Good afternoon, and welcome to day one of the Jefferies Global Healthcare Conference. My name is Lucy Codrington. I'm one of the European Pharma and Biotech team based here in London. It's my pleasure to introduce Adam Steensberg, the President and CEO of Zealand Pharma. This is a fireside chat. If anyone would like to ask a question, and we can get a mic to you, please do raise your hand. But starting off, I think if we focus on obesity to begin with, I guess a lot of the focus initially has been on the depth and rate of weight loss. But how do you think that could evolve with time and with use in the real world? And how is Zealand's pipeline positioned within that?
Yeah. Thanks for that question, and thanks for the invitation to be here. So, I think you're right. For several years, you know, as an industry, we have been kind of pursuing that ultimate dream of what people would describe as bariatric surgery-like weight loss. And at least in my mind, I think we are moving a little bit beyond that, also based on real-world evidence and experiences. And I think in the future, it's going to be much more about the quality of the weight loss, getting enough weight loss, and then really around the comorbidities. How do you address the comorbidities of obesity? Of course, there will be patients who are in need of also these 30% weight loss and so on, but my belief is that the majority will actually do with less.
I think at Zealand, we have a very differentiated pipeline, which actually specifically address both comorbidities but also quality of weight loss for the future.
Great. And then over the weekend, we obviously had the detailed SELECT data in terms of cardiovascular outcomes for, Novo Nordisk, Wegovy. What are the implications for that in terms of Zealand's pipeline? And I'm thinking in particular of your, assets or targets outside of GLP-1, your amylin and GLP-2. And also, is this weight loss... Is this benefit beyond weight loss, and is that specific to GLP-1, or are you also positioned there with, with your other targets?
Yeah, I do think it's very supportive of the class of GLP-1 containing molecules, the SELECT data. But I'm also one of those people who believe that, of course, there's also molecule-specific activities here, so you cannot just ascribe this to the class. But I think it's very supportive, and I also say that based on observations from and similar data being generated in patients with type 2 diabetes and so on. So it's now also being demonstrated in obese individuals with comorbidities. So I would say it provides a lot of hope for the class of medicines within obesity as well, I believe. But even more so, of course, it supports Novo's GLP-1 right now.
So, when it comes to molecules outside of the GLP-1 class, I'm again a firm believer that we are not developing weight loss medications just to achieve weight loss. We're doing this to achieve health outcomes, which ultimately will be either CV outcomes, outcomes on NASH, kidney disease, Alzheimer, other diseases which can be associated with obesity. So, I mean, I think in the future, you will have to to address those outcomes in longer-term studies as well with your specific molecules.
Okay. So if we focus on your leading obesity asset, survodutide, which is partnered with Boehringer, I guess its tolerability profile has got almost as much attention as its weight loss profile, which is very competitive. What drives confidence that that tolerability can be improved in the Phase III program, which is about to start any day now?
Yeah. So we are very confident in this, and of course, that's based on not only seeing the data but also dialogues with Boehringer and some of the investigators who participated in those trials. And I think if you look at the early data that were generated with some of the competing molecules, which have, like you will see quite similar nausea and vomiting rates and discontinuation rates in Phase II, where most often people have been a little bit more strict on how patients were to follow the titration schedules, and also meaning quite fast titration without a lot of flexibility, but also that people did not allow or companies did not allow use of antiemetic medication.
What often happens when you then get into phase III is you allow a little bit more flexibility in your dosing titration, which we know will reduce the nausea and vomiting that you see with the GLP-1 molecules. And, of course, you do that because these are longer studies, so you have more time to titrate into target. And the other thing which is often seen is that you allow use of antiemetic medication just around the Cmax of these titration steps, which will again reduce the burden for these patients when they undergo that. Some competitors have started to allow some of this in phase II as well. You have to be a little bit careful due to adverse events of antiemetics. So BI did not use this in phase II. We do believe that they will do it in phase III.
