Zealand Pharma A/S

Good day and thank you for standing by. Welcome to the Zealand Pharma results for Q3 2024 conference call. At this time all participants are in a listen only mode. After the speaker's presentation there will be a question and answer session. To ask a question during the session you will need to press star 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1, 1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Anna Kraskowska, Vice President, Investor Relations and Corporate Communications. Please go ahead.

Thank you. Welcome and thank you for joining us today to discuss Zeeland's results for the first nine months of 2024. With me today are the following members of Zeeland's management team. Adam Steinsberg, President and Chief Executive Officer, Henrietta Wittnicker, Chief Financial Officer, David Kendall, Chief Medical Officer, and Eric Cox, Chief Commercial Officer. You can also find the related company announcement and interim report on our website at zeelandpharma.com. As described on slide two, I caution listeners that we will be making forward-looking statements that are subject to risks and uncertainties. Moving to slide three, I will turn the call over to Adam Stainsberg, President and CEO. Adam?

Thank you, Anna, and thanks to everyone for joining today. I'm extremely pleased with the achievements that we have made in the first part of 2024. At Obesity Week on Tuesday, we presented detailed data from the 16-week Phase 1 trial with Petrinatide, our long-acting aminine analog, which we are developing as an alternative to GLB1-based therapies for the management of overweight and obesity. We believe that these results strongly support that Petrinatide is very well tolerated and could provide a better patient experience than incretin-based therapies while providing similar degrees of weight loss. We expect the first participant in the Phase IIb trial with Petrientide to be dosed very soon. And we are also now exploring collaboration opportunities with large pharma companies. With the right partnership, we believe we have an opportunity to not only develop Petrientide as an alternative to GLP-1-based therapies, but also a potential future foundational of first-line therapy for weight management. In that regard, I'm pleased that with us on the call today for the first time is Eric Cox, who recently joined our management team in the role as Chief Commercial Officer. Eric brings 25 years of commercial and business development experience from biotech and leading global biopharma companies. He'll be a very important contributor as we explore co-development and co-commercialization opportunities. for our differentiated obesity programs. We are also very pleased to have reported positive and encouraging top line data from part one of the phase 1B trial with our GP1, GP2 dual agonist dabiglutide. We believe that this candidate holds the potential to be a first in class therapy for obesity and inflammation related comorbidities. The reported data gives us the confidence needed to progress Babiglutide into a comprehensive Phase IIb trial, which is planned to be initiated in the first half of 2025. On the back of the impressive Phase II data with servolutide en masse presented earlier this year, our partner Berner Ingelheim recently announced the initiation of a large global Phase III program for servolutide en masse. Berner also announced that cervidotide has received U.S. FDA breakthrough therapy designation for the treatment of adults with non-cirrhotic mass and moderate or advanced fibrosis. There is a significant overlap between obesity and mass. And with the clinical data reported to date, the ambitious Phase III program, and the recognition by regulators, we believe that cervidotide holds potential as a leading inquisitive therapy for obesity and mass. Turning to slide four, I would like to emphasize the reasons why we are so excited about the potential of betrunentide. We have seen the impact of the first two once-weekly GFP1-based therapies to be approved. In phase three clinical trials of longer duration, they have demonstrated potential for 15 to 21 mean weight loss in patients with obesity and positive outcomes on several obesity-related comorbidities. On the flip side, GLP-1-based therapies are associated with a number of gastrointestinal adverse events, including nausea, vomiting, diarrhea, and constipation. Real-world data suggests that up to 30% of patients with obesity on a GLP-1 treatment stop within a month before reaching their target dose, and that within one year, only 60% to 70% of patients withdraw from treatment. With Petranitide, we are targeting DLB1-like weight loss of 15% to 20% in longer-term phase 3 trials, with potential for higher quality weight loss and a different and better patient experience. As evident by recent data with Petranitide presented at a BCTV, we are confident that Petranitide has potential for significantly improved GI tallability profile compared to DLB1, receptor agonist, suggesting both lower frequency and milder severity of GI adverse events. And with that, let's move to slide five, as I turn over the call to our Chief Medical Officer, David Kendall, to discuss our R&D pipeline. David?

