HEICO Corp

NYSE:HEI

Good day, and thank you for standing by. Welcome to the Zealand Pharma Results for Q3 2024 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, Anna Krassowska -- apologies, Anna Krassowska, Vice President, Investor Relations and Corporate Communications. Please go ahead.

Thank you. Welcome, and thank you for joining us today to discuss Zealand's results for the first 9 months of 2024. With me today are the following members of Zealand's management team: Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, 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 zealandpharma.com. As described on Slide 2, I caution listeners that we will be making forward-looking statements that are subject to risks and uncertainties.

Moving to Slide 3, I will turn the call over to Adam Steensberg, 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 half -- in the first part of 2024.

At ObesityWeek on Tuesday, we presented detailed data from the 16-week Phase I trial with petrelintide, our long-acting amylin analog, which we are developing as an alternative to GLP-1-based therapies for the management of overweight and obesity. We believe that these results strongly support that petrelintide 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 petrelintide to be dosed very soon. And we are also now with strong collaboration opportunities with large pharma companies. With the right partnership, we believe we have an opportunity to not only develop petrelintide as an alternative to GLP-1-based therapies, but also a potential future foundational 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 of Chief Commercial Officer. Eric brings 25 years of commercial and business development experience from biotech and leading global biopharma companies. He will 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 1 of the Phase Ib trial with our GLP-1/GLP-2 dual agonist, dapiglutide. We believe that this candidate holds the potential to be a first-in-class therapy for obesity and inflammation-related comorbidity. The reported data gives us the confidence needed to progress dapiglutide 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 which survodutide in MASH presented earlier this year, our partner, Boehringer Ingelheim, recently announced the initiation of a large global Phase III program for survodutide in MASH. Boehringer also announced that survodutide 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 MASH. With the clinical data reported to date, their ambitious Phase III program, and the recognition by regulatory, we believe that survodutide holds potential as a leading incretin-based therapy for obesity and MASH.

Turning to Slide 4, I would like to emphasize the reasons why we are so excited about the potential of petrelintide. We have seen the impact of the first 2 once-weekly GLP-1-based therapies to be approved. In Phase III 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 suggest that up to 30% of patients with obesity on a GLP-1 treatment stop within 1 month before reaching the target dose; and within 1 year, only 60% to 70% of patients withdraw from treatment.

With petrelintide, we are targeting GLP-1-like weight loss of 15% to 20% in longer-term Phase III trials, with potential for higher quality weight loss and a different and better patient experience. As evidenced by recent data with petrelintide presented at ObesityWeek, we are confident that petrelintide has the potential for a significantly improved GI tolerability profile compared to GLP-1 receptor agonists, suggesting both lower frequency and milder severity of GI adverse events.

And with that, let's move to Slide 5, 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 petrelintide, let's move to Slide 6. In the trial design of the recently presented detailed data of Part 2 of our Phase Ib trial. This was a randomized, double-blind, placebo-controlled Phase Ib trial enrolling a total of 48 adults with overweight and obesity. Participants were randomized into 1 of 3 dose cohorts assessing multiple ascending doses of petrelintide using a dose titration scheme or to match placebo. Study medication was administered weekly for 16 weeks in an outpatient setting, followed by a 9-week safety follow-up period. I would also like to highlight that in this trial, we evaluated doses of petrelintide up to 9 milligrams and note that the 2 higher dose cohorts received the maximum assigned maintenance dose for a period of only 6 and 8 weeks, respectively.

Turning to Slide 7. Shown here are the mean weight loss curves across each of the individual dose cohorts and placebo. Petrelintide treatment resulted in a reduction in mean body weight of 4.8%, 8.6%, and 8.3% from baseline after 16 weeks of treatment across the 3 dose cohorts, while placebo treatment resulted in a mean body weight loss of 1.7%. 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 8. 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 petrelintide-related AEs, which occurred after the third dose while also starting at a higher 1 milligram initial dose.

