Global Healthcare Conference. I'm Lucy Codrington. I'm one of the European Pharma and Biotech team . It's my absolute pleasure to introduce Adam Steensberg, the CEO of Zealand Pharma. We're gonna do a fireside today, but if anyone in the audience does have a question, please raise your hand and just wait for the microphone to get to you. And with that, we'll kick off with our questions. I suspect most people in the room are familiar with the story, Adam, but perhaps it'd be helpful to kick off with a quick intro to Zealand for anyone that might not be.
Absolutely, and thanks for the invitation to participate. It's always a great pleasure. Yeah, Zealand Pharma is a Danish-based biotech company. We are actually 25 years in the making. We are focused only on peptide drug discovery and development. Throughout those 25 years, we have taken products all the way to the market, and I think on the topics we are going to discuss today, it's really important to understand that peptide drug discovery and development, metabolic diseases are is not something that is new to Zealand. It's something we have been working on for a long time, and also this thing that we have taken products all the way through development and regulatory to the market is important as we are approaching these huge opportunities.
Great. So I think it probably makes sense to, to start with obesity, given that's where most of the focus is at the moment. We've seen a lot of evolution within the obesity space, and I guess, how would you say that the landscape is evolving in terms of what the target weight loss is, how you get to that weight loss, and what other factors should be considered when developing a product for... a new product for obesity now?
Yeah. It is, of course, a fast-moving and you can say area, for good reasons, because we are talking about one of the biggest healthcare challenges I believe this globe has ever faced, at least in modern times. So we need to do something about it, and the fact is that it has been overlooked for many years by big pharma. We have two companies who, in the last few years, have started to focus on obesity treatments. It's really grown out of you can say the diabetes space, where we had two products that were being used for diabetes, but demonstrated weight loss, and then companies developed to progress those opportunities into weight management.
As we are starting to see how patients embrace these therapies and also starting to see how, you can say, comorbidities beyond diabetes is being addressed by these treatments, I just foresee that we will continue to see, you can say, more and more uptake. One of the key themes that we have been pursuing for a long time as an industry when it came to weight management is approaching this bariatric surgery weight loss of 30%, which is really something that is, you can say, perhaps needed for the most morbidly obese patients. So there's been, for a long time, a lot of focus on who can get the most weight loss.
I am extremely certain that going forward, as we approach what I would call clinically meaningful weight loss, the key themes in the future are going to be around how well do you address comorbidities to obesity? Which specific products are better suited for that patient rather than, than the other patient, instead of just who provides the most weight loss? And then, as we will hopefully also discuss later, we need alternatives. There's not a single large chronic therapy area which does not provide alternatives, and right now, the modalities that we have out there, and most of which are in late development, are all built on GLP-1 as a backbone. And, you know, if you don't tolerate a GLP-1 or you one GLP-1, you're not likely to tolerate the other one either. So we need alternatives for patients.
Patients are not all the same, and that's where we come in. Really, I would say, with molecules that are differentiated on how they can address comorbidities and, and also developing what I think is one of the most promising alternatives to the GLP-1 class.
Talking about your most promising alternative, it probably makes sense to start with petrelintide, your long-acting amylin. Perhaps you can talk us through what we've seen, in terms of data to date, and what's really driving excitement about that program.
So we have, and, you know, it's for the amylin as a class, it's actually not new, that amylin can provide weight loss. Even the short-acting pr- pr- amylin analog, pramlintide, which was approved for management of, diabetes more than 20 years or 20 years ago, probably, showed up to 10% weight loss. It's a product you need to inject three times daily with a half-life of minutes. What we have seen with the longer-acting, amylin molecules that are in development right now, including our own, is, you know, after 6 weeks, we could achieve 5% weight loss. Novo have shown with their amylin analog 10, 10.5% weight loss after 26 weeks.
