-2 receptor dual agonist, dapiglutide targeting obesity and low-grade inflammation. And then our amylin analog now named cagrilintide as an alternative to GLP-1-based therapies. And then finally, the glucagon GLP-1 receptor dual agonist, semaglutide, co-invented by Zealand and Boehringer Ingelheim and being developed by Boehringer Ingelheim, targeting obesity and NASH. After each presentation, there will be a Q&A session. And we will also have a 20-minute break after the second presentation at around 2:30 local time here in London. So our speakers for today from Zealand management will be Adam Steensberg, our Chief Executive Officer; and David Kendall, our Chief Medical Officer. And I am delighted to introduce our 3 external experts today. Dr. Daniel Drucker is an endocrinologist and Professor of Medicine in the Division of Endocrinology and University of Toronto. His discoveries have enabled development of several new GLP-1-based therapies for the treatment of diabetes and obesity and GLP-2 analogs for intestinal failure. Dr. Drucker has been elected to the Order of Canada, the Canadian Medical Hall of Fame. He is also a fellow of the Royal Society of London and the National Academy of Sciences and National Academy of Medicine in the United States. Dr. Lou Aronne is a leading scientific and clinical authority on obesity and its treatment, having been involved in the application of peptide therapeutics for the treatment of obesity for over 30 years. He is a Stanford Sanford I. Weill Professor of Metabolic Research and the Director of the Comprehensive Weight Control Center currently in the division of endocrinology, diabetes and metabolism at WIL Cornell Medicine. Dr. Aronne is the past President of the Obesity Society and a founder of the American Board of Obesity Medicine. Dr. Carel le Roux is a professor and experimental Pathology at the University College Dublin and the Director of the Metabolic Medicine Group. Dr. le Roux is the Irish Research Council researcher of the year. He has previously received various other awards, including the President of Ireland Young Researcher Award. Dr. le Roux holds a Welcome Trust Clinical Research Fellowship his work on how the gut talks to the brain. And with that, I would like to turn the day over to Adam Steensberg, our CEO.

Thank you, Ana, and thank you, everyone, for participating today, both here in person and online. This is a very special day for us, and I really want you guys to remember 3 numbers after my speech. And the first number that is 300,000. And the second number that's 50 and the last number that is 3 million. Humans have lived in this earth for 300,000 years. And for 300,000 years, we have survived as a species due to our ability and desire to seek food, store energy and preserve energy whenever we could in order to prepare ourselves for times of starvation. And yet for 300,000 years, the number of -- the proportion of individuals with obesity and overweight have remained low and relatively stable from the first humans evolve until recent modern times. Then something happens. And that brings me to the next number, which is 50. 50 years ago and just in my lifetime, and actually, if you think about it just in the blink of history of humans. The prevalence and proportion of people living with obesity globally have raised to 40% and it's still accelerating. 50 years ago, we saw a dramatic change in how we live in modern societies, and we had a technological revolution. So, we no longer prepare food how our parents and grandparents did. There's a very, very abundant access to processed food, and there is cars and screens that cause us to live very sedentary lifestyles. And it's not just about obesity. It's about this number, 3vmillion. 3 million excessive deaths every year can be ascribed to the obesity pandemic that we see today. And 3 million bets that is the same number of people who died from corona every year during the peak years of corona. And this is just the start because it's not just about obesity or not obesity. It's actually about the duration of obesity. The longer people are obese, the more their organs will be affected. So, it's the duration of for how long people have been obese will cause the comorbidities that can be ascribed to obesity, all the chronic diseases that we know are associated with obesity. So, the 3 million deaths that we are looking into today, that reflects obesity, as we have known it for some time, meaning people who became obese when they were middle-aged. What will that number be for people who have been obese since their early childhood. I do believe that we are facing a Tsunami of chronic diseases and I do not believe that we have the means, whereby we will completely reshape our society and bring it back to how it was 50 years ago. So that Tsunami of chronic diseases that are -- where we are looking into fueled by the global obesity pandemic is, in my mind, the biggest health care prices that we have faced in modern times. The good news is that we have now seen the launch of the first keys on medicines that can actually help address this problem. And at Zealand Pharma, we are developing the next-generation molecules that we think can help address this health crisis. And then our hope is and my firm belief, when we look back in 5 years from now, the obesity pandemic will just have been a small blip in the history of humans. So, our goal really is that if we as a society now embrace this historic moment, if we rise to the channels together, then we can address the biggest health care channels that we have ever faced at least in modern times. And at Zealand Pharma, many of you know this, but the mission and what we are committed to is to bring life-changing medicines and next-generation peptides to the market. And we have a very strong ambition becoming the best peptide drug discovery and development company. So that brings me a little bit into some of the aspects that we consider important for the potential future or for the future obesity market. We do believe that there is a change in attitude towards just going for higher and higher weight loss of maximizing the weight loss, which has been a focus for companies for some time toward products that can achieve higher quality weight loss. And then more importantly, you can say, and most importantly, how you can differentiate by addressing different comorbidities associated with obesity. After all, this is why we treat obesity. It is to prevent the comorbidities. If you look at the right-hand side of this slide, that's a very important consideration as well. Traditionally, when you launch therapies for chronic therapies or you develop new markets is always targeting the prescriber and the payer segments. I will, however, address a little bit how we see also the future [ of BT] market on a more patient pool or consumer-driven market because there is this very large desire among many of these individuals to lose weight. We already see this today with people paying out of the page to get access to medicines that can help them achieve their goals when it comes to weight loss. First of all, if we look into the reimbursement segment, as I said before, I think the key parameter for differentiation and access in the future will be that you have enough weight loss but then more importantly, how well you can address different comorbidities. That will be a key aspect for many prescribers and for payers to support new medicines. Of course, safety, tolerability and also quality of weight loss, preservation of muscle mass, for instance, will be key focus areas for this segment. In addition to that, and I think it's something that is sometimes overlooked because so far, most people just talk about weight loss, but it is equally important to consider weight maintenance. It is, at least in my mind, a long, long way to go before we can think about having cured obesity, which means that we have to consider that patients will need not just support to lose weight, but also to maintain their weight loss. If we look into the patient pool -- the self-pay segment where we also see a great opportunity to help improve health outcomes. Then we do believe that people are really looking for alternatives to the first generation of weight loss medications, things that can be better tolerable, things that can fit better into their ways of living. And we also know, and I think our faculty will discuss this later today. Obesity is a very complex disease, so we do need different modalities to for different patients. But convenience, something that will allow patients to live more normal life while still maintaining their weight loss will be important for the future management of obesity. So, looking into the -- what some people would describe as a very crowded space now, in my book is still not that crowded, to be honest, considering the magnitude of the problem. But if you look into the different approaches in development right now that are at least getting the most attention, then you will see a lot of approaches that are built on GLP-1 as a backbone with the first-generation mono-GLP-1s like SEM, then you have the first dual-acting peptides like cagrilintide but they all try to leverage the potential of the GLP-1 class -- the GLP-1 molecule in inducing weight loss and also several of the other benefits that we know from type 2 diabetes, cardiovascular protection and so on. So, these products will all provide -- aiming for providing significant weight dose, probably these next-generation medicines will provide 20-plus percent weight doors approaching 25%, perhaps even a little bit more for some of them. But more importantly, we believe they will differentiate on how well they address different comorbidities, that being NASH, cardiovascular disease, neuroinflammation, Alzheimer, kidney disease, that's going to be the true differentiator because most of them will provide weight losses that are in the same area. They will, however, also all carry one common theme, and that is the side effect profile of nausea, vomiting and constipation, and they will also make people lose their appetite. A lot of people are okay with that because they have such a high desire to lose their weight. But you cannot underestimate that for a large proportion of patients, it is an issue to have these side effects and some will even drop off therapy because of side effects. And that's one reason why we do believe you need alternative modalities to address also those patients, again, not only in the weight loss period but also in the weight maintenance. So, we do expect several new modalities that are based on non-engaging approaches to also reach the market in the coming period. And here, we see Amylin as one of the prime candidates, and we'll discuss that much more today. But so far, at least in our experience, we have seen Amylin as a molecule that is more tolerable, it as we observed less nausea and vomiting. And very importantly, it works through a different mode of action in helping people lose their body weight. We'll discuss that much more today. So yes, it is quite crowded when we hear about all the different modalities. However, when you think about different modalities, it's actually not that crowded, and we actually believe we have one of the leading opportunities outside in citing space with our amylin analog. So, with that, I will just also highlight to everyone today that today's event is about our sealant’s obesity pipeline. We do have opportunities to address very significant unmet medical need and rare diseases, and we have a very interesting early pipeline addressing chronic inflammation. But as I said, the focus is on obesity today, and I look very much forward having further discussions and insights from our faculty members and from David and David, I would like to invite you up now to take it from here.

Again, welcome, everyone. Pleasure to join you on behalf of many of my Zealand colleagues and the work that's not only Zealand but Zealand with our Boehringer Ingelheim partners will put forth today. It is my pleasure to introduce the first of our 3 faculty and Dan Drucker, who was introduced by Anna is someone who not only has made seminal contributions to the incretin therapeutic space, but his efforts to support other scientists to broaden the opportunities that came from the discovery of Extended4 all the way through the development of GLP-1-based therapies for diabetes. And again, seminal work that brought forth GLP-2 as a therapeutic option, both in development and clinically available for the management of intestinal failure, Dan's work, I think, is well known to all of you and Dr. Drucker and his laboratory have been instrumental in particular, in providing an understanding on the topic you see here, which is targeting obesity and the systemic low-grade inflammation that I hope you will at the end of this discussion, understand can be well targeted by the combination of GLP-1, GLP-2 receptor [ agonist ]. So with that, I welcome Dan Drucker to discuss the science of GLP-1, GLP-2. Dan.

