Zealand Pharma A/S

The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 1 1.

good day and thank you for standing by welcome to the zealand farmer results for the full year 2022 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 and 1 on your telephone you will then hear an automated message advising your hand is raised. To withdraw your question, please press star one and one 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 Krasowska, VP of Investor Relations. Please go ahead.

Anna Krasowska Thank you, Operator. Welcome and thank you for joining us today to discuss VLIN's full year results for 2022. With me are the following members of Zeeland's management team. Adam Steinsberg, President and Chief Executive Officer, Himalaya Davinika, Chief Financial Officer, and David Kendall, Chief Medical Officer. You can find the related company announcement and annual report on our website at zeelandpharma.com. As described on slide two, we will be making forward-looking statements that are subject to risks and uncertainties. With that, I will turn the call over to Adam Steinsberg. Adam?

Thank you, Anna.

and thanks to everyone for joining today. I'll begin on slide three.

2022 was a transformative year for Sealand, and I'm proud of the progress our team has made since announcing the change in strategy to prioritize investments in peptide therapeutics R&D. We achieved key milestones across our clinical pipeline, reporting positive phase three results for both our assets target targeting rare diseases, fantastic work on newborns and children with congenital hyperinsulinism, and for people living with short-life syndrome. We also advanced our portfolio of peptides targeting obesity. Following our decision to scale back commercial operations, we executed two partnerships for our marketed products. We sold the Vigo insulin delivery device to Mankind Corporation, and we entered into a partnership with Novo Nordisk to commercialize SeekerLock. Finally, despite the challenging financial markets, we were able to strengthen our balance sheet through equity raises and extend our cash runway into mid-2024. Continuing this momentum, 2023 looks to be a very exciting year for Sealand. Turning to slide 4, We have three key strategic objectives aimed at maximizing the value potential of our portfolio. Our first objective is to progress our rare disease assets, StasiGluAgon and Lipaglutide, towards regulatory submission. Our second objective is to advance our BGC portfolio. For the blue GLD1 dual agonist, DI456906, Berner is planning to share the results of the Phase 2 obesity trial with the scientific community in the coming months. Berner has also informed us that in parallel they are engaging with health authorities to discuss plans for Phase 3 for people living with an overweight and obesity. Regarding our wholly owned assets in obesity, we expect to present data from the AMELIN phase 1 program during the year and initiate new clinical studies with all three assets. Finally, our third key objective is to engage in partnership discussions in alignment with our change in strategy. As we evaluate future partnerships, we will seek to continue to participate in the programs across the value chain leveraging our strengths and capabilities to maximize the value of the asset. In addition to these three key objectives, we are also focused on activities that support our programs in type 1 diabetes management. This includes submitting a marketing of our patient application to the European Medical Agency for Zika lock, which we are responsible for under the global agreement with Novo Nordisk. I would like to spend a few minutes on our DASIC-Urban program in children with congenital hyperinsulinism, or CHI, as we are approaching the NDA submission in the first half of this year, and we believe it represents significant opportunity for C-Land to address a major unmet medical need for children and their families. Moving to slide five, CHI is a rare disease that affects babies and children. A defect in the pancreatic beta cell results in an overproduction of insulin, leading to frequent episodes of severe hyperglycemia that may result in brain damage. Care for patients with CHI is complex, and more than half may be suboptimally treated with current therapies. We've completed a phase three program, demonstrating the clinical potential of dastic urethane administered as a continuous subcutaneous infusion We are a viable pump. If approved, we expect to utilize the DECA infusion pump to provide DASIK-Glo1 to patients. Shown on slide 6, we estimate that there are up to 800 children with diffuse CHI that may be eligible for DASIK-Glo1 treatment in the US. Most of these children are treated or closely followed by pediatric endocrinologists in a few centers of excellence. To the right of the slide, we present examples of other products targeting ultra rare diseases with high clinical burden that command premium pricing in the US. And if approved, we do believe that DASIG-LORAN has the potential to provide comparable clinical value, thus also representing a significant opportunity for C-Land. Advancing to slide seven, I'll now turn over the call to our Chief Medical Officer, David Kendall, to discuss the risks of the IV lifetime. David.