So we really think we're looking into a class of molecules which can provide GLP-1-like weight loss, and what is really, really exciting is it seems to do so with less tolerability issues, so significantly less nausea, vomiting, which is a major, you can say, issue for many patients taking a GLP-1. And on top of that, and what really excites me about the class is it's actually working. The way it reduces calorie intake is very different from how a GLP-1 would do it. While a GLP-1 would reduce your appetite, which means that you turn up at the buffet and you say, "Not for me, I'll wait for later," then what we know with the amylin class, it works on satiety.
So that sense of fullness, that means that you will engage in your calorie intake, but you will just stop earlier, so you'd eat smaller portions. We think it's a more pleasant, more natural way of reducing calorie intake.
Great, and there's a lot of focus on your upcoming 16-week data, this month. What would be considered success in this trial, both in terms of weight loss, but also the tolerability potential benefits we've talked about? And is this trial using titration, and why would it need titration if it's supposed to be so much more tolerable?
Yeah. These, these are fantastic questions, you know. You know, we already know from the six-week study, in my mind, that amylin and our pramlintide in particular, is more tolerable than what we have seen with GLP-1s. We also know that it provides significant weight loss. You know, when people ask me what is the weight loss number we can expect, I would then, the number I'd give back is I would like to see a weight loss within the 7%-9% area, and say, where does that come from? It really comes by starting with the end in mind, and what is it I want to develop?
I want to develop an alternative for the GLP-1 class, and if I get to that weight loss number in a 16-week study, I will also get to 15%-20% in a long-term study, which is where I think we need to be in the longer term. So, but I really think, of course, the, you can say the actual number is not that important here because we are developing an alternative for the GLP-1s, and where the key thing is that is this thing about tolerability. We have significantly less nausea and vomiting than what we see with the GLP-1s.
You know, today, in a world where there are no alternatives, within one year, 70% of patients stop taking a GLP-1 for different reasons, but I believe a large extent of that is due to tolerability issues. So remember, in a world where, or imagine a world where there is alternatives, how many patients would actually say, "Could I please try that instead of this rather cumbersome therapy?" So yes, weight loss is important. For me, the important part is that I still believe that we'll be on a path to develop 15%-20% weight loss in a phase III. I don't try to beat the GLP-1s, I'm developing an alternative to the GLP-1s.
It sounds to me like 7%-9% should be considered success. There is potential for more than that, but it doesn't matter if it's not more than that, given what you're trying to achieve.
There's, of course, you can say potential for more because we saw 5% at the six-week study. If you look into cagrilintide, which was tested up to 4.5 milligrams, they provided, I think, around 8%. When you look at the phase II data, you could argue that maybe they should also have tested even higher doses, and who knows what would have happened if they had tested even higher doses. We don't know because it was not done. So there is, of course, potential for more, but it's just, it doesn't really change the, the profile of the target that I'm going for. And then I would just again urge people to, to, to really understand that this is a Phase 1b study. We have not optimized for weight loss.
We have not introduced dietary means or exercise protocols, and we don't allow use of antibiotic medication and all these things that you do to try and push the weight loss to the highest numbers in phase II-A or II-B studies. So... And it's small numbers, so you can say, that's why I think we... Yeah.
And I guess just on the tolerability, the titration element, like, how big a role might that play when we're interpreting these results in terms of the tolerability profile? It doesn't seem like this trial is gonna be optimized to show its best tolerability either.
No, and that's the nature of a phase I study. I mean, it's 16 weeks. You wanna push the doses as fast as possible, so you can also get steady state exposure, so you can move into phase II with confidence also from a safety perspective. If you look back, I mean, in our single ascending dose, when we just gave patients a single dose of 2.4 milligrams, there was no, there was nausea and some degree of vomiting. When you look into the 6 weeks data, if they want 0.6 and 1.2, it looked pretty benign, perhaps a little bit more nausea in the 1.2. Now, we are dosing significantly higher using titration steps, so there could be specific titration steps where there will be some nausea.