Thanks David... And Hi, everyone, has to be here. And this is a reminder for the young people in the audience, this has been 35 to 40 years of science with a lot of excitement, starting with GLP-1 in the mid-1980s and 10 years later, GLP-2. And we often hear people say these GLP-1 obesity things. There are new drugs, we really worried about them, but we have an enormous foundation of both basic science and 18.5 years in the clinic and for GLP-2 more than 12 years in the clinic. So this is, I think, a very well-established group of molecules. This is very familiar to you how GLP-1works. We started off with the beta cell and the pancreas and glucan inhibition. And 10 years later, we moved to the brain, and we have the control of geomotility and gastric aging. So I think this is very well established now and the biology is conserved not only in animals but in people with or without type 2 diabetes. What's less, I think well studied is the GLP-2 story. This started out as a growth factor and ultimately led to the approval of to dapiglutide over 10 years ago for intestinal failure. But beyond the gut, GLP-2 also has some very interesting actions, and it works in the brain to control peripheral metabolic and vascular effects. It has anti-inflammatory effects in the liver and also has very important control of gut barrier function, which also will reduce systemic inflammation. So why are we seeing these amazing effects of GLP-1 in the reduction of kidney disease in people with type 2 diabetes, we saw the flow study, and we see the [ Selectra ] seemingly with reduction of cardiovascular events well before profound weight loss and we have evidence for benefits in the liver. And what ties all these disparate disorders together is increased inflammation. And chronic inflammation really drives the chronic cardiometabolic complications of disease. And that, I think, is one of the areas that will differentiate the various molecules as Adam has alluded to. And so we think it's attractive not only to have GLP-1, which is profoundly anti-inflammatory, but also GLP-2 also reduces inflammation. And so this is a really emerging but I think unique concept that if one marries the anti-inflammatory effects of GLP-1 together with the anti-inflammatory effects of GLP-2, will we see a greater suppression of inflammation which may enable a profound reduction of the complications of cardiometabolic disorders, and that's the hypothesis that we'll be looking at, I think, very carefully both in preclinical studies as well as in the clinic. And so let's just take a look at this in a little bit more detail. Some examples from the preclinical literature. Here we have the classical actions of GLP-2 on gut inflammation, and we see the top panel of reduction in circulating biomarkers of inflammation in this most model in the context of lipopolysaccharide administration. And on the bottom panel, a reduction in tissue markers of inflammation and oxidative stress. And this is very well worked out in the gut, which has been the major focus of GLP-2 action for some time. But we're very interested in the cardiovascular space because not only does GLP1 have the demonstrated activity to reduce MACE and heart attacks, room cardiovascular death. But it's interesting to me to look at the emerging actions of GLP-2 beyond the gut, which includes the control, not just of hepatic inflammation, but a systemic inflammation. And it would not surprise me going forward, if we start to see a lot more interest in the potential anti-inflammatory and cardiometabolic actions of GLP-2. Just a couple of examples that you may not have been intimately familiar with or GLP-2 receptors in the liver. They are most prominent in stellate cells. If one takes away the GLP-2 receptor and knockout MACE you have more inflammation, more stellate cell activation, if one activates these stellate cell receptors as I'll show you in a minute, we have less inflammation in the liver. And we also have profound effects of GLP-2 in the liver on the gut barrier function. If one looks at GLP-2 receptor knockout MACE, they have higher rates of metabolic endotoxemia, and circulating LPS. If we give GLP-2 really within 30 minutes, both in animals and in human studies, we see a reduction in inflammation and improvement in barrier function. So here's just an example of the liver disease. We've studied this in our lab and this is an independent publication but you can have a very nice benefit of hepatic inflammation on the left and some histological evidence of fibrosis on the right by not only activating the GLP-1 receptor or the GLP-2 receptor but combined activation of both receptors seems to have very useful benefits to reduce hepatic inflammation. Adam also mentioned the next frontier, which is the brain and neurodegenerative disorders, and we have some very interesting data going on with GLP-1 in Parkinson's and obviously, the [ Vogue ] trial with semaglutide. And there's also evidence that GLP-2 will reduce neuroinflammation. These are preclinical studies. And I can tell you, we're starting to do some of this work in our lab and GLP-2 is profoundly anti-inflammatory independent of its actions in the gut. And so what happens if one combines the activities of GLP-1 and GLP-2 preclinically. Here, you can see a head-to-head study on the left with a GLP-1, GLP-2 coagonist versus tirzepatide, very profound weight loss, which matches that achieved with tirzepatide and very favorable effects on body composition, so predominant fat mass and relative sparing of lean mass loss. So I have been used to studying GLP-2 predominantly for the last 20 years in the context of gut injury, but we've recently begun to study GLP-2 action in the absence of gut injury, particularly in the context of inflammation. And I can tell you, it is in our preclinical studies, not yet published almost as profoundly anti-inflammatory as is GLP-1. So we're still working out those mechanisms, but the data is pretty exciting. And so I think the potential for combining GLP-1 and GLP-2to have distinct activities that reduce inflammation, I think, bode well for the challenge we all face, which is to reduce the cardiometabolic complications of disease, which are driven by inflammation. So I'm going to turn it back over to Dr. Kendall.

[indiscernible] I hope you'll agree, Dr. Ducker's quick survey and review through a very elegant, I think, compelling and for us, incredibly exciting opportunities combining the effects of GLP-1 and GLP-2. And as many of you know, dapiglutide which is the first-in-class GLP-1, GLP-2 receptor agonist in the clinic, derived from the GLP-2 molecule that modified to leverage significant GLP-1 receptor agonist effect and designed specifically given the known effects of the GLP-1 incretin mechanism on weight loss and inflammation to leverage that GLP-1 receptor activity while maintaining a significant amount of GLP-2 receptor activity, but also as is part of our peptide platform to generate stable molecules, which can be formulated at physiologic pH and which are long acting to address the issues that Adam referred to in his opening, which is the opportunity for convenience, less treatment dosing and continued effect over long periods of time, dapiglutide based on its half-life greater than 120 hours, clearly suitable for once weekly administration. And as Dr. Drucker so elegantly described the opportunity of activation of these 2 unique receptors to not only leverage GLP-1 effects on the pancreas and pancreatic function in the setting of dysglycemia in type 2 diabetes, but to improve body weight through central and peripheral mechanisms and GLP-2s effects, not only on the GI tract where it has been employed in intestinal failure as a specific agonist. But here, dialing in GLP-2 effects to address that low-grade systemic inflammation that occurs in the setting of obesity and now increasing evidence as to how it contributes to the complications and comorbidities associated with obesity. So with that, I'd like to review, again, clinical data that many of you have seen. These are data from the first multiple ascending dose trial performed with dapiglutide and presented last year at the American Diabetes Association meetings. Dapiglutide in this clinical study in separate cohorts demonstrated a dose-dependent reduction in body weight. And shown here is dapiglutide particularly at its highest exposure doses, this only 4 weekly doses but achieving weight reductions over that period of time in excess of 4% in a very short, but to us, a very instructive multiple ascending dose trial. I think as importantly as the mean weight reduction that was observed in this trial was the fact that every individual treated at the highest doses of 3.5 up to 6 milligrams over only 4 weekly doses, ad body weight reductions over the course of observation. In this study, dapiglutide was generally considered to be well tolerated, no serious or severe adverse events. There were no withdrawals and no antidrug antibodies detected. So this, for us, was the first bit of compelling evidence as to the potential application of dapiglutide in the setting of obesity and leveraging GLP-1 and the potential effects on inflammation through GLP-1 and GLP-2 activation. As many of you also know, there is an ongoing mechanistic study, a Phase IIa trial, investigator-led study, the so-called DREAM trial evaluating the effects of this specific molecule dapiglutide. -- on body weight measures, got integrity and got permeability as well as measures of systemic inflammation in a total of 54 subjects in this actively recruiting study, adults with obesity exposed to dapiglutide at doses previously assessed in the multiple ascending dose trial up to 6 milligrams with exposures out to 12 weeks. We will evaluate not only the change in body weight as an important pharmacodynamic measure of the potential of dapiglutide as an obesity therapy. But just as importantly, looking at categorical weight loss over these 12 weeks and a number of important measures of gut permeability, systemic markers have got health and these systemic markers of inflammation. So for us, the first proof of principle, if you will, that leverage the very characteristics that Dan so elegantly described in the nonclinical studies. We anticipate a readout from this study in the first half of 2024. And this, combined with our ongoing Phase Ib study, which is a dose titration trial using dapiglutide. This Phase Ib trial with dose escalation, higher doses of dapiglutide much longer exposure than the previous 4-week multiple-ascending dose trial and at higher doses than we saw in either the multiple ascending dose or the DREAM trial. This will be for a total of 13 weeks of exposure in adults with both overweight and obesity, higher doses, which are targeted to be achieved and the longer duration of exposure. As with other Phase Ib studies, obviously, the tolerability and evidence of treatment-emergent adverse events will be a primary measure but key secondary endpoints, better understanding the pharmacokinetics and most importantly, the pharmacodynamic effects of dapiglutide on body weight over an extended exposure, and we anticipate then fully informing progression into Phase IIb and dose selection for later clinical development. So we are excited that the first of our wholly owned assets of the 3 that Adam described earlier, this unique GLP-1, GLP-2 first-in-class molecule for the clinical application in obesity that can also target systemic inflammation. These data we anticipate will be available in the second half of next year. So dapiglutide as I've said, the potential first-in-class unique dual agonist, GLP-1, GLP-2 targeting obesity and systemic low-grade inflammation we would anticipate and at least project weight loss in the range that Adam described sort of the price of entry weight loss in the double digits, 20% or more, a unique mechanism of action, targeting both obesity and low-grade inflammation. We would also anticipate similar tolerability to other GLP-1-based molecules as those described by Dan and as we'll discuss with semaglutide later in this program. I think importantly, it is not -- it is no longer for Zealand and others simply a targeting of weight losses, a numeric reduction, but targeting, in particular, the risks associated with cardiovascular disease and the potential cardioprotective benefits both GLP-1 and GLP-2 through its anti-inflammatory actions and the potential to target other comorbidities where low-grade inflammation may affect other end organs, including the liver, the central nervous system and beyond. So with this, obviously, we are incredibly excited to have this amongst our portfolio of unique assets targeting both obesity and the associated comorbidities. So with that, I'll invite Dr. Drucker and Adam and Anna back up to the front, and we welcome your questions and any clarifying comments that we can provide. So, Anna, I'll turn it to you.

[indiscernible] Michael [ you are first ] [indiscernible] coming around to people. So wait for either Adam or [indiscernible].

Michael Novod from Nordea. A question for Dr. Drucker in terms of GLP-2 safety because I guess that's sort of on top of mind. It was also on top of mind when the data was initially presented at ADA. I know it was a competing company that raised the question, but we know there's been discussions around GLP-2 safety, polyps, a growth factor in intestine, et cetera. So maybe your comments to that, we also start to have these dual acting molecules.

Sure. So I think we have 2 sort of insights from clinical medicine. One, as you know, teduglutide is being marketed since -- I get this right, but I think it's about 2000, but at least 10, 11 years, 12 years on the market. I don't think I've seen a single report of colon cancer. But certainly, there have been some small bowel pulps and some gastric polyps. Probably the more interesting experience clinically relevant to dual GLP-1 and GLP-2 receptor ageism comes from the bariatric surgery experience. So as you know, RYGB people have very high levels of all of the LC products. So high levels of GLP-1, high levels of GLP-2 for decades. We have the SOS study, and you don't see an increase in colon cancer in those people. I don't know, David, if you want to talk to the particular attributes of dapiglutide, perhaps that's for another discussion. But I think it's a reasonable question, but if we actually look at the clinical experience so far, it hasn't been something that's been overly concerning to date.

Yes. And I'll add, Michael. Our own experience, obviously, with the glepaglutide program. We've got long-term follow-up of a relatively modest population, but safety evaluation there, and I'll refer back to Dan's comment on the experiment of nature, if you will, from gastric bypass, particularly Run, where these exceedingly high levels, not only are not associated with significant increase in cancer risk, the long-term study showing a reduction in cancer mortality. So I think that combined with what Dr. Drucker referred to, which is this molecule, in particular, has dialed in significant potency around the GLP-1 component, not unlike semaglutide, which has a much stronger preference for GLP-1 receptor activation in [ lecagon ] here dialed back, but not dialed away the GLP-2 receptor activity. So I think all 3 lines of evidence give us great confidence. And obviously, clinical programs will be required to do the appropriate surveillance. So I won't jump past what the regulators and others will ask for. But I think scientifically and clinically, we have great confidence in safety and obviously, the benefits that could come with significant weight reduction and the anti-inflammatory effects, which are not only not pro-carcinogenic but potentially protective.

[indiscernible]

It's Rajan Sharma from Goldman Sachs. Just in terms of the DREAM trial, what level of inflammation reduction or biomarkers of inflammation reduction would you be looking for to kind of validate that hypothesis on the low-grade inflammation? And I guess, secondly, is that trial going to be long enough to be informative?

Yes. I'll begin. First of all, thanks for hosting. And secondly, I'll start and maybe ask Dan and Adam to comment. This is a small trial with relatively low doses and relatively short duration. So it will be our first glimpse. So I would say the absence of a signal, of course, isn't what we desire. But looking across both the measures of gut integrity and systemic inflammation based on the nonclinical data that we've seen from rodent studies and that this is a relatively high-risk obese population that's being randomized. Even at these low doses, I would anticipate that across the broad look and there is a very broad look of biomarkers, given that this is the first study of mechanistic study of drugs in this class with human exposure. But I think the real test will come down, not just to the biomarkers, but obviously, ultimately, to assessing comorbidities, cardiovascular risk, ultimately and cardiovascular outcome study. But I would say the study is reasonably powered. But because it's the first look doing full power calculations and trying to estimate the outcome will be challenging. Adam, you had a great hand in this as well. Any additional comments?

No, I completely agree what you said there. It's, of course, an exploratory study. I think what -- but it's interesting to note is also some of the remarks by Dr. Drucker how rapidly the 2 can actually take certain anti-inflammatory effects. So of course, we have hopes that we will start to see some of these effects already in a short-term study like this. So -- but it is, of course, exploratory in nature.

