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's also joining us online. I'm 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.
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 three presentations that cover the scientific mechanisms and the clinical potential of the candidates in our pipeline. First, we'll start with our two 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 petrelintide, as an alternative to GLP-1-based therapies. And then finally, the glucagon/GLP-1 receptor dual agonist, survodutide, 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 P.M. local time here in London.
Our speakers for today from Zealand Management will be Adam Steensberg, our Chief Executive Officer, and David Kendall, our Chief Medical Officer. I am delighted to introduce our three external experts today. Dr. Daniel Drucker is an endocrinologist and professor of medicine in the Division of Endocrinology at 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. Louis 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 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 Weill Cornell Medicine. Dr. Aronne is a past president of the Obesity Society and a founder of the American Board of Obesity Medicine.
Dr. Carel le Roux is a professor in experimental pathology at 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 Wellcome Trust Clinical Research Fellowship for his work on how the gut talks to the brain. With that, I would like to turn the day over to Adam Steensberg, our CEO.
Thank you, Anna, 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 three numbers after my speech. 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 on 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. Yet, for 300,000 years, the proportion of individuals with obesity and overweight have remained low and relatively stable, from the first humans evolved until recent modern times.
Then something happens, and that brings me to the next number, which is 50. Fifty 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 risen to 40%, and it's still accelerating. Fifty years ago, we saw a dramatic change in how we lived 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's cars and screens that cause us to live very sedentary lifestyles. And it's not just about obesity, it's about this number, 3 million. 3 million excessive deaths every year can be ascribed to the obesity pandemic that we see today.
And 3 million deaths, 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 that will cause the comorbidities that can be ascribed to obesity, or 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 we are looking into, fueled by the global obesity pandemic, is, in my mind, the biggest healthcare crisis that we have faced in modern times. The good news is that we have now seen the launch of the first keys of 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 50 years from now, the obesity pandemic will just have been a small blip in the history of humans. So our call really is that if we as a society now embrace this historic moment, if we rise to the challenge together, then we can address the biggest healthcare challenge 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 of 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, 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, or 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, it's always targeting the prescriber and the payer segments.
I will, however, address a little bit how we see also the future obesity market on a more patient pool or, or consumer-driven market, because there is this very large desire among many obese individuals to lose weight. We already see this today with people paying out of their pocket 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, for many prescribers and for payers to, 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-paid segment, where we also see a great opportunity to help improve health outcomes, then we do believe that people are really looking for alternative, 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 what some people would describe as a very crowded space now, in my book, it's 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 sema, then you have the first dual-acting peptides like tirzepatide with GLP-1/GIP. 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 loss. Probably, these next-generation medicines will provide 20+% weight loss, 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's, kidney disease. That's gonna 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 the weight. But you cannot underestimate that for a large proportion of patient, it is an issue to have these side effects, and some will even drop off therapy because of side effects.
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. We do expect several new modalities that are based on non-incretin approaches to also reach the market in the coming period. 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 does. We observe 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. 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 the incretin space with our amylin analog. So with that, I will just also highlight to everyone today that today's event is about our Zealand'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 insight 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. A pleasure to join you on behalf of many of my Zealand colleagues and the work that not only Zealand, but Zealand with our Boehringer Ingelheim partners will put forth today. It is my pleasure to introduce the first of our three faculty. 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 Exendin-4 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 co-agonism. So with that, I welcome Dan Drucker to discuss the science of GLP-1, GLP-2. Dan?
Thanks, David, and hi, everyone. Nice to be here. Just as a reminder for the young people in the audience, this has been 35-40 years of science with a lot of excitement starting with GLP-1 in the mid-1980s, and 10 years later, GLP-2. We often hear people say, "Oh, these GLP-1 obesity things, they're new drugs. We're 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-1 works.
We started off with the beta cell and the pancreas and glucagon inhibition, and ten years later, we moved to, to the brain, and we have the control of gut motility and gastric emptying. So I think, you know, 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, I think well studied is the GLP-2 story. You know, this started out as a gut growth factor and ultimately led to the approval of teduglutide 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, you know, are we seeing these amazing effects of GLP-1 in the reduction of kidney disease in people with type two diabetes? We saw the FLOW study, and we see the SELECT trial seemingly with reduction of cardiovascular events well before profound weight loss.
You know, 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, you know, 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?
That's the hypothesis that we'll be looking at, I think, very carefully, both in preclinical studies as well as in the clinic. 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, a reduction in circulating biomarkers of inflammation in this mouse 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 GLP-1 have the demonstrated activity to reduce MACE and heart attack, strokes, and 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 of 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. There are GLP-2 receptors in the liver. They are most prominent in stellate cells. If one takes away the GLP-2 receptor in knockout mice, 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 mice, 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 an 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 for 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, you know, the next frontier, which is the brain and neurodegenerative disorders, and we have some very interesting data going on with GLP-1 and Parkinson's, and obviously the EVOKE 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, you know, 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 co-agonist versus tirzepatide. Very profound weight loss, which matches that achieved with the 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.
I think the potential for combining GLP-1 and GLP-2 to 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. I'm gonna turn it back over to Dr. Kendall.