Thank you, Adam. Today, I would like to focus my remarks on the continued advancement of our obesity programs and provide a brief update on our other development activities. Beginning with our novel long-acting amylin analog, Petrelentide, let's move to slide six and the trial design of the recently presented detailed data of part two of our Phase 1B trial. This was a randomized, double-blind, placebo-controlled Phase 1B trial enrolling a total of 48 adults with overweight and obesity. Participants were randomized into one of three dose cohorts, assessing multiple ascending doses of Petrelentide using a dose titration scheme or to match placebo. Study medication was administered weekly for 16 weeks in an outpatient setting, followed by a nine-week safety follow-up period. I would also like to highlight that in this trial, we evaluated doses of petrolentide up to nine milligrams, and note that the two higher dose cohorts received the maximum assigned maintenance dose for a period of only six and eight weeks, respectively. Turning to slide 7, shown here are the mean weight loss curves across each of the individual dose cohorts and placebo. Petrelentide treatment resulted in reduction in mean body weight of 4.8, 8.6, and 8.3 percent from baseline after 16 weeks of treatment across the three dose cohorts, while placebo treatment resulted in a mean body weight loss of 1.7 percent. We find these data to be even more compelling given that the study population was predominantly male with a relatively low BMI, and these results were achieved in the absence of any background lifestyle modification, suggesting that the response observed may have been muted in participants included in this study. Moving to slide eight. Shown here are the individual study participant data on both adherence to study medication and to the dose escalation and maintenance scheme over the 16-week treatment period. These data demonstrate that there was both a high degree of compliance with dose escalation and adherence to and completion of study treatment for the vast majority of participants. Only a single trial participant discontinued therapy due to treatment related or petrolatide-related AHEs, which occurred after the third dose while also starting at a higher one milligram initial dose. In addition, one participant in the nine milligram arm was maintained for an additional week on the seven milligram dose due to reported tolerability issues. The two other participants who discontinued therapy did so for other reasons unrelated to study medications. Notably, all other subjects followed both the dose escalation steps defined in the protocol and completed petrolentide treatment as planned. We believe that the ease with which participants achieved their target dose and the proportion of those treated who remained on petrolentide treatment over the course of this trial support our conclusion that treatment with petrolentide is both well-tolerated and readily dose-escalated further differentiating this treatment from incutin-based therapies. Turning now to slide 9 and the tolerability profile. Additionally, the vast majority of treatment emergent adverse events reported, including those related to GI tolerability, were reported as mild, and only a single participant in the highest dose cohort discontinued treatment due to treatment emergent adverse event. Moving to slide 10, the data reported in this Phase 1b trial further demonstrated that all gastrointestinal-related treatment emergent adverse events were mild, except for the single event of moderate nausea and vomiting, both of which were experienced by a single study participant, the same subject that discontinued treatment. Notably, no other participant reported vomiting, and there were only two reports of diarrhea, both of which were mild, Nausea was reported in up to 33% of the petrolentide-treated participants, as compared to 17% reported by participants in the placebo group. Additionally, three participants in the highest-dose cohort reported constipation, all episodes of which were reported as mild. These data support the observation from earlier trials with petrolentide and further support our conclusion that petrolentide offers the opportunity to limit issues of GI tolerability. Overall, these data support and further our ambition for Petromatide, supporting that this novel treatment offers the potential for GLP-1-like weight loss and an improved patient experience as compared to that reported in both clinical trials and the clinical use of GLP-1-based therapies. Moving to slide 11 and the Phase 2b design. As mentioned in the last call, we will continue to progress our development of petrolentide as a standalone therapy in a large and comprehensive Phase IIb program. The first Phase IIb trial in persons with obesity or overweight with weight-related comorbidities, either hypertension or dyslipidemia, will initiate in the coming days. This larger trial with longer treatment exposure will enroll up to 480 adults and will compare multiple doses of petrolentide or placebo over 42 weeks of treatment with five dosing arms, the highest being 9 milligrams as in the Phase 1B Multiple Ascending Dose Part 2 trial. Participants will be continuing blinded treatment for 42 weeks with a primary endpoint of percentage change in body weight from baseline at 28 weeks. The primary completion is set for November 2025 and will enable us to more fully assess both the efficacy and safety of petrolentide across a wide dose range to inform the doses to be used in longer-term Phase III studies. Note that the primary endpoint at 28 weeks will be solely used for regulatory interactions about registrational trials with unblinded data readout only after completion of the 42-week treatment period. Key secondary and exploratory endpoints in this Phase IIb study will include an assessment of body composition by magnetic resonance imaging , change in HbA1c, change in fasting lipids, and change in high-sensitivity C-reactive protein . In addition to this Phase IIb study, we expect to initiate a second Phase weight loss in a population with type 2 diabetes and prediabetes, where data support that amylin agonism can potentially deliver weight loss comparable to that observed in non-diabetes population, further differentiating petrolentide treatment from GLP-1 receptor-based treatments, where muting of the weight loss response has been observed in those with diabetes. Moving to slide 12. and turning our attention to our other wholly-owned obesity asset, dapiglutide, a potential first and best-in-class GLP-1, GLP-2 receptor dual agonist. Dapiglutide is designed as a potent GLP-1 agonist targeting significant weight reduction and offers the potential to leverage GLP-2 pharmacology to improve gut barrier function and directly address the low-grade inflammation associated with metabolic disorders differentiated incretin asset. As we have recently reported, dapiglutide was evaluated in a single-center randomized double-blind placebo-controlled Phase 1b trial in participants with overweight or obesity. In Part 1 of this trial, a total of 54 participants, approximately 85% of whom were male, with a median baseline BMI of 30, were randomized to receive 13 weekly doses of either dapiglutide or placebo within three-dose cohorts. At week 13, the estimated mean placebo-adjusted body weight decreased by up to 8.3% with dapiglutide treatment. Dapiglutide doses of up to 13 milligrams were assessed to be both safe and well-tolerated with GI adverse events consistent with the frequent therapies. We are both excited and encouraged by these data, and we look forward to presenting detailed results at a future scientific congress. In addition, in part two of this trial, we are evaluating even higher doses of dapiglutide, up to 26 milligrams over 28 weeks of treatment. We expect to report top-line results of this part in the first half of 2025. And note that this added component of the Phase 1b study will not impact the timing for initiation of a Phase 2b trial in people with overweight or obesity, which we expect to initiate in the first half of 2025. We will obtain valuable additional insights on the optimal dose and dose escalation scheme to inform both the Phase 2b trial and additional studies investing the potential of dapaglutide in obesity and selected inflammation-related comorbidities, including liver disease, cardiovascular disease, inflammatory bowel disease, and neurodegenerative diseases. Moving now to slide 13 and cervidutide. Along with our Beringer-Ingelheim colleagues, we believe that the data from the cervidutide phase two trial in metabolic dysfunction associated steatohepatitis, or MASH, is the strongest clinical data set on improvements in MASH and liver fibrosis reported to date. Positioning cervidutide is a potential leading incretin-based therapy for the treatment of obesity in MASH. This leads me to slide 14. We are very excited that our partner, Beringer Engelheim, has initiated a large Phase III program for cervidutide in MASH, in addition to the ongoing studies in obesity. Liverage and liverage cirrhosis are global Phase III clinical trials investigating the efficacy and safety of cervidutide in adults with MASH and moderate or advanced fibrosis, and in those with compensated MASH cirrhosis, respectively. Turning to slide 15 and a few remarks on our rare disease franchise, starting with daziglucagon for the treatment of congenital hyperinsulinism. Following the complete response letter issued by the FDA last month, which was due to the timing of findings and conclusions from the reinspection of the third-party manufacturing facility, we eagerly await the new inspection classification. We remain confident in the approvability of this therapy for the and are committed to working with the FDA and our third-party manufacturing partner to bring Daziglucagon to patients living with this devastating disease in the months ahead. We still expect to submit the requested and detailed analysis from existing continuous glucose monitoring datasets supporting use of Daziglucagon beyond three weeks by the end of the year. In addition, the US FDA has set a regulatory decision goal date of December 22nd for our long-acting GLP-2 analog glopaglutide, which possesses potential best-in-class characteristics for the treatment of short bowel syndrome with intestinal failure. And with that, I would like to move to slide 16 and turn the call over to Eric Cox, Chief Commercial Officer at Zeeland Pharma, to review our near-term and future commercial opportunities for our rare disease franchise and obesity portfolio. Eric?