Thank you, Adam. Today I will focus my remarks on our obesity portfolio, but first I would like to provide a brief update on glpaglutide, our long-acting GLP-2 analog that is being developed for the treatment of short bowel syndrome and intestinal failure. Please turn to slide eight. As many of you know, in September of 2022, we reported positive top-line data from the EASE-1 Phase 3 trial, which demonstrated that glopaglutide treatments given twice weekly when compared to placebo significantly reduced parenteral support volume required in individuals living with SPS and intestinal failure. In addition, we observed that approximately one in eight patients treated with glopaglutide in weaned off parenteral support within 24 weeks, achieving so-called enteral autonomy, while no placebo-treated patients were able to achieve this enteral autonomy, a feature we believe is differentiating from current treatments. We look forward to presenting the results of EASE-1 at upcoming scientific congresses in the coming months, including data on the response in specific subgroups. A total of 96 patients who completed EASE-1 enrolled in EASE-2, the first of two long-term safety and efficacy extension studies. Interim data from these extension trials, as well as from the EASE-4 study assessing long-term effects of glopaglutide on intestinal fluid and energy uptake, will all be a part of the regulatory package for glopaglutide. We had previously anticipated interim results from EASE-2 before the end of 2022, and from EASE-3 in the first quarter of 2023. However, having the positive results of EASE-1 in hand, we made a decision to extend the interim analysis to include 24-week data from all individuals enrolled into EASE-2. This will include data from patients who were on placebo in EASE-1, and thus, this will allow us to hopefully expand our understanding of the potential for glupaglutide to reduce or eliminate the need for parenteral support as we observed in EASE-1. As such, the interim results from EASE 2, 3, and full results of EASE 4 are now anticipated in the first half of this year. Importantly, extending the follow-up period for EASE 2 and 3 will not impact the timing for a potential regulatory submission, which we anticipate in the second half of 2023. Advancing to slide 9 and focusing on our obesity portfolio. There is little doubt that obesity represents one of the most significant healthcare challenges of our time, and we are excited to have a rich and differentiated pipeline of novel assets for the potential treatment of obesity. Obesity is a complex disease that can be treated pharmacologically by targeting a number of unique metabolic pathways. While single modality therapies have shown significant to achieve even greater degrees of weight loss, comparable to that seen following bariatric surgery. We are using two specific approaches at Zeeland, dual pharmacology to target two receptors with one peptide, and potent and differentiated single receptor agonist that can be used alone or in combination with other peptides as loose combination or in co-formulations. Please turn to slide 10. In this figure, we present a representation of our differentiated peptide molecules targeting obesity. Each peptide in our portfolio has been designed to target important neurohormonal pathways that are important in the regulation of body weight, including food intake, energy expenditure, food composition, and satiety, any one of which can play important roles in achieving weight loss. Our therapeutic approach aims, one, to achieve increased weight loss, and two, to provide additional effects to address specific needs or comorbidities of obese or overweight individuals. Our novel dual hormone candidates are designed with GLP-1 receptor agonism as a foundation to provide weight loss through reduced food intake and delayed gastric emptying, and to offer the potential to improve glycemic control, while adding agonism to a second receptor for complementary effects. With each of these molecules, we are targeting weight loss that can exceed that observed for GLP-1 receptor agonism alone, with the potential, based on non-clinical and clinical observations to date, to be on par with other dual hormone candidates currently in development. Turning our attention to BI-456906, an asset co-invented with Berger Ingelheim, where the additional effects of glucagon receptor agonism are designed to complement GLP-1 agonism and are postulated to stimulate energy expenditure and improve the trafficking of fat, with the potential to further improve weight loss and target disorders of liver fat. BI-456906 is in active clinical development with our Beringer Engelheim partners for the management of obesity and NASH. In 2022, very encouraging data on both glycemic control and weight loss in patients with type 2 diabetes were reported following only 16 weeks of treatment. We very much look forward to having BI share the results from the 46-week phase 2 trial of BI-456906 in overweight and obese individuals at a scientific congress in the coming months. Dapiglutide is a first-in-class dual GLP-1, GLP-2 receptor agonist, leveraging the effects of GLP-2 agonism, a peptide hormone that is co-secreted with GLP-1 following meals. The rationale driving use of dapiglutide is the potential to provide weight loss through potent GLP-1 receptor agonist activity, combined with the known effects of GLP-2 agonism on intestinal barrier function. It is postulated that improvements in intestinal barrier function can improve gut function and target the low-grade inflammation that is associated with syndromes of obesity. We are actively investigating a number of these mechanisms through an investigator-led clinical study due to start in the coming days. We also believe, based on data from clinical studies, that GLP-2 receptor agonism can also contribute to improved tolerability of the associated GLP-1 agonist. And in closing, we note that our portfolio also includes two single receptor agonists. The islet hormone amylin is known to play an important metabolic role and is a validated target for the potential treatment of obesity. Amylin treatment results in weight loss by reducing food intake by increasing satiety, and amylin is known to restore leptin sensitivity, which may contribute to more lasting weight loss effects. We believe amylin agonism can play an important role both as a standalone treatment for obesity, serving patients who may not tolerate or adequately respond to GLP-1-based therapies, and amylin as a non-incretin hormone can be used in combination with other incretin-based treatments to provide additional weight loss. Zeeland's novel long-acting amylin analog is specifically designed to allow for once-weekly administration and for co-formulation or co-administration with other peptide-based therapies. We are currently advancing our amylin analog, ZP8396, through phase one multiple ascending dose studies and plan to share clinical data from this program this year. Finally, we are planning to bring our unique standalone GIP receptor agonist into clinical studies in the second half of 2023. We are both excited and encouraged by the strong momentum across our development pipeline in rare diseases and obesity and look forward to providing additional updates as we advance our programs in 2023. I will now turn the call over to our CFO, Henrietta Wenneke, to review the full year financial results for 2022. Henrietta?