In addition, 1 participant in the 9-milligram arm was maintained for an additional week on the 7-milligram dose due to reported tolerability issues. The 2 other participants who discontinued therapy did so for other reasons unrelated to study medication. Notably, all other subjects followed both the dose escalation steps defined in the protocol and completed petrelintide treatment as planned. We believe that the ease with which participants achieve their target dose and the proportion of those treated who remained on petrelintide treatment over the course of this trial support our conclusion that treatment with petrelintide is both well-tolerated and readily dose escalated further differentiating this treatment from incretin-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 events. Moving to Slide 10. The data reported in this Phase Ib 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 participants reported vomiting, and there were only 2 reports of diarrhea, both of which were mild. Nausea was reported in up to 33% of the petrelintide-treated participants as compared to 17% reported by participants in the placebo group. Additionally, 3 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 petrelintide and further support our conclusion that petrelintide offers the opportunity to limit issues of GI tolerability. Overall, these data support and further our ambition for petrelintide, 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 IIb design. As mentioned in the last call, we will continue to progress our development of petrelintide as a stand-alone therapy in a large and comprehensive Phase IIb program. The first Phase IIb trial in persons with obesity or overweight weight-related co-morbidities, 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 petrelintide or placebo over 42 weeks of treatment with 5 dosing arms, the highest being 9 milligrams as in the Phase Ib multiple ascending dose Part II trial.

Participants will be continuing blinded treatment for 42 weeks with a primary end point 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 petrelintide across a wide dose range to inform the doses to be used in longer-term Phase III studies. Note that the primary end point of 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 end points in this Phase IIb study will include an assessment of body composition by magnetic resonance imaging, or MRI, change in HbA1c, change in fasting lipids, and change in high-sensitivity C-reactive protein or hs-CRP.

In addition to this Phase IIb study, we expect to initiate a second Phase IIb study in the first half of 2025, exploring 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 populations, further differentiating petrelintide 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 disease, representing a truly differentiated incretin asset.

As we have recently reported, dapiglutide was evaluated in a single-center randomized, double-blind, placebo-controlled Phase Ib 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 3 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 frequency and intensity reported in studies of other incretin-based 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 2 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 Ib study will not impact the timing for initiation of a Phase IIb 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 IIb trial and additional studies [ investigating ] the potential of dapiglutide in obesity and selected inflammation-related comorbidities, including liver disease, cardiovascular disease, inflammatory bowel disease, and neurodegenerative diseases.

Moving now to Slide 13 and survodutide. Along with our Boehringer Ingelheim colleagues, we believe that the data from the survodutide Phase II 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 survodutide as a potential leading incretin-based therapy for the treatment of obesity and MASH.

This leads me to Slide 14. We are very excited that our partner Boehringer Ingelheim has initiated a large Phase III program for survodutide in MASH, in addition to the ongoing studies in obesity. LIVERAGE and LIVERAGE-Cirrhosis, our global Phase III clinical trials investigating the efficacy and safety of survodutide 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 dasiglucagon 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 substantial unmet clinical needs in CHI and are committed to working with the FDA and our third-party manufacturing partner to bring dasiglucagon 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 data sets, supporting the use of dasiglucagon beyond 3 weeks by the end of the year.

In addition, the U.S. FDA has set a regulatory decision goal date of December 22 for our long-acting GLP-2 analog, glepaglutide, 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 Zealand Pharma, to review our near-term and future commercial opportunities for our rare disease franchise and obesity portfolio. Eric?

Thank you, David, and hello, everyone. I'd like to start briefly talking about our near-term commercial opportunities through our rare disease franchise. Our dasiglucagon product is under evaluation for the treatment of congenital hyperinsulinism, an ultrarare 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 effective treatment options. Our prelaunch 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 in 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 glepaglutide product, which is currently under evaluation for short bowel syndrome, we are currently undertaking pre-commercial activities to enable a launch once approved by the FDA. As glepaglutide 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 petrelintide has the potential to become a future foundational therapy, including a first-line option for weight management.