I hope you'll agree, Dr. Drucker'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. 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, but 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 frequent 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 two unique receptors, to not only leverage GLP-1 effects on the pancreas and pancreatic function, in the setting of dysglycemia and type 2 diabetes, but to improve body weight, through central and peripheral mechanisms.
GLP-2's 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 four 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 mg over only four weekly doses had 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 anti-drug 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 of gut integrity and gut 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 mg, 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 of gut health, and these systemic markers of inflammation. So for us, the first proof of principle, if you will, that leveraged the very characteristics that Dan so elegantly described in the non-clinical 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 four-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 a 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 three 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 survodutide later in this program. I think importantly, it is not... it is no longer, for Zealand and others, simply a targeting of weight loss as a numeric reduction, but targeting, in particular, the risks associated with cardiovascular disease and the potential cardioprotective benefits of 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.
Michael, you are first. There's a microphone that's coming around to people, so wait for either Adam or Evan to-
pull you up to the bar.
Thank you very much. Michael Novod from Nordea. A question for, Dr. Drucker, in terms of, GLP-2 safety, because I guess that's on, 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 the intestine, et cetera. So maybe your comments to, to that. We also start to have these dual-acting molecules.
Sure. So I think we have two sort of insights from clinical medicine. One is, as you know, teduglutide has been marketed since, I want to 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 polyps and some gastric polyps. Probably the more interesting experience, clinically relevant to dual GLP-1 and GLP-2 receptor agonism, comes from the bariatric surgery experience. So as you know, RYGB people have very high levels of all the L-cell 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.
Yeah, 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, the experiment of nature, if you will, from gastric bypass, particularly Roux-en-Y, where these exceedingly high levels, not only are not associated with the significant increase in cancer risk, the long-term studies showing a reduction in cancer mortality. So I think, that, combined with what, Dr. Drucker referred to, which is the, this molecule in particular, has dialed in, you know, significant potency around the GLP-1 component, not unlike survodutide, which has, a much stronger preference for GLP-1 receptor activation than glucagon. Here, dialed back, but not, dialed away the GLP-2 receptor activity.
So I think all three 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 the 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.
Rajan, I think you were asking? Go on.
Thanks. 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?
Yeah, I'll begin. First of all, thanks for hosting. And secondly, I'll start and maybe ask Dan and Adam to comment. You know, 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 non-clinical 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 m echanistic 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, in cardiovascular outcome study. But I would say the study is reasonably powered, but because it's the first look, doing, you know, 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 with what you said there. It's, of course, an exploratory study. I think what is interesting to note is also some of the remarks by Dr. Drucker around how rapidly GLP-2 can actually exert anti-inflammatory effects. So of course, we have hopes that we will start to see some of these effects already even in a short-term study like this. So, but it is, of course, exploratory in nature. Mm-hmm.
Dan, any other comments on what might be expected with-
No, I think we really haven't looked at GLP-2 in a, you know, actually in a population like this, or certainly not GLP-1, GLP-2 combined activation. So in mice, we see very rapid anti-inflammatory effects, 30 minutes to an hour, we're suppressing peripheral inflammation. But these are not mice, these are humans, and they're getting dapiglutide. So it'll be exciting to look at the data.
Thank you.
Over here. Oh, hello. Thank you.
Charlie Mabbutt from Morgan Stanley. Thanks for taking my questions. Firstly, does the separation in the early separation of the curves in the 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 you go into a bit more detail on why impacts on lean body mass could be different with the GLP-2 combination? I think I saw that on the slide. Thank you.
Yeah, it's really apples and oranges, right? With the SELECT trial, looking at the endpoints, which is, you know, heart attack, strokes, cardiovascular death, whereas that's not, those are not the endpoints in the 13-week study. But I do think it highlights the fact that changes occur rapidly, and they're 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, clinically relevant changes in ultimately risk factors that translate into cardiovascular risk. So it's fascinating to see.
We just don't know what we're gonna see in those trials, but I'm not worried about the duration of the study, given what we've seen in SELECT.
Yeah, and I'll, I'll add, I mean, certainly, both in the diabetes 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, you know, 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. You know, 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, you know, 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 co-agonists, and dapiglutide in particular, I think, all of the data to date, you know, 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.
Okay. Adam, yeah.
Hi, it's Ben Yeoh from RBC Asset Management. Just to follow up, I guess, on the anti-inflammatory and neuroprotective effects, and maybe some of this is at 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%-50%, or what sort of-- 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 seem 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 a strategy in developing, it seems a bit tricky.
Are you gonna look at anything in neuroprotective early or go, you know, obesity, diabetes, down the metabolic pathway first, 'cause it's easier, and the trials and neuroprotective is just gonna be more speculative? Thanks.
So when you say what proportion of the benefit is from inflammation, you're talking about effects on neurodegeneration? Is that what you're-
You can take it. Well, I guess all of the outcomes that we're currently seeing or all of the kind of clinical and the things that we're seeing, whether you're gonna talk about it in terms of biomarkers that we see or seeing it 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-
Yeah.
is important, and so I'm interested in your view as to-
Yeah, so-
how important that is, as across that, both maybe classes and whether there'll be molecule effects.
So with apologies to the non-sports fans here. So GLP-1, I always say, has three 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 two weeks in Cell 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.
