Ep. 88 – From Satiety to Muscle: Zealand CEO Steensberg on Amylin’s Edge in Obesity

Thank you. I'm pleased to be here.

Yes. So I think we are extremely excited about the potential of petrolintide and also more broadly amylin as a class to actually offer the first true alternative to the GLP-1 based therapies for weight loss. And I think it's extremely important to recognize and realize that even though GLP-1s are very effective molecules in helping people lose weight, a lot of patients struggle to stay on these therapies due to side effects, GI side effects, and also just the way they work where they make people lose their appetite, which can be an annoying thing especially once you have achieved your weight loss and you get into weight maintenance. And we think with amylin and in particular with petrolintide, with what we have seen thus far, we can actually deliver the weight loss that the majority of obese individuals are looking for in a more pleasant way, and thereby we can also help more patients not only lose their weight but also maintain that weight loss, which is absolutely critical if we are to achieve the long-term health outcomes and health benefits that we are all aiming for with these medicines.

Yes. So we think there are actually multiple ways an amylin can be used. We think by far the biggest opportunity is to develop a true alternative to the GLP-1s, and that would be a molecule that could deliver on average between 15 to 20% weight loss, because that is the weight loss that most patients are looking for. If you ask obese patients, they would say they would be going for a 10 to 20% weight loss, and if your average is between 15 and 20, you will actually meet the need of most patients. So that would be a true alternative for the patients who are otherwise only have GLP-1 as an offering. The other opportunity, of course, is to combine an amylin together with a GLP-1, and that would be a potential great product for patients who are looking for the highest degree of weight loss. So those could be patients who would otherwise be candidates for bariatric surgery. So aiming for that 30% weight loss or 25 to 30% weight loss, that's where we see a combination of GLP-1 and amylin could be interesting.

And then there are other segments such as obese individuals living with type 2 diabetes, where we actually know that the GLP-1s are very effective in helping people control their glucose but significantly less effective when it comes to weight loss in patients with type 2 diabetes. In contrast, amylin actually seems to work extremely well also from a weight loss perspective in patients with type 2 diabetes. So by combining the GLP-1 and an amylin, we could really see an opportunity to address also significant weight loss in obese individuals living with type 2 diabetes. So the ambition we have with petrolintide is to develop this as a novel foundational therapy for weight management. If it has this profile of having significantly less side effects and also we believe a more pleasant experience in how it helps people take in less calories, we think it should be the first choice treatment, and then you can start to combine it with the GLP-1s if you need more.

There's no question the most effective way to lose weight is by taking in less calories, and that, you can say, is something that both the GLP-1s and the amylins are helping people with. The way the GLP-1s mostly work is by decreasing people's appetite. So you basically turn up at the buffet and you're not hungry. Some people even feel, 'Could you please get me out of this room with food because I really don't feel well when I have all this food in front of me?' Amylin, in contrast, works on satiety. So that is by helping people feel full faster. So you will actually turn up at the meal, you will engage, you'll be happy, but you will eat a smaller portion. And that, we believe, will be a more pleasant way to reduce your food intake and your calorie intake than always turning up not being hungry. And it does so by actually activating the leptin pathway. So leptin is a hormone that is released from fat tissue and signals to the brain to inform people to stop eating once they have taken in enough calories. But many obese individuals are resistant to that signal, and amylin has been shown to make people sensitive to leptin again. So we think it's a more natural way for the body to reduce food intake and calorie intake than how the GLP-1s are working.

That is definitely our ambition with petrolintide. We also do recognize at launch, of course, the GLP-1s will have had so much clinical experience and so many clinical data that if you can tolerate a GLP-1, you should of course start on a GLP-1 before you get exposed to second generation molecules. So over time, once we have established data to also demonstrate the long-term health outcomes with amylins, and here we are very confident in what we have seen thus far that amylin is also reducing all the risk factors for cardiovascular disease, once we have established those clinical measures as well, we think it is realistic to consider amylin to be the first-line therapy. Because as we discussed before, it is actually not just about helping people lose weight, it's much more important to help people maintain that weight loss, and if people cannot stay on the GLP-1, it's a huge problem because then we will see the majority of patients actually regaining the weight, and we have known for many many years that that yo-yo in weight up and down is actually very unhealthy for organs. So once we have established the durability of this concept over the GLP-1s, we think it has a very fair shot of becoming actually first line.