So we are very confident that they will actually achieve, you can say, GLP-1 class-like nausea and vomiting and discontinuation.
Great. In addition to the phase III program, it's also in a phase IIb in NASH, for which we're expecting data in the first half of next year. Perhaps you could frame expectations as we go into that data.
Yeah. And personally, I have high expectations, and I also think it's a very important data set for survodutide because, of course, we recognize that survodutide will launch if it's approved quite late into a market where we both have semaglutide and tirzepatide. But I think with the NASH study, if that comes out the way we hope, it has a huge potential to actually differentiate this molecule. It was actually the key scientific concept when we developed the molecule with BI to address not only weight loss but also NASH, because glucagon is known to kind of go into the liver and get fat out of the liver. So I think it has a huge potential in NASH, and I think-...
Again, it perhaps is a little bit overlooked today that data demonstrates that 75% of obese and overweight individuals, they have NAFLD, and 30% actually have some degree of NASH. So there's a huge unmet medical need, and I actually think it's one of the biggest reasons to manage obesity in the future, that is to prevent development and further development of NASH. So if they hit that one, I think it can actually take the molecule and really position it as a, as a potential winner within the GLP-1 class. Otherwise, it will be somewhat late, still providing a lot of weight loss, very competitive weight loss, but with a strong NASH data and a potential approval in that indication as well, it could really, I mean, change the, the, the future of this molecule.
Okay, very clear. Also, as part of the obesity program, there's a cardiovascular outcomes trial. How should we think about that trial in terms of the patients included, where it also has patients with type two diabetes and chronic kidney disease? I know you can't speak for Boehringer, but perhaps how is that best positioned to show the benefit of survodutide? Oh, sorry, survodutide. I will let you go.
Servo.
Servo, exactly.
No. Yeah, and again, we will have to make, Boehringer will have to address the specific considerations around how they designed this study. But if I should just discuss in general terms, I would say, first of all, when you do cardiovascular outcome studies, it should represent the the group of patients that you address in the future. And I think you do that best by also including, let's say, patients with diabetes type two, because that's 20% of the, of the obese population. Then you can think about why was that not the case for the, you can say, the some of the former GLP-1s, and there, I think you have to look into the development history, where they were first developed for type two diabetes, and then they had a huge desire to also address independent effects beyond diabetes.
So that's probably why patients with diabetes were excluded first from some of those programs. But I think what you will see going forward in this space of anti-obesity medications, I think you will see a development towards more representative groups of patients. Chronic kidney disease is a huge predictor of future cardiovascular risk, so why not have them in the programs? I think we have... maybe earlier, you have excluded them because of concerns of different aspects. Boehringer clearly have a lot of experience, not only in CV outcome, also in renal protection studies. I mean, having worked with the SGLT2 class of drugs. So we have a lot of confidence in their decision-making, and I actually think it's some of the trends that you will see in future studies as well, that they are kind of leading right now.
Great. And then some way off, potential commercial launch, but do you have any... What's your understanding of Boehringer's manufacturing capabilities, given the capacity constraints we've seen with competitors?
Yeah. We have, again, a lot of confidence in Boehringer's ability to produce, yeah. And, of course, we are aware, and I'm sure Boehringer is as well, around the shortcomings for this current supply chains, which, I mean, the companies who are facing them are also very aware of and are doing a lot to address. So let me put it this way: if we will face supply shortcomings, I think that will be a positive news for us.
Very good. Okay, moving on to your long-acting amylin. Perhaps you could talk us through the data to date and explain what drives such excitement for you guys about this program.
Which one, sorry?
Your long-acting amylin.
Yeah. So the long-acting amylin, I honestly think this is the crown jewel in our pipeline. It's still early days with regard to data, but of course, we can also evaluate some of the data that has been generated by competing programs, with cagrilintide from Novo Nordisk. And we truly believe that the potential here with amylin as a monotherapy, as an alternative to the GLP-1 class, is very significant. And I say that also having a few GLP-1 molecules in the basket and in development. But GLP-1 provides a lot of weight loss, and it's also, as we have now seen, have huge potential for reducing comorbidities and then other aspects of obesity.