In people with type 2 diabetes, we saw a 22% reduction with albiglutide Harmony Outcomes, no weight loss whatsoever, like an 800-gram weight loss or after two 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 outcome 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 EVOKE 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 weight loss. 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, too, at 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, even to a higher degree than other GLP-1s based therapies and treatment. So it is something where you should expect us to actually pursue, you can say, comorbidities surrounding obesity within the phase II 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.
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 poorer cardiovascular outcomes and a risk for neurodegenerative diseases. So ultimately, the mechanisms by which you flip that the other way may be 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, you know, 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.
Hi, Lucy Codrington, from Jefferies. Forgive me if I'm mistaken, but the API 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 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?
Yeah, so 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 suggest that a 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 approached the clinical development of this molecule, we did see an opportunity within short bowel syndrome as well.
People who have followed us for a long time know that also is very close to us, that disease area, and, You, probably around 2015 or 2016, there were some compelling data coming out from clinical studies showing that the combination of a 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, when also when we look into receptor activity in humans.
Yeah. I'll say, I mean, we have some remarkable peptide chemists who come up with these, but getting that balance, you know, exactly right, to Adam's point, you know, understanding the historical data where the combination... And there are data that suggest if you co-infuse GLP-1 and GLP-2, there's better tolerability, but what exact ratios are required for each of these effects? I think, to your last question around what, you know, what's the future of this molecule? Are there, opportunities for backup? Given where we are with tox exposure, given where we are now with clinical exposure, DREAM is well underway. We have initiated the phase Ib. We have a great early confidence in this molecule.
And I think all 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 survodutide molecule, where, you know, intentionally getting potent GLP-1 agonism with adequate, but not excessive glucagon receptor agonism was equally important. And Carel 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, Rajan. Another one up here in the front.
Thank you. Yeah, just on Dapi, what do you think, if any, potential there could be on renal outcomes? Just because kinda thinking about where competitive landscape is right now, that seems like a 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?
Yeah, I'll start and then maybe ask Dr. Drucker to comment. It wasn't a main focus. I think the understanding we have now around Sema and FLOW, and the outcomes there, no question that this population, whether dysglycemic or not, overweight and obesity, contribute to a significantly higher risk of adverse renal outcomes. GLP-1 receptor agonism, I think, now has established itself, along with SGLT2 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, portends potential for favorable outcomes on renal disease. I'll defer to Dr. Drucker to talk about any potential effects of GLP-2 on renal health.
Yeah. So I don't think we've ever looked, actually, to see... 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-2 do anything. So it's a good future experiment.
If Dr. Drucker hasn't looked, I'm pretty sure no one has.
Charlie? Oh, yeah.
Sorry, can I just follow up on the lean mass question?
Mm-hmm.
I think I saw it on your slide. Yeah, could you go into a bit more detail on why, on why GLP-2 may have a promising impact on GLP-2 relative to GLP-1?
Yeah, there's not a lot of data. 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 dapiglutide 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.
Well, I think this will be possibly the last question.
Perfect. Thank you. It's Ben Jackson from Jefferies. Just two short questions, if I may. One around the confidence around the over 20% weight loss and where that's 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 completely discrete to action at the receptor, or is there any overlap with the agonism there between the two molecules and the receptors? Thank you.
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, you know, 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 four-week study, to us, is on par with what is seen with short exposure with other potent, long-acting GLP-1 receptor agonists. So that 20%+ weight reduction over extended exposure, which is usually now, you know, more than 52 weeks of exposure.
At least early indications suggest, not just from non-clinical data, but from the early clinical data, that that is likely with potent, long-acting GLP-1 receptor agonism. You know, whether there is added benefit from the GLP-2 receptor on true body weight loss alone. I'll defer to Dr. Drucker to discuss the receptor activation crosstalk between GLP-1, GLP-2.
Yeah, so, so those are experiments that we're discussing actually right now with, with Zealand to basically say, if we take dapiglutide and we administer it to GLP-1 receptor knockout mice or GLP-2 receptor knockout mice, and 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 Cell Metabolism, December 18th, you'll see we've done that with tirzepatide. And surprisingly, tirzepatide still reduces inflammation in the GLP-1 receptor knockout, implying that GIP also has anti-inflammatory effects. So these are experiments we can do in mice and really get a lot of insights.
And I would also follow up. I mean, what David shared here was our target product profile, and I think the data, as you discussed, David, support this potential. But I, 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, the newer long-acting GLP-1, dual and triple-acting molecules will be. So that is our benchmark, and then we would, 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 GLP-1 as their backbone. There, you could have lower expectations and still have very interesting molecules.
Great.
Very good.
Well, 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. Stretch your legs, breathe, and we'll be back in 20 minutes. So is that about 10 to, I think?
Beautiful.
I made it. Train plane from Baltimore.
Exactly.
Nice to meet you.
Welcome. Thanks for coming.
Presentation. Thank you. Everybody is still there.
Not that I just make my way to-- I'm gonna take the tube.
Follow up. So I completely get the sense of one, three channels, three mechanisms. Okay.
Okay, so I think we're ready to start the next session, and I will hand it over to you, David.
