Good day, and thank you for standing by. Welcome to the Zealand Pharma Interim Report Half Year 2025 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Adam Langer, Vice President, Investor Relations. Please go ahead.

Thank you, operator, and thank you to everyone for joining us today to discuss Zealand Pharma's results for the first 6 months of 2025. You can find the related company announcement on our website at zealandpharma.com. As described on Slide 2, I caution listeners that during this call, we will be making forward-looking statements that are subject to risks and uncertainties. Turning to Slide 3 and today's agenda. With me today are the following members of Zealand Pharma's management team

Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, Chief Financial Officer; and David Kendall, Chief Medical Officer. All speakers will be available for the subsequent Q&A session. Moving to Slide 4. I will now turn the call over to Adam Steensberg, President and CEO.

Thank you, Adam, and welcome, everyone. Today, we stand in a unique position to realize our vision to become a key player in the management of obesity. We have a clearly differentiated mid- to late-stage obesity pipeline with 2 leading programs, petrelintide and survodutide, backed by strong partners in Roche and Boehringer Ingelheim. Both programs are rapidly approaching key clinical readouts with Phase II data for petrelintide and Phase III data for survodutide in our sites. Over the past 2 years, we have strengthened our organization and our internal capabilities, including recent appointments to our leadership team. Utpal Singh, as Chief Scientific Officer, will drive the next wave of innovation; and Steven Johnson as Chief Development Officer, will lead our development and regulatory strategies. Finally, our robust financial position ensures the strongest possible foundation as we approach major upcoming catalysts for our leading obesity programs. With this momentum, Zealand Pharma is entering a pivotal new chapter, and I'm truly excited what lies ahead. Turning to Slide 5. The Roche alliance for petrelintide has begun exceptionally well. With Roche, we are rapidly advancing the petrelintide monotherapy program. Once the 28-week data from the ZUPREME-1 Phase II trial are in hand, which is expected by the end of this year, the unblinded teams can move forward with the end of Phase II meeting with the U.S. FDA. We expect to report the 42-week data in the first half year of 2026 and initiate the Phase III program with petrelintide monotherapy in the second half of 2026. Meanwhile, we expect to initiate Phase II for the first petrelintide-based combination product under the collaboration, petrelintide combined with Roche's leading incretin asset, CT-388, a potential best-in-class GLP-1/GIP receptor dual agonist in the first half of 2026. So it's full steam ahead with the Roche collaboration on the petrelintide clinical development program. Under the collaboration, Roche is responsible for all investments into commercial manufacturing and supply for petrelintide and the petrelintide-based fixed- dose combination. With regards to manufacturing readiness, we are truly impressed with the decisiveness and firmness with Roche moves forward. The early commitments and planning around manufacturing were a big reason why we chose them as our partner. They are already building out capacity at scale, including a state-of-the-art high-volume, high-throughput fill-finish manufacturing facility in the U.S. These early and meaningful investments will significantly contribute to unlocking the full value potential of petrelintide and our shared ambition to establish the leading amylin-based franchise. At the Roche Pharma Day on September 22, we expect that they will provide further insights into their obesity strategy. And at our Capital Markets Day in December, where our obesity strategy will take center stage, we look forward to sharing updates on the programs and on our efforts to become a key player in the management of obesity. Let's move to Slide 6. It is without a doubt that new and better treatment options are needed to tackle one of the greatest health care challenges of our time. And with only a small fraction of eligible patients receiving pharmacotherapy today, we are clearly at the very early stage in the evolution of this market, which will require many therapeutic options with a range of different mechanisms to adequately address this chronic disease. Real-world treatment persistence with the GLP-1-based therapies remains a challenge, highlighting a clear need for more tolerable, simple and patient-friendly options. As an industry, we have to move away from focusing on speed and magnitude of weight loss. This is not consistent with what the vast majority of people with overweight and obesity desire. We believe that a product with the best potential to become the preferred therapy for a broad population with overweight and obesity should deliver weight loss in the range of 10% to 20%, which the vast majority desire through a mechanism that offers a more positive patient experience with improved tolerability, including fewer and milder gastrointestinal events so that patients can better achieve and importantly, maintain a healthy reduction in their body weight. This is why we are so excited about the potential for petrelintide to become a foundational therapy for weight management. And with that, let's move to Slide 7 as I turn over the call to our Chief Medical Officer, David Kendall, to discuss our R&D pipeline. David?