Dan, any other comments on what might be expected with the…

No I think we really haven't looked at GLP-2 action in a population like this or they're certainly not GLP-1, GLP-2 combined activation. So in mice, we see very rapid anti-inflammatory effects, 30 minutes to an hour were suppressing peripheral inflammation. But these are not mice. These are humans, and they're getting API. So it will be exciting to look at the data.

Charles Mabbutt from Morgan Stanley. Firstly, does the separation in the early separation of the Carson SELECT study give you more confidence that you will see a stronger signal in the 13-week study in the second half given the rapid effect? And secondly, please could go into a bit more detail on why impacts on lean body mass could be different with the [indiscernible] combination? I think I saw that on the slide.

Yes. It's really apples and oranges, right, with the SELECT trial, looking at the endpoints, which is heart attacks, strokes, cardiovascular death, whereas that's not -- those are not the end points in the 13-week study. But I do think it highlights the fact that changes occur rapidly and they are clinically significant changes. So whether those will be fully captured in the patient population study, it's hard to know. It's not a huge study. But I think there is reason you talked about the short duration of the studies, but the SELECT trial tells us that in people living with obesity, we can see very profound clinical relevant changes in ultimately risk factors that translate into cardiovascular. So it's fascinating to see. We just don't know what we're going to see in those trials. But I'm not worried about the duration of the study given what we've seen in [ Sal ].

Yes. And I'll add. I mean, certainly, both in the setting of diabetes with GLP-1 receptor agonists and then the SELECT trial in a high-risk population with obesity and established cardiovascular disease. At least my early interpretation is there are clearly things that are separate from the change in body weight because you don't lose 10%, 15% of your body weight in the first few weeks. Whether that is a direct consequence of the anti-inflammatory effects of GLP-1 and to what degree GLP-2 and its anti-inflammatory effects will contribute both early and long term. It would be a profound speculation at this point. But I think as we're looking forward beyond Phase Ib and Phase II and ultimately to cardiovascular outcomes, which we believe will be a very important comorbidity in the potential application of GLP-1, GLP-2 receptor coagonist and DAPI in particular. I think all of the data to date, there is barely a GLP-1 that hasn't demonstrated benefit and adding additional anti-inflammatory effects to me could only at least set the hypothesis of equal or greater effect.

It's Ben Yeoh from RBC Asset Management. Just a follow-up, I guess, on anti-inflammatory and neuroprotective effects and maybe some of this is a class level and some of this is at the molecule level. But how much do you think is mediated then by anti-inflammatory effects? Are we talking maybe 30% to 50%? Or what is the kind of thinking around the strength of the anti-inflammatory part? And then in your presentation, you talked a lot about Neuroprotective effects, which seemed to be a little bit interlinked with that. There's also some speculation that we might see some effects in dementia, Alzheimer's and the like. What do you think are the chances we might see something of that in the class? And then in terms of the strategy in developing, it seems a bit tricky. Are you going to look at anything in neuroprotective early or go obesity, diabetes found the metabolic pathway first because it's easy and the trials and neuroprotective is just going to be more speculative.

So when you say what proportion of the benefit is from the information, you talked about effects on neurodegeneration. Is that what you're...

You can take it -- Well, I guess all of the outcomes that you're currently seeing or all of that kind of clinical and the things that we're seeing, whether you're going to talk about it in terms of biomarkers that we see or seeing in terms of outcomes that we're looking at. Obviously, no one's really decided what it is, but there seems to be a consensus that anti-inflammatory is important. And so I'm interested in your view as sort of how important that is as across that, both maybe classes and whether there'll be molecule effects.

So the -- with apologies to the non-sports fans here. So GLP-1 I always has 3 shots on goal in terms of this chronic complication story. So one is, clearly, there is a contribution from glucose control and weight loss. Those are generally good for you, but they take much longer to become apparent. -- we have GLP-1 receptors on the target organs. There are some GLP-1 receptors in the blood vessels, in the heart, in the liver, et cetera. And I think those do play some role. And then we have this effect on inflammation, which I think is substantially through the brain. You'll see a paper coming out in 2 weeks in so metabolism. That's our latest story on how this works. And so I think they all contribute to some extent to reducing these events that we see. And in people with type 2 diabetes, we saw a 22% reduction with albiglutide harmony outcomes, no weight loss whatsoever, like 800-gram weight loss after 2 years. So we knew that there were weight-loss independent effects. And now with SELECT, we're seeing evidence for weight loss independent effects. So I think for the cardiovascular MACE sort of Triad, I think it's very clear there are multiple ways that we can do this. For neurodegeneration, we have much less compelling data, right? We just don't have the results of these randomized controlled trials. We have hints from real-world data. We have hints from the cardiovascular come trials. We have a ton of preclinical data, which is almost never predictive of outcomes in Alzheimer's. So I think we have to be much more cautious, cautiously excited but very cautious and we have to wait for [ Evoque ] and other trials like that. But for cardiovascular data, I'm convinced there are multiple contributions, including the liver. We see multiple ways that GLP-1 reduces inflammation in the liver beyond simply wait less. So lots of different moving pieces that all converge on benefit.

And I would also add, I mean, because your questions were also a little bit about where to take this molecule. And I think as we tried -- or at least I tried to do in the start, there is quite a lot of GLP-1-based molecules in treatment. And for Zealand Pharma, it's extremely important to develop something that is differentiated. And for this specific molecule, as David also mentioned, the reason we are excited is its potential to address comorbidities -- selected comorbidities to a higher degree than other GLP-1-based therapy can treatment. So it is something where you should expect us to actually pursue, you can say, comorbidities surrounding obesity within the [ Phase III ] program once we get into that and not just looking into weight loss because when you have GLP-1 as a backbone at least for us, who try to develop differentiated molecules, we will have to address comorbidities early on as well.

And I'll add to Dan's answer. I think the flip side is we've learned quite clearly that the chronic risks of both diabetes, dysglycemia and long-standing obesity portend for cardiovascular outcomes and a risk for neurodegenerative diseases. So ultimately, the mechanisms by which you flip that the other way, maybe less important than whether you see the outcomes, improvements either in eliminating or slowing cognitive decline or in the case of cardiovascular disease, I think the jury is in the GLP-1-based mechanisms, but also through other mechanisms now, we can further leverage the improvements. So exciting times ahead to understand what additional value add these can provide. I think our early clinical data and the studies we have in place soon in the clinical program will provide an exciting glimpse and take us into late stage.

Lucy up here. Lucy.

Lucy Codrington from Jefferies. Forgive me if I'm mistaken, but that originally was going to be developed for short bowel syndrome. So when designing the molecule for the ratio of GLP-1 to GLP-2, was that focus with -- was obesity specifically in mind when you were deciding that ratio? And therefore, how certain are you that you have that ratio correct now? And do you have any backup molecules in development.

Yes. Since I'm the one who has been around for the longest, maybe I should address this question. And you can say it was actually originally when we came up and pursued this in the early research days, it was with NASH in mind. There were some quite compelling data coming out around 2010 that suggests that that GLP-2 could truly do something about the gut barrier function and that could have positive as also reviewed by Dr. Drucker could have very positive aspects on the liver inflammation. So that was actually the prime focus. And then you are correct, at one point when we approach the clinical development of this molecule, we did see an opportunity within short-syndrome as well. People who have followed us for a long time know that also is very close to us that disease area and probably around 2015 or '16, there were some compelling data coming out from clinical studies showing that the combination of the GLP-1, GLP-2 was actually synergistic in SBS. So we saw an opportunity to pursue that with this molecule, but it's also correct, as David has stated here that it is a molecule that is biased towards GLP-1 much more than GLP-2. So you can say, as we have gained even though still limited, more clinical experience, I would say, we are quite determined in the path for this molecule now also when we look into receptor activity in humans.

And I'll say, I mean, we have some remarkable peptide chemists who come up with these, but getting that balance exactly right, to Adam's point, understanding the historical data, where the combination and there are data that suggest if you co-infuse GLP-1 and GLP-2 is better tolerability, but what exact ratios are required for each of these effects? I think to your last question around what's the future of this molecule, -- are there opportunities for backup, given where we are with tax exposure, given where we are now with clinical exposure, Dream is well underway. We have initiated the Phase Ib. We have great early confidence in this molecule. And I think all of that has been learned about the importance of potent GLP-1 receptor agonism and then dialing in some GLP-2 receptor agonism. I won't call it a mistake of protein design, but I think it is like the servant molecule where intentionally getting potent GLP-1 agonism with adequate but not excessive glucagon receptor agonism was equally important and Carl and the rest of us will talk about that later in the program, but very good questions, Lucy. Thanks.

We still have time for a couple more. If there's a couple more questions No. Yes, there is [indiscernible] I'll pay in the front.

Just on DAPI, what do you think, if any, potential could be on renal outcomes just because kind of thinking about where competitive plans is right now, that seems like an important driver of outcomes to your point earlier. And I guess, is there any evidence that suggests GLP-2 could have a benefit there? Or would you be relying on the GLP-1?

Yes, I'll start and then maybe ask Dr. Drucker to comment. It wasn't a main focus. I think the Drucker to understanding we have now around [indiscernible] and the outcomes there. No question that this population, whether dysglycemic or not overweight in obesity contribute to a significantly higher risk of adverse renal outcomes. GLP-1 receptor agonism, I think, now has established itself along with SGLT-2 inhibitors as having an important place in clinical outcomes. So having a potent GLP-1 component to DAPI in this space, at least to me, pre potential for favorable outcomes on renal disease. I'll defer to Dr. Drucker to talk about any potential effect GLP-2 on renal health.

Yes. So I don't think we've ever looked Actually, is, I'm pretty convinced that GLP-2 is going to reduce inflammation systemically, but we really haven't looked specifically in experimental kidney disease to see if GLP doing anything. So it's a good future experiment.

And if Dr. Drucker hasn't looked, I'm pretty sure no one has.

Sorry, can I just follow up on the lean mass question. I think I saw it on your slide about -- could you go in a bit more detail on why GLP may have a promising [indiscernible] GLP relative to GLP-1.

Yes. There's not a lot of it. I think there was just a little bit of preclinical data in some animals. So I think we'll learn more once we start to see the results from GLP-1, GLP-2 in the form of DAPI in the clinic. But I don't think we have a lot of human data to really determine whether GLP-2 has any unique effect on lean mass. Just not enough data.

[indiscernible] I think this will be last question.

It's [ Ben Jackson ] Jefferies. Just 2 short questions, if I may. One, around the confidence around the over 20% weight loss and where that is coming from? Is it purely from that preclinical data that we've seen versus tirzepatide? Or is there anything else that we should also look at there? And then is the GLP-1 and GLP-2, are they completely discrete action at the receptor? Is there any overlap with the agonism there between the 2 molecules and the receptors?

I'll take the first, maybe with Adam and turn it to Dr. Drucker for the second. I think that confidence comes in great part from the early looks from our clinical data set. Obviously, we have not yet seen the final data set from Dream. We won't until it's fully randomized, but the potency of GLP-1 receptor agonism in that molecule and what we see in a 4-week study to us, he is on par with what is seen with short exposure with other potent long-acting GLP-1 receptor agonist, so that 20-plus percent weight reduction over extended exposure, which is usually now more than 52 weeks of exposure. At least early indications suggest not just from nonclinical data, but from the early clinical data that, that is likely with potent long-acting GLP-1 receptor agonism. -- whether there is added benefit from the GLP-2 receptor on true body weight loss alone. And I'll defer to Dr. Drucker to discuss the receptor activation and cross-talk between GLP-1.

So those are experiments that we're discussing actually right now with Zealand to basically say, if we take DAPI and we administer it GLP-1 receptor [indiscernible] or GLP-2 receptor [indiscernible], we look at food intake, body weight, control of inflammation, what proportion of the different receptors is responsible. I'll just give you a teaser, if you go online to some December 18, you'll see we've done that with tirzepatide. And surprisingly, tirzepatide still reduces inflammation in the GLP-1 receptor [indiscernible] that GIP also has anti-factor. So these are experiments we can do in mice and really get a lot of insights.