That's something we can account for on a Phase IIb study, which we are going to start in the second half of the year. The other thing I really think is important when it comes to titration is that we do believe there will be need for some degree of titration, even for the amylins. But where we also think it will differentiate from the GLP-1s is that what we expect is that most patients will be able to follow that titration schedule. What we learn with the GLP-1s is that many patients will not be able to follow the titration schedules that are recommended in the labels because they, they have to go slower because of side effects.
Great. And you mentioned about Novo's Cagri. There's also been progression from both Lilly and Astra now with their own amylins in development. I appreciate that there are a lot of unknowns there, but perhaps you can talk about how you think your molecule may sit relative to those others, and where are the points of differentiation when it comes to amylin, potentially?
Yeah. So I think we still have very little information on the competing programs, and I would also say we have also released only very little data on our program. What we have communicated is that we have designed a molecule that is active on both the amylin and the calcitonin receptor. We actually think that's important to achieve the most weight loss. There's animal studies that shows that if you only hit the amylin receptor, then you will not get to the highest degree of weight loss that you can achieve with these molecules. And in endogenous human amylin is actually also working on both receptors.
I think both Lilly and Astra has been out communicating or indicating that they have molecules that are more or less only on the amylin part of the receptor, which would be a different design principle compared to what we have done and also how we believe cagrilintide is working. So, so we think that that's a key differentiator, but we need to, of course, see the clinical data to see if we are right on that one. Yeah.
Okay. Are there any implications of having the neutral pH versus Cagri at least being acidic, other than the ability to co-formulate and potentially injection site reactions?
Yeah, this, again, is just speculations, of course, because we have this molecule is stable at neutral pH, and you know, we have not seen injection site reactions right now. We can see from the studies reported on cagrilintide that there are this, and there are also homogeneity. So, I mean, I think it could be allowing us to actually dose higher and allowing providing some benefits. It could also be what helps us with higher bioavailability and what have you, because, you know, once you inject high amounts of drug into a neutral environment you could see some, you know, some fibrillation if it's only stable at acidic formulations, which we don't expect to see with our molecule.
Great. And then, I guess when it comes to the role of a half-life with amylin, at the moment, obviously, you're dosing once weekly. Is there any scope for you potentially to be dosed less frequently? And has there been any evidence of desensitization of receptors with chronic dosing?
Yeah, I don't think we have seen that yet. I mean, and of desensitization, if you look into the GLP-1 class, it's pretty evident that when it comes to gastric emptying, for instance, that with the long-acting GLP-1s, you actually is desensitizing the effects. So where it's a short-acting, you will continue to see, effects on the gastric emptying. We don't know if it will be the same with the long-acting amylin analogs. When it comes to dosing less frequent, it is an interesting question, in particular, when you have a half-life of 10 days and also a molecule which is, we believe, better tolerable. I mean, so you could potentially allow more drug to an ADI, more excursions here. So you could consider less frequent dosing.
It's something we would consider along the development, but it's not the primary focus right now.
Great. And then, I guess on amylin’s potential profile in terms of, cardiovascular benefits, obviously, we now know with, obviously, the SELECT trial that Wegovy has that, that cardiovascular benefit. So what might amylin provide, on top or in addition to, to GLP-1 when it comes to cardiovascular? And how important will be demonstrating that cardiovascular benefit for a commercial drug?
You know, ultimately, I think it will be extremely important. I mean, we are in this business to address the comorbidities to obesity and overweight. So you need to address these comorbidities, including cardiovascular risk. Again, if you look into data released from the only longer-term study with cagrilintide, I mean, that I would say provides a lot of, you can say, support for the observation that amylin could also provide benefits here. So if you look into blood pressure, I would say probably at least the same decreases as we see with the GLP-1s. Amylin doesn't seem to carry the liabilities and heart rate that you see with the GLP-1s, where you have slight increases in heart rate. Some products have seen quite high increases in heart rate.
Amylin is either neutral or reduced slightly. CRP, so an inflammatory marker, is reduced significantly with amylin, and so is the lipids and the cholesterol. So I think all the cardiovascular risk factors are pointing in the right direction, so we have high expectations on that end as well, just as with the GLP-1 class, but it's still early days, as you know.