But they are difficult molecules to be on, and I think history has shown us if there are alternatives that can provide you with the same benefits but in a more benign way, that creates a huge potential. So we actually see amylin, with the data that we have seen thus far, we see it as an alternative that could give you GLP-1-like weight loss with less nausea and vomiting. And also, the quality of the weight loss could be different because it works, at least data, preclinical data, which suggests that it works more on satiety versus reducing your appetite. And those are two very different human experiences, which we think could potentially drive, you can say, amylin to be a preferred weight loss medication, both for weight loss but also importantly for weight maintenance. Where...
And again, if you look into chronic therapy areas, you will see patients are shopping a little bit around. They stay on one therapy, and then they move to another one. And very often, if you are not happy with what you're on, you need to move to another category and not stay within the same, because then you would have the same experience. And that's where we see amylin as a unique opportunity to actually develop it as a monotherapy, as an alternative to GLP-1s. It also have fantastic opportunities as a combination therapy. We have developed our molecule or designed our molecule, so it's stable at neutral pH, so it can be co-formulated with all the GLP-1s we know of. But we see the biggest opportunity as a monotherapy, and that's something that we look very much forward to discussing more.
So next year, in the first half of next year, we're expecting 16-week data for your long-acting amylin. What would you say are the expectations for that data? What would be considered a success?
So with the six-week data we reported this summer, we saw around 5% weight loss, which is more or less on par with the GLP-1 molecules and also on par with what Novo reported for cagrilintide. This was using very low doses of our amylin, up to 1.2 milligram with the 16-week data, we will of course dose longer, and we will also apply significantly higher doses. And I would say, if we get into the 7%-8% weight loss, then we would be on the same trajectory as the mono-acting GLP-1s and also CagriSema. And that, I would say, for me, is a success criteria, because then I think we will, with longer-term studies, get into what I would consider the weight loss that most patients are looking for, meaning somewhere in the teens.
And then I think we could potentially sit with a future winner.
Okay. You mentioned Novo's Cagri. Other than the kind of comparing the weight loss profiles, are there any other potential differentiating features of ZP8396 relative to Cagri?
I mean, the one we know of is, of course, where it's stable, where our molecule is stable at neutral pH, and at least we believe that cagrilintide is at quite acidic conditions, and that's why it can be difficult to co-formulate with the GLP-1 class of drugs. So, otherwise, our... We have a, you know, a molecule that is quite balanced on the amylin and the calcitonin receptor, which we believe is important to achieve the weight loss that we are observing. But, yeah, so that's where we are on that one.
Okay. And what about amylin in terms of cardiovascular health? Are there any potential benefits other than the weight loss?
Yeah. And this is actually something that we look forward discussing much more in details at our R&D event here, December 5th, coming up in London, where we will have experts in the field reviewing also amylin biology. And I would say, if you look again into data that have already been generated, and you look at the traditional or classical risk factors for cardiovascular disease, you will actually see very positive effects on blood pressure. You will actually see neutral to perhaps even reduction in heart rate. That is in contrast to the GLP-1 class, where you normally see a little bit of an increase in heart rate. You'll see quite significant reductions in CRP, which is a known marker, again, for risk, for inflammation and cardiovascular risk.
If you look into the lipids, I think it's really striking to see how amylin can affect your lipids. You have increases in HDL and lowering of VLDL to triglycerides, and so on. It looks very, very strong from a cardiovascular risk reduction perspective. Again, it's early days, but if you just look at the data that have been generated up to 26-32 weeks, it looks very strong, the amylin class.
Great. And what's your development and/or partnering strategy for amylin? Are you confident that you can keep your position as kind of the second-most advanced amylin on your own?