And I would also -- I would follow up. I mean what David shared here was our target profile. And I think the data, as you discussed, David support this potential. But I think it's also at least our opinion that for next-generation weight loss medications that contain a GLP-1 component, it's expected to be above 20% because that's where the newer long-acting GLP-1 dual and triple acting molecules will be. So that is our benchmark, and we would consider the program if we didn't think we could achieve that with this molecule. I think it's a very different story when it comes to new modalities that doesn't carry the other one as the backbone there you could have lower expectations and still have very interesting molecules.

I think with that, we will now close this session. And I think we have a little break with some refreshments next door where you were before. Spread your legs, breath, and we'll be back in 20 minutes. So is that about [ 10:02 ] I think. So I think we're ready to start the next session, and I will hand it over to you, David.

Thank you. Welcome, back. And it's now my pleasure to kick off part 2 of this program and our discussions around 2 other very exciting novel assets in the Zealand portfolio. As Anna introduced the faculty earlier, it's my pleasure to introduce Dr. Lou Aronne. Lou, as was said, has been in this space since I can't even say when. But I've known Low since the late 1990s. What is often not known about his background is he was around and worked with the team that identified both the molecule and the actions of leptin. And his understanding, particularly of amylin agonism as it relates to leptin sensitivity is as deep as many in this field. He brings a distinct and unique combination of a very busy clinical practice and a clinical perspective. And in fact, he's second on the program because I know he has an overbooked clinic tomorrow to which he has to return. But with that, a great understanding of the importance of the science of amylin agonism that he will provide detail on and we will then follow with a discussion of the data and the clinical program for what is now no longer ZP8396 but [indiscernible], the INN name has been granted. So [indiscernible] will have to go into your nomenclature going forward. So with that, welcome Dr. Lou Aronne. Thanks, Lou.

Thank you very much, David. Really appreciate the opportunity to talk to you and the opportunity to be here today. In a different world, I often say that we would have been giving this talk and talking about the development of new amylin analogs 15 years ago. That's when it should have happened. But the GLP-1s took over at that point in time and amylin went kind of to the back burner. And it could be because of the company that bought it from Amylin, where I met David or not clear why. But this is something that has been around for a long time. The concepts have been around for a long time. And I think that it is very exciting to see it finally come to fruition. Also, as he mentioned, I was present for the discovery of the hormone left in at Rockefeller University. I knew it was going to be discovered about 7 years before, in 1987, and that's when I really began to focus on obesity treatment. I did the first trial that I performed of an anti-obesity medicine in 1989. And I'd like to point out that of the 65-plus trials I've done in my career, the first 60 didn't go that well. It's just in the last 5 or so that have really [indiscernible]. So I don't know what maybe persist for so long, but I'm very happy that I did. And when you look at the mechanisms, what we're going to talk about, you'll see why amylin can play a unique role. So we're very familiar with the GLP-1 receptor agonist. And one of the issues that we have in using these are the tolerability issues, you read about that all the time and maybe you've seen it. But these drugs were originally developed for type 2 diabetes, but we found that they produced very robust weight loss. But again, initially, people thought that the reason weight was reduced was because of the nausea. But if you look at the first generation of drugs like exenatide, there was so much nausea that you couldn't get weight loss, like the nausea hit before you got enough weight loss. But this new generation, possibly because of the gradual onset of action is not as nauseating but it still can be in many of the subjects. And you're well aware that GI side effects are the leading cause of dropouts from our trials. So why have we been so focused on it, and it's been because there are limited alternatives. I look at the field of obesity like the field of hypertension. So if you go way back in history to the ancient era before there were antihypertensives. Blood pressure was thought to be a behavioral problem someone who is Type A, when they were under stress, their blood pressure went up. And it wasn't until the 1960s when they had some terrible but effective blood pressure medicines like [ onefidine ] and reserpine that lower blood pressure than it was shown that within a relatively short period of time, you could lower blood pressure and reduce the risk of stroke and heart attack and mortality. And then it took another 15 years before ACE inhibitors and calcium channel blockers became available, and that's when the field exploded. And now there are 10 categories of drug, there are over 120 drugs to treat hypertension, and I would submit that we need far more drugs to treat obesity. Well, maybe not 120, but we need more than we have. We need more than 2 or 3. So I think that the area is really open for discovery and for compounds that are uniquely effective in various individuals. Even the drugs that have come and gone, we would find would work incredibly well in a subset of the patients we treated. So I can't tell you how many patients I have who lost 15% of their body weight taking something like sibutramine which is no longer available. Now I would say 20% of people would lose that amount of weight. So we need to find new mechanisms of action and be able to apply that to this field. So again, improved tolerability and higher quality weight loss is the other thing you're going to be hearing a lot about. You haven't heard about loss of muscle, loss of lean mass with weight loss, then you haven't been listening to the stuff that I have. Now when we look at amylin, it is a non-incretins -- it doesn't come from the gut, and it increases satiety the sense of fullness in contrast to GLP-1s, which primarily reduce appetite. They also do give a society effect, but they primarily reduce appetite. Amylin's 37 amino acid peptide. It's produced in the pancreatic beta cells. It's co-secreted with insulin. And you can see that it reduces insulin secretion because it's an insulin sensitizer. It also suppresses glucagon secretion and suppresses that accumulation in the liver where it is increasing insulin sensitivity. And in the central nervous system, this is the thing that initially attracted me to it is that it is clearly a leptin sensitizer. And one of the things we found over the 20 years that I was trying to give people leptin to get them to lose weight was that, number one, it didn't work because humans are resistant to leptin. And number 2, that amylin is a leptin sensitizer. It's the best leptin sensitizer that we found. But if we can sensitize leptin, we get a number of the effects that we're describing here. We get an increase in energy expenditure, thyroid hormone function is improved. Body composition is improved with leptin sensitizers. So I don't know if all these effects of amylin are from leptin sensitization, but it fits with the physiology that we understood back in the '90s and early 2000s of what being able to give more leptin efficacy, not necessarily more leptin, but more efficacy from the effect of leptin would do. So it's very, very exciting for me to see finally people going down this path. Here's one of the early trials we participated in this. It was led by Dr. Steve Smith, and this is a randomized Phase IIb trial, pramlintide in varying doses. And the doses we used were the standard dose for type 2 diabetes, pramlintide was the first synthetic short-acting amylin analog, which was used in the treatment of patients who are taking insulin because it was a very good insulin sensitizer. And the dose of the time pramlintide 120 micrograms TID. But you can see that we use significantly higher doses in an effort to get greater weight loss. But here, you see weight losses of as much as 9% over this 12-month period of the trial and 40% of patients who received the pramlintide 120 micrograms TID achieved greater than 10% weight loss. Now at the time, this was kind of the best that we could do. And I had advocated to Dr. Kendall and others to continue developing this to have long-acting analogs. But I think is that when you sold it, amylin sold it to Bristol-Myers Squibb and everything did not happen. So I don't know, don't blame me. Don't blame [ PIM ]. That's what happened. But again, this isn't people with obesity, not with type 2 or type 1 diabetes who are on insulin. This was specifically an anti-obesity trial. And now when we shift to the current day, we see cagrilintide, a long-acting synthetic amylin analog. And look at this weight loss at 26 weeks, very robust weight loss and greater than in this trial, liraglutide 3 milligrams. So this is comparable to what's been seen with semaglutide in the Phase III trials. But here is an even more interesting finding. This is from a study of people with type 2 diabetes looking at cagrilintide or Sema, or the combination, CagriSema. And here, you see the semaglutide arm, 5% cagrilintide, 8%. And then the combination more than additive looks like it may be somewhat synergistic, but you can't really tell based on this. But the point is that cagrilintide is more effective, producing weight loss than semaglutide. Why isn't it being developed as a monotherapy? I mean I don't know what Novo Nordics plans are, but I have heard that they are only developing it as the combination CagriSema. And I would argue that a monotherapy amylin agonist, right, here's the blockbuster, semaglutide, and we see significantly great, you can argue, 60% more weight loss at 32 weeks than semaglutide. So I think amylin agonism is a very robust mechanism for weight loss that we will continue to see work. As far as tolerability, this is, again, an issue that goes back 15, 18 years, and we clearly need a lot more data right now with the current analogs. And we know that slowing down the absorption of these and the onset of action reduces the GI tolerability. But it's possible that increasing satiety will produce a more physiologic effect than reducing appetite. And again, you'll have to take my word for it. We'll have to look at the data that we have with [indiscernible] and with cagrilintide as the research goes on. Actually, we may not see more with cagrilintide since it's all going to be CagriSema. But I believe that we will see a better tolerability profile over the coming trials that are going to come on. And specifically, while we've seen nausea, we saw much less vomiting when we were using the shorter-acting version pramlintide. So nausea, but no vomiting. And again, it's going to take time to build the database to see what happens. Another important point, this is a Phase II trial of cagrilintide and people with obesity and overweight without type 2 diabetes and look at the change in blood pressure, and this is against liraglutide. So you see the cagrilintide having an impact on systolic blood pressure that's greater than lira. We see diastolic blood pressure greater than lira. If we look at the absolute change in lipid profiles, we see that cagrilintide is equivalent as monotherapy. If we look at heart rate, heart rate is a big issue. Now that we have the SELECT trial, the cardiologists are not as concerned about heart rate, but you can see here a significant reduction in heart rate with cagrilintide. Will that mean that the cardiologists really would want this more than they would want a GLP-1, I can't tell you. But to me, this looks like it's something favorable to the cardiologists. They tend to like heart rate going down, right, rather than going up or staying stable. And then finally, the anti-inflammatory effect that we know is turning out to be so important with the GLP-1s, and we see that similar reductions in CRP, high sensitivity CRP with cagrilintide compared to lira. And here in patients with type 2 diabetes, we look at the effect of cagrilintide versus semaglutide. And once again, the reduction in systolic diastolic blood pressure, we see improvements in the lipids, specifically the triglycerides the change in heart rate and the reduction in C-reactive protein. Again, this is type 2 diabetes, but you see it's at least equivalent to the effect of semaglutide. Let's look at some animal data. What this data, I believe, shows is that amylin agonism facilitates fat mass loss and may help preserve lean mass loss. And again, this has been an issue with the pure GLP-1 agonists that are now there like semaglutide. I mean, I hear this twice a week, someone calls me is, "Oh, what do we think about the muscle loss. Well, remember that when you lose weight, when you have obesity, not only do you have too much fat mass, you also have too much muscle mass. That's point number one. Point number 2 is now that we have the SELECT trial, a matter what anybody says, we see that there is benefit. We see improved outcomes. So that's an important point number 2. So nobody can criticize the reduction. But I believe that having more lean mass, if we could preserve more lean mass, it would be better. To me, that sounds like a better idea, and we hope that we'll be able to prove it over time. In this trial, we see the use of amylin versus a vehicle in rats with diet-induced obesity, and these rats were able to select either a high fat or a low-fat diet over an 11-week period of infusion. So the ones in Greg got the vehicle, BosinPurple, you see you got the amylin and gained far less weight. Rats grow throughout their lives, so their weight goes up. over time, even though they have relatively lost weight compared to those who are on the -- in the control arm. And if we look in the right panel, we see the increase in fat mass in those on the vehicle injection and those with amylin have a reduction in fat mass and virtually no change in their lean mass. So really favorable change. Here's a different animal trial. And in this one, the vehicle results are corrected. So instead of seeing it go up, what the authors have done is to make it 0. So instead of seeing it go up as it was on the last slide, we're seeing that, that's 0. And so you can see that with the infusion of amylin, in both these trials, they were infusing native amylin. This is not a specific compound. This is amylin infusion. You see the reduction in body weight and overall body weight. And then on the right, you see a reduction in fat mass and an increase in lean mass in diet-induced obesity. So this is the best we have for now, are these preclinical models, but we're hopeful that as time goes on, we will see something similar. So in conclusion, I think amylin analogs hold potential as the next generation. It could have been the last generation, but whatever. [ Life ] is what happens. And I think that a non-incretin we need other mechanisms of action besides just GLP-1. We've seen what happens with GIP, even though it's an incretin adding that to GLP-1, greater weight loss. We've known for a long time that monotherapies are great, combinations may be better. Think about adding a compound like [indiscernible] to some of the highly active GLP-1s, wow, I wouldn't want to be a bariatric surgeon right now. I guess that's what I have to say. And then finally, the potential for reducing cardiovascular disease risk. I think that there's absolutely very solid potential for that. Thanks for your attention.