With the magnitude of obesity and obesity-related comorbidities, we believe that we are facing the biggest health care challenge of our time. Not only is it the pandemic associated with tremendous direct medical costs, particularly to the health care systems, it's also the cause of too many preventable deaths. Of the 41 million adult deaths each year due to noncommunicable 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 5 and 19 are expected to live with overweight and obesity by 2025 -- or 2035, which means this is not only a problem of today but well into our future.

Even though we've seen the first 2 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 mechanisms of action other than the GLP-1-based therapies approved today. The need is 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 2/3 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 early due to their unwillingness to accept gastrointestinal adverse events, including nausea, vomiting, and diarrhea. From the perspective of the health care professional, including primary care physicians, we know they have a limited time for really complex patient situations. They seek to avoid multiple follow-ups and want an overall good patient experience. This is where petrelintide's profile is expected to deliver.

This leads me to Slide 18 and the target product profile of petrelintide. We believe the target product profile of petrelintide holds 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 IIb clinical trial.

And with that, I'd like to turn it over to our Chief Financial Officer, Henriette Wennicke, to review our financial results for the first 9 months of 2024. Henriette?

Thanks, Eric.

Turning to Slide 19 and the income statement. Revenue for the first 9 months of 2024 was DKK 54 million. This was mainly driven by the license and development agreement with Novo Nordisk for Zegalogue. Operating expenses for the period were DKK 919 million, 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 U.S. FDA of the late-stage rare disease centers.

Selling and marketing expenses of DKK 50 million primarily relate to the pre-commercial activities associated with our rare disease assets. The increase in admin expenses is a 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 DKK 81 million are mainly driven by the interest income from liquidity investments in marketable securities, which is significantly higher compared to the same period last year, as a result of recent capital increases.

And that takes me to Slide 20 and the cash position. In the first 9 months of 2024, I am very pleased with the fact that we have secured DKK 8.6 billion through capital raises and disbursements as part of the loan facility provided by the European Investment Bank. As of September 30, 2024, cash, cash equivalents, and marketable securities were DKK 9.2 billion, and our strong cash position truly enables 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 DKK 1.25 billion and DKK 1.35 billion. And with that, I will move to Slide 22 and turn the call back to Adam for concluding remarks.

Thank you, Henriette. I'm extremely satisfied with our progress in the first 9 months of the year, which has created a very strong platform for Zealand to accelerate our growth and pursue our ambition of becoming a key player in the growing obesity space and thus play our part in addressing what we believe is the biggest healthcare challenge of our time.

Based on the strong performance in '24, we are also building momentum into '25 with additional clinical progress anticipated by our proprietary obesity assets. For petrelintide, in the first half of '25, we expect to initiate the second planned Phase IIb trial, while we [ then ], later, in '25 also plan to initiate a Phase Ib combination trial with petrelintide and GLP-1 receptor agonist.

In the first half of next year, we also will initiate a Phase IIb trial for our potential first-in-class GLP-1/GLP-2 dual agonist, dapiglutide. In the same time frame, we also expect to announce top line results from a cohort of the Phase Ib trial evaluating even higher doses of dapiglutide with longer treatment duration. Thank you all. And I will now turn over the call to operator for questions.

[Operator Instructions] Our first question comes from the line of Lucy Codrington from Jefferies.

A couple from me. Just firstly, on the Phase IIb design. The 5 dose arms, can I just confirm, sorry if this has already been said, but is that 5 different doses? Or fewer doses but with different titration regimes being evaluated across the different cohorts? And I note you said the dose is plural for the Phase III. So is the intention to take more than one does through to a Phase III trial?

Secondly, one of the competitors was showcasing initial data for their amylin assets at ObesityWeek as well and talked about the calcitonin activity having potential taste consequences just to GI tolerability. But is taste aversion something that is -- you are -- something you're hearing about from patients taking petrelintide?