Thank you, David, and hello to everyone. I'd like to start briefly talking about our near-term commercial opportunities through our rare disease franchise. Our DASI glucagon product, is under evaluation for the treatment of congenital hyperinsulinism, an ultra-rare and devastating disease, primarily in neonates and children. Our focus is on bringing this product to patients as quickly as possible, as there are a few existing treatment options, excuse me, there are a few existing effective treatment options. Our pre-launch activities are in full swing, and we're ensuring that our capabilities across the commercialization spectrum are in place so that we're ready for a U.S. launch and the first half of 2025 contingent on regulatory approval. Our goal is to serve the patients, and all effort is being focused on setting up the necessary structure and resources to accomplish this. For our glupaglutide product, which is currently under evaluation for short-term bowel syndrome, we are currently undertaking pre-commercial activities to enable a launch once approved by the FDA. As glupaglutide is expected to be launched in markets With a large commercial footprint, we're focused on finding a commercial partner for the product to reach as many patients who need these alternatives and ensure commercial maximization. Turning to slide 17 and focusing on the future commercial opportunities of the obesity programs. In particular, I want to talk about why we strongly believe that pentrelatide has the potential to become a future foundational therapy, including a first option for weight management. With the magnitude of obesity and obesity-related comorbidities, we believe that we are facing the biggest healthcare challenge of our time. Not only is it the pandemic associated with tremendous direct medical costs, particularly to the healthcare systems, it's also the cause of too many preventable deaths. Of the 41 million adult deaths each year due to non-communicable diseases, such as diabetes, stroke, and coronary heart disease, 5 million are driven by high BMI and this may be underestimated. The obesity pandemic is rapidly accelerating, and by 2030, it's expected that 50% of adults will live with overweight or obesity. Additionally, utilizing present trends, it's estimated that 40% of children between the ages of five and 19 are expected to live with overweight and obesity by 2035, which means this is not only a problem of today, but well into our future. Even though we've seen the first two GLP-1-based therapies be approved and marketed, a huge unmet need still persists. There is a need for novel and alternative treatment options with different mechanism of actions other than the GLP-1-based therapies approved today. The need focuses on providing a new approach to better quality of weight loss, particularly improved adverse event profiles and preserving muscle. Specifically, we see an opportunity to establish a new foundational first-line therapy for weight management. When people are looking for weight loss, we know that approximately two-thirds of adults who want to lose up to 20% of their weight and are looking for a good overall experience in their weight loss journey. However, a significant portion of adults are stopping current GLP-1 therapies because early due to their unwillingness to accept gastrointestinal adverse events, including nausea, vomiting, and diarrhea. From the perspective of the healthcare professional, including primary care physicians, we know they have limited time for really complex patient situations. They seek to avoid multiple follow-ups and want overall good patient experiences. This is where Pantrelatide's profile is expected to deliver. This leads me to slide 18 and the target product profile of petrolatide. We believe that the target product profile of petrolatide holds a significant potential to become a future first-line foundational therapy for weight management, addressing both the needs of patients and HCPs by targeting weight loss on par with GLP-1s, but with a significantly improved GI tolerability profile and a potentially higher quality of weight loss including muscle preservation, all coupled with its simplicity, making it easy for HCPs to prescribe and manage. We very much look forward to further evaluate the potential in the upcoming large Phase 2B clinical trial. And with that, I'd like to turn it over to our Chief Financial Officer, Henrietta Wendeke, to review our financial results for the first nine months of 2024. Henrietta? Thanks, Aaron.