David M. Kendall: Thank you, Adam. Today, I would like to focus my remarks on the continued advancement of our leading programs in obesity and obesity-related comorbidities. Let's move to Slide 8. Together with our partner, Roche, we are exceedingly well positioned to establish the leading amylin-based franchise for weight management and rapidly expand into obesity-related comorbidities. As Adam just mentioned, petrelintide holds the potential as an effective and well-tolerated stand-alone therapy to address the needs of the majority of people with overweight and obesity. The broad scope of the collaboration set forth in the Zealand Pharma-Roche alliance enables us to fully explore and unlock the potential of petrelintide. The first combination product under the alliance will target the segment of people who need and desire greater weight loss and/or improved glycemic control while still leveraging the better tolerability of higher dose petrelintide and adding optimized doses of the incretin-based therapy, CT-388. Turning to Slide 9. In recent months, research and development activity in amylin-based treatments for weight management has increased significantly. Two years ago, we faced some skepticism about our approach to amylin as an effective and appealing stand- alone therapy and as an important alternative to GLP-1-based therapies. Today, however, amylin is emerging as the next major class of potential therapies for weight management. In June, we saw the first detailed Phase III data for a long-acting amylin analog, cagrilintide. The long-term data showed no unexpected safety signals and a gastrointestinal tolerability profile that demonstrated considerably fewer and less severe GI adverse events than observed with GLP-1-based therapies. These data represent a major derisking event for the petrelintide program as petrelintide shares both a very similar receptor profile and a structure based on the human amylin backbone like cagrilintide. That said, there are several key molecule-specific differences that potentially make petrelintide superior, which are worth reiterating. These differences include petrelintide's chemical and physical stability, particularly around a neutral pH, the ability to administer higher milligram doses, a longer half-life and greater bioavailability. We have also seen additional early-stage data from other amylin-based programs, including analogs derived from different backbones such as salmon calcitonin or analogs with different receptor binding and activation profiles. While these analogs contribute to the growing body of data available for amylin-based therapies, we remain highly confident in petrelintide's consistent clinical response with a very favorable tolerability and safety profile and the peptide construct itself, underscoring petrelintide's unique value proposition and potential to become the leading amylin-based treatment and a foundational therapy for weight management. Our confidence is grounded in the totality of data we have generated to date. Petrelintide has demonstrated the potential to deliver the weight loss that the vast majority of people with overweight and obesity desire. Even in studies that were conducted in a predominantly male population with relatively lower baseline BMI, both factors that likely muted the overall weight reduction observed. To support this, we were pleased to present on Slide 10, the additional data on individual responses of participants in our 16-week Phase Ib trial with petrelintide at this year's ADA 85th Scientific Sessions held in June. Of note, every individual participant treated with petrelintide in this trial lost weight during the study. Importantly, while only 21% of the trial participants were female, a greater treatment response was observed in females across all 3 petrelintide dose groups. This leads me to Slide 11 for a brief status update on the petrelintide Phase II ZUPREME program. We have previously shared the trial designs for ZUPREME-1 and ZUPREME-2, so I will not go into further detail here. Back in March, we announced the completion of enrollment of more than 480 participants in ZUPREME-1. And today, we are sharing the preliminary baseline characteristics of the participants in this trial. ZUPREME-1 has a population with a mean BMI of approximately 37 kilograms per meter squared at baseline and includes a balanced gender distribution with 53% of the participants being female, notably different than the population studied in our Phase I trials. And we look forward to reporting top line results from ZUPREME-1 in the first half of 2026. Turning now to Slide 12 for a brief update on dapiglutide, our first-in-class GLP-1, GLP-2 receptor dual agonist. We were very encouraged by the top line results from Part 2 of the Phase Ib trial with higher doses of dapiglutide announced in June. These data showed a weight loss that is highly competitive compared to the currently available GLP-1-based therapies for weight management at similar time points, despite dapiglutide being studied in a predominantly male population again with a relatively lower baseline BMI. That said, we recognize that differentiation is absolutely essential, and our strategy is to leverage the dual mechanism of dapiglutide, which includes GLP-2 activity and move into a dedicated Phase II obesity-related comorbidity trial in the second half of 2025. Now turning to Slide 13 and survodutide, a potential best-in-class glucagon GLP-1 receptor dual agonist in late-stage development for the treatment of obesity and MASH. We are rapidly approaching top line data from SYNCHRONIZE-1 and SYNCHRONIZE-2 Phase III trials, which are evaluating the efficacy of safety and safety of survodutide in people with overweight or obesity, both with and without type 2 diabetes, respectively. The design of the SYNCHRONIZE Phase III program builds on key learnings from the Phase II obesity trial where trial participants achieved mean weight loss of up to 18.7% after 46 weeks. Notably, these Phase III trials will assess even higher maximum doses of up to 6 milligrams. We remain extremely excited about the potential of survodutide and novel dual agonist therapy for weight management and look forward to top line results from SYNCHRONIZE-1 and 2, likely to be reported in the beginning of 2026. We are also very excited on Slide 14 about the ongoing survodutide Phase III program in people with metabolic dysfunction-associated steatohepatitis or MASH, a serious obesity-related comorbidity with significant unmet medical need. Shown on this slide is an indirect cross-trial assessment of clinical trials with incretin-based therapies in MASH compared with the only approved therapy today, thyroid hormone receptor beta agonist. In the Phase II trial with survodutide in people with MASH and liver fibrosis, 38.6% of adults with moderate to advanced scarring achieved a placebo-adjusted biopsy confirmed improvement in fibrosis without worsening of MASH after 48 weeks of treatment. We believe this represents the most compelling and strongest clinical data set to date on the important endpoint of liver fibrosis improvement. The LIVERAGE program initiated in 2024 is the largest ever Phase III MASH program with an incretin-based therapy and the only program to also include patients with compensated cirrhosis. With the best-in-class MASH Phase II data and the robust ambitious Phase III program underway, we believe survodutide has the potential to become the therapy of choice in a large and growing market, offering a much needed treatment option for people living with...

Excuse me, Mr. Kendall. Apologies for interrupting you. Unfortunately, your sound is breaking up and dipping in and out. So we're finding it difficult to hear you.

Can you try to say something, David, again?

David M. Kendall: Yes. Can you hear me now, operator?

Much better.

I can hear you now, yes.