Thank you. Welcome back. It's now my pleasure to kick off part two of this program and our discussions around two other very exciting novel assets in the Zealand portfolio. As Anna introduced the faculty earlier, it's my pleasure to introduce Dr. Louis Aronne. Louis, as was said, has been in this space since I can't even say when. I've known Louis 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. 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 ZP-8396, but petrelintide, the INN name has been granted. So petrelintide will have to go into your nomenclature going forward. So with that, welcome, Dr. Louis Aronne. Thanks, Louis.
Thank you very much, David. Really appreciate the opportunity to talk to you and, the opportunity to be here today. You know, 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, you know, 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 leptin at Rockefeller University. I knew it was gonna be discovered about seven 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 like to point out that of the 65+ trials I've done in my career, like, the first 60 didn't go that well. It's just in the last five or so that have really hit paydirt. So I don't know what made me persist for so long, but I'm very happy, very happy that I did. And when you look at the mechanisms, what we're gonna 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.
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 was 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 guanethidine and reserpine that lowered blood pressure, that 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 two or three.... 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, you know, 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 gonna be hearing a lot about. If 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-enteral. It doesn't come from the gut, and it increases satiety or the sense of fullness, in contrast to GLP-1s, which primarily reduce appetite. They also do give a satiety effect, but they primarily reduce appetite. Amylin's a 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 fat 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 two, that amylin is a leptin sensitizer. It's the best leptin sensitizer that we found. But if we can sensitize to 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 1990s and early 2000s of what being able to give more leptin efficacy-- you know, 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 two diabetes.
Pramlintide was the first synthetic, a short-acting amylin analog, which was used in the treatment of patients who were taking insulin because it was a very good insulin sensitizer. And the dose at 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 him. That's what happened. But again, this is in 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, 10.8% at 26 weeks. Very robust weight loss and greater than, in this trial, liraglutide 3 mg. So this is comparable to what's been seen with semaglutide in the phase III trials. But here's 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 Nordisk's 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 could argue 60% more weight loss at 32 weeks than a 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 petrelintide and with cagrilintide as the research goes on. Actually, we may not see more with cagrilintide since it's all gonna be CagriSema. But I believe that we will see a better tolerability profile over the coming trials that are going to come on.
Specifically, while we've seen nausea, we saw much less vomiting when we were using the shorter acting version, pramlintide. Nausea, but no vomiting. Again, it's gonna take time to build the database to see what happens. Another important point, this is a phase II trial of cagrilintide in 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 liraglutide. We see diastolic blood pressure greater than liraglutide. 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, 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 cardiologist really would want this more than they would want a GLP-1? I, I can't tell you, but to me, this looks like it's something favorable to the cardiologist. They, 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, in, CRP, high sensitivity CRP with cagrilintide compared to liraglutide. And here in patients with type two diabetes, we look at, the effect of cagrilintide versus semaglutide, and once again, 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 and say, "Oh, what do you 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 two is now that we have the SELECT trial, no matter what anybody says, we see that there is benefit. We see improved outcomes. So that's an important point number two. 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, you know, 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 gray got the vehicle, those in purple, you see, 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 zero. So instead of seeing it go up as it was on the last slide, we're seeing that that's zero.
And so you can see that with the infusion of amylin, and 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, in 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, 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. They could have been the last generation, but whatever, you know, 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. You know, we've known for a long time that monotherapies are great, combinations may be better. You know, think about adding a compound like petrelintide to some of the highly active GLP-1s. Wow! You know, I wouldn't wanna be a bariatric surgeon right now. I guess that's what I'd 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 de force through what is not only possible but has been established as proof of principle from the days of pramlintide onward. And I'm pleased to again announce that the baby has a name, that ZP-8396 is petrelintide. 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, but with specific modifications, including acylation, to induce the ability for an extended half-life.
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. 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 two related receptor families, the amylin receptor and the calcitonin receptors, are important, critically important for 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. That 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 petrelintide, and shown here are the data we reported earlier this year from the single-ascending dose study with escalating doses, single doses of petrelintide up to 2.4 mg, shown here at the three highest doses from the single-ascending dose study, with weight reductions in excess of 4% 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 mg dose, not only do you see significant weight reduction 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 mg 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 One is six once-weekly doses of relatively lower doses of petrelintide, at 0.6 and 1.2 mg, given sequentially over six weeks of exposure.
And in this dataset, you can see a weight reduction in excess of 5% at the two relatively low doses tested. And again, consistent with single ascending dose, this six-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 petrelintide in the phase Ib data reported to date was quite positive, meaning while adverse events were reported, they were essentially consistent across placebo and petrelintide 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 anti-drug antibodies detected, at least over this short-term exposure. So beyond part one of this trial, we are now actively recruiting and completing part two of this trial. All three 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 or significantly longer exposures. Against once 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 three subsequent cohorts. The next step in the development program for petrelintide 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 non-clinical data from rodent studies in diet-induced obesity exposed to petrelintide 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 petrelintide 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 petrelintide exposure in a rodent model. So we believe that petrelintide is among the most exciting of the three 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 reduction, with a better, tolerability profile than that seen for the class of GLP-1 receptor agonists. We believe, based on both the non-clinical data and the evidence from the early clinical exposures, that a 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. A mechanism that, as Dr. Aronne alluded to, works uniquely by improving or increasing that sense of fullness or satiety when eating, in contrast to prospective food intake or appetite, that tends to be the predominant mechanism by which GLP-1 receptor agonists 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 agonists, 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 agonists, 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 petrelintide 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 petrelintide program.