Thank you, Dr. Aronne. And again, I think elegant and comprehensive tour to force through what is not only possible but has been established as proof of principle from the days of pramlintide to onward. And I'm pleased again to announce that the baby has a name that ZP8396 is cagrilintide. And as many of you know, this was developed not only as a stable molecule, which was suitable for formulation at physiologic pH but is a long-acting compound, which we believe carries the potential for best-in-class amylin agonism. The molecule is based on human amylin with specific modifications, including isolation to induce the ability for an extended half-life and this half-life has been estimated at approximately 10 days, making it clearly suitable for once weekly injection. We are not only excited about the construct of this molecule, but also the fact that both as monotherapy, we believe it offers significant potential, as Dr. Aronne alluded to, to serve as a best-in-class non-incretin mechanism for the management of overweight and obesity. But its stability, its formulatability at Neutral-PHs has also been demonstrated that either by co-administration or co-formulation with other assets, this offers a potential as an additive therapy as well. The potent effects on the 2 related receptor families, the amylin receptor and the calcitonin receptors are important, critically important or its physiologic and pharmacologic effects. So again, another rationally designed peptide dialed in with characteristics that make it fully suitable for once weekly injection, and we believe applicable for the management of chronic diseases like overweight and obesity. As Dr. Aronne alluded to, the proof of principle of amylin agonism for weight reduction was established in the early 2000s with the data from pramlintide. But we believe with these newer agents, the long-acting agents, including cagrilintide. And shown here are the data we reported earlier this year from the single ascending dose study with escalating doses, single doses of cagrilintide up to 2.4 milligrams shown here at the 3 highest doses from the single ascending dose study with weight reductions in excess of 4% and after a single dose. And I think just as I highlighted for dapiglutide, when you look at those who received the 0.7, 1.4 and 2.4 milligram dose, not only do you see significant weight production after this single dose, but every individual in each of these categories lost weight. So this is a consistent and, in this case, a dose-dependent effect with the greatest reduction seen at 2.4 milligrams in this single ascending dose study. Beyond that, just several weeks ago at the Obesity Week meetings in Dallas. We reported the first part of the Phase Ib trial. This part 1 is 6 once weekly doses of relatively lower doses of cagrilintide to 0.6 and 1.2 milligrams given sequentially over 6 weeks of exposure. And in this data set, you can see a weight reduction in excess of 5% at the 2 relatively low doses tested. And again, consistent with single ascending dose, this 6 weekly dose regimen resulted in weight reduction in every individual exposed. So a consistent effect, a dose-dependent effect even from the early readout of Part 1 of this Phase Ib study, which is ongoing. And as many of you know, this not only resulted in significant weight loss, but to Dr. Aronne’s comment about tolerability, the tolerability profile of cagrilintide in the Phase Ib data reported to date was quite positive, meaning while adverse events were reported, they were essentially consistent across placebo and cagrilintide doses. And importantly, while GI adverse effects were reported every GI adverse event reported in the first part of this Phase Ib study were reported as mild. In addition, given the neutral formulation and the assets of this molecule, no injection site reactions and again, no antidrug antibodies detected at least over this short-term exposure. So beyond Part 1 of this trial, we are now actively recruiting and completing part 2 of this trial. All 3 cohorts are currently active and exploring not only higher doses, but longer durations of exposure now out to 16 weeks. So significantly higher doses in the subsequent cohorts for significantly longer exposures against -- again, once weekly doses now using a dose escalation scheme to achieve the higher doses in a total of 48 individuals with either overweight or obesity. These data are expected by the end of the first half of 2024 with the full readout from each of the 3 subsequent cohorts. The next step in the development program for cagrilintide is a comprehensive Phase IIb program, which is being developed, and we anticipate first patient initiation in the second half of next year. To return to the comment, Dr. Aronne made about the quality of weight loss and the preservation of lean mass in the setting of significant weight reduction, we do have unpublished but nonclinical data from rodent studies in diet-induced obesity exposed to cagrilintide and compared to doses of liraglutide in this study. You can see a similar pattern to what he described in the previous clinical studies using amylin or rodent amylin where cagrilintide not only achieved significant weight loss, but it was to a greater degree in this diet-induced obese rodent model than that observed with liraglutide. And again, the loss of fat mass, particularly at the highest doses with preservation of lean mass. So in the setting of a unique mechanism of action, leveraging amylin agonism, not only significant weight reduction that we believe can be on par with that achieved with GLP-1 receptor agonists, but a quality of weight loss that by its mechanism preserves lean mass and sacrifices fat mass during weight reduction. Again, unpublished data, but cagrilintide exposure in a rodent model. So we believe that cagrilintide is amongst the most exciting of the 3 very exciting assets we're talking about today, again, a wholly owned asset for Zealand. We believe a potential best-in-class long-acting amylin analog for weight production with a better tolerability profile than that seen for the class of GLP-1 receptor agonist. We believe based on both the nonclinical data and the evidence from the early clinical exposures that weight reduction in the 15% or more range is possible with this as monotherapy, and it could represent a very important monotherapy for the management of overweight and obesity. Mechanism that, as Dr. Aronne alluded to, works uniquely by improving or increasing that sense of fullness or society when the heating in contrast to prospective food intake or appetite that tends to be the predominant mechanism by which GLP-1 receptor agonist work, importantly, through improving leptin sensitivity, something that is lost in the setting of obesity. Finally, that tolerability profile that we believe will be improved upon as compared to GLP-1 receptor agonist and exciting data that suggests that markers of cardiovascular risk, blood pressure, lipid profile maintenance of heart rate and reduction in inflammatory markers can offer the potential to reduce cardiovascular risk, something obviously established for GLP-1 receptor agonist. And we believe, at least based on cardiovascular risk profiles can be achieved with amylin agonism as well. So with that, an exciting tour through the cagrilintide data with more to come in the first half of 2024, and proceeding on to Phase IIb in the latter half of next year. With that, I'll welcome Dr. Aronne back up, Adam Steensberg and Anna to take questions on the cagrilintide program.

Thank you, David. You were standing right next to Thomas. So maybe you can give him the first or anyone.

Thomas Bowers from Danske Bank. So 2 questions. Just on the receptor affinity. I guess this is heavily biased towards amylin. So maybe if you can get some flavor on this? And then maybe how important do you think the calcitonin component are in this product? And then second question, just on the SAD data. Can you maybe explain, we saw a rather dramatic 4% weight loss after 1 week. Do you have any details on whether this is fat mass loss or primarily related to fluids?

Maybe I can start by commenting on the relative balance on Amylin and calcitonin, -- we have not reported on that. We actually believe it's important that you approach both receptors, but the relative balance we will still need to report on. But we think we actually need to activate both in order to achieve the data that we have seen with our molecule.

Yes. And I'll add to that. Again, we haven't reported the actual balance. But if you look at nonclinical data on true DACRAs, [indiscernible] they're called the dual amylin calcitonin -- the important characteristics come with calcitonin activation, which is an extended half-life of the weight reducing effects and the satiety effect, at least in animal models and fairly good nonclinical evidence that activating both appropriately, and I'll just use that word as a general term, Thomas, is what is both necessary and I think allows for significant weight reduction. I'll let Dr. Aronne comment on how people lose 4% of their body weight in 7 days.

Yes, there -- I understand what you're saying, like what are you going to lose, but what to me, it speaks to is a dramatic reduction in appetite. So I'm sure they don't have body composition. Some of that is going to be fluid because you tend to lose fluid first, but it comes from eating a lot less. So I think it's very clear that it's effective.

And I'll add that, I mean, encouraging when we saw the first bit of 6-week data that it's likely not all fluid loss, but yes, with reduction in food intake, water loss -- obligated water loss occurs quickly. It's what gives us hope when we're attempting weight loss. But I think the 6-week data, and obviously, when we get the 16-week data to we hope confirm what we've seen in the [ RODIN ] data that show that that mass is what is ultimately reduced give us great hope that, that's where cagrilintide is headed.

[indiscernible] front.

Laura from Berenberg. So with the Phase II program that you anticipate starting in the second half of next year, over what time period will you conduct this trial for? And how did you select this time frame? And then will you include any of the inflammation biomarkers as endpoints that you touched on earlier with the DAC program?

So I'll begin and welcome Adam to add any additional comments. I think there are 2 components to the exposure. One is obviously the regulatory requirement, generally 36 weeks or beyond. And you've seen with a number of other Phase II programs, including those data that Carel will speak to with semaglutide that the best indicator of informing Phase III likely comes with between 36 and 48 weeks of exposure. We have not yet finalized and won't declare the total exposure, but those both for regulatory requirements. And I think to best inform Phase III are the guidelines that can give you some sense of the duration of exposure. As regards to biomarkers, as I said, the full protocol is not yet finalized and developed, but we're actively in that process. I think it behooves us to at least get a first glimpse of biomarkers without leading these individuals dry, but to give us some evidence of whether these data you've seen in the rodent models and the Cagrilintide program are recapitulated with cagrilintide will certainly be a very important part of our consideration in designing the Phase IIb. Adam, anything else to add?

No, I completely agree with that. And I would also again perhaps go back to what you said before, David, that we actually believe we might have a best-in-class amylin analog here. And we have a very unique opportunity to be one of the first non-incutin weight loss medications on the market if everything goes well as a monotherapy, but also potentially as combination therapies later on. What is incredible important for us, when you have such an opportunity is to do things right. And that means that the Phase II study that you will see will also be the largest study that we have ever conducted. So if you have a diamond like this, I mean, better treated nicely. That's how we think about this. So we will do this the right way and not try to do too many shortcuts. As we are seeing people are doing due to the, I would more or less call Gold Brice right now.

Michael.

Michael from Nordea. A question for Dr. Aronne in terms of how would you position -- how would you position this for patients? Is it a maintenance drug? Is it something that comes prior to GLP-1 or the GLP-1 combos or after GLP-1, GLP-1 combos. Maybe just get some flavor on that. And then just secondly, relating to your pipeline now you're going into a partner program afterwards. But do you have anything going on in the earlier R&D phases regarding longer duration of your molecules or even that you can formulate them on an oral basis?

So I would say that based on what we're seeing here, I could easily see this as a primary therapy. So again, there's a long road to go here. But if the data looks as favorable as it does with GLP-1s, I would see no reason not to use it. Remember that back in the day, like 2005, '06, '07, we use pramlintide more than we used exenatide. So in the first generation, this was more usable, and we found that we could get better weight loss. And we also used it in combination at that point in time. We actually did a trial with either phentermine or sibutramine showing a dramatic increase in weight loss. So circa 2005, that is how we were approaching patients. And then subsequently, we used it with other drugs, and we were able to get a great result, which we did not see, by the way, with exenatide. So I think it could be used in any way.

And maybe to your question about what next longer half-life, I would say, 10 days for this molecule certainly gives consistent exposure. We know that from the PK data. Obviously, the [ PD ] data are encouraging. We have, within our research program, what we designate as obesity plus, some of which will leverage what can be done in addition to leveraging the amylin agonism asset? Can you do other things to further reduce inflammation. These are obviously in the idea phase. Similarly, while approaching the development of oral peptides has not been for the faint of heart. I can name on close to 0 fingers, the number of time this has been done successfully. But that is part of our research planning in its current phases. I can't add more detail at this point. Adam, anything else to add there.