David M. Kendall: Okay. Don't know the problem, but thank you, and I'll continue. Turning now to Slide 15, and apologies for the difficulties with the sound. Survodutide is licensed to Boehringer Ingelheim, as mentioned by Adam, and BI is a family-owned leading biopharmaceutical company with a strong legacy in cardiovascular, renal and metabolic diseases and a global presence across 130 markets. Boehringer Ingelheim holds sole responsibility for the global development and commercialization of survodutide. Zealand Pharma has no financial obligations to either development or commercialization under this agreement, but is entitled to percentage royalties on global sales ranging from high single digit to low double digit. In addition, we are eligible for up to EUR 350 million in remaining outstanding milestone payments. Notably, Boehringer Ingelheim is an established leader in the CVRM and diabetes space, having developed and launched the leading SGLT2 inhibitor, empagliflozin. The company has been instrumental in demonstrating empagliflozin's benefits in reducing cardiovascular risk, slowing the progression of chronic kidney disease and alleviating the burden of heart failure. Moving to Slide 16 for a brief update on our rare disease programs. For dasiglucagon in congenital hyperinsulinism, our third-party manufacturing facility has not yet received a classification upgrade. In the meantime, we have implemented a supply contingency plan that includes the qualification of an alternative to supplier to ensure we can bring this product to patients in need as quickly as possible. For glepaglutide for the treatment of short bowel syndrome with intestinal failure, the Phase III EASE -5 trial remains on track for initiation in the second half of 2025 to further support regulatory submission in the U.S. In June, we were pleased to announce the submission of a marketing authorization application to the European Medicines Association seeking approval of glepaglutide in the EU. We remain incredibly excited and encouraged by the clinical profile of glepaglutide as a potential best-in-class long-acting treatment for the management of short bowel syndrome with intestinal failure. With that, thank you very much for your attention. I would like to now turn the call over to our Chief Financial Officer, Henriette Wennicke, to review our financial results for the first half of 2025. Henriette?

Thanks, David, and hello, everyone. Let's turn to Slide 17 and the income statement. Revenue in the first 6 months of 2025 was DKK 9.1 billion, driven by the initial upfront payment under the collaboration and license agreement with Roche. Of the DKK 9.2 billion in upfront payment received in June, DKK 9.0 billion was recognized as revenue in connection with the closing of the agreement in May 2025. The remaining DKK 262 million of the initial upfront payment is associated with progression and completion of the Phase II trials with petrelintide, of which DKK 167 million was deferred as of June 30, 2025. Net operating expenses totaled DKK 968 million for the first half of 2025, of which 78% was spent on research and development. The R&D expenses are mainly driven by the development of petrelintide, including the last Phase II trial and preparation for Phase III. R&D expenses also reflect preparation for Phase II with dapiglutide, increased investments in the Kv1.3 ion channel blocker as well as development and regulatory activities related to the rare disease programs. Net financial items amounted to negative DKK 157 million. This is driven by exchange rate adjustments, which primarily relate to USD deposits and currency revaluations on account receivables and cash equivalents. This was partly offset by interest income from the investment in marketable Securities. Let's move to Slide 18 and the cash position. As of June 30, 2025, our cash position totaled DKK 16.6 billion, a significant increase compared to the DKK 9 billion at the beginning of the year. This is, of course, driven by the initial upfront payment of DKK 9.2 billion from Roche, partly offset by operating expenses for the period and the purchase of treasury shares to support Zealand Pharma's long-term incentive programs. I would like to use the opportunity to remind everyone that on top of this very solid financial position, we are entitled to receive a total of USD 250 million in anniversary payments over the next 2 years under the Roche collaboration as well as potential development milestone of up to USD 1.2 billion. The vast majority of these development milestones are tied to the initiation of Phase III trials with petrelintide monotherapy. As I stated on our last quarterly earnings call, I'm pleased with our strong financial position. We can fully honor our obligation under the comprehensive Roche collaboration for petrelintide and at the same time, accelerate investments in the early-stage pipeline to build the next wave of innovation. Let's turn to Slide 19 and the financial guidance. I will keep this short as there are no changes to the outlook for the year. We confirm the financial guidance on net operating expenses, which are expected to be between DKK 2 billion and DKK 2.5 billion, excluding transaction-related costs associated with the Roche agreement. And with that, I will move to Slide 20 and turn the call back to Adam for concluding remarks.

Thank you, Henriette. Two years ago, at our Obesity R&D event in London, we laid out a bold vision to become a key player in the management of obesity through innovations that address one of the greatest health care challenges of our time. Today, I can say with confidence that we are exactly where we want to be towards realizing that vision. We have the survodutide Phase III obesity data and survodutide Phase II data in our sights. And we have significantly strengthened our capabilities to execute and our financial position to both advance our clinical portfolio and invest in the next wave of innovation. So please save the date for our Capital Markets Day on December 11, where we will share further insights and updates and discuss why we are so excited about the prospects for Zealand Pharma. I will now turn over the call to the operator, and we'll be happy to address questions.

[Operator Instructions] We will take our first question, and the question comes from the line of Rajan Sharma from Goldman Sachs.

I've got a couple on petrelintide. So firstly, Adam, David, it would be good to get your perspectives on the eloralintide data that we saw at ADA in June. Just be interested in your thoughts on how petrelintide compares and any learnings on what this means for the ongoing debate between amylin selectivity versus DACRA? And then secondly, just on body composition, which I know is a secondary endpoint in ZUPREME-1, but at ADA again, we saw that data from Novo's REDEFINE trial suggests that there was no benefit on body composition from the amylin component of CagriSema relative to the GLP-1. So just wondering if there's any reason why petrelintide may be different? Or should we expect any benefit here to be sort of an upside to your base case assumption?

Thank you, Rajan. Maybe, David, you would take a first go on answering these questions. Can you hear us, David?