Turning to slide 19 and the income statement. Revenue for the first nine months of 2024 was 54 million DKK. This was mainly driven by the license and development agreement with Novo Nordisk for Stigalov. Operating expenses for the period were 919 million DKK, driven by research and development, which represented 72% of the company's operating expenses. The increase in R&D expenses compared to the same period last year is due to the clinical advancements of the obesity pipeline and activities supporting the regulatory review by the US FDA of the latest rare disease assets. Selling and marketing expenses of 50 million DKK primarily to the pre-commercial activities associated with our rare disease assets. The increase in admin expenses is the result of the additional legal expenses related to our patent portfolio, as well as the strengthening of our organizational capabilities at large. The net financial items for the period of 81 million DKK are mainly driven by the interest income from liquidity invested in market securities, which is significantly higher compared to the same period last year as a result of the recent capital increases. And that takes me to slide 20 and the cash position. In the first nine months of 2024, I am very pleased with the fact that we have secured 8.6 billion DKK through capital raises and disbursements of part of the loan facility provided by the European Investment Bank. As of September 30, 2024, cash, cash equivalent and marketable securities were 9.2 billion DKK. And our strong cash position truly enable us to make significant investments into our obesity programs. And this takes me to slide 21 and the financial guidance. I will keep this brief as our guidance is unchanged. We continue to guide for net operating expenses of between 1.25 and 1.35 billion DKK. And with that, I will move to slide 22 and turn the call back to Adam for concluding remarks.

Thank you, Henry. I'm extremely satisfied with our progress in the first nine months of the year, which has created a very strong platform for Zealand to accelerate our growth and pursue our vision of becoming a key player in the growing obesity space, and thus play our part in addressing what we believe is the biggest health care challenge of our time. Based on the strong performance in 24, we are also building momentum into 25, with additional clinical progress anticipated for our preparatory obesity assay. For Petrinatide, we, in the first half of 25, expect to initiate the second planned Phase IIb trial while we're in this. Later in 25, also plan to initiate a Phase Ib combination trial with Petrinatide and a DLP-1 receptor agonist. In the first half of next year, we also will initiate a Phase IIb trial for our potential first-in-class DLB1, DLB2 dual agonist dapaglutide. In the same timeframe, we also expect to announce top-line results from a cohort of the Phase 1b trial evaluating even higher doses of dapaglutide with longer treatment duration. Thank you all, and I will now turn over the call to the operator for questions.

Thank you. As a reminder, to ask a question, you will need to press star 1, 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1, 1 again. We will take our first question. Our first question comes from the line of Lucy Codrington from Jefferies. Please go ahead, your line is open.

Hi there. Thanks for taking my questions. A couple from me. Just firstly, on the, say, 2B design, the five dose arms, can I just confirm, sorry if this has already been said, but is that five different doses or fewer doses but with different titration regimes being evaluated across the different cohorts? And I note you said doses, plural, for the phase three. So is the intention to take more than one dose through to phase three trials? Certainly, one of the competitors was showcasing initial data for their amylin asset at Obesity Week as well, and talked about the calcitonin activity having potential taste But is taste aversion something that is something you're hearing about from patients taking petrolintide? And then finally, just to clarify on the desaglutagon filing, is the part two... data set already complete and it's just a case of waiting for part one to be de-risked, or is there still additional work ongoing? I'm just trying to work out the timing of what's holding up filing that part two. And any read across, at what point do we start worrying about the glapaglutide approval when this classification hasn't been granted? Thank you.

Yes, thank you for your questions, Lucy. I will just start by addressing the last two and then hand over to David. On the dactylurgon resubmission, we do expect to resubmit both, as David said, both the up to three-week indication and also the chronic indication. And that, you can say, with the limited time left of the year also means that you can say that data analysis and so on are completed for both. And we do expect As David also mentioned, an updated regulatory status for the CMO in the near term. Of course, this is a dialogue between the FDA and the CMO, so it's not in our control. But based on the feedback, we feel quite comfortable that they will change the regulatory status. And of course, if they don't, it could also affect the glyphosate. But again, as I said, we feel comfortable also reassured by the fact that there was no repeat findings. So the findings that caused the original inspection deficiencies have been solved. And we truly believe this is a matter of timing of the re-inspection, which came later into the year than anticipated, and it takes time to make these reports. So David, I will hand over to you on the two first questions, if you will address those.