I would... I completely agree, and it is, of course, also something we are looking into. I do, however, believe that a lot of people kind of in my mind, at least overestimate the opportunity to make injectable peptides all. My experience and my understanding is that for most patients, it will actually come rather long down the list for what they would wish for if you had a conversation around how could you improve on the current therapies? There would be other aspects such as perhaps not having the same degree of nausea, vomiting, perhaps not having constipation, maybe having this satiety versus losing your appetite. And then at one point, people would probably say it would be nice with an oral therapy, especially if I don't have to do fasting and so on before. So I think I do, however, also recognize that if you have a small molecule, I mean, that could open up some opportunities, perhaps also for trace, you can say, modalities in the future. But I think we overestimate you can say the need and the desire here. I think there are many other obstacles that are needed to be broken. And I think it's more important to develop new modalities that coming back to what we discussed the hypertension space that can help address this obesity pandemic instead of having such a narrow focus on just trying to go oral. Having said that, we are, of course, working on it on like a small scale, making sure that we could go that way.

One more quick one for [ Jon ], I think, or -- Yes, that's fine.

James Sym, River and Mercantile. So I'll ask them separately because that's only unconnected. So from an R&D perspective, you mentioned the preferential appearance of fat loss over muscle mass loss. Could you just maybe touch on the mechanism by which you think that might be happening?

So I think we obviously don't know completely, but we've seen that leptin sensitization is potentially one of the mechanisms. So in other studies in animals, where leptin sensitizers have been used, we see the exact same thing. It has been sales and we, like I have done that animal experiment, but it has been seen that there's much less lean mass loss and very robust fat loss. So I think it's entirely possible that, that is a mechanism of action.

Maybe I think also from a physiological perspective, you can add as was also shown, amylin actually reduces the insulin secretion, GLP-1 increase essentially secrete in which could actually, you can say, contribute to building up fat, while we know the net effect is reducing fat. So that could, of course, be one. And I think you also demonstrated the ability to actually increase energy expenditure, which could also be a direct effect on activating brown and based in humans and animals. So I think there are multiple opportunities here, which could add to that. But again, as we have shared, there's quite a lot of preclinical data supporting this phenomenon, we still need to establish this human evidence and that is something that, of course, will be hugely important going forward.

And then my second question, and it's been touched on a couple of times, but I don't think we've had a sort of direct answer. What's the competitor -- it's more of a commercial question. What's the competitive landscape look like for this class of drug? And linked to that, I guess, at what point would you benefit from the input of big pharma on the program?

So you can say we are aware of, of course, our own molecule and then [indiscernible], which Novo is pursuing as a fixed-dose combination with semaglutide in you can go to clinical trust at governance that really have 2 programs in Phase I. And [indiscernible] just announced this, I think, summer that they were initiating a Phase I program. We don't know where these -- you can say, the feature of the relative balance between amylin and calcitonin, half-life and other features around these molecules. But -- so there is general interest, but as David also shared, we believe we are among the leaders here, and we are also potentially best-in-class with our amylin. Regarding partnership, I think that's, of course, a question that I get a lot. I would just say that for amylin's non-incisional of action and alternatives to the GLP-1 class, I believe it's much less complicated to develop this molecule as compared to the one we discussed before, where we truly have to differentiate on clinical outcomes. And amylin as a monotherapy, we are the ones who have been pursuing this, we're the one who sets the direction and we are extremely ambitious on the potential as amylin for monotherapy as I sometimes says, if we just walk in the steps of a giant like and their choices, you will never win. So we will not partner before there is a partner who sees the opportunity to win and not just be a follower. We don't want to be a follower in this space. We actually want to win because we think we have something that could be of that caliber.

And I'll add to the development of amylin agonists. This is not for the faint apart. I know my time at Amylin Pharmaceuticals developing the first pramlintide was not without significant challenges for fibrillation stability. There's a reason there aren't a dozen amylin agonists out there. Lilly has had several programs that have failed to progress the clinic and now have 2 more opportunities. But I think based on what I've shown you in the protein peptide design that we have with cagrilintide, this clearly gives us the opportunity, Adam alluded to be not only first with monotherapy, but best-in-class given the stability of formulatability and the neutral-PH formulation for this asset. So not a small challenge, but one I think our peptide chemists and research developers have tackled very successfully.

That brings us to the end of amylin. Okay. That is. So thank you, and we'll now invite [indiscernible].

So thank you for both your patience, and we needed to install and pause while Professor Dr. le Roux made his way from Dublin, but he made it successfully and navigated his way. It's a pleasure to introduce Carel who's been not only instrumental in the semaglutide program. Obviously, co-invented with our partners at Boehringer Ingelheim. They have a representative here who's been part of the that program. Professor le Roux beyond his bio has had a long-standing interest in how they got to the brain and all these tissues speak to one another. He served as a principal investigator for the semaglutide Phase II program and is currently serving as a principal investigator for the Phase III program in obesity. So without further ado, turn it to you, Carel, for discussion of semaglutide.

Thank you so much. That's for kind the introduction. So I start with this famous painting that hangs the London gallery. And I think that sort of represents your own feelings right now to these discoveries that's been made. So let's imagine, right in the middle, you've got the scientist, that's maybe Adam coming up with these fancy drugs now. And you can see yourselves maybe the 2 gentlemen at the front, they're deep thinking about this, how is it going to change the market, how is it going to change the whole space. But you can also recognize what's happening in the rest of society. There are some young people at the front. They're completely frightened about this idea, but can you really medicalize the disease of obesity. And of course, a lot of people on the side that they just don't care either. So that sort of reflects. But what I'm here to do and the little boy there opening up some light just to shine some light on the question, so that we can really understand the science because it's the science that's going to change society in this space. And I think I was part of the first infusion of natural oxyntomodulin. We took the peptide, we infused it in demand for the first time. And it was very interesting because this peptide had no receptors there's no option to module receptor. So oxyntomodulin make it, I make it every day after you've eaten a meal. And this peptide binds both the GLP-1 receptor and the glucagon receptor. And of course, what this drug has done is actually used build on this, albeit that the ratios are a little bit different. So you need to think about these drugs, both you can think of it, if you wish, in a GLP-1 glucagon action, that's perfectly reasonable, and that's the way it is really being put forward and the science is consistent with that, but also know that you make option to modular that naturally binds these receptors every time you've had a meal that drives it. And of course, if you actually look at the glucagon action and the GLP-1 action, you could see how it is synergistic. And it's really the readout that's coming later in the year, and we're going to hear more about that when it comes to the liver that excites us because up to now, we have not really been able to bind the glucagon receptor in the liver. And I think those human studies that's coming out, I haven't seen the data, but I would be very excited to see that based on the animal data that we have. We already now know all the positive things and the negative things about GLP-1. And therefore, we are quite comfortable with dealing with these [indiscernible]. And again, just going back to that point. So I built my whole career as an internal medicine doctor, are trying to understand bariatric surgery. And it turns out bariatric surgery, you had a gastric bypass operation in the 1970s you would have lost exactly the same amount of weight that if you have a gas to bypass operation in 2023. So the efficacy of the treatment has remained the same. Of course, the safety of the operation has dramatically improved. But when we try to understand why does bariatric surgery allow people to lose weight and maintain weight in a long time, it was really understanding how the guy talks to the brain David just alluded to and understanding that what bariatric surgery does, it has this perfect combination of peptides. So it doesn't only make GLP-1. It doesn't only make PYY. It doesn't only make option to modular. It makes these in concert and hence why it's so exciting now that you and myself in clinic can combine this and why these assets that do combine approaches are so exciting. So looking at the -- especially the glucagon action on [indiscernible] in mice and especially in humans as well from the hepatocyte, I think that is going to be some of the differentiating factors. The fact that we could reduce inflammation that we can reduce the fat in the liver and that we can even reverse fibrosis as seen in rodent models is are we going to be able to show that in humans, we'll know very soon. But also this idea is that what we are able to do with these medications is we are able to blunt what we call metabolic adaptation. So if you or your mother or your aunt go on a super duper diet and lose a whole bunch of weight. What happens is they turned down their energy expenditure because that's what you're supposed to do physiologically. However, if you use these treatments and you treat the disease of obesity, that's very different from calorie restrictions. So if you treat the disease of obesity, what happens if you do not have the metabolic adaptation that defends the body fat mass. So these drugs are not weight loss drugs. We call these drugs health game drugs but they really are treating the disease of obesity. And that's why we are seeing the changes in energy expenditure. They don't increase energy expenditure, but what they do is they blunt the metabolic adaptation, and that's what we can measure in human studies as well -- well, we're going to hope to measure it in human studies, but certainly in animal models. So if you look at the effect of these treatments on people with type 2 diabetes and obesity, what you then see is the improvement in weight. But what's very important is that we see this improvement in glycemia because you'll be familiar if I just inject a person with type 2 diabetes with glucagon, I'm not going to reduce the way. Glucagon is supposed to increase glycemia. But if you think about the natural experiment with oxyntomodulin, what you do see is you do see an improvement in glycemia as well. So sometimes people get confused. How can you give glucagon and the glycemia gets better. But again, you need to think of the natural physiology about natural peptide. So if you can see if you bind both the GLP-1 and the glucagon receptor, then you actually -- the changes in glycemia is not that much of a surprise. But of course, that's also very comforting to us because it means the first rule of medicines do no harm. And here what you're doing is you're not increasing glycemia. You're not making people's glycemia worse. In fact, you are improving it dramatically. So what happens if you treat people without type 2 diabetes. So these are people with obesity. And what you can see now is a clear dose response in the Phase II study there. So I'm showing you the protocol data there, so 18.7% of weight loss. And that's again reassuring. And what you also will see on that slide is that because this is a Phase II study, only going to 46 weeks, those curves are just still pending down. We have not yet reached a [ Nadia ]. And we now see with most of the assets that we have, we only reaching [ Nadia ] somewhere between 52 and 68 weeks -- so that's very -- that bodes very well also for the Phase III program. That is just about -- that started, and you know this first into -- the first patient first visit has already happened. I always say this, but my old professor of pharmacology always thought this there's only 2 types of drugs, drugs that don't work and drugs that have side effects, right? And these compounds are no different. But the real benefit is that the side effects unknown. And most of it is mild and moderate. But we need to learn to manage that. And just on the break, Lou and myself are talking about this, these compounds are so amazing, the assets even in the market now that every time I go to clinic, I'm learning something. And I think what we are learning is how to manage these side effects. And one of the things that we are doing already in clinic is that we are just slowing titration schedules down. We are being more flexible when it comes to titration schedule. And I must say now if anybody in my clinic has nausea, I feel personally responsible for that because I don't have to have nausea. The nausea has got nothing to do with weight loss. And I don't have to make people suffer to have these benefits, and we now know how to do this. Of course, the pharmaceutical companies have challenges because you will know very well that to get these drugs through the regulatory process, you must have the drug at top dose for 52 weeks. That is what the regulators require. So of course, you need to ramp it up. You need to get to top dose so that the clock can start ticking, right? About what we're doing in clinical practices, I don't have to do that. I can slow it down. And by slowing it down, we're really able to tolerate the side effects much more. And in the Phase II study, somebody call this the ride of the [indiscernible]. You have to pump people through the system because you have very limited time. And that's why we saw a large number of effects, side effects that happened early on because the titration schedule was very aggressive. And of course, in the Phase III study, that has been adjusted from what we've learned. But it's -- and again, I'm coming back to this point, these are not weight loss drugs, right? These are obesity drugs. And if you treat the disease of obesity, you have health dates. I don't run a slimming club. I don't care what people weigh, but I really care about how -- what health gains we can have. And now what we see the health gains also when it comes to blood pressure is very impressive. And again, that's very helpful to us because we think about a lot of the complications that obesity have is also driven by blood pressure. We also see the synchronized programs now. This is the Phase III study. One is in people without type 2 diabetes, to some people with type 2 diabetes and 3 is the cardiovascular outcome study. So those studies are also built specifically to capture their health gains. And one of the biggest health gains is that patients come when they come and speak to us in clinic. yes, it's wonderful if I don't develop diabetes. It's wonderful if I don't have cardiovascular disease. But the thing that's going to drive stay time of these medications is the functional gains. So you imagine if you live and you cannot tie your shoe laces, you cannot do this. You can't bend over and do this because you're mechanically obstructive. But if I can help you to lose 20%, 25% of your body weight, suddenly now you can play with your kids or your grandkids, you can go out with your friends. You can just do these activities at daily living. And that's the value proposition to patients. And that, I think, is something that we are now capturing and that's something that I think we need to focus on as we move forward. So there's significant overlap between obesity and liver disease. And I think that's going to be another major driver for us -- it's another organ that we can affect. And we're not only talking about taking the fat out of the liver. We're also now seeing that it is possible. It's physiologically possible to reverse fibrosis. And we know that from bariatric surgery. So those trials have been done. Now what we need to see is can we do this without a knife. And I think judging from the animal models, the data is very promising, and that's what we're going to see very soon when the [indiscernible] study report. And I'm really excited to be able to do that. So I'm going to hand over to David at this point and happy to take some questions later.