David M. Kendall: Happy to unmute and hopefully clear on the microphone. Rajan, thanks for your question. I'm happy to provide perspective. I think the Alora data, which are obviously early phase data in a relatively small population, as we alluded to in the prepared remarks, show us that one of the other key players in the space, Eli Lilly, has a great interest in amylin-based therapies. I think there was some excitement over both the dosing regimen and the clinical response. I would say from our perspective, 2 very important key points, one you alluded to, data that colleagues from Novo Nordisk reported in a separate session, separate from the Alora poster presentation suggested that Alora, like other balanced amylin agonist does result in an acute lowering of serum calcium in animal models, which suggests that Alora, despite what is reported and what has been in some hands an amylin-specific receptor profile is very likely a more balanced or pan-receptor activator across the calcitonin amylin -1 and amylin -3 receptors. That said, the clinical response in our mind, particularly at the 2, I'll call them, middle to high doses, is quite consistent with other drugs in this class despite the exuberant response in their highest dose group and the dosing interval. I think given the small data set, there are also a lot of unknowns about this asset, in particular, the reports of several neuropsychiatric adverse events, which is distinctly different than what has been reported both with cagrilintide and with petrelintide as well as headache, which has been reported with other amylin agonists and indeed with pramlintide back in the day. Provocative tests to initiate or trigger headache were enhanced with another amylin agonist -- amylin receptor agonist. So I'd say certainly encouraged that there is attention to this space. We do not see these data as clearly differentiating from other amylin-based therapies, including petrelintide. And as I alluded to, we are quite pleased with the consistent and now comprehensive data sets we have pulled together from all the Phase I trials. And obviously, Phase II will tell us much more about that treatment response. To your question about body composition, Adam, I'm happy to turn it back to you or make comments myself.

Please comment, David.

David M. Kendall: Yes. I think the Novo data in a relatively small subset using a less precise, but a broader and more applicable approach, which is DEXA, did not provide clear evidence of changes or preservation of muscle mass. However, as you well know, Rajan, that there is now broad evidence from nonclinical models, and I emphasize nonclinical models that amylin agonists are associated with significant preservation of lean mass, particularly in these high fat-fed animals who are gaining weight. Now that is very different than older adults or those in clinical trials who are usually at a high weight, but stable who then enroll in clinical trials. But we still remain quite confident that amylin-based therapies, including petrelintide, particularly using the MR-based measurements we are using in the subset of patients in ZUPREME-1 can and will be the -- both the approach and the studies that will demonstrate as clearly as possible what happens to lean mass. Importantly, while lean mass preservation to us is important, it is really a value add on top of what Adam and I alluded to, and that's a significant weight loss, particularly in the range of 10% to 20% that the vast majority of patients desire and the tolerability profile. Effects on other biomarkers, effects on lean mass, we think, are significant value adds, but not key to the success of these molecules.

We will take our next question. Your next question comes from the line of Kirsty Ross-Stewart from BNP Paribas Exane.

This is Kirsty Ross-Stewart from BNP Paribas. So 2 questions from me. Firstly, on the kind of safety and tolerability profile of survodutide. You've kind of spoken about the target weight loss between 15% and 20% annually before. But I was wondering if you can give some more color on what you believe would be clinically meaningful in terms of side effect profile. And I noticed your slide indicating that kind of over half of patients are not willing to accept any GI AEs. So in light of that, kind of what do you believe would represent a sufficient improvement over GLP-1s to induce a kind of meaningful uptake in intolerant patients? And maybe one also on dapiglutide and any read across that you see from the upcoming evoke data from Novo. Maybe you could talk to the potential for dapiglutide to address diseases such as Alzheimer's, where a microglial inflammation plays a role. And what you'd like to see maybe in your own exploratory data or Novo's upcoming data to give you the confidence to go here beyond the program that you're starting later this year? That would be great.

Thank you, Kirsty. Maybe I'll start and then see if David has additional insights to add. On the ratio between efficacy and safety and tolerability, I think it is, as we also alluded to in the prepared remarks, a super important question. Because if we look out today, most patients actually have the tools available that can provide them with the weight loss they're looking for. The problem is most patients don't ever get to their highest doses, and we think a large part of those are because of side effects. And the other thing that we -- if you do market research, you will learn is that if you ask individual patients, they would -- overall, most of these patients would come back and tell you that they're looking for a 10% to 20% weight loss. But it's also clear that the biggest challenge is to not actually achieve the weight loss today, but actually maintain that. If you don't stay on therapy, then most patients will regain the weight. So when we talk about a tolerable profile and how we are designing our program with petrelintide, it is actually with that in mind to make sure we target not only the maximum weight loss, but the optimal ratio between weight loss and side effects. And what we have seen from our program thus far, as David also alluded to, is a very robust set of data suggesting that ultimately, with the dosing that we are pursuing, we would expect to get into a mean weight loss of between 15% and 20%. And if you look into the GI, in particular, side effects, but also other side effects, we have seen minimum to no GI side effects in these cohorts when dosed at the levels and with the titration regimes we use. And it is actually important to note also, as we saw from the cagrilintide Phase III data. That is, of course, not just about nausea or vomiting or other GI effects, it's also the severity of these. Are they mild, moderate or severe? And we at least saw with interest that even with cagrilintide at the doses where they delivered just around 12% weight loss, it was almost entirely mild event, which was in contrast to what you see with GLP-1-based therapies. So it's not only the event rate, but also the severity of these side effects that we think we can reduce significantly with our approach to amylin. And then on dapiglutide, and of course, I think the evoke study will be super important. Remember, it's rather low doses of a GLP-1 that is applied into that study. But we have also recognized that the profile of a GLP-1 and GLP-2 could be interesting in a disease like Alzheimer's. It could also be interesting in a more GI-driven inflammatory conditions such as IBD. David, do you want to add further insights?

David M. Kendall: Yes. Just one thing to add then, Kirsty, thanks to Adam's comment about we clearly believe with amylin agonist less common, less severe, but I would also add that different character of those GI side effects. And while that's difficult to tease out in clinical trials in the clinic, and particular experience back with pramlintide, this sense of fullness, satiety, that sense of feeling full more quickly, feeling full faster is very different than the food aversion signal and the nausea. We think similarly, we'll have a different character to Adam's point, in our Phase I program. To date, only a single patient who discontinued treatment with petrelintide out of all those exposed, and in particular, when we started at lower doses in the multiple ascending dose and titrated up in a scheme, even though it was every other week, that tolerability profile demonstrated, I'll say, substantially fewer events and less severe and what we believe will be different characters or characteristics of that adverse event profile. The other comment I would make is what I emphasize, which is a distinct difference between tolerability, particularly in a clinical trial, which is designed to keep people on therapy. Yes, if the only therapy available to me is an incretin-based therapies, I may tolerate it. But when options become available, is it the most acceptable therapy. So we will obviously strive to look more carefully at not just tolerability, the reported effects, but how acceptable is this to those who take an amylin-based therapy versus any experience with an incretin-based therapy.