That is definitely our belief. And when we look at the risk markers such as blood pressure, heart rate, lipids, cholesterol, CRP or marker of inflammation, we see that they are reduced to the same extent with an amylin analog as they are with the GLP-1 class. So we would definitely expect that that translates into clinical benefit to a number of these organs that we have also seen the GLP-1s provide benefit for. And it is very significant, and to the core of why Zealand is actually developing medicines for obesity, that is of course to address the comorbidities associated with obesity. Because this obesity pandemic, where we will soon have around 50% of the population being overweight and obese, is driving so many, up to 220 diseases can be ascribed associated with the obesity pandemic, and we simply have to do something about that. And that is our true belief that we can also ultimately prove that with the amylins, but we need of course the clinical data, and that we will be focusing on generating in the coming years.

Yes. So there's no question, of course, if you are aiming for weight loss, you would prefer it to be mostly fat and less muscle. But it's also a fact that most weight loss regimes are associated with some degree of muscle loss because you carry less weight. So unless you start to significantly exercise more, it's a natural thing that you will lose a little bit of muscle. Then we have seen perhaps with some of the more aggressive approaches with the GLP-1s, we have seen reports that maybe we'll see extensive muscle wasting with the most if you go for the fastest weight loss on the GLP-1. So of course there's a higher degree of interest in looking for modalities that could reduce the muscle wasting and more have a preferential fat loss when you lose weight. And you're right, in pre-clinical studies in different species, these are very robust findings for the amylin class that the amylins actually preserve muscle to a larger extent than the other ones. We still need to see evidence in humans, and we did see an early very small data set here coming out of the American Diabetes Association which didn't really capture any differences. What Zealand is doing in our large phase 2b study is applying a quite different technology, MRI, which has a more sensitive method to actually look into lean body mass and also fat distributed into different regions and so on. So I would put it this way: it's still an unanswered question in my mind in humans, but we need further data, and it probably has to be using more precise mechanisms to address this.

Ultimately, if we talk about muscle preservation, of course it also has to be functional muscle. And remember, a lot of these imaging modalities actually measure fluid and water content in different tissues. So to have the ultimate proof, you need a functional measure to also show that there's actually some benefit of that muscle, or perhaps even a metabolic chamber where you can demonstrate that there could be a higher resting energy expenditure. I think ultimately that is probably the biggest contributor. If you could maintain a little bit more muscle and thereby also maintain your resting energy metabolism a little bit higher, that can really help in the weight maintenance phase because you can take in a little bit more calories and still maintain your weight. So it's early days here. We need to apply different methodologies to assess not only the mass but also the function of the muscles, and then ultimately I think the biggest benefit will be in the weight maintenance setting if we achieve muscle preservation.

Yeah. No, we were extremely pleased with this deal, and of course having Roche as a partner, it's really the ideal setup for us and also the ideal partner. So we got the significant 16-week data in June last year, and after that decided to start a structured process to reach out to most of the large pharma companies to understand really what their ambition was in this space, because we do see obesity as the biggest unmet medical need of our times and one of the biggest healthcare challenges, and we would expect more large pharma companies to be in this space outside just Lilly and Novo. And so we reached out, and there were of course a number of companies who were interested to have conversations. And I would say what really drove the competitiveness of this process was that it's easy for most large pharma companies to understand that it's actually more relevant to try and lead in a novel category than trying to tap into a very established category as we are seeing with the GLP-1s. So I think it was very appealing to a lot of these pharma companies who don't really have a strong presence in obesity yet to actually lead with what could become and what looks to be the best-in-class amylin that we have out there. So it was a very competitive process for us. It was extremely important to find a partner who have actually a true ambition of leading in this space, because it does require a lot of investments. It's not just about a deal announcement and an upfront; it's investments into organization and very importantly into manufacturing capacity. And with the interactions we had with Roche, that team and with Thomas, they really convinced us that they are here in the long term, they really want to be a leader in this space, they recognize the need to treat obesity, and also with the manufacturing plans that they communicated to us during the diligence process, and now we have seen some of that where they announced a huge plant in North Carolina which will be fit for these products. We really felt that it was the right partner.

Of course it also helped that, as you mentioned, they decided to also provide us with 50% profit share on the combination products, of which they have this GLP-1 GIP which we actually think is a very strong GLP-1 GIP molecule. So to have the profit share not only on amylin but also the combination product adds a lot of value and strategic opportunity for Zealand and us together as we progress these programs. And then ultimately, cultural fit is important when you engage in a true co-development and co-commercialization partnership because it's not just a licensing agreement; it's actually an agreement where we will work alongside each other for a number of years, or for the product lifetime. So cultural fit was also very important for us, and all that ended up with us really tickboxing all the parameters that we were looking for.