Thank you, David. You were standing right next to Thomas, so maybe you can give him the first or anyone. Lost control.
Thank you. Thomas Bowers from Danske Bank. So two 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 one week. Do you have any details on whether this is fat mass loss or primarily related to fluids? Thank you.
Yeah, 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. So-
Yeah, and I'll add to that. Again, we haven't reported the actual balance, but if you look at non-clinical data on true DACRAs, as 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 a fairly good non-clinical 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 seven days.
Yeah, I understand what you're saying, like, what are you gonna 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 gonna 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.
Yeah. And I'll add that, I mean, encouraging when we saw the first bit of six-week data that it's likely not all fluid loss. But yeah, with reduction in food intake, water loss, obligate water loss occurs quickly. It's what gives us hope when we're attempting weight loss. But I think the six-week data, and obviously when we get the 16-week data to we hope confirm what we've seen in the rodent data that show that fat mass is what is ultimately reduced, give us great hope that that's where petrelintide is headed.
Adam, here in the front.
Hi, Laura from Berenberg. Thanks for taking my question. So with the phase II program that you anticipate starting in second half of next year, over what time period will you conduct this trial for, and how did you select this timeframe? And then will you include any of the inflammation biomarkers as endpoints that you touched on earlier with the dapiglutide program? Thanks.
So I'll begin and welcome Adam to add any additional comments. I think there are two 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 survodutide, that the best indicator of, you know, 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 biomarkers, as I said, the full protocol is not yet finalized and developed, but we're actively in that process.
You know, I think it behooves us to at least get a first glimpse of biomarkers, without bleeding 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 petrelintide 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-incretin weight loss medications on the market, if everything goes well, as a monotherapy, but also potentially as combination therapies later on. What is important for us when we 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 treat it nicely. That's how we think about this.
So we'll 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 rush right now.
Michael.
Evan in the back.
Thank you. Michael from Nordea. A question for Dr. Aronne, in terms of how would you position this, sorry, 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, some flavor on, on, on that. And then just secondly, relating to your, 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, 2006, 2007, we used 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, you know, 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.
Maybe to your question about, you know, what next, longer half-life, I would say in 10 days, for this molecule, certainly gives consistent exposure. We know that from the PK data. Obviously, the PD data, PK 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. You know, can you do other things to further reduce inflammation? These are obviously in the idea phase. Similarly, you know, while approaching, the development of oral peptides has not been for the faint of heart, I can name on close to zero fingers the number of times this has been done successfully.
But, that is, you know, part of our research planning, at its current phases. I can't add more detail, at this point. Adam, anything else to add there?
No, 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 oral. My experience and my understanding is that for most patients, it would actually come rather long time 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.
Mm.
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 cheaper, 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 and making sure that we could go that way.
One more quick one for John, I think. Or, yeah, that's fine.
Okay, well, I had two. Am I allowed two?
Yeah, of course.
Thanks. James Sym, River and Mercantile. So I'll ask them separately 'cause they're totally 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 seen, I was saying "we," like I've 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. The GLP-1 increases insulin secretion, 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-
Yep,
... which could also be a direct effect on activating brown and beige fat in humans and animals. So I think there are multiple opportunities here-
Mm.
... which, 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 the human evidence, and that is something that, of course, will be hugely important going forward.
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 competitive... 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, on the program?
So you can say we are aware of, of course, our own molecule and then cagrilintide, which Novo is pursuing as a fixed-dose combination with semaglutide. Then you can go to clinicaltrials.gov and see that Lilly have two programs in phase I, and AstraZeneca 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, since it's a non-incretin, novel mode of action and alternative 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 a 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 which could be of that caliber.
Yeah, and I'll add to the development of amylin agonists. This is not for the faint of heart. 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 to clinic, and now have two more opportunities. But I think, you know, based on what I've shown you, and the protein peptide design that we have with petrelintide, this clearly gives us the opportunity Adam alluded to, to be not only first with monotherapy, but best in class, given the stability, the 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-
Thank you.
Today, that is. So thank you, and we'll now invite-
I'll give a quick-
You too.
So thank you for both your patience and we needed to stall and pause while Professor 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 survodutide program, obviously co-invented with our partners at Boehringer Ingelheim. They have a representative here who's been part of that program. Professor Le Roux, beyond his bio, has had a long-standing interest in how the gut, the brain, and all these tissues speak to one another. He served as a principal investigator for the survodutide phase II program and is currently serving as a principal investigator for the phase III program in obesity.
Without further ado, turn it to you, Carel, for discussion of survodutide.
Well, thank you so much. That's very kind, you know, the introduction and... You know, so I start with this famous painting that hangs in the London Gallery, and I think that sort of represents your own feelings right now, you know, to these discoveries that's been made. So, you know, let's imagine right in the middle, you've got the scientist, that's maybe Adam, you know, coming up with these, you know, fancy, you know, drugs now. And you can see yourselves, you know, maybe the two gentlemen at the front, they're deep thinking about this, how's it gonna change the market? How's it going to change the whole space? But you can also recognize what's happening in the rest of society. You know, there's some young people at the front, they're completely frightened about this idea, about can you really medicalize the disease of obesity?