We will take our next question. The next question comes from the line of Michael Novod from Nordea.

Michael from Nordea. A couple of questions. So first, maybe can you discuss sort of around the commitment priorities, et cetera, with Roche. Obviously, we've seen a lot of movement in the obesity market and also a lot of movement to obesity market sizing forecasts over time. So has there been sort of any big discussions in the collaboration? And has that also changed sort of what the bar is in terms of what an amylin can do in terms of monotherapy weight loss when we look into the Phase II readout in the first half of 2026 for petrelintide? And then secondly, maybe you can just try to discuss the sort of potential licensing or partnering strategy around dapiglutide. Will the Phase II that you're doing with regards to comorbidities, would that lead to sort of conclusive results in order to start potential partnering discussions? Or how should we sort of evaluate the road ahead for dapiglutide following the Phase IIb?

Thank you, Michael, and I will take a shot on these answers -- these questions. So if you think about the developments in the obesity market right now, we have been saying for quite some time that we think people are too focused on who gets the highest weight loss and who get -- who can deliver the fastest because market research with patients would actually suggest the opposite. Most patients are looking for 10% to 20% weight loss. And actually, some patients struggle if it's too fast. They want a visible weight loss, they want to see that something happens, but it can also be too fast. So I think that is the market condition we are looking at. That is what I would describe as GLP-1 launch fatigue and actually not obesity fatigue. And for, you can say, companies who have set out on a mission to address what we consider the biggest health care challenge of our time. For us, and I would include us in that kind of statement, that is an opportunity what we are looking into at the moment. That is basically identifying the shortcomings of the current medicines out there and suggesting where we can actually play. We can be out there with a medicine that delivers the weight loss that are quite similar to what we -- what the products are doing today, but hopefully, with a more tolerable profile and thus allow more patients to stay on therapy. A key part for why we chose to partner with Roche was that they already a few years ago, took a big step into this space, and they have had a very strong commitment to wanting to get into this space and lead. So this -- we wanted somebody who have the same ambition as us, somebody who don't just want to get in because it was the talk of the town, but a company who really means it. And this is what we tried to allude to during the prepared remarks that we are extremely impressed to see the firmness with which they move forward. We were, of course, extremely pleased to see also the investments into manufacturing capacity. I think sometimes it's overlooked that it's not just about a clinical data set and then a decision to move forward. Because once you decide to move forward, if you want to be launch ready, you need to make very substantial investments into manufacturing. Otherwise, you will face the issues that the 2 frontrunners faced with supply constraints and what follows there. So our sense in our dialogue with Roche is that they are as committed, if not even more, as they have been for a long time to come into this market and become a leading company to address what we -- both companies see as the biggest health care challenge of our time. And if anything, I would say the bar for success is being lowered in my mind these days because more and more people realize that it's very few patients that are going for that 25% plus weight loss. And realistically, those patients who need the highest weight loss are more likely to benefit for combination therapies rather than single modalities. That is how you treat chronic diseases, that is by combining different modalities if you need more effect than what one modality can do. You very seldom see people maxing out on one modality because often you will see side effects and safety concerns following pushing things too much. It's much better to combine. So I think we are just being confirmed in these months and years on the strategy, and I think Roche feels the same. On the dapiglutide Phase II program, I think it's a very fair observation that -- our focus right now is to get the Phase II study started to clearly identify the differentiation potential for dapiglutide in addressing inflammation to a larger extent than the other GLP-1s. And then our hope, of course, will be that following those data, we will go out and discuss with potential partners on that program. But we also recognize that we need those data in hand before we will have sufficient clinical excitement to progress partnership discussions on that.

We will go to our next question. Your next question comes from the line of Andy Hsieh from William Blair.

I appreciate the additional color about the ZUPREME-1 baseline characteristics, potentially hinting at a better outcome than what we've seen before. Two questions for us. One has to do with Roche's manufacturing infrastructure that you announced in the press release and the synergy that can be derived from that project. I'm curious if both petrelintide and 388 are produced with the same means, i.e., synthetic or recombinant. So I'm just curious if you can comment on that. The second one has to do with the titration strategy when it comes to the Phase II combo study that is expected to start later this year with petrelintide and CT-388. Are you thinking about something that could be a little bit different from what we've seen in REDEFINE-1 and 2 with the in sync titration or maybe staggered titration, basically titrating 1, followed by the other the following week. Just curious about how you think about this titration strategy that could optimize tolerability profile?

Thank you, Andy. I will answer your first question and hand over to David. When we announced the manufacturing capacity expansions that have been announced in North Carolina by us is a high-capacity, high-volume fill/finish capacity. So that is drug product and filling lines. And it's actually the critical part of getting products to patients that to have these -- the filling capacity up running for prefilled pens. It is where we have seen supply constraints historically, and it's probably where we need the biggest investments. When it comes to API or synthesis of the program, it's actually easier to handle and it can be handled with suppliers and infrastructure that are more or less -- I mean, we will need investments there as well, but it's actually the fill/finish and drug product filling lines that are causing shortage. It's also where you can probably gain the biggest benefits by making sure you have high-volume lines because it is the most costly part of your food product. On the synthesis part, we have, you can say, all things in place to support the amount of drug substance needed for launch. Those plans were actually already being built by us before we entered the partnership. So David?