Thank you, and Lucy, thanks for your questions. On the Phase IIb design, as I think is apparent from the schematic, what these dose arms identify is different top or maximal exposure doses. So this is classic dose-ranging Phase II with a similar dose escalation scheme across each And as noted in the schematic, it will be monthly step-ups in the dose escalation, as is for us consistent with both clinical and pharmacy practice. And phase three, as I referred to it, doses. I have some experience in this space. I'm referring back, for example, to Duluglutide, the Trulicity asset at Lilly. We don't obviously know until these data are available whether a single dose will declare itself as clearly the most effective and or well tolerated. So we will obviously with the data from this trial and the 28-week readout submit those data for regulatory review and with the agency determine if a single or multiple doses are necessary. So my reference wasn't a certainty, but keeping open the option as is often the case, both for dose escalation and maximal top exposure dose that you have a maximum and potentially a half maximum dose. So again, the dose arms will have different top doses, but similar dose escalation scheme across the treatment cohorts. The comments on the reports from another compound and the reference to taste aversion consequences, first and foremost, we have not seen reports at all of taste aversion either in ours. I'm not aware of them in the cagrelentide nor previously in the pramlentide programs. Obviously, both cagrelentide and petrolentide, at least in our hands, have significant balanced calcitonin enamel and receptor agonism. Many of the preliminary reports and the non-clinical data that speak to this potential for taste aversion is actually not mediated through the calcitonin receptors to our reading, but actually the CGRP receptor component. And in our hands, petrolentide does not have any significant activation of that receptor component. So first and foremost, we do not expect, unless there is CGRP activity for an asset, that this would rear its head and that calcitonin receptor agonism, as we've stated previously, actually is necessary central signaling in calcitonin for the positive metabolic effects of pharmacologic exposure to amylin or amylin calcitonin agonists. So to us, not something we've observed, nor is it in our mind actually specifically related to calcitonin, but the CGRP receptor component.

Very helpful. Thank you.

Yeah. Thanks, Lucy.

Thank you. We will take our next question. And the question comes from the line of Charlie Hayward from Bank of America. Please go ahead. Your line is open.

Yeah, thank you. Charlie here with Bank of America. I've got two questions, please. So first is, you've obviously stepped up your partnering conversations a few months ago. So I wondered if you could share any color on how the early discussions are going and what, if any, are the key debates you're having. And on that, I guess, you've previously talked about targeting, having a seat at the table with a co-commercialization, co-development agreement. I don't believe you stated that today. So can you confirm that's still your ambition? and do you remain confident in achieving that post-initial conversations? And then the second question is, we've got fairly imminent data for Cagri-Semakine. So obviously we've seen in the early data you showed superior weight loss to Cagri. I'm interested in how you think the Petri molecule compares to Cagri and what differences you'd call out there, and whether you think you've been able to dose effectively higher than Cagri has in its phase three. Thank you.

Thank you, Charlie. I will address the first question and then hand over to David after that. We are very, very pleased with how our partner discussions are going. As we have been public around, we had the full, you can say, data set in the house in August from the Phase 1 B trial, which we discussed at the BGT Week earlier this week. And we have started the partnership discussions more formally here in September onwards. So we are making, I would say, we are extremely pleased with where we are in these discussions. We do believe we have a very unique value proposition to, as discussed on the call today, to really bring forward a potential future foundational and even first-time therapy for the management of obesity, developing one of the first tools that are non-inputting based. I must say that we are extremely pleased with the feedback we have from the discussions with potential partners. We also believe, you can say, we have a very interesting value proposition in the sense that we are going for a co-development and co-commercialization opportunity. Remember, many large pharma companies are not deeply invested or deeply, you can say, engaged yet in obesity and obesity issues. related diseases that we think we can offer a lot at least in the first part of the collaboration and then on the request on co-commercialization so far we have not met a significant pushback on that i think the parties we discussed that they recognize that that is an important need for semen it's the way we can develop our company the way we want. And so I do not foresee this will be a major hurdle in the discussions. We'll just have to align on how to do this. And again, as I said, it's not something we get pushed back on. Our focus will be U.S. and potentially other major markets. So that is where we would look for profit sharing. And then you can say perhaps being less involved in other markets. So At least so far, we have received a lot of positive feedback on this and also not something that I would describe as a negative part of the conversations, but deep understanding and also deep appreciation that we have a lot to contribute with based on our deep knowledge and experience in this space as we partner with a large farmer partner. So overall, we are extremely pleased with where we are. expect to progress these discussions in the coming months. And David, will you take the other question?

Happy to, Adam, and thanks, Charlie. As regards the Cagri-Semaph data like you, we anxiously await seeing what the potential additivity of Cagri with the obesity doses of semaglutide readout and report. As to comparison, obviously we have no direct head-to-head comparative data. I think there are a number of characteristics that exist, both from our understanding of each of the molecules and their formulation, as well as what we have seen in terms of dose, dose exposure, and the clinical effects. As we've stated previously, and as I think many know well, CAGRI is formulated at a different isoelectric point, requires an acidic formulation to ensure and maintain stability. And as such, we believe that limits CAGRI dose exposure, both due to injection site tolerability, injection site reactions. a greater degree of immunogenicity reported for CAGRI, and whether that is dose and exposure related or related to other characteristics of the molecule, we do not know. We have to date seen no anti-drug antibodies to petrolentide. I think the most important part of this, regardless of the potential causes, is that we now know that petrolentide is well-tolerated at doses from 4.8 up to 9 milligrams, so significantly higher dose or milligram dose exposures. And in our hands, while both are balanced amylin calcitonin receptor agonists, They appear to be equipotent at the receptor, so we believe we can get to and up to 4X greater dose exposure than the planned maximal dose of Cagri, which is 2.4 milligrams. I think the last and perhaps most important part of dose exposure to Cagri, we believe can and will be tied to semaglutide tolerability. We know that semaglutide, like other GLP-1-based therapies, can limit maximal dose exposure just because of GI tolerability. And as a consequence of this being a fixed dose combination, you may limit CAGRI exposure simply as a consequence of semaglutide tolerability. Now, all of those are, at least in our minds, potential reasons that we believe petrolentide can and will meet or exceed what is seen with CAGRI. We think CAGRI is a an effective compound, no question. And if the data from Phase 1b bear out to see this continued reduction in body weight, we fully anticipate that, given those characteristics, it will meet and very likely exceed the weight-lowering effects of Kegrel and Tide. So I hope that's a reasonable set of reasons that can help you understand how we're viewing Petralentide is potential best in class. Many thanks. Yep. Thanks, Charlie.