Yep. And I guess we've got the phase 1b data coming up. You know, how actively are you preparing for the next steps for this, this asset? And combined with that, how are you thinking about potentially partnering it?
So we're extremely engaged in preparing for the next phase, and we have been so for more than a year. I mean, this is not just something you wake up one day and then say, "Now I'm moving to a phase, last phase II-B study." We are also hugely engaged in scaling up manufacturing, batch sizes, and so on, so we are ready to move forward without any delays. So it's been a key focus for me and the rest of the management team in the last year to really set the organization up to deliver on these studies. So we are ready to go and expect to start the study in the second half of the year. And again, it's not just down to clinical conduct, it's also all the CMC, the quality aspects, where we are investing big time right now.
On partnering, what, what's your strategy there, and, and what are the kind of qualities you'd be looking for in a potential partner?
So amylin is a special opportunity here because we are developing it as an alternative. So we actually think, at least as the next steps, we can we don't need a partner to drive the phase IIB, but of course, before we engage in phase III, that is a relevant time to have a partner on board, and it could also be earlier in order to have these preparations together. So what we are looking for in a partner, in a potential, in a future partnership, that is somebody who is committed to win in obesity, and then you can say: What does that mean? Well, I'm not looking for somebody who's just trying to get 5% market share and a nice equity story.
I'm actually looking for somebody who is committed to win and who believes that amylin can provide another class, potentially become the biggest class of medicines for weight management. And, you know, that is back to somebody who's ready to commit to manufacturing capacity, somebody who's ready to commit to a global program and, and going beyond U.S. and, and Europe. So it's really about commitment and then teaming up in a true partnership rather than, you can say, just wanting to be in obesity because it's hot right now. And, so, so that's, that's where we are on that one, and, you know, because, of course, the it will require big manufacturing investments, but again, if you want to go for a big opportunity, it also... I mean, you need to invest.
Great. I'm conscious I've taken up quite a lot of time with amylin. So if we move on to survodutide, your asset that's in partnership with Boehringer Ingelheim and is in phase III for obesity. Perhaps you could give us an overview of what, what excites you specifically about that program and where you think it could be positioned. And obviously, we have the upcoming data in NASH or MASH on Friday, so how important that is for its profile?
But, first of all, I mean, we have seen with the GLP-1 containing molecules that they provide benefits and a lot of comorbidities to obesity beyond diabetes, cardiovascular. And there's also signs that you can say they will provide evident benefits in liver health. I mean, any, I would say any weight loss would be expected to provide some indirect benefits on liver health. But why we are so excited about survodutide is that we have built additional pharmacology into this molecule, so it also specifically addresses the metabolic state of the liver by adding glucagon. So in principle, we should also have we should have more direct positive effects on liver health compared to just the GLP-1, other GLP-1 containing molecules. So...
You know, we have high expectations for this molecule, not only in weight loss, but in particular in treatment of MASH, which we consider one of the biggest, you can say, unmet medical needs associated with obesity.
What's your understanding of Boehringer's commitment to MASH in terms of potentially running a dedicated biopsy-based phase III? Or do you think that's somewhat contingent on what we find out on Friday?
No, I think Boehringer have already been out now stating that they are fully committed to progress this molecule in both MASH and in obesity. So, we see them as a fantastic partner here. It is actually, again, it's a private company. Many people in this audience forget that they are one of the most committed companies in the cardiometabolic liver space for many, many years. It's the fifteenth largest pharma company in the world and fifth largest manufacturer, so we're very comfortable with how they move this forward.
You touched on manufacturing. That's obviously been a significant constraint, I guess, in the rollout of the current therapies. So I guess, what's your understanding of Boehringer's manufacturing capabilities and what they might be doing ahead of potential success in the survodutide-type phase IIIs?
Yeah, again, I cannot share more. They have been out, you can say, committing that they are ready to support the launch of the molecule, which I would expect them to be. So, so and that gives us a lot of confidence.