David M. Kendall: Yes. Thank you, Adam. And Andy, thanks for the question. I think you already alluded to what for us is an opportunity to do things significantly differently than was executed in the REDEFINE redefined program where, as you know, both assets, the cagri and sema doses were essentially tied together, meaning you escalated one, you escalated the other. Similarly, the goal in that program, while the studies were complex, was to push to higher doses and also to push to greater weight loss, tough to answer in a single study. With the fixed-dose combination with petrelintide and 388, obviously, Phase II data will provide us the necessary information to understand which doses can optimize the clinical response. But balancing what Adam and I have both referred to, which is the tolerability and acceptability profile of each asset, we are discussing multiple options. But instead of maximizing each, I would say our goal in Phase II will be to optimize each. And we would anticipate that, that is higher dose amylin-based therapy, petrelintide at the maximally effective doses. If it, in fact, remains as well tolerated as we've seen in the early phase trials, while then adding what I'll call an optimized, but not necessarily maximal dose of the incretin-based therapy to provide additional weight loss, glycemic control for those with diabetes, potentially cardiovascular risk reduction, so in discussions with our Roche partners. Whether this will be, I'll call it, a high petrelintide, low 388, high-mid or high-high, I think we collectively in the alliance with Roche agree that if you go to high doses of both, you will achieve the greatest weight loss, but balancing that with an acceptability and tolerability profile where we think we can fully leverage the better tolerability of the amylin-based therapy while still adding adequate or optimized doses of 388. So that is our current strategy, pending all of us having line of sight to the Phase II dosing data. And then finally, creating a simplified a dose escalation scheme as possible. So you don't have multiple doses or changes. Obviously, this is intended as a fixed dose co-formulated asset. So Phase II will teach us a great deal. Great question and more to follow, Andy.

We will take our next question. Your next question comes from the line of Prakhar Agrawal from Cantor.

Congrats on the quarter. So maybe first, there's a massive disconnect between the stock price and the value of petrelintide ascribed by Roche during the deal. I'm sure you'll agree with that. And you have so much cash in hand and we'll have milestones from Roche next year with high probability of achievement. So why not consider something like a share buyback given the disconnect? And if not share buyback, could you consider BD in the metabolic disease space as there are many opportunities out there, for example, in China? And then one clinical question. Coming out of ADA, the other question on the CagriSema data was the impact on CV and inflammation markers, which were more modest compared to GLP-1s even for CagriSema and cagrilintide. So what are your thoughts on the CV inflammation data and implications for petrelintide when ZUPREME-1 reads out?

Thank you, Prakhar. I will take the first question and hand over to David for the second. Remember that the announcement -- we announced the partnership with Roche in March and we closed in May is a historic and transformative partnership in that it's a true co- development and co-commercialization partnership. It's not a licensing agreement. We will have in order to realize the full potential of the 50% value and future profits of not only petrelintide, but also the combination product of petrelintide and CT-388, we of course have to carry our share or cover our share of the development costs. So it is incredibly important for us to be well funded as a company to deliver on that opportunity to have 50% of future profit from this partnership. Of course, we don't have to invest into manufacturing, which us will carry all the manufacturing investments, but we will have to carry our share of the development cost and the prelaunch costs. So for me, it is actually more important to make sure that we stay as well capitalized as possible so we can deliver on our commitments into this partnership. The last thing I want to do is to put Zealand in a position where we cannot honor our financial obligations into the partnership. So while we are extremely well capitalized, we also believe it is super important for us to be in a position where we can continue to honor our obligations from a financial perspective. And also recognizing that we are a company -- we are an innovation company, we are a biotech company who have delivered again and again, great innovations. We do expect to continue to invest in the rest of the pipeline to deliver on our ambition to become a leading player in the obesity space and the associated diseases. We think we have a significant opportunity to leverage our 25 years of expertise and experience in peptide drug discovery and development and tap into these unique opportunities that are now coming true in obesity and all these related diseases. So you should not expect a share buyback program from Zealand. And on the next question, David, I will hand over to you.

David M. Kendall: Yes. Thank you, Adam. And Prakhar, a very important question, and we saw what you and others did in the cagri data. I will simply state that while amylin-based therapies clearly are not GLP-1-based therapies, GLP-1s have demonstrated cardiovascular risk reduction in both diabetes and obesity, likely have pleiotropic effects due to receptors on multiple tissues. Both the magnitude and direction of CV risk markers for us in our early phase program with limited data in the broader cagri program, including their Phase II readouts still demonstrate directionally what we consider very positive evidence that blood pressure, potentially markers of inflammation, and body weight, all 3 very important determinants of CV risk. There's also nonclinical evidence of direct effects of amylin agonism on cardiac tissues, not through receptors, but likely through other mechanisms, either through vagal afferents or through body weight reduction. So in our mind, and as Adam alluded to, we are not looking to go toe-to-toe with GLP-1s. We are looking to develop a unique class with unique benefits. You and I discussed at a recent fireside chat that one sure way not to get cardioprotection from GLP-1-based therapy will be that you cannot take it or will not take it due to tolerability issues. So we strive to leverage our data with petrelintide and the program looking at cardiovascular outcomes to determine if amylin-based agonist with these improvements in risk markers can and will, as we would hypothesize, reduce cardiovascular risk. So yes, lesser magnitude but to us, both directionally and more broadly across clinical programs, evidence that cardiovascular risk markers all trend in the direction that will support cardioprotection from amylin-based therapies, including petrelintide.

We will take our next question. Your next question comes from the line of Cerena Chen from Wells Fargo.

So I wanted to ask what you think is the real addressable market opportunity for patients who cannot tolerate GLP-1 since we've heard anecdotally from doctors that discontinuation due to tolerability is fairly low and much less than that 60% discontinuation within 1 year that's commonly cited. I was curious perhaps what your market research indicates is the real discontinuation rate from the more current GLP-1s like semaglutide and glepaglutide?