Thank you, Professor, le Roux. I'm going to backtrack for just a moment and ride on the coattails of Carel's enthusiasm about the potential, not just of semaglutide, but if semaglutide in its mechanisms to address far more than the disease of obesity, but the broader disease of obesity and its complications. I think much of the excitement beyond the GLP-1 receptor agonist to monotherapies in this case, semaglutide as the leading in-class glucagon GLP-1 receptor agonist is to leverage that known oxyntomodulin effect, the effects on free fatty acid metabolism, the effects on blood pressure and cardiovascular risk, but looking at these circles, these are not just circles drawn by those of us in the pharmaceutical industry. We know there is substantial overlap between the disease of obesity and these critical comorbidities. Questions earlier about the impact on chronic kidney disease, but the size of these circles is reflective of the size of the potential health burden, NASH and NAFLD, now so-called [ MASH and NAFLD ] as critical components of the comorbidity risk of the disease of obesity, along with type 2 diabetes and cardiovascular disease. And I don't think we can underestimate the excitement that comes with semaglutide leveraging of the glucagon agonism and the opportunity to affect not just the disease of obesity, cardiovascular risk, but to the potential impact on liver disease in the setting of obesity. And with that in mind, this is an ongoing Phase II study in the setting of liver disease that many of you know about, adult, both males and females with known liver disease, designated by the Class F1 through F3 which is all but the most severe classes of liver disease driven by fat accumulation and fibrosis. Importantly, in this study, these are not all individuals with overt obesity, but individuals with BMIs of 25 and above. And this will have a histologic readout really the [ sinacanona ] of understanding how therapies can affect outcomes in fatty liver disease. I think importantly, the size of the unmet need, the absence of therapies for fatty liver disease and the progression to fibrosis and liver failure cannot be understated and the potential application and the excitement around leveraging both glucagon agonism and GLP-1 receptor agonism for weight reduction and those salutary effects that Professor Lou alluded to. Very important primary and key secondary endpoints in an area with substantial unmet need. So we've talked a great deal about differentiation, particularly of GLP-1-related therapies. The excitement of GLP-1, GLP-2 in inflammation. I think here, when these data read out in the first part of next year, when made public, we'll have a greater understanding of the excitement that surrounds semaglutide as a potential application for liver disease in the setting of overweight and obesity. So in summary, for this part of our 3-part program, semaglutide holds immense potential. Our Boehringer Ingelheim colleagues who are driving the development program for this, see this not solely as a weight loss medication, but driving the management of the disease of obesity and its related comorbidities into 2030 and beyond. Significant weight loss potential is evidenced by the data from the Phase II study with no need in weight reduction and improvements in glycemic control. And again, a very important component of the biased GLP-1 receptor agonism dialed in glucagon receptor agonism that resulted in significant improvements in glycemic control, even over 16-plus weeks of exposure in a type 2 diabetes population. This novel mechanism, the bias towards GLP-1, safety and tolerability, as Professor Lou said, on par with what is known about GLP-1 receptor agonists and how they will be used in the management of the disease of obesity, the potential for cardiovascular protection and the synchronized CVOT study that is already off and running and understanding that cardiovascular risk factors all move in directions that would suggest to the potential benefits of this molecule, like others in the GLP-1 class. And then finally, the excitement around the readouts for liver disease in an area with significant and substantial unmet need. So with that, again, thanks to what is really, I would say, the who's who in the obesity space. Dr. Drucker, Dr. Aronne, Dr. le Roux, and thanks to all of you for your time and attention. We will close right now with questions around the semaglutide program. So I invite Professor le Roux, Adam Steensberg up before we have our program closing. Anna.

In the front here, Adam, hard to see from your angle.

Lucy from Jefferies. Just -- we obviously saw some data last week from a competitor program. Is there any reason to expect your lipid profile with semaglutide to be different to that team with your competitor?

So lipids, typically, when we look at these medications are not the most striking feature. So if I want to reduce somebody's total cholesterol I use a statin. I'm not going to use a weight loss treatment or obesity treatment for that purpose. But I think every time we look at all of these compounds and assets that all go in the right direction. But I think what we have seen, I think, Dr. Drucker's presentation was so interesting about how it's now shifting to inflammation. So I think the inflammation side of the story is very interesting. So I'm reassured from a lipid point of view. I'm not sure that we're going to see -- and certainly from the Phase II study, we didn't see anything that went the wrong way. So I think that's reassuring.

Yes. And I'll add, Lucy, the collective of cardiovascular risk glycemia, blood pressure, inflammatory microenvironments and the -- not just the absolute change in lipid profile, but the characteristic of the atherogenic versus non-atherogenic profile. I think -- and it was alluded to by Dr. le Roux, the critical importance of not moving glycemia in the wrong direction and certainly applying appropriate balance between glucagon and GLP-1 receptor agonism so that you see what I would say is striking improvements in glycemic control with semaglutide, which is an equally important part of that collective mix of cardiovascular risk used to run a lipid clinic or I could spend 20 minutes just thinking about lipids. Unfortunately, the body doesn't care if it actually adds it all up. So I think an important consideration. Thanks for your question.

We will down the road [indiscernible].

Just on the kind of target weight loss that you talked to from the Phase III. Obviously, that's kind of if you get to the upper end of that range, it's kind of significantly higher than the top dose that we saw in the Phase II. So just interested in what gives you confidence of being able to get to that upper level? Is it the fact that you're using the higher dose in the Phase III? Or is it a function of improving tolerability?

So I think it's going to be both. The higher dose because we see a clear dose response effect. But secondly, when you look at the slopes of the curve, even if we just continued with those doses, it would plateau between 52 and that can be modeled. And these guys are pretty good at modeling that now. So I certainly would have thought that we're going to end up certainly in the low mid-20s. That would be my prediction. But what is really interesting is the categorical weight class. So with this amazing drug, we're going to have patients that's not going to lose any weight, right? And we're going to have some patients that lose half of their body weight, right? So we are seeing -- and we're seeing that with all of the medications. So what we are learning about obesity is that it's not one disease. There's going to be semaglutide responders, and it's going to be semaglutide non-responders. And it's not the smart people that respond and the people that don't listen that don't respond. It really is biology. And that's why we need more compounds and we need more combinations because what it will do for Lou and myself is it allows us those non-responders to one drug may respond to another treatment. So we would argue we need more compounds in the space. But certainly, what I'm interested in is -- and I think you started talking about it, targets. And that's the next thing to think about is we talk about obesity as a disease, but it's the only chronic disease that has no targets, right? We've never until now been able to say we need to get people to a BMI of 27 or BMI of 30, whatever that is, we don't even know what that number is. But that's what happened in type 2 diabetes and hypertension. And that's where we can really make a difference. But before we couldn't do that, but now with drugs that you're going to give you 25% weight loss, we will be able to get people to target and also combining those drugs ultimately.

And maybe just one follow-up. I mean it's been a question in each of the sessions, but any sense of what may be driving the weight loss is there kind of lean muscle mass as opposed to fat?

So the current thinking, the best thinking in the space, and we are trying to build the science to support this, but it's almost like the minute it gives this drug to the patient. The patients subcortical areas of the brain because that's where the compound binds and that's where the receptor sit in the hypothalamus and the area postrema the nucleus solitarius. The minute you give the drug the patient's body is under the impression, it's 25% too heavy, right? And what it does is it just naturally goes to where it is supposed to be. And so what you see on that route when patients do lose weight, they feel less hungry, they feel more full, the minute they get to where they're supposed to be, they just feel normal. Hunger returns, fullness goes down, they eat more food, but the weight doesn't change. So what these drugs are doing, it's almost cutting the link between what people eat and how much they weigh, right? And that's, hence, why thinking about -- so what we are really focusing on is this negative energy balance is the weight loss phase. But ultimately, these drugs, as we've seen in select, they work if you give it for 4 years and more. So we need also to understand the weight maintenance phase. And at that point, what we're going to see is everything is going to come back into balance, and that's what we're seeing. So I'm not excited when people talk about increases in energy expenditure in the weight loss space. What I really want to see is what happens in the maintenance phase. But suffice to say, if we continue these treatments, the weight loss or the way just flat lines. And that's what Select showed, just flatline now with semaglutide only at 10%, we hope with this new compound at substantially more.

Michael [indiscernible].

2 questions for Dr. le Roux. One is on the Phase III trials that are to be done in the industry around MASH or method. How do you see those being done? Is it more sort of trying to do a less of progression from obesity into [indiscernible] and then progression into MASH. How do you think the trial should be done? Because I guess it's also there's a plain effect of treating the obesity. And then to the obesity trial in Phase III, is there an exclusion for the use of antiemetics in the trial? Or can they be used.

So the antiemetic people can use them. And I think that's also going to improve tolerability. As to your question about how to approach this, it depends a little bit on which part of the pond you come from. So if you come from a European-centric view, you would say we need to do studies that's going to drive public reimbursements of these drugs, right? And it turns out weight loss on its own doesn't have what's called a utility gain on a health economic model. But what does have utility gain is if you can reverse organ damage. So for example, if you can reduce the risk of people developing type 2 diabetes, that has massive utility game or if you can reduce the time to another cardiovascular event that has massive utility gain. Now what we're going to do. So the studies that I would like to see, and I'm not part of the MASH program, but the studies that I would like to see as a clinician is to show me that fibrosis can be reversed. Because we know the liver is an amazing organ that can really better than any other organ, I think, can heal itself. We just need to buy at time. So I think what these drugs are going to do without having seen the data only from the animal point of view, I think it's going to reduce that in the liver. It's maybe even going to normalize fat and deliver. And with the reduction in inflammation, it's going to create this environment for the liver to reverse fibrosis. And we know it's possible because of the bariatric surgery. So we know it's physiologically possible. And I think these drugs are going to create the microenvironment and the liver to allow that to happen. Now if you can show your reverse fibrosis. Now you have a massive utility gain and your health economic models change and therefore, your ISA your cost per quality drops below 20,000 and these drugs become publicly reimbursable.

[indiscernible] then Laura, then Charlie.

It's not necessarily a direct question on servo, but with so many experts in the room, I thought I'd ask it. And it is to your point that you've just made about the plateauing effect of weight loss. We've heard a lot about the various different mechanisms. What's the sort of best estimate from you guys as to what happens in 5, 10 years' time? Do people come off these drugs and maintain a healthy weight? Or is there something about their physiology, their makeup that makes them put the weight back on and therefore, because that massively informs the overall size of the market for all of these drugs.