Of course, a lot of people on the side that just don't care either. That sort of reflects. But what I'm here to do, I'm the little boy there, you know, opening up some light, you know, 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, you know, in this space. And I think, you know, I was part of the first infusion of natural oxyntomodulin. You know, we took the peptide, we infused it into man for the first time, and it was very interesting because this peptide had no receptors. There's no oxyntomodulin receptors. So oxyntomodulin, you 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 use 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, you know, in a GLP-1 glucagon action, that's perfectly reasonable, and that's the way it, it is really being put forward, and the science is consistent with that. But also know that you make oxyntomodulin that naturally binds these receptors every time you've had a meal, that drives that. 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 readouts 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, you know, we have not really been able to bind the glucagon receptor in the liver, and I think, you know, 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, you know, with dealing with these gut hormones. And again, just going back to that point, so I built my whole career, as an internal medicine doctor, by trying to understand bariatric surgery. It turns out bariatric surgery, if you had a gastric bypass operation in the 1970s, you would have lost exactly the same amount of weight that if you have a gastric 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 the long time, it was really understanding how the gut talks to the brain, you know, 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 oxyntomodulin, it makes these in concert, and hence why it's so exciting now that Lou and myself, you know, in clinic can combine, you know, this and why these assets that do combine approaches are so exciting.
So, you know, looking at the, you know, especially the glucagon, you know, action on survodutide, you know, in mice and especially in humans as well from the hepatocyte, you know, I think that is going to be some of the differentiating factors. You know, 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 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, you know, and lose a whole bunch of weight, what happens is they turn 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 restriction. So if you treat the disease of obesity, what happens is 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 gain 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 gonna reduce the weight. Glucagon is supposed to increase glycemia, but if you think about, you know, the natural experiment with oxyntomodulin, what you do see is you do see an improvement in glycemia as well. So sometimes people get confused, you know, how can you give glucagon and the glycemia gets better? But again, you need to think of the natural physiology about natural peptides.
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 in medicine is do no harm, and, you know, 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 per 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 tending down. We have not yet reached a nadir. We now see with most of the assets that we have, we only reach a nadir somewhere between 52 and 68 weeks. So that bodes very well also for the phase III program that is just about, you know, 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 taught us there's only two 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 are known, and most of it is mild and moderate, but we need to learn to manage that, you know. And just in the break, Lou and myself were talking about this, you know, you know, these compounds are so amazing, you know, 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, you know, 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, you know, 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? But what we're doing in clinical practice is I don't have to do that. I can slow it down, and by slowing it down, we're really able to tolerate, you know, the side effects much more. And in the phase III study, somebody called this the Ride of the Valkyries.
You know, you have to pump people, you know, through the system because you have very limited time, and that's why we saw a large number of 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, you know, from what we've learned. But it's and again, I'm coming back to this point, you know, these are not weight loss drugs, right? These are obesity drugs, and if you treat the disease of obesity, you have health gains. I don't run a slimming club, you know. I don't care what people weigh, but I really care about, you know, how, what health gains we can have. And now what we see, the health gains also when it comes to blood pressure, you know, is very impressive.
Again, that's very helpful to us, you know, because we think about a lot of the complications that obesity have is also driven by blood pressure. We also see that the synchronized programs now, this is the phase III study. One is in people without type two diabetes, two is in people with type two diabetes, and three is the cardiovascular outcome study. So those studies are also built specifically to capture the health gains. And one of the biggest health gains that patients come when they come and speak to us in clinic, you know, yes, you know, 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 shoelaces, you cannot do this. You can't bend over and do this because you're mechanically obstructed. 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 of 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, you know, there's significant overlap between obesity and liver disease, and I think that's going to be another major driver for us.
That'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, you know, judging from the animal models, you know, the data is very promising, and that's what we're going to see very soon, when the liver study reports, and I'm really excited to be able to do that. So I'm gonna hand over to David at this point and happy to take some questions later.
Great. Thank you, Professor Le Roux, and I am gonna backtrack for just a moment and ride on the coattails of Carel's enthusiasm about the potential, not just of survodutide, but of survodutide and 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 monotherapies, in this case, survodutide, 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 MAFLD, as critical components of the comorbidity risk of the disease of obesity, along with type 2 diabetes and cardiovascular disease. I don't think we can underestimate the excitement that comes with survodutide, leveraging of the glucagon agonism, and the opportunity to affect not just the disease of obesity, cardiovascular risk, but 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-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 sine qua non 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 Le Roux alluded to, very important primary and key secondary endpoints in an area with substantial unmet needs. So we've talked a great deal about differentiation, particularly of GLP-1 related therapies, the excitement of GLP-1, GLP-2 and 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 survodutide as a potential application for liver disease in the setting of overweight and obesity.
So, in summary for this part of our three-part program, survodutide 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 nadir 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+ weeks of exposure in a type 2 diabetes population.
This novel mechanism, the bias towards GLP-1, safety and tolerability, as Professor Le Roux 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 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 survodutide program. So I invite Professor Le Roux, Adam Steensberg up before we have our program closing. Anna?
In the front here, Adam. It's hard to see from your angle.
Thank you. I'm 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 survodutide to be different to that seen with your competitor?