Thank you for the question. And I think it's -- number one, I think we have clearly witnessed that once these molecules are utilized in a clinical setting with perhaps sometimes less experienced prescribers, discontinuation rate remains very high. I think David alluded to another extremely important question, and that is around acceptability. Remember that right now, we are in a world where there's no alternatives. So at least one opportunity or one situation we could be in is that people are actually ready to accept more side effects than if there was an alternative. Imagine a world where there would be an alternative, which would provide the same degree of weight loss, but where you have less GI side effects, where you do not lose your appetite and your interest in food, but more fill-full faster and thus can enjoy social events around food. I think history has shown us that people once they have choices, will actually go for those choices. And if there are choices, people are ready to accept less than if there is only one solution. So we are quite firm not only considering the discontinuation rates we have seen today, but also anticipating that if there is a more tolerable approach, acceptability would actually drop even further for the current therapies in our ambition to position petrelintide as a future foundational therapy for those patients who wants to potentially have a more pleasant weight loss experience if we can continue to deliver on the data that we have seen thus far with this molecule.

We will take our next question. Your next question comes from the line of Yihan Li from Barclays.

Yihan from Barclays. So I have 2. The first one is on petrelintide. So again, thanks for sharing the baseline data. So actually based on our very quick calculation according to what the petrelintide showed in Phase Ib, it seems like based on your -- like today's shared baseline data, it seems petrelintide could potentially reach around like 10% weight loss at week 16 in the [indiscernible] trial after adjusting male-female ratio, baseline BMI and slowed titration schedule. So I think it's indicating very promising to reach [ Wegovy ] like around 13 to 15 week loss at 42 weeks. Just curious, is this something you are looking for? And also, could you please remind us what kind of parameters you will share in the top line in the first half of next year, and we should expect an investor call post the [ PR ], right? And the second one actually is kind of like a follow-up. It's kind of like the efficacy durability for the amylin class. So because we saw at ADA like the REDEFINE-1 trial from NOVO, the cagrilintide had a relatively slow weight loss from around 44 weeks versus semaglutide or CagriSema actually showed a very clear continued weight loss post 44 weeks. So there are some concerns or more of a question marks for me, like how amylin class may produce, I don't know, it's like strong early weight loss, but the efficacy may potentially win faster than the GLP-1s over time? So just curious how should we think about this weight loss durability of the amylin class?

Thank you for your question, and maybe I'll just answer quickly. So we were actually quite impressed to see cagrilintide at the dose of 2.4 milligram delivering close to 12% weight loss in a 68-week study because we consider 2.4 milligram of cagrilintide to be a very low dose of amylin compared to the 9 milligrams we are testing now with much higher -- of our amylin analog with much higher bioavailability. And at least as one comparison, I think if you consider utilizing a very low dose of GLP-1, you would also, at one point, see that there would not continue to be weight loss. So we are excited about the potential for us to test even higher doses as, of course, as you also alluded to, we would expect higher doses to provide more weight loss and thus also the ability to achieve longer-term continuous weight loss. We, of course, as David also alluded to in his prepared remarks, are very aware of the fact that in general, women or females lose more weight in these studies than males, and we had only around 20% in our Phase I studies, now will be just around 50% females in the upcoming Phase II. And most often, people report from the Phase III trials around 60% to 65%, up to 70% females. So there's, of course, an opportunity here that just the trial design and the inclusion of the patients into these studies can help on the numbers. What we are firmly focused on is to achieve a weight loss that hits that bar of around 15% to 20% weight loss in the most pleasant way for a patient. So we somehow refuse to be into a very tight numbers game. As long as we are confident that based on our 28 and 42 weeks' data that we can achieve that 15% to 20% weight loss in a Phase III study and with a very pleasant experience and less side effects, we will be extremely bullish for the opportunity for petrelintide.

[Operator Instructions] We will take our next question. And your next question comes from the line of Sophia Graeff Buhl Nielsen from JPMorgan.

Could you provide any updated thoughts on how you see the opportunity in MASH, not only in light of the upcoming [indiscernible] data, but also with the potential label expansion for Wegovy in the U.S. in the second half?

Thank you for that question. And I think it's highly relevant. As we have also tried to indicate in our call today, I think perhaps people do not ascribe significant and enough value and also, you can say, opportunity around the semaglutide franchise. I think we still need to realize -- most people still need to realize that up to 35% of obese individuals have some degree of MASH. It is one of the most underserved consequences of living with NASH, and we only have one new FDA-approved treatment for these, which provided around 11% ease in fibrosis without worsening of MASH. If you look into the data that Boehringer have presented last year in MASH with dapiglutide semaglutide, as they themselves described as groundbreaking, we will agree to that. It was approaching 40% reduction in fibrosis without worsening of MASH. And then I would say, then we are looking at something that can truly change the needle for those patients who live with that condition or are at risk for that. I think if you look into the Phase III program that Boehringer are investing in MASH, which is in at least to our knowledge, by far the largest program, not only targeting [ F2 and 3 ], but also cirrhotic patients including very strong commitments to follow these patients on to clinical outcomes. That's a testament to also Boehringer's belief in their ability to differentiate semaglutide into this and provide a treatment option for these patients that can make a meaningful clinical impact.

We will take our next question. Your next question comes from the line of Benjamin Jackson from Jefferies.

Great. I'll keep it short. Adam, I mean, specifically for you here, I guess we've seen recently that the market in the GLP-1 sense develop to expand in a cash pay setting in a DTC setting. I think previously, we've -- you've had questions about whether you think that the obesity market ever could get to a state where it could be OTC, and this is probably one of the closest steps you can get towards it. So I'm wondering what you're thinking here in terms of amylin and how you could -- whether you believe that is something you can position in a cash pay setting in the future? Or is very much your focus being on a long-term -- long adherence population and market. So any thoughts or any changes in the way you envisage the market developing, that would be great?