And then finally, just to clarify on the dasiglucagon filing, is the Part 2 data set already complete, and it's just a case of waiting for Part 1 to be de-risked? Or is there still additional work ongoing? I'm just trying to work out the timing of why -- what's holding up finding that Part 2. And any read across at what point do we start worrying about the glepaglutide approval when this classification hasn't been granted?

Yes. Thank you for your questions, Lucy. I will just start by addressing the last 2 and then hand over to David.

On the dasiglucagon resubmission, we do expect to resubmit those -- as David said those -- up to the 2-week indication and also the chronic indication. And that, you can say, the limited time left of the year also means that -- you can say data analysis and so on are completed for both. And we do expect, as David also mentioned, an updated on 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 regulatory status.

And of course, if they don't, it could also affect [ dapiglutide ]. 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, which have been solved. And we truly believe this is a matter of timing of the reinspection, 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 2 first questions, if you will address those.

Yes. 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 [ perhaps ] consistent with both clinical and pharmacy practice. And Phase III, as I referred to it, doses, I have some experience in this space. I'm referring back, for example, to dulaglutide, 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. 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 a maximum dose. So again, the dose arms will have different top doses, but a similar dose escalation scheme across the treatment cohorts.

The comment on the reports from another compound and a 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 petrelintide, nor previously in the pramlintide programs. Obviously, both cagrilintide and petrelintide, at least in our hands, have significant balanced calcitonin and the amylin receptor agonism. Many of the preliminary reports and the nonclinical 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, petrelintide does not have any significant activation of that receptor. So first and foremost, we do not expect, unless there is CGRP activity for an asset, that this would rear its head. And calcitonin receptor agonism, as we've stated previously, actually, it is necessary for 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.

We will take our next question, and the question comes from the line of Charlie Haywood from Bank of America.

Charlie Haywood with Bank of America. I've got 2 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 the co-commercialization, co-development agreement. I don't believe you stated that today. So can you confirm that's still your ambition and you remain confident in achieving that post initial conversations?

And then the second question is -- we've got fairly imminent data for CagriSema coming. So obviously, we've seen in the early data, you showed superior weight loss to cagri. I'm interested in how you think petre 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 III?

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 school, you can say, data sets in the house and in August from the Phase Ib trial, which we discussed at ObesityWeek earlier this week. And we have started the partnership discussions more formally 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 in the call today to really bring forward a potential future foundational and even first-line therapy for the management of obesity. Developing one of the first tools that are non-incretin-based.

And 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, you can say, 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 invested or deeply, you can say, engaged yet in obesity and obesity-related diseases. I also think we can offer a lot, at least in the first half of the collaboration.

And then on the request and co-commercialization, so far, we have not met, you can say, a significant pushback on that. I think the third parties we discussed, they recognize that there is an important need for [ Sema ]. It's the way we can develop our company the way we want. And so I do not foresee this would be a major hurdle. And the discussions will just have to align on how to do this. Again, as I said, it's not something we get pushback on.

Our focus will be U.S. and potentially other major markets. So that is where we would look for profit sharing. And then we can say, perhaps, be 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 to contribute based on our deep knowledge and experience in this space, as we partner with a large pharma partner.

So overall, we are extremely pleased with where we are, and we expect to progress these discussions in the coming months. David, will you take the other question?

Happy to, Adam, and thanks, Charlie.

As regards to the CagriSema data, like you, we anxiously await seeing what the potential adaptivity 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 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. There is also a greater degree of immunogenicity reported for cagri, 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 antidrug antibodies to petrelintide.

I think the most important part of this, regardless of the potential causes, is that we now know that petrelintide 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 it 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 petrelintide can and will meet or exceed what is seen with cagri. We think cagri is an effective compound, no question. And if the data from Phase Ib 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 cagrilintide. So I hope that's a reasonable set of reasons that can help you understand how we're viewing petrelintide as potential best-in-class.

Your next question comes from the line of Rajan Sharma from Goldman Sachs.