Yeah. I mean, at least I'm confident that we are doing all the right things right now. And then, and I also know, because we are in the budget discussions right now, that we are doing everything, all the investments needed to push this as fast as possible forward and also front-loading activities to get it into a phase IIb study. So... And I think as a company, we do have a lot of experience with actually getting products all the way to the market. So it's not new for us to do device development, upscaling, and so on, preparing all the things that we normally don't discuss here at conferences like this. So we think we are the right company to progress this, but we also recognize at one point, of course, we will need more muscle to truly position this one.
It is an asset which we expect to partner at one point, but for the near term at least, we believe we are the right company to push it forward.
Okay. And then perhaps in the interest of time, perhaps you could briefly outline your earlier-stage obesity assets, and what your strategy is for these.
Yeah. So we have another asset in phase I, IIa, our GLP-1, GLP-2, which we actually consider one of the few clearly differentiated GLP-1 containing molecules, if you look into the early pipeline. And that's one where we believe we can address inflammation, low-grade inflammation that you have in these diseases, to a larger extent than with some of the other molecules. So that one is one we also are pushing forward, and we have high beliefs in addressing what we know is, is causing a lot of the organ damage, the inflammatory component of metabolic diseases. Then we have a GIP analog, which has, in our minds, only potential as a combination therapy, and we don't believe that has potential as a standalone.
And then I would say that if you look into early-stage programs, it's actually going to be within chronic inflammation that we expect to push some molecules into the clinic next year.
Okay. Your assets at the moment are all given subcut. Are there plans or is it possible for your assets to be developed as an oral formulation?
Yeah. So we only work with the peptides. That's something we've been doing for 25 years, and we will stay within that modality. Peptides are best suited for injections, but of course, Novo have shown that you can actually make a peptide orally available with a low bioavailability, but you can do it by using formulation enhancers. So we could do that as well. But I would normally say, with a peptide, that's something that comes a little bit later in the development phase. You would progress this as a subcutaneous injection first, and then you can work as a lifecycle management and to make it orally available. It will sometimes come with some shortcomings that you need maybe to fast before you before and after you take the pill, and so on.
I'm not completely convinced that it's the preferred mode of action, because it can introduce some complexity. It sounds easy to take an oral, but reality, if you need to fast and so on before, maybe a lot of patients would actually prefer a once-weekly injection.
Makes sense. Okay, moving on from your obesity pipeline, you also have a late-stage rare disease pipeline that perhaps doesn't get the attention it might deserve these days. FDA's accepted your filing for dasiglucagon to treat CHI. But took the decision to split that filing into two, with a decision on the under three-week dosing by the end of the year, and then the second part for over three-week dosing later. What do you think could explain the FDA's decision to split the filing?
So you, you might remember that we have actually done two phase three studies to support this indication. One, which was focused on small babies in the hospital, and another one, which was an outpatient situation. And the second one in the older kids, we actually failed the primary endpoint where we used finger prick to establish blood glucose levels. But we also applied continuous glucose monitoring, blinded in that study, where we saw a 50% reduction in hypoglycemia, which is really the issue that these kids are struggling with. So we have had a good dialogue with FDA on this failed study, how that could support the label, and we went into these, to the NDA, under the assumption that it should just be a supportive data set for the chronic use.
Then, during the review, I think we had some very good interactions with the FDA, and we have the sense that it could actually get a more prominent place in the label, but that also implies that it, yeah, that we have to treat the data as a primary endpoint data set, which requires a lot of quality testing. And continuous glucose monitoring for many years, that's a lot of data. So we could basically not meet the information request deadlines that FDA put ahead, and we think it's a very sensible proposal by FDA to then say, "Let's split it," because they see the need for these patients to get some novel treatments that are none today.
So we are very, very confident in the interactions, but it was a data load, you can say, that we could not meet here with the limited group we are after all, and we will submit part two of the NDA first half next year. We are working with FDA right now towards the PDUFA date for the first initial label, and then, until we have the full label, we will make the product available in the U.S., if approved.