Thanks, David, and hello, everyone. Let's move to slide 11 and the income statement. Revenue for 2022 was 104 million DKK driven by the development agreement with elections and the partnership agreement made in Q2 2022 with Novo Nordisk. CELAN received an upfront payment of 25 million DKK from Novo. The operating expenses for the period were 941 million DKK within our guidance for 2022. This is slightly above last year when comparing the continued operations. The increase is driven by the progression of our research and development activities, especially our late-stage clinical programs. The sales and marketing expenses decreased compared to last year, following the announced restructuring in March 2022. Other operating items increased due to restructuring costs related to continued operations and costs related to the U.S. NASDAQ delisting in September 2022. Net financial items for the period resulted in a loss of 135 million DKK compared to 25 million DKK for the same period in 2021. These costs are primarily driven by the loan agreement with Oberland. As a result of the amount restructuring, all income and expenses related to commercial efforts related to VEGO and SIGA law are accounted for as discontinued operations. Net result for these discontinued rates in 2022 was a loss of 237 million CKK. Let's move on to slide 12 and the cash position. In 2022, we were able to strengthen our balance sheet with gross proceeds worth more than 1 billion CKK, despite very challenging financial markets. We also pay down half of the sustainability with Oberland and make significant investments in progressing our pipeline. At year end 2022, cash equivalents and marketable securities were approximately 1.2 billion DKK. With this, we have a cash runway to mid 2024, which allow us to continue investments in progressing our R&D pipeline in 2023. Talking about 2023, let's move on to slide 13 and the financial guidance for the year. As Adam said, 2023 looks to be a very exciting year for T-Land. We will invest in progressing our rarest seed assets towards regulatory submission in 2023, while at the same time investing in our B2T portfolio. Consequently, in 2023, we guide for net operating expenses of between 800 to 900 million DKK. This is somewhat lower than recent year's expense level and do reflect the restructuring initiative implemented last year. In 2023, we will also engage in partnership discussions, as Adam mentioned, aligned with our changes strategy. However, we will not provide guidance on revenue anticipated from existence and new license and partnership agreements due to uncertainty related to the timing as well as the size of such revenue. And with that, I will turn the call back to Adam.