So it'd be really interesting to understand from everybody in rooms an expert. What your view is on that? So what I teach my fellows when they come to clinic, I said, if you're ever stuck with obesity, just imagine the patient in front of you had hypertension and what will you do, right? And if you treat somebody with a blood pressure of 180 over 100 and you treat them with 3 effective medications, you make the blood fish 120 over 80. If you stop those drugs within 2, 3 days, the patient's blood pressure will be 180 over 100 again. So the way we are thinking about these drugs is we are thinking about -- and rheumatoid diseases, so rheumatoid arthritis is another classical example. And my son has ankylosing spondylitis. He takes a biologic, and it's amazing how that is controlling its disease. The minute he stops that biologic, the disease will relapse. And it will take a little bit of time before you have pain again, but that's how we are thinking about obesity now. So these drugs don't cure the disease. It doesn't reset the set point, but what it does is it controls it. And hence, the minute you stop the treatment, what will happen is the disease will relapse. And the first sign we hear is that people tell us they're hungry. They are thinking about food, they become driven to food. And the next thing that happens is they eat more food and then they regain the weight. So that is our biggest challenge. It's how do we convince our patients that this is a drug you'll have to take for the rest of your life. And this is how do we get that reimbursed. So that is -- but it also -- so I think if you model on hypertension, you're going to be very close to what is going to happen with this disease going forward?

Yes. I'll add. I mean I'm a metabolism physician as well and there's not, to my knowledge, a metabolic disease where we can start to and stop effectively, lipid disorders, hypertension, viral disease. And I think we're having completely different conversations than 2 years ago where you lose 20%, 25% of your body weight. Now we're asking how you can keep it off. I think the science, the clinical science there is quite young. And the only experience probably comes from bariatric surgery. But these are the conversations many of us in the field have been excited to have. How do we keep 20% or 25% of the body weight off, whether that will be different mechanisms, I think, to lose a presentation to Carel's, it's an unknown, whether satiety plays a more important role than hunger or whether some combination but I'm delighted these are the conversations we're having. I remember sibutramine and the phentermine era where we were excited about 3%, 4%, 5% body weight loss and how we kept that off. So just the conversations we want to have for the next decade or more.

Laura Hindley from Berenberg. I've got a question for Professor le Roux again. Which type of patient would you prescribe this drug to. So earlier we heard that we could see amylin used in first line. If we look down the line, how do you see each of these different therapies being positioned? Is there potential for this to be used in the first line? Or is there a perfect patient that you have in mind? And then more generally on semaglutide, how do you see the competitive landscape evolving and specifically thinking about the threat from triagonist. So can semaglutide differentiate versus molecules that may also include a [indiscernible] component?

So I -- when it comes to weight loss, I've seen thousands of patients. I tell you, I'm about as good as flipping a coin when it comes to choosing one treatment above another. And whether or not I choose or the patients choose, we have the same chance of being right. So what we want is we want more options, nutritional therapies, pharmacotherapies and surgical therapies, and we need to pitch them in equipoise to the patient and help patients make informed decisions. And whatever they decide we can work with. And I imagine now that we're going to have more compounds we are going to have those same discussions. We're going to be able to show all of these compounds in equipoise and some may be further along with cardiovascular outcome data, but less weight loss. Some may have more benefits on the liver, for example. So it's infrequent that I would steer a patient towards it. But for example, if somebody has type 2 diabetes, I would steer them, for example, to a GLP-1 and a lock instead of a small molecule, some of the other treatments that we have currently available because of the additional benefit on glycemia. I don't -- I keep saying it because I genuinely don't know the data from the liver side. But if the liver side holds up as the animals do, then I could imagine a patient, for example, where I do have more concerns about [indiscernible] or MASH, I would steer those patients towards a medication that has glucagon component. So that's how I would think of that.

Charles Mabbutt from Morgan Stanley. So firstly, NASH is obviously where there's been a consistent benefit of adding glucagon, but there any other comorbidities where you believe semaglutide could have particular benefit? And secondly, how do you think about the likelihood of driving a fibrosis benefit in a 48-week study given the time frame needed to create the right environment as you previously discussed for...

So I'll take the second question, and then I'll back the first one to you. But -- so we -- the so-called BRAVE study that was done with bariatric surgery, acid bible gastrectomy showed changes in fibrosis on liver biopsies in 1 year. Okay? So we know that it is possible and the weight loss was certainly in the same area in the ballpark that we are seeing here. So -- and with bariatric surgery, we increased oxyntomodulin. So that may be part of the -- there may be other factors as well, of course. So I would be quietly confident that we will see changes in fiber. And that was a very small number of patients, of course. So with larger numbers, I think we will have more confidence. I think there is also -- if you think about where the glucagon receptor sits, we can also see some additional value in other organs. And somebody just mentioned to me the other day and it's really sometimes with [indiscernible] of course, you always think about the smart stuff. But I didn't think about it. One thing we're talking about now is we talk about muscle mass yes. And that's a real issue, right? But of course, the way we measure muscle mass is not that sophisticated. And of course, most of you over the weekend is going to have some really nice stake and some of you may have a little rib with a bit of fat inside it. But what we will also see is removal of fat in the muscle, right? And that's a really positive thing. But of course, the mass of the muscle is going to change, or when we're going to image it, we're going to see that. So we also are now becoming more sophisticated. If we can start taking fat out of the liver, we can also start taking it out of other organs, and we know that's a driver of disease in multiple spaces. But maybe you can talk about specifically.

I think reflecting on that, I mean, mass in liver disease is a complex multifactorial process. So you talk about fat in the liver, you talked about the inflammatory process that comes from excess or ectopic fat, whether it's in the hepatocytes or elsewhere. And then the fibrotic process, which is the consequence of those first 2. I mean the road is littered with failures in the mass MASH space probably because it targets a single component, even antifibrotics fibrosis in some ways, is good. That's how we repair other tissue damage. But I think referring back to Dr. Drucker's talk where you target inflammation broadly and you extract fat from the liver based on at least the animal models, glucagon agonism which affects free fatty acid trafficking, GLP-1 and glucagon, which may affect the inflammatory environment. I think the more prongs to your work in liver disease, the more likely you are to see a difference. Now that doesn't allow me to predict what the outcome will be. I think, yes, the BRAVE study, as well as other studies that have shown the most effective reduction in progression of liver disease within a year is not unreasonable But obviously, where you are in the course of that disease depends. I think the Phase II study is designed to give that first look. Adam, I don't know if you have other thoughts on that beyond you need multiple prongs to your work in this space.

You have time for a quick one?

A question for Professor Roux. So do you think that it's -- it's a problem with, for example, [indiscernible] molecule that it doesn't work on SBR or does that not affect your treatment decision when deciding between the 2? And if I can take a quick one more, do you think this molecule [indiscernible] biased enough to the glucagon? Or is it just a very effective high-dose GLP-1?

So your second part of the question is I'm going to duck the first one is that the combination at the moment is it is what it is. And I think we are really learning -- and I would find it difficult to imagine you guys designed this thing specifically. So it has this magical combination. I think sometimes we make discoveries, and it turns out you run with it. And so if you -- this combination seems to be working incredibly well. Now whether or not it could be tweaked up or down, that I think there will be evolution, et cetera. But I think for the compound that we have that we're working with now in Phase II and Phase III, it really seems to be doing what it's supposed to say on the 10. And I think that is reassuring. I think there will be evolution. I think that's a good thing that there will be evolution. But at the moment, this is something that works pretty well.

And of course, I will have to step in here as well and I'm sure [indiscernible] colleagues can testify to this as well. It was actually by purpose that we achieved this balance of the molecule. Of course, what we did not know was if that was the right balance got into humans.

And I'll take the glucagon agonism glycemia question without talking about Altimmune specifically. But in the setting of the disease of overweight and obesity, the diseases of dysglycemia is exceedingly common and becomes more common with time. So the absence of a glycemic effect from my clinical perspective is less desirable than a glycemic effect given what we know about controlling glucose as soon as possible or as long as possible, whether you progress to type 2 diabetes or not. And yes, by design, having adequate glucagon agonism to hopefully leverage those beneficial effects on fatty acid metabolism and other markers like energy expenditure, but leveraging what is Dan Drucker talked about 18.5 years of experience using GLP-1 in the setting of glycemic control. And if you like to talk about accidents of nature, John [indiscernible], who ultimately patented discovered extended floor and exenatide, he wasn't looking for a diabetes therapy. He was looking for related peptides and that turns out he injected it into a few mice and lo and behold, here we are. So by design, but not always by perfect design.

Thank you. That's... We'll wrap up the session and then Adam give some final remarks from you before we...

Yes. So first of all, thank you very much for attending today, both online and here in person. I really want to conclude by saying I think it's important that we, as a society, we start to embrace obesity as a disease. We have to start to recognize the importance of treating that disease. Otherwise, we will be, you can say, hit by Tsunami of chronic diseases that we have not seen the start of yet. So -- and that is really important for me to convey that message today that as a society, we need to change the conversation. We also have to embrace that it's actually a problem that has been to elastically established over the last 50 years by how we have changed society. So this is not a personal issue. This is how we have created society. And the reason I say this is because I think a lot of the conversations we hear today are around people's personal choices. And I just want to remind us all that for 300,000 years. It has been a survival instinct. The survivors are the ones who energy, excessive energy been available and store it and had a tendency to preserve energy meaning being not active. And now we have create society where that doesn't work for you anymore. So this is not an individual problem. This is a society problem. We need to address that. And that, I think, is a conversation that needs to change now in order to address this problem. The good thing and the reason that it's important to have that conversation now is that we have the first tools, as we have heard today that can address this problem. 20 years ago, people were using very exploratory means to try and achieve these goals. Today, we have the first approved therapies that can provide weight losses, but we need many more tools. And at least from our perspective, the importance now is not to just be following in the footsteps as well as we're already out there, but try to develop truly differentiated molecules that can address the comorbidities of obesity that can provide different choices to people who cannot stay on a current treatment, but would like to try something else. And we believe that Zealand, we have at least 3 of those potential very differentiated molecules that are being progressed through clinical development. And I will start with the lower one semaglutide, which our partner Boehringer is progressing. We are extremely happy, of course, with that collaboration and the efforts that Boehringer putting into this program and truly believe semaglutide has the potential as a leading GLP-1 in the future, in particular, if we see strong data in NASH as we have discussed. For cagrilintide I think it's no secret to those of you who are closest to us that we are extremely excited about this, and we probably see it as the crown jewel in our pipeline because it has the potential to define a completely new category of waters medications. We look very, very much forward to the next set of clinical data that are going to be reported. And then with dapiglutide, as we highlighted in the start, there are actually very -- there's a large group of GLP-1 consenting molecules right now in development, of course, fueled by the huge success that people have seen with the first molecules, the mono acting and the GLP-1 IPs. But that's very few differentiated GLP-1 containing molecules. And with dapiglutide we have one which has the potential to also address inflammation, which we believe is actually one of the major drivers of organ damage associated with obesity. So it gives us, I mean, a lot of hope, but also a lot of pride that we actually sit with these molecules with the potential now to address one of what we see the biggest health care channels that we are facing of modern times. So of course, it's also relevant then to consider what's next and David review the different developments of the programs. And I would say for all of these 3 programs to [indiscernible] equity story, we have very important data readouts in the first half of next year. But dapiglutide see the dream data from the Phase IIa exploratory study, which can help enlighten us more on the potential for controlling inflammation and that will be followed up by higher doses in a Phase Ib study later in the year. Dapiglutide will get the 16-week data, which, again, if those confirm what we already saw in the 6-week datas and then also follows the same trends that have been seen with other amylin agonist, you can say, of course, our excitement will only be confirmed and even enhanced. And then as David also shared and we discussed it a little bit during the question and answers. We are in full planning now and making the commitment to start this Phase IIb study to truly try and build a best-in-class next-generation [indiscernible] novel treatment for obesity. And then with semaglutide, as we discussed, extremely thrilled to see that Boehringer have this program in Phase III. And I think a lot of people fail to recognize that Boehringer is actually the third company now that are in Phase III with a program for development within the obesity. So I think that's something to be proud of. And of course, then we have these very important NASH data that will read out next year. So all in all, we look very much forward to keep engaging with all of you and look forward to the progress that we will make in these programs over the coming period. And again, thank you for attending. Thank you for the faculty and to support here and the discussions and David as well. So thank you guys.