Thank you. We will take our next question. Your next question comes from the line of Rajan Sharma from Goldman Sachs. Please go ahead. Your line is open.

Hi, thanks for taking my question. Just got a couple. Firstly, on galactic glutide, could you maybe just help us understand what this potential early launch could look like from a Zeeland perspective? It sounds like there's not going to be a partnership on that one before a potential approval. So just in terms of what a go-to-market strategy could look like, potential investment there, and whether you'd require kind of incremental SG&A costs and personnel costs from here. And then secondly, Eric, you talked about potential for developing petrolintide as a foundational first-line therapy in obesity. In order to do that, ultimately, do you think you need a head-to-head trial against current JLP1 agonists? Even if you didn't, do you think that could be a logical trial to run just to cement the differentiation that you talked to? And then finally, just one on petrolintide, a follow-up from the Obesity Week presentation. We didn't see a split of kind of weight loss in males versus females in the presentation. So could you just confirm on the trial, was there higher weight loss in female participants? I'm conscious there are only a few of them, but it would be helpful to get some color on that. Thank you.

Thank you for your question, John. And I will just take the last one and then hand over to Eric to put a little bit more color into our thinking. But we have... not shared the detailed data on gender, you can say balances for weight loss yet, and that will be up for a later conference. But we have indicated that you can say you should probably expect the same phenomenon as we have seen with the ones that females tend to lose more weight on amylin as well compared to males. So we will present those data at later conferences, but clearly something we also believe could become the case on amylin that females lose more weight And, Eric, will you take the next call on the question on glipactotide and also on pretranatide on the head-to-head, need for head-to-head service?

Sure. And thanks, Rajan, for your question. I think with regard to kind of commercialization, I think we first have to look at commercialization for desiglucogon. We know that that's going to be a small footprint, I think, as we launch that one. As we think about glipa, I think it will be a little bit more expanded, recognizing that the prescribing population is larger but it would still not be a significantly large footprint. Would expect SG&A to go up a little bit, but recognize that it's a very, very focused population. We will be looking for that partner and have had several conversations with potential partners to really kind of figure out how we can expand that reach as we move forward. But overall, I would say you'd still have a fairly limited footprint, very similar to what you see in kind of rare diseases and probably more on the smaller end of it as well. With regard to kind of foundational therapy and head-to-head, I think, and David, you can speak to this as well, but I think that we are looking at it. We're looking at what is the appropriate timing and what is the appropriate place we would want to look at a head-to-head. We recognize that we'll learn more out of our phase two data and really what is the appropriate dose, and then we'll look at what is the appropriate timing to create that differentiation. Do think that the head-to-head will be important for us to kind of better understand kind of how this stacks up relative to... to the GLP-1s, but I do think we'll start to see where we go with a head-to-head in the future.

Yeah, thanks, Eric and Rajan. I can comment, as Eric mentioned, critically important before we even consider such a trial that we fully understand the maximum dose and the magnitude of that response at each of the doses. I mean, that's not to say we don't have confidence in the potential for a head-to-head, but without our understanding of what those go-to-market or go-to phase 3 doses will be. I think you can anticipate, and we're having discussions about whether phase 3 or phase 3B is the most appropriate space in which to complete those studies. I think you can understand as well the complexity, how much do you force titrate and work to keep people on those maximum doses versus doing this in sort of a real-world clinical exposure setting where tolerability may impact a top dose of any asset. So, Yes, certainly part of our conversation around the Phase 3 and Phase 3B planning, awaiting data from Phase 2 as well as the Phase 2 in those living with prediabetes or diabetes. So best I can tell you today is that it is on the planning sheet and more to follow as we get readouts from Phase 2. Okay, thank you very much.

Thank you. We will take our next question. And the next question comes from the line of Suzanne Van Vultersen from VLK. Please go ahead. Your line is open.

Hi, Dean. Thanks for taking my question. My question relates to Obesity Week amylin data. First, on petrolenside, we noted that there was also a reduction in the heart rate. I'm curious if you have some thoughts what could explain this mechanistically and how you look at this additional interesting finding in the overall picture for the asset. And secondly, on the acyzenic amylin data that was also shown this week, clearly not as good weight loss and more adverse events as you compare it to petrolensides. But could you frame what you think is behind the differences with betrelentide, assuming here different receptor potency, but are there other elements such as the shorter half-life that can be factors driving the difference in risk-benefit? Thank you.