Thank you, Henriette.

2022 was a year of significant evolution for our company. And through our strong clinical progress and successful partnering efforts, we are well positioned to achieve our strategic priorities in 2023 and beyond. We look forward to NDA submissions for our rare disease programs and significant progress for our clinical programs targeting obesity while striving to be the world's best peptide drug discovery and development company. Thank you all, and I will now turn it over to the operator for questions.

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

Yes, thank you very much. A couple of questions here from my side. So to just kick off, we're kicking off here with the BI45. So you comment in the report that the BI is currently engaging with health authorities to discuss the phase three plan. So could you maybe just add a bit of color on the advancements made by BI recently and also the reason for you to now be able to communicate what seems like quite material increased certainty that this candidate will go into phase three. And secondly, just on this being, you could say, devil's advocate here, so that phase three planning comment you made, I guess that's, of course, related to obesity and not just interactions for type 2 diabetes, obviously, just to rule out any misunderstandings here. And then my last question relates to CHI, so of course the partner situation. I noticed you have raised your peak sales expectations due to, of course, all the drug pricing strategy and then after some peer feedback. But so what does this actually leave you regarding the outlicensing, the partnering situation? I sort of sense a change of mind here. So can you maybe just elaborate what's your plan A and plan B, so to say? So anything that could, first of all, materialize pre-NDA or pre-approval, and also if you actually end up going alone here, is this actually something that maybe could even also have some impact on your OPEX guidance for 2023? Yeah, I think that was basically it. Thank you.

Thank you, Thomas, for your question.

And I will start out, and you may hand over also to David at one point but if we just start with CHI as a first thing it is with the new strategy we have it is our clear ambition to have a commercial partner for CHI and as we approach an NDA submission in this first half year and we would hope to see a fast review round of six to eight months with the FDA it is of course important to have a partner on board this year in order to become to pursue those timelines. So it is clearly our plan A to have a partner. And as we also have shared, we have had very good interactions and are making good progression on these discussions. But we've also been clear that we wanted to get the NDA file in place before we truly activated these discussions, because it is more simple to have a dialogue with multiple parties if you have the full data set in an NDA format. So we feel very confident on this path, and that is our strategy. Having said that, as we also shared and I shared here in our prepared remarks, then it is our ambition to play a role in these strategic partnerships. We are not just looking for strategic opportunities on paper. It is our ambition to continue to play a role, but to collaborate with companies who have rare disease commercial infrastructure in place, so we will not have to build that meeting sealant will still play a role there. But of course, that also depends on the discussions as they progress. And I would also say all the commercial activities needed this year for pre-launch activities, they are built into our budget, so there should be no impact here. When considering our glucagon GLD1, the Bi456906 molecule that Boehringer is developing, We have been very clear for a long time and of course it's based on our own review of the early data that the product looks extremely strong and we have also communicated and based on feedback from Boehringer that they have a lot of confidence in the molecule. You are right that now they actually allowed us and informed us that first of all they expect to share the data in the coming months from the obesity phase 2 study and that they are having parallel discussions on Phase 3 planning for overweight to obese individuals with health authorities. In our mind, that's, of course, a stronger messaging than what we have done before, but it's in line. It's a step forward in the messaging, and it just underscores the confidence we believe that Beringer have in the program and also have towards the opportunity to move into Phase 3. As you know, I cannot comment further on the details because we have not seen the Phase 2 data yet. And it is up to Bernd to provide the further details to the program. But we sense a lot of confidence in the program and also confidence towards the opportunity to move towards Phase 3.