Just got a couple. Firstly, on glepaglutide. Just could you maybe help us understand what this potential early launch could look like from a Zealand 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 of developing petrelintide 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 GLP-1 agonists? Even if you didn't, do you think that could be a logical trial to run just to cement the differentiation that you talk to?

And then finally, just one on petrelintide, a follow-up from the ObesityWeek presentation. We didn't see a split of kind of weight loss in males versus females in the presentation. So could you just confirm if in the trial, was there higher weight loss in female participants? I'm conscious that there are only a few of them, but it would be helpful to get some color on that.

Thank you for your question, Rajan. 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 yet the detailed data based on gender. You can say, balances for weight loss, yes, that would 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 other ones, that females tend to lose more weight on amylin as well compared to male. So we will present those data at later conferences, but clearly something we also believe could become the case for amylin that females loose more weight.

Eric, will you take the next call on the -- next question on glepaglutide and also on petrelintide on the head-to-head -- need for head-to-head, sorry?

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 dasiglucagon. We know that that's going to be a small footprint, I think, as we launch that one. As we think about glepa, 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 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 II data and, really, what is the appropriate dose, and then we'll look at what is the appropriate timing to create that differentiation. I do think that the head-to-head will be important for us to better understand kind of how this stacks up relative to the GLP-1s, but I do think we'll start to see where we go with head-to-head in the future.

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-markets or go to Phase III doses will be, I think you can anticipate, and we're having discussions about whether Phase III or Phase IIIb 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 III and Phase IIIb planning, awaiting data from Phase II as well as the Phase II in those living with prediabetes or diabetes. So best I can tell you today is that is on the planning sheet and more to follow as we get readouts from Phase II.

The next question comes from the line of Suzanne van Voorthuizen from VLK.

My question relates to ObesityWeek amylin data. First on petrelintide, we noted that there was also a reduction in the heart rate. Curious if you have some thoughts on 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 AstraZeneca amylin data that was also shown this week. Clearly, not as good weight loss and more adverse events as you compare it to petrelintide. But could you frame what you think is behind the differences with petrelintide, 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, 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 incretin-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 petrelintide, that neutral to lowering of heart rate with the amylin class. But David can provide more flavor on that.

On the AstraZeneca asset we now saw -- it's, of course, extremely early days. We saw reporting from a single ascending dose. It gives us a lot of confidence in our approach to develop petrelintide as a best-in-class amylin agonist. And at least we note, you can say, a 4-day half-life for that program compared to the 10 days we have. We know -- it's also communicated that it is 15-fold more active on the amylin receptor.

And then we note that we can say, at least a similar degree 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 given data Phase I study with that competing program was stopped due to severe adverse events, quite close to where they have 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 analog.

David, any more flavor?

Yes, 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 petrelintide or other compounds, reduce heart rate. I think knowing that amylin signaling, particularly in the hind-brain 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 look, 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 amylin 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 petrelintide and the balanced signaling, which, in our mind, is not only necessary but has been demonstrated with both cagri and petrelintide to, not only raise fewer GI tolerability issues but clearly is part of the benefit in terms of the metabolic effects on body weight.

So very early data with the other compound. If it is targeted to amylin agonists, 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.

Your next question comes from the line of Julian Harrison from BTIG.

This is Ray on for Julian. Congrats on the progress so far. You mentioned earlier on a partnership for both petrelintide and glepaglutide. We were just wondering what an ideal partnership term 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.

Yes. And so thanks for the question. I think from a partnership perspective, we're exploring all partners. I think at the end of the day, we do know that there are some opportunities on the glepa 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 are other opportunities for life cycle management, but it would definitely be a strong commercialization partner on the CHI or the dasiglucagon.

I think it is a new market, and people are still trying to assess the opportunity that it exists. So we are still looking for commercial partners and potential partners that would be willing to consider both options to commercialize and build more of a full rare disease franchise. So we are looking for commercialization partners for the most part.