Thank you, Suzanne. I'll just give a few comments before handing over to David. especially if you look into the GLP-1 class, there's always been some concerns around increases in heart rate. I would say especially probably with some of the newer GLP-1 increasing-based therapies where we have seen very extensive increases in heart rate, which is not normally something you would see as a beneficial thing in a metabolically cardiovascular-challenged obese person. So we're actually very encouraged that amylin does not seem to carry that liability. And I think it's quite similar to what has also been seen with carburentide, that neutral to lowering of heart rate with the amylin class. But David can provide more flavor on that. On the AstraZeneca, as we now saw, it's of course extremely early day. We saw reporting from a single ascending dose. It gives us a lot of confidence in our approach to develop the carburentide as a best-in-class amylin agonist, at least we note, you can say, a four-day half-life for that program compared to the 10 days we have. We note it's also communicated that it is 15-fold more active on the amylin receptor, and then we note that you can say at least a similar degree of activity of nausea which again to us suggests that targeting both calcitonin and amylin as we do do not carry any liabilities in particular considering that you can say the phase one study with that competing program was stopped due to severe adverse events quite close to where they observed some degree of weight loss. So we feel very comfortable and are pleased to continue to develop what we think could become a best-in-class amylin analogue. David, any more flavors?

Yeah, just very quickly, Suzanne, thanks for the question on heart rate. I can't say, at least to my knowledge, that we know a specific reason why amylin agonism would, either with ptrolentide or other compounds, reduce heart rate. I think knowing that amylin signaling, particularly in the hindbrain and the effects acutely, for example, on gastric emptying, are mediated through vagal afferents. So there is the potential that some modest increase in vagal tone, which would lower your heart rate, could play a role, but that is speculation. I think to Adam's point, the increase in heart rate that comes, particularly with higher dose exposures of GLP-1, is something that we looked, obviously, to avoid through amylin agonism and Clearly, our early data suggests that there is no increase and perhaps this modest decrease. If that, combined with lower blood pressures that have been reported in larger trials with other amyloid agonists bear fruit, that obviously then lowers the cardiac effort, which we would expect to have a potential benefit on cardiac function and cardiovascular risk, but obviously too early to tell. With our assets, to Adam's point, we think the prolonged half-life of petrolentide and the balanced signaling, which in our mind is not only necessary but has been demonstrated with both Cagri and petrolentide, to not only raise fewer GI tolerability issues but clearly is part of the benefit in terms of the metabolic effects on body weight. Very early data with the other compound, if it is targeted to amylin agonist, we know one of the risks there is that you do lose some potency at the receptor, meaning higher milligram doses may be required for the same effect. But beyond that, I won't try to speculate too much given the very limited amount of data available with other compounds.

Thank you. We will take our next question. Your next question comes from the line of Julian Harrison from BTIG. Please go ahead. Your line is open.

Hi, good morning. This is Rae Ann for Julian. Congrats on the progress so far, and thanks for taking our question. You mentioned earlier on a partnership for both petrolentide and glupaglutide. We were just wondering what an ideal partnership term or deal would look like.

Thank you for that question, and I'll hand it over to you, Eric, to just give some flavors on our thinking there.

Yeah, and so thanks for the question. I think from a partnership perspective, I think we're exploring all partners. I think at the end of the day, we do know that there are some opportunities on the GLAPA side that are a little bit larger of opportunities, so we would want to look at a commercialization partnership as we move forward on that one. I think they would also then explore if there's other opportunities for lifecycle management, but it would definitely be a strong commercialization partner. On the CHI or the DASI glucagon, I think it is a new market, and I think people are still trying to assess the opportunity that exists. So we are still looking for commercial partners and potential partners that would be willing to consider both options and to commercialize and build more of a full rare disease franchise. So we are looking for commercialization partners for the most part.

Got it. Thank you. Very helpful. And just a follow-up, if I may, do you expect any residual allegiance to Gatix, or are you planning for most of the short bowel syndrome market to convert to less frequent treatment options?

I think there's two components on the short bowel syndrome side of things. I think you have the GADx patients. We know that they're not overly well controlled. So there's one option, I think, as we look at some of the GADx patients as well, as well as the more convenience. But we still recognize there's a significant portion of patients that are not being treated. And that is still an opportunity for us. So we do look at it as across the entire spectrum of all those customer segments, both the GADx side of it, those people that are not well controlled, those people that are looking for better convenience, and then those that are currently not being treated.

Thank you. Very helpful. Thanks again.

Sure. Thank you for the question.

Thank you. We will take our next question. And the question comes from the line of Prakhar Agrawal from Kanta. Please go ahead. Your line is open.

Hi. Thank you for taking my questions and a great presentation at Obesity Week. One thing that maybe we are still hoping to get more clarity on is on the dose response. The weight loss trajectory looks fairly similar for the 4.8 and 9 milligram dose. even in the initial titration period, but you clearly believe that based on individual patient data, there should be dose response and longer duration. So anything that you would note based on the data that drives this conviction. And a couple more, if I may, on partnership discussions for petrolentide, what will be some of the important factors for you in the deal structure? Is having a co-commercial structure in the U.S. important? And then lastly, just quickly, you talked about the Cagri-Semmer data coming in 4Q. Maybe just talk about the implications for petrolentide from the cagrelentide monotherapy arm in the trial. Just wanted to understand what you're hoping to see on that from an efficacy and safety standpoint. And thank you so much.