So lipids, you know, typically when we look at these medications, are not the most striking feature. You know, so if I want to reduce somebody's total cholesterol, I use a statin. You know, 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, they all go in the right direction. But I think what we have seen, I think, you know, 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.
I think that's, that's reassuring.
Yeah, and I'll add, Lucy, the collective of cardiovascular risk, glycemia, blood pressure, inflammatory microenvironments, and 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, you know, what I would say is striking improvements in glycemic control with survodutide-
Mm-hmm.
-which is an equally important part of that collective mix of cardiovascular risk. Used to run a lipid clinic where I could spend, you know, 20 minutes just thinking about lipids. Unfortunately, the body doesn't care, it actually adds it all up. So I think an important consideration. Thanks for your question.
We'll go down the row then, Rajan next.
Thank you. Just on the kind of target weight loss that you talked to-
Mm.
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, you know, the higher dose, you know, because we see a clear dose-response effect. But secondly, when you look at the slopes of the curve, you know, even if we just continued with those doses, you know, it would plateau, you know, between 52, and that can be modeled, and, you know, these guys are pretty good at modeling that now. So I certainly would have thought, you know, that we're going to end up certainly in the low-mid 20s. You know, that would be my prediction. But what is really interesting is the categorical weight loss. 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 now we're seeing that with all of the medications. So what we are learning about obesity is that it's not one disease. You know, there's going to be survodutide responders, and there's going to be survodutide 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, so we would argue we need more compounds in this space.
But certainly, you know, what I'm interested in is, and I think you started talking about it, you know, 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 a 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 are going to give you 25% weight loss, we will be able to get people to target and also combining, you know, 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 it kind of lean muscle mass as opposed to fat?
The current thinking, the best thinking in the space, and, you know, we are trying to build the science to support this. But it's almost like the minute you give this drug to the patient, the patient's subcortical areas of the brain, because that's where the compound binds, and that's where the receptors sit, in the hypothalamus, in the area postrema, the nucleus tractus 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 their weight doesn't change. So what these drugs are doing is it's almost cutting the link between what people eat and how much they weigh, right? And that's hence why, you know, thinking about... So what we are really focusing on is this, 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 four 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's going to come back into balance, and that's what we're seeing. So, so I'm not excited when people talk about increases in energy expenditure in the, in the weight loss phase.
What I really want to see is what happens in the maintenance phase. But suffice to say, if we continue these treatments, the weight just flatlines. You know, that's what SELECT showed, you know, just flatlines. Now, with semaglutide only at 10%, we hope with these new compounds at substantially more.
Michael, then Laura, then Charlie, maybe.
Thank you. Two questions for Dr. Le Roux. One is on the phase III trials that are to be done in the industry around MASH or MAFLD. How do you see those being done? Is it more sort of a trying to do a less of progression from obesity into MAFLD, 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 antiemetics, people can use them, and I think that's also going to improve tolerability. You know, as to your question about how to approach this, it depends a little bit on which part of the pond you come from, you know? 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, right? 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 gain. 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 it time. So I think what these drugs are gonna do, without having seen the data, only from the animal point of view, I think it's going to reduce fat in the liver. It's maybe even going to normalize fat in the liver, and with the reduction in inflammation, it's going to create this environment for the liver to reverse fibrosis.
We know it's possible because of the bariatric surgery, so we know it's physiologically possible. I think these drugs are gonna create the microenvironment in the liver to allow that to happen. Now, if you can show you reverse fibrosis, now you have a massive utility gain, and your health economic models change, and therefore, your ICER, your cost per QALY drops below $20,000, and these drugs become, you know, publicly reimbursable.
Maybe over here to... Oh, yeah, at the back first, then, then Laura, then Charlie.
It's not necessarily a direct question on survodutide, 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 five, ten 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 the room who's 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 three effective medications, you make their blood pressure 120 over 80. If you stop those drugs, within two, three 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 his disease.
The minute he stops that biologic, the disease will relapse, and it'll take a little bit of time before he has 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 are 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, is how do we convince our patients that this is a drug you'll have to take for the rest of your life?
This is, you know, how do we get that reimbursed? So that is, but it also, so I think if you model on hypertension, you're gonna be very close, you know, to what is going to happen with this disease, you know, going forward.
Yeah, 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 and stop effectively lipid disorders, hypertension-
Mm-hmm.
-thyroid disease. And I think we're having completely different conversations than two 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, 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.
Mm-hmm.
I remember sibutramine and, you know, phentermine era, where we were excited about 3, 4, 5% body weight loss and how we kept that off. So, just the conversations we wanna have for the next decade or more.
Thank you. 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 survodutide, how do you see the competitive landscape evolving, and specifically thinking about the threat from triagonists? So can survodutide differentiate versus molecules that may also include a GIP component?
So, when it comes to weight loss, you know, I've seen thousands of patients. I tell you, I'm about as good as flipping a coin, you know, 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 patients and help patients make informed decisions, you know, and whatever they decide, we can work with. And I imagine now that we're going to have more compounds, you know, we are going to have those same discussions. You know, 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 analog instead of a small molecule, some of the other treatments that we have, you know, 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 MAFLD or MASH, you know, I would steer those patients towards a medication that has glucagon, you know, a component. So that's how I would think, you know, of that.