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

I think there are 2 components on the short bowel syndrome side of things. I think you have the Gattex patients. We know that they're not really well controlled. So there's one option, I think, as we look at some of the Gattex patients, 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 across the entire spectrum of all those customer segments, both the Gattex side of it, those people that are not well controlled, those people looking for better convenience, and then those that are currently not being treated.

Next question comes from the line of Prakhar Agrawal from Cantor.

Great presentation at ObesityWeek. 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 doses, 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 will note based on the data that drives this conviction?

And a couple more, if I may. On partnership discussions for petrelintide, what would 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 CagriSema data coming in 4Q. Maybe just talk about the implications for petrelintide from the cagrilintide monotherapy arm in the trial. Just wanted to understand what you're hoping to see on that from an efficacy and safety standpoint?

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 with will share the vision and ambition for petrelintide, to develop this as a future foundational and first-line 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 that we will continue to contribute and develop, seeing it along, you can say, the development of this molecule towards -- as it approaches the market where we would also are have co-commercialization rights. How these are going to play out specifically is something we will discuss with -- 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 so it will be important for us to maintain rights, and also the commercial end, but operate alongside a partner.

Then maybe just one flavor on the cagrilintide, CagriSema data that reads out. We are, of course, as anyone else, extremely excited to see how this 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 priority, very different molecule with regard to formulation and other aspects. But it will be interesting for us to see also the Novo Nordisk report on the cagrilintide mono arm, what the 2.4 milligram of cagrilintide can deliver.

Of course, when looking into that, for us, it will be important to recognize that we believe we have a significant, higher bioavailability. And also we know we will be dosing much higher in our studies, as David shared. So while it can produce some -- 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 petrelintide.

David, will you add some more flavor?

Yes, happy to. The dose response, I think, to your point, this is obviously a limited data set: 12 participants exposed in the 2 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 at 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 have a very low 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- to high dose and the higher dose at 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 3x to 4x the potential dose exposure to get maximal response. But like you, we're going to await Phase IIb to finalize that statement on the separation.

Given that we have tax 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 in a future congress give us confidence that looking in Phase IIb 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 mono-arm will hopefully give us even greater confidence in the double-digit weight loss, 15% to 20% potential of petrelintide.

And maybe just one other note on the 4.8 and the 9-milligram dose. I think you also perhaps important to recognize that these are still quite low BMI participants and in the Phase II and on next studies, of course, if they're with even higher BMI. So for us, it will be extremely important to carry you can say, the full dose opportunity into Phase IIb and then see which is the right dose to bring forward into Phase III.

We will take our final question Your final question comes from the line of Thomas Bowers from Danske Bank.

Yes. Just a couple of questions remaining here from my side.

So just on petrelintide. Do you actually have any CRP reduction data from that Phase I? I'm not sure whether you actually tested for that. Also, dapiglutide, is that something that we could expect from the Phase I as well?

And then just on the GLP-1 combination with petrelintide, 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 ObesityWeek's. So when I zoom in on the efficacy curve, would 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 of actually both of the high-dose cohort? So I know, of course, it's a very small sample side. 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're targeting? Or could this maybe be also an effect of a low baseline BMI for these patients in the study?

Yes. Thanks for those questions, Tom. 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 studies from Novo Nordisk, the cagrilintide, that you see reductions in -- at least the cagrilintide, in CRP. So we would also expect that from this molecule.

When it comes to combination therapy with petrelintide and GLP-1, I think -- at least our thinking is potentially quite different from the approach that our competitors taken. Since we want to reserve petrelintide 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 transition 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. We think it's the 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 in -- for those patients who would potentially meet combination therapies, which we believe will be the most morbidly obese. So only a smaller fraction of the large obesity opportunity.

On the slope of the weight loss, it's really not something we see. I mean, what -- 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 rate you can achieve in a small study. You also have to really think about this as a Phase I study, where you don't apply 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 for an amylin analog. And so it's not a concern we share. So I hope that answers your question.

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

With that, 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.