That's great. Thank you very much.

Thank you. We will take our next question. Your next question comes from the line of Brian Bolshin from Jefferies. Please go ahead. Your line is open.

Hey, it's Brian from Jefferies. Just a quick clarification on BI-906 and obesity. Is there a potential milestone associated with the initiation of that phase three?

Thanks for that question, Brian. We only guide on the, you can say, outstanding milestones and royalties, and we have around €350 million in outstanding milestones and high single to low double-digit royalties to the program. I think it's fair to assume that it's a classical preclinical deal that we made, and we have received milestones, as you can see in our earlier reports when we initiated phase two, which was around €20 million. So I think it's fair to assume that we would get something also when we pass specific development steps and also with regulatory and commercial. But we do not guide on this specific value. So that is back to what Henrietta said. Those will only come once we know them.

Got it. Thanks very much.

Thank you. We will take our next question. Our next question comes from the line of Michael Novud from Nordea. Please go ahead. Your line is open.

Thank you very much.

So a couple of questions from my side as well. First on the pigletite, would you expect that it's possible to have the initial results available sort of by year end 2023 or early 2024 from the investigator-sponsored phase 2 trial? And secondly, on BI 456906, given sort of traditional timelines, would it then be fair to assume that data will be out at ADA? And secondly, also, that at that point in time, Beringham will have likely clarifications of the ongoing discussions regarding Phase III plans with the regulatory authorities, i.e., that they would also like to be able to communicate around ADA. whether it's a go or no-go decision to start the phase three. It definitely sounds like a go decision, but we just need the firm announcement and the timing of that. And then lastly, maybe just sort of a, of course, a smaller question to Segalog. Now it's in the hands of Novo. We haven't seen any sort of notable traction thus far. When would you expect that we start to see something on Segalog? I know it's not a key question, drug for you guys, but still it would be nice to see that it gains some traction in the U.S. Thank you very much.

Thank you, Michael, for good questions. If I just start on Zika, you can say we handed this product over to Novo Nordisk in the second half of last year, and of course we would expect to see some traction coming into the year once they get their hands around it. But as we have also all the time said, it is not the most important part of our value or equity story to see that it's an incredibly important product for patients. And we are extremely happy to see that it's in the hands of Novo Nordisk. But of course, we would expect to see traction and also that the product starts to provide some contributions to our revenue in the future. And one of the activities that we are focused on this year is the marketing authorization application. So we could also potentially get the product into the European market. Berner collaboration 906 and assumptions around when BI will make decisions and so on. I'm really sorry that I cannot make more comments. I think we have gone as fast as we can go right now in the commenting, but as I said before, we feel very confident that BI is confident in how to move this product forward and I think we it's also clear that they see it as a very important potential product in their pipeline. So I cannot comment further on this. Those speculations I will have to leave with you guys. On dabigrutide, we are just about to start the study, as David said, and maybe, David, you can share a little bit more light on what we intend to achieve here, but I think it's more likely early 2021.

Michael, thanks for the questions around DAPI. The investigator-led trial, we have successfully navigated the requirements now in Europe for CCA, CCIS, and as I said, we anticipate the initiation of the first patient within the coming days. The timing of the final data availability and disclosure to Adam's point is very likely to fall right around the change in years. So we would anticipate that in early 2024, we would have those data. And obviously, we ourselves are planning progression to the dose ranging and titration study phase 1B. So all of that is in for this calendar year, and we look forward to more comprehensive data availability from the investigator-led trial in our own programs in the first part of next year.