Yeah. So in five years, I think the GLP-1s will of course still be the major category because they've been around for such a long time, but we will hopefully have seen the launches of the first alternatives being the amylins. Of course we also expect to see oral GLP-1s entering the marketplace. We as a company are less excited about those opportunities on behalf of patients because we actually think that the oral GLP-1s will have at least if not more of these side effects that make people stop taking the GLP-1. So we don't really think the oral GLP-1s solve this issue of helping patients to stay on therapy for longer. They might be a nice alternative for those who are afraid of a needle, of which we actually believe there are very few. So what will excite me is the launch of course of novel therapies that can truly expand and provide new opportunities for that very large group of patients who do not want to be on a GLP-1. The other thing I foresee is that within the GLP-1 class, I do expect that you will see companies who have more differentiated GLP-1s will start to tap into specific subsegments of obesity, so either targeting obese individuals with fatty liver disease or obese individuals with another specific disease to kind of differentiate from the first generation GLP-1s. For instance, there's our product with Boehringer, survodutide, which has a glucagon as part of the mix. That glucagon component could be a fantastic molecule for obese individuals with fatty liver disease if the data that they generate in phase 3 will continue to deliver what we have seen in phase 2.

I just don't see a patient who are happy on an injectable GLP-1 wanting to try and go to an oral GLP-1 based therapy, in particular not with, but of course it's still early days, but thus far it looks like there might be more side effects such as diarrhea and other side effects. So why change it if you're one of those few patients who actually are okay with being on the injection that you're on and you have already been on it for let's say 6 months, why would you change it? Because it's a once-weekly injection, so I don't see that as a huge opportunity for the orals. Of course, there will be a segment of patients who don't like to inject themselves once a week, but what we have seen thus far in this category, I think there's been very few barriers to injections. And you even see a lot of patients, probably one-third of patients in the US are going with vial and syringe and not even these very convenient auto-injectors. So I think we are looking into a different category where there's a much bigger acceptance for injections, and definitely for maintenance therapy, I think people shy away from any therapy that carried more side effects than whatever they were on before.

I actually think there will be a lot of personalized medicine, but here I actually more think about people's lifestyles. How does this treatment fit into the life that a patient wants to live? Because precision medicine, I do expect will be very far out when it comes to obesity. But personalized medicine, making sure you develop medicines that can help people not only lose weight but also fit into the life they want to have once they have achieved their weight loss. And that's back to even if you can tolerate a product that gives you let's say 25 or 30% weight loss, maybe that is not the life you want to live because it will require you to really change your eating habits lifelong if you are to maintain such a weight loss. So maybe some patients would still prefer only a 10% weight loss even if it came at zero side effects versus the 30%. So we really have to think about making sure that we have treatment that fits the life of patients so they stay on therapy. It's actually a little bit interesting to think about. In the last 30 years, we have had plenty of programs that can help people lose weight, it just requires a lot of effort with counseling and so on. But it's also a fact the minute we give up on those things, people regain weight. And so it's really about how we personalize it so we make sure these treatments help patients maintain their weight loss. I think that's going to be the goal for a very long time. And then talking about precision medicine, it is a very heterogeneous situation with obesity. There are going to be so many both environmental, genetic and other reasons. But I would say I think it's still pretty long out before we start to do a blood sample and then say you have to get on this treatment because you cannot test in the blood how patients like to eat or have a glass of red wine once in a while.

I think it's a brilliant question and it's one which everyone should ask themselves because there's of course a limit to how many GLP-1s we need out there, especially because the patient experience is going to be quite similar. So our way of thinking about this is that if you want to develop a molecule that has GLP-1 within it, you really have to think about what does that added pharmacology provide. And with dapiglutide, our GLP-1 GLP-2, we're trying to target even more control of inflammation. So obese individuals have low-grade inflammation, and it's believed that a large part of that can be driven by inflammation from the gut, and we think a GLP-2 component can actually reduce that inflammation from the gut, and also GLP-2 in itself has some anti-inflammatory properties. So it's really about trying to give the patients the weight loss they can expect from a GLP-1 but then control inflammation to a larger extent, and thereby hopefully be even better at addressing some of the comorbidities to obesity, because the low-grade inflammation is believed to drive so much of disease associated with obesity. So for us, it's about controlling inflammation to a larger extent. We will likely target this molecule into some specific subsegments of obesity, just as we discussed before with Boehringer really having explored survodutide in MASH beyond weight loss. We will also look to focus in on certain comorbidities where we think inflammation plays an even larger role.

It could be, but of course, with where we are right now where we also have profit share on the CT388 as it from Roche, I would say our focus for dapiglutide will be developing that as a monotherapy, if you will, even though it touches two receptors therapy for a specific indication initially. Then you can always consider loose combination, but it will not be a fixed-dose program initially, for the focus at least.

Thank you.