Thank you for that question. And I think as you alluded to, it is, of course, something that we have been following closely, and we've also been clear in our statements around this. In order to ultimately address the obesity pandemic and all the diseases that follows, we need novel ways to get these patients to -- these products to patients. And direct-to-consumer, once you have enough safety and experience around them is one way to go for sure. The cash market, I think we're already now seeing how important it is. Maybe people have been surprised how fast it has moved. But I don't think anyone could honestly question if it would come because we know how interested patients are in getting on these treatments and the willingness to pay for these treatments has also been clear for a long time. So it's just a matter of how fast it comes. And it really opens unique opportunities for companies like us and Roche as we enter the market. But of course, it's something we have to discuss and plan for. But if you look at a profile like the one we have for petrelintide, I would say that, of course, lends itself extremely well into that segment if it turns out that it is an easier prescription, it is an easier product to be on, and it will deliver the patients -- the weight loss that patients are looking for. So I don't see a disconnect between consumer payments and then long term, staying on treatment for a long term. I actually think a lot of patients would be willing to also pay for staying on treatment as long as the weight loss and weight maintenance experience is one which they will accept. Thank you for the question.

We will take our next question. And the question comes from the line of Julian Harrison from BTIG.

This is Rei, on for Julian. You mentioned the value-add effects and the importance of weight loss quality. Is there a number you would like to see on body composition in ZUPREME? Or is less lean mass loss relative to existing therapies enough to translate into preference in practice?

Thank you for your question. We cannot provide a specific number. I would say, as David also alluded to, any weight loss program will be associated with some degree of muscle loss because you carry less weight. What we would be looking for in our program is, of course, that we don't have exaggerated muscle wasting as we may have seen with some of the GLP-1s when you lose weight too fast and too dramatic getting into a very negative energy balance and reducing -- increasing your insulin levels, et cetera. So we are probably -- it's too early to provide a number, but healthy weight loss for us is one which at least does not exaggerate the muscle wasting during the weight loss.

We will take our next question. And the question comes from the line of Jacob Mekhael from KBC Securities.

I have a question on the Phase II trial for dapiglutide in an obesity linked condition in the second half of this year. Can you share what that condition would be? And given that there are multiple obesity linked diseases that you can pick from, could you walk us through the criteria that you use to select that indication?

Thanks for your question. And it's probably one quarter too early to share the specific indication, but we'll come back in not that distant future. But clearly, for us, it's about differentiation. We don't want to be among those companies who develop undifferentiated weight loss agents that do not make a true difference for patients.

In the interest of time, we have one final question. And the final question comes from the line of Carsten Lonborg Madsen from Danske Bank.

I just had a question to Slide 10, where we shared this gender data was quite impressive weight loss for the females in the trial. But at the same time, isn't it also a little bit concerning to you that you see maybe no additional response or maybe even less response in the male part of the trial when doubling the dose from 4.8 to 9 milligram? I was interested to hear your view on this.

I mean, David, I don't know if you have further comments to this one. But number one, remember, a small data set. It could be -- again, we don't know what doses are the right ones. That is what we explore in Phase II. Even if you look at the mid-dose or the 4.5 milligram dose, if you look at those numbers, you can say -- that could, of course, deliver the weight loss we are looking for also in a long-term study. That's why we are entering the phase -- such a rich dose finding in Phase II. When we looked into the early responses in the Phase I study, there was a tendency for differences in how fast these people lost weight. So we still, would say, believe that the higher doses could provide more regardless of the end number in this study suggested that the 2 high doses were equally effective. David, any further comments?

David M. Kendall: Yes. I think 2 points, Adam. One is actually in this cohort, the 4.8 milligram, we saw this group lose weight at similar doses more quickly. So that may have actually overemphasized, as Adam said, in this small cohort, it's difficult to differentiate. And you actually see in the 2 higher dose cohorts, particularly the 9-milligram, there is significant individual variation and in a small data set that can provide you a number of questions, but doesn't provide the clarity. I think the 480-plus participants in the full Phase IIb will be a better way to address that. The other is to be aware that across weight loss approaches, and that's diet and exercise as well as medical therapies, women, on average, lose 3% to 5% more body weight over a year or more of exposure. So I think those are the things we weigh our gender balance on. And I think Phase II will be a much more robust data set for us to address your question and the dose finding for us.

Excellent. And then a small quick follow-up to that one, which is also part of my first question, but completely unrelated. In terms of Phase III trials, we have learned so much about the obesity space over the last 52 weeks that it's developing rapidly all the time. Should we expect that you're planning for sort of a classic Phase III setup with overweight, overweight diabetics, et cetera? Are there room for some new Phase III trials? I'm thinking maybe sort of GLP-1 naive or GLP-1 failures where you could sort of differentiate petre even more versus what's on the market today?

Thank you for your question, Carsten. These are super important considerations, which we are discussing with us right now, and we will have to wait a little bit to provide updates. But I would kind of also say that since we are developing an alternative, it's probably super important just to get out there. You don't need to -- as long as you provide the first alternative with a more pleasant side effect profile, most patients do not stay on therapy on the GLP-1 today. So I don't need to go out and convince the patients to stop taking something and then get on your new treatment. Most patients who have been exposed to a GLP-1 will at the time we launch it, not be on a GLP-1. So this focus on shifting and so on from being on a GLP-1 to getting to a novel modality, I think it's less of an issue here because we know from market data that patients -- most patients do not stay on GLP-1 for a long time. Thank you all for attending and for your questions today. We look very much forward to future announcements and updates and to connecting in the coming weeks and months.

This concludes today's conference call. Thank you for participating. You may now disconnect.