Thank you. I'll just discuss perhaps a little bit more on the partnership front before handing over to David. So it is very important for us in the partnership that whoever we partner up with will share the vision and ambition for Katrina type to develop this as a future foundational and first time therapy and that also of course means committing to the associated investments into clinical conduct positioning and of course also manufacturing. What we would be looking for is a true partnership where we will continue to contribute and develop sealant along you can say the development of this molecule towards as it approaches the market where we would also ask to have co-commercialization rights well how these are going to play out specifically is something we will discuss with the in through these partnership discussions but it will be extremely important for us to stay involved in the program we will focus as i said before on the u.s and potentially other major markets and and and so it will be important for us to maintain light on also the commercial end, but operate alongside our partner. Then maybe just one favor on the chagrinatide chagrinsima data that reads out. We are, of course, as anyone else, extremely excited to see how these data reads out. And of course, you can say, as David has also shared several times on the call today, we have a quite similar receptor biology. a very different molecule with regard to formulation and other aspects, but it will be interesting for us to see also if, no one always report on the chagrin type mono arm, what the 2.4 milligram of chagrin type can deliver. Of course, when looking into that, for us, it will be important to recognize that we believe we have a significant high variability and also we know we will be dosing much higher in our studies as David shared. So while it can provide us with some guidance and insight, we also recognize that we need to conduct our own phase IIb to fully understand the full potential of the train type. David, will you add some more?

Yeah, happy to. Hi, Prakhar. The dose response, I think, to your point, this is obviously a limited data set, 12 participants exposed in the two dose groups, 4.8 and 9. But as we have alluded to, it was really that early response with a lower starting dose in the 4.8 group. They had a fairly robust early response and then a relatively linear mean response after those first few weeks of the titration scheme. Can I, based on these data and others, say that the lines will cross and 9 will continue to decline at a more rapid rate and exceed 4.8, no. But I think both those observations, the fact that in both groups we had a very limited number of female participants who tend to lose more, that obviously the Phase IIb that we've described will allow us between that what I call mid-high dose and the higher dose of 9 milligrams allow us to explore if separation is possible. So, I don't want to overstate what gave us the confidence that we may see a continued decline in the 9 milligram dose. What I can say is that, obviously, we believe we've got at least twice and potentially up to 3 to 4X the potential dose exposure to get maximal response. But like you, I'm going to await Phase 2b to finalize that statement on dose separation. But given that we have tox coverage, the evidence in rodents suggests that higher exposure will permit greater effects on body weight and at least some suggestions from the individual data that you'll see at a future Congress. give us confidence that at least looking in Phase 2b can help elucidate the dose at or above the 4.8 to 5 milligram range that can maximize the response. Nothing more to add to Adam's comments on Cagri. I think the monoarm will hopefully give us even greater confidence in the double-digit weight loss 15 to 20 percent potential of Petromantide.

I got maybe just one other note on the 4.8 and the 9 milligram dose. I think it's also perhaps important to recognize that these were still quite low BMI participants. And in the Phase II and on next studies, of course, we expect people with higher BMI. So first, it will be extremely important to carry, you can say, the full dose opportunity into Phase IIb, and then which is the right dose to bring forward into phase three.

Thank you. Thank you. We will take our final question. Your final question comes from the line of Thomas Bowers from Thanks Good Bank. Please go ahead, your line is open.

Yes, thank you very much. Just a couple of questions remaining here from my side. So just on the pertinent side, Do you actually have any CRP reduction data from that phase one? I'm not sure whether you actually tested for that. And also, diapiglutide, is that something that we could expect from the phase one as well? And then just on the GLP-1 combination with the petendetide, is this going to be a combination with what you can say commercially available once-weekly approved GLP-1 in obesity, or is it something that you also have internally in the pipeline? And then my last question, so looking at the slides from Obesity Week, so when I zoom in on the efficacy curve, wouldn't it be fair to sort of make a conclusion that we at least see an indication of the weight loss effect tailing off a bit after 12, 13 weeks for actually both of the high dose cohorts? So I know, of course, it's a very small sample size and I'm playing the devil's advocate, but is there anything that we should be a little bit concerned about at least arguing for the 20% rate reduction that you are targeting, or could this maybe be also an effect of a low baseline BMI for these patients in the study? Thank you.

Yeah, thanks for those questions, Thomas. I'll just start. CRP, you should not expect that from a small study like this, but we, of course, know from the Phase II study from known as the catrinatide, that we see reductions in at least the catrinatide and CRP. So we would also expect that to this molecule. When it comes to combination therapy with the catrinatide and CRP1, I think at least our thinking is potentially quite different from the approach that our competitors have taken. Since we want to develop the catrinatide as a future foundational therapy, it will be extremely important for us to, number one, identify, you can say, the effective dose of amylin, and then consider to add a little bit of GLP-1 on top of that, instead of using what is considered the most effective dose of GLP-1 for weight management, adding a little bit of amylin. I think it's a more patient, potentially more patient-friendly approach to add just a little bit of GLP-1 on top of a maximum effective dose of an amylin, which could further, you can say, contribute to limiting side effects for those patients who would potentially need combination therapies, which we believe will be the most morbidly obese, so only a smaller fraction of the larger BCT opportunity. On the slope of the weight loss, it's really not something we see. I know you have brought this up a few times. It's not how we read the data. I think you are right. If you have a low BMI population, there's, of course, a limit to how much weight you can achieve in a small study. you also have to really think about this is a phase one study where you don't apply the diet and exercise. So I would say all data, including data from competing programs that we have looked into, suggest that the weight loss will continue, also called an amygdala loss. And so it's not a concern we share. So I hope that answers your question.

That's great. Thank you very much. Thank you.

Thank you. This concludes today's question and answer session. I now hand the call back to Adam Steensburg for closing remarks.

I would like to thank everyone for your participation today and we look forward to future updates and interactions. Thank you so much.

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