Great. I'll just take a pause in case there are any questions from the audience. Otherwise, I can move on. Nope? Okay. Your other wholly-owned obesity asset is dapiglutide, which is a dual GLP-1, GLP-2 agonist. What's the rationale for the added GLP-2 activity in the treatment of obesity?
There's a lot of data that suggests that, you know, the reason that we see so much organ damage associated with obesity is an underlying inflammation, a low-grade inflammation in, at the organ level. We have added GLP-2 to this molecule to better address the low-grade inflammation and thus organ damage associated with metabolic disease. So it's really about achieving good enough weight loss, as we discussed before, but then being better at addressing some of the comorbidities to obesity with this molecule.
Great. And you recently reported headline phase IIa data from an investigator-sponsored study. You had very good safety, weight loss of about 4.3% at 12 weeks. What are the implications of these data for your future development plans, and how does that trial differ to the ongoing trial that's due to report during the second half?
So we only applied, you can say, low doses, up to 6 milligrams here, and we are now in the ongoing phase IB study beyond 13 milligrams of exposure and expect to go higher in the patients. So, in the healthy volunteers. So you can say it's really on the low end of the dose-response curve. That's also why, you know, we only saw the 4.5, 4.3% weight loss and a very benign profile. You can say that's probably more compared to the diabetes doses of other GLP-1. So we're very comfortable that we are on the right track to develop a molecule that can give you north of 20% weight loss in longer term studies.
The mechanistic study was really designed to better address what does GLP-2 contribute with, into organ-specific inflammation. We're doing it in intestinal biopsies and so on, so those will be analyzed and reported later, those... But the more important data set is the ongoing Phase 1b study, where we see the higher doses.
I guess on that biomarker and gut biopsy data, given that the dose seems almost subtherapeutic, at least from a weight loss point of view, will those data actually be informative, or do you think the weight loss level relative to the inflammation effect is there a disconnect there?
Yeah, I mean, again, that, that remains to be seen. That could be one case, but again, it, it's when you have these dual-acting molecules, it's always difficult to dissect what contributes to what. We know already GLP-1s on their own do some on inflammation, especially at the higher doses. So it could actually be good to be at the lower dose level, where we, it would be easier for us to dissect the specific GLP-2 contributions. But it could also be that we need to go a little bit higher to get the full picture. But, I mean, let's see. As you said, it is an investigator-initiated study, which we started a few years back, so it's, it's, it's the less important part of the program.
Very clear. And then, unless there aren't any, are any questions, we could touch on your non-obesity assets, which get very little attention these days, but are actually more advanced, arguably. Perhaps you could give us an update on what's happening in terms of those assets and the partnership situation for those.
Yeah, and you know, we still spend significant time internally, as you can imagine, since both are with FDA right now. They have PDUFA dates in the fourth quarter this year. So one is the dasiglucagon for congenital hyperinsulinism, and the other one is glepaglutide for short bowel syndrome. So we have good progress with the FDA and are, you know, making all the preparations to be ready to have these products on the market. And in parallel with this, we have partner discussions. As we have communicated, we have good progress. The key focus right now for us is on glepaglutide with a PDUFA date in late December. That's a good opportunity.
Is that something that Zealand could consider launching on its own until you find a partner, or is a partner a prerequisite for launch?
I would say for glepaglutide, for sure, the scenario for us is that we will have a commercial partner to launch with. You know, we have not committed, as you know, to that we will have a partnership in place this year, and that would mean that we would have an approved product before we partner. But I would say we have good progress in discussions, and we have the capabilities to do all the pre-launch activities. We had a commercial infrastructure. We have retained a lot of talent and also capabilities, processes, and structures. So we're doing the things needed to progress, but as we approach in getting to the launch phase, I mean, we will want to have a partner there. For CHI, it's a more simple story.
It's like 6-8 clinics that are treating the majority of the patients, so it's easier to handle without having too much commitment.
Great. And with that, we've run down the clock, so I'd like to take this opportunity to thank Adam for his time and for the audience for your attendance.