Mm-hmm.
Thank you. Charlie Mabbutt from Morgan Stanley. So firstly, NASH. NASH is obviously where there's been a consistent benefit of adding glucagon, but are there any other comorbidities where you believe survodutide 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 timeframe needed to create the right environment, as you previously discussed, Professor?
So I'll take the second question, and I'll bat the first one to you. But so the so-called BRAVE study that was done with bariatric surgery, gastric bypass, sleeve gastrectomy, showed changes in fibrosis on liver biopsies in one year. Okay? So we know that it is possible, and the weight loss was certainly in the same area, in the ballpark that we're seeing here. And with bariatric surgery, we increase 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, you know, in fibro, and that was a very small number of patients, of course, so with larger numbers, I think we will have more confidence.
You know, I think there is also, if you think about where the glucagon receptor sits, you know, we can also see some additional value in other organs. And somebody just mentioned to me the other day, and it's really something. It was Lee Kaplan, of course, he always thinks about the smart stuff, but I didn't think about it. So one thing we're talking about now is, you know, we talk about muscle mass loss, 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 steak, and some of you may have a little rib eye, you know, with a bit of fat inside it.
But what we will also see is removal of fat in the muscle... Right? Now that's a really positive thing, but of course, the mass of the muscle is gonna change, you know. Or when we're going to image it, we're going to see that. So we also are now becoming more sophisticated. You know, 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. So maybe you could-
Yeah.
You know, talk about specific organs.
I think reflecting on that, I mean, MASH and liver disease is a complex multifactorial process. So you talk about fat in the liver, you talk 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 two. I mean, the road is littered with failures in the MASH, NASH space, probably because it targets, you know, a single component, even anti-fibrotics. 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, you know, prongs to your fork 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, yeah, 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, y eah, you need multiple prongs to your fork, in this space.
We have time for a quick one?
Yes.
Other one. Oh, okay. Jesper, quickly.
A question for Professor Le Roux. So do you think that it's a problem with, for example, Altimmune's molecule, that it doesn't work on SPARC, or does that not affect your treatment decision when deciding between the two? And if I can take a quick one more, do you think this molecule, survodutide, is biased enough to the glucagon, or is it just a very effective high-dose GLP-1?
So your second part of the question, which I'm gonna duck the first one, you know, is that, you know, the combination at the moment is, you know, it is what it is. And I think, you know, we are really learning, you know. And I would find it difficult to imagine you guys designed this thing specifically, you know, so it has this magical combination. I think sometimes we make discoveries, you know, and it, and it turns out you run with it. And so if, if you know, this combination seem to be working incredibly well. Now, whether or not it can be tweaked up or down, you know, that I think, you know, there will be evolution, et cetera.
But I think for the compound that we have, you know, that we're working with now in phase II and phase III, you know, it really seems to be doing what it's supposed to say on the tin, 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 our BI colleagues can testify to this as well. It was actually by purpose that we achieve this balance of the molecule. Of course, what we did not know was if that was the right balance-
Right.
- when we got into humans.
And I'll, 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, you know, controlling glucose as soon as possible for 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, as Dan Drucker talked about, 18.5 years of experience using GLP-1 in the setting of glycemic control.
You know, if you like to talk about accidents of nature, John Eng, who ultimately patented, discovered exendin-4 and exenatide, he wasn't looking for a diabetes therapy. He was looking for related peptides, and 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.
Well, thank you. That's-
Adam.
I think, wrap up the session, and then, Adam, some final remarks from you before we...
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, 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 a tsunami of chronic diseases that we have not seen the start of yet. So, 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 a large degree, 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. A nd I, the reason that 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. These, the survivors are the ones who took energy, excessive energy when available, and stored it and had a tendency to preserve energy, meaning being not active. And now we have created a 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's, 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 of what is already out there, but to 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 treat, treatment but would like to try something else. And we believe at Zealand we have at least three of those potential very differentiated molecules that are being progressed through clinical development.
I will start with the lower one, survodutide, which our partner, Boehringer, is progressing. We are extremely happy, of course, with that collaboration and the efforts that Boehringer is putting into this program, and truly believe survodutide 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 petrelintide, 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 weight loss 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 a large group of GLP-1 containing 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/GIPs. But there'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 healthcare challenge that we are facing of modern times.
So of course, it's also relevant then to consider what's next, and David reviewed the different developments of the programs. And I would say for all of these three programs to Zealand's equity story, we have very important data readouts in the first half of next year. But dapiglutide, we'll see the topline data from the phase IIa exploratory study, which can help enlighten us more on the potential for controlling inflammation, and then that will be followed up by higher doses in a phase Ib study later in the year. Petrelintide, we'll get the 16-week data, which again, if those confirm what we already saw in the six-week data and then also follows the same trends that have been seen with other GLP-1 amylin agonists, I—you can say, of course, our excitement will only be confirmed and even enhanced.
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 commitments to start this phase IIb study to truly, truly try and build a best-in-class, next-generation, non-incremental novel treatment for obesity. And then with survodutide, as we discussed, extremely thrilled to see that Boehringer now have this program in phase III, and I think a lot of people fail to recognize that with Boehringer is actually the third company now that are in phase III with a development program 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 support here in the discussions and David as well. So thank you, guys.