Okay, and I guess you have committed to partnering this asset, but how feasible is it for Zealand to commercialize it in the absence of a partner? And I guess, how should we think about the timing of a potential partnership with the split NDA?
No, and we are still pursuing partnerships for this asset. We believe it's more likely that this will happen next year rather than this year, based on the complexity that was introduced with the splitting of the NDA. I would say for Zealand, it's very feasible to make the product available in the U.S. after a potential approval, before we also have the full label. Remember, we had... Until last year, this time, we actually had commercial infrastructure in the U.S. We are still supplying, actually, one of our partners with a product that they then distribute and sell.
with only, let's say, six main clinics in the U.S., it's an effort that we can easily handle without significant investments, and that's something we plan to do until we have a commercial partner in place.
Okay. I'm conscious of time. If anyone does have a question in the audience, otherwise, I'll move on to glepaglutide. Oh, yeah.
Adam, is the idea...
I think a mic is coming to you.
Thanks. Adam, is there the idea that having weight loss that is more subtle than more profound might be also durable? A lot of the problems with Ozempic, Wegovy, is people off the medicine start rebounding rapidly, and therefore, maybe the durability of the medicine for those patients having a more subtle weight loss, we've often talked about, is better. What are your thoughts?
Yeah. I think that's part of it, and I know there's a lot of discussions for or back if you can—if you have to stay on therapy. I think any experience thus far on weight loss programs informs you that you have to stay on that program, whether it's medicine or whatever program, otherwise you'll regain weight. I think that's why we have to face that the world we live in here today, we need to be on maintenance therapy. I think if you're—you need more benign pro-molecules to be on, in order to stay on, because, you know, let's face it, you are more motivated with the weight loss early on. When you are getting into the more steady stage, your motivation reduces a little bit, and you will accept less, you can say, side effects.
Just on that then, in terms of a role for amylin as a maintenance therapy, how do you go about showing that, or what type of studies might be needed to develop it as a maintenance option?
Yeah, but I don't think they are very different than you can say just a classical program. First, you will show weight loss potential, and then, of course, you can speculate if you want to also do studies where you take patients who are already on established therapies and then re-randomize them to continuous on that, whatever they are on, and then versus amylin and so on. These are very specific designs, but I think you can address most of it in the like the programs we see today.
Okay. Any more questions from the audience? I was told I wasn't allowed to ask any questions after 32 min, 22 minutes, but we still have three minutes to go. So, just quickly on glepaglutide, perhaps you could talk us through how you think that's positioned in the kind of potential face of Gattex generics and what advantages it could offer in short bowel syndrome.
Right. So we expect to submit the NDA later this year, and then, again, next year, engage in partnership discussions for that program. I think with Gattex has demonstrated this value that's being used by a number of patients today and generating around 700 million in sales annually and still growing. But it's a once daily product that you need to mix before you inject it, actually quite cumbersome mixing procedure. And with our product, it's a twice a week, looks to be a twice a week product if approved, and delivered via an auto-injector, so very simple. So it's a very different experience from the patient when they take it. It's also a dose where you don't have to adjust for weight, so simplicity here in how you take the product.
And then with our phase three study, I think we were at least very, very happy to see the number of patients who we could wean off parenteral support. So we think we have some potential strong claims around our molecule and also the experience that we-- that you can say, the qualitative experience we hear from investigators on how people are doing on the product is encouraging. But of course, we will not be in a situation where there can be any superiority claims for anything, because we have not done those studies. But I just think the overall experience, the data that we have generated so far and the mode of administration is a significant differentiator. Generic Gattex is something that a lot of people have talked about for a long time.
We don't know the stages, and if it will happen. I would just re-emphasize that selling products in rare disease indications is not a traditional generic play. You need infrastructure to support patients getting on medication, staying on medication, and so on. So it's not as easy done as said.
Okay. I think with that, we've run down the clock. I'd like to thank Adam for his time today, and close the session. Thank you.
Thank you.