Okay, great. Maybe I can just throw in one additional follow-up question to sort of the partnering preferences, because you're getting phase one data for YAML and analog during the year. You're getting depicted data during sort of turn of the year or into early 2024, what would be sort of the partnering preferences? Is it to do a potential larger strategic collaboration where you sort of also play a smaller role? Or would you rather prefer to do individual partnerings on these projects like the Amelin, the Piclotype, and also the GIP?

That's a very good question, Michael. And I would say we are open to both scenarios. I think the most important part for us is we believe, especially for the three preparatory assets where we have all rights, we believe this represents a very, very significant value potential for the company. And we are in a unique situation here. It's actually not that often that biotech companies find themselves in a situation where even though it's still early clinical programs, they are quite mature when you compare across the industry, if you look outside India and the world. And we know there is a large farmer, a group of companies who you would normally expect to be in this space, but they do not have the richness of the pipeline you would expect. So we are in a very, very unique situation. And we also, as we have said today, fully committed to continue investing and putting all the effort into these programs as needed in the next couple of years. Before we end the phase three, it would be very logical to have a partner involved And I would say also, of course, it could also be logical to have a partner on board earlier for these programs because of the potential value they carry. But our focus is perhaps not so much if it's one partner for all three assets or even stuff we have in the preclinical pipeline or the individual partnerships. The most important part for us is that it's the right partnership. It's a 100% committed large pharma company and we have the opportunity to continue to contribute and thereby also retain more of the value for these programs because of the value potential we see with them.

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

Thank you. We will take our next question. Your next question comes from the line of Sushila Hernandez from Van Lanshot. Kempen, please go ahead. Your line is open.

Yes, thank you for taking my question. So for the MLN analog single ascending and multiple ascending dose data set that is coming out in H1 and H2 respectively, can you provide some context on what we should expect in terms of number of subjects and metrics and biomarkers? And what is in your view key to show in this study? And also a second question on the partnership. So could you further elaborate on your plans for Where are the discussions now versus late last year, and what do you look for in a partnership, and what should we expect in terms of timing? Thank you.

Thank you. I'll start, and then I'll hand over to David. Partnerships of the PacLutide, it's a little bit of a similar situation as we have with CHI. We really like to have all our data in place before we open up data rooms, but having said that, we have multiple interested parties, as with CHI, and we have progressed dialogues, but we do not anticipate to open up data rooms until we have all data in place. Basically, it makes it too complicated if we have half-baked data stories. So that will give you a little bit of an idea on the timeline for that. And I would say for Gleba, it's a little bit the same type of partnership as with CHI. Perhaps you can say for Gleba, you need organizations who have a little bit stronger commercial footprints Because it is going to be a competitive situation, whereas for CHI, we are going to be potentially the first that can introduce something for these patients. So there, it's enough just to have the Radices infrastructure to support the products get to the market. On the timelines and the data and studies on amylin, because it is one of our key ability assets, I will ask David to just comment a little bit on that.

Yeah, thanks for the question. And yeah, phase one, as you well know, is not always the space for the most creative study designs. So safety and tolerability and ensuring we have adequate exposure to our aminal analog that will inform dosing for phase two is obviously key to those studies. But as we have reported, we've completed the single ascending dose study. And those data, we believe, will give us the first glimpse at the potential impacts on body weight, much, as you may recall, for our dapiglutide asset. Despite relatively short exposure, one gets an early perspective on the potential for its impact on body weight, and Phase 1b will give us even greater insights into dosing, dose escalation, and longer exposure that will allow an even more granular look at the potential clinical impact, specific in terms of body weight loss targeting this asset for obesity. So I won't overpromise from a Phase 1B set of studies, but much as we've seen with other assets in the obesity space, I think we can insights as to their clinical effect, even in the safety tolerability and dose finding studies.

Thank you.

Thank you so much.

Thank you. We will take our next question. Your next question comes from the line of Jesper Nilsson from Carnegie. Please go ahead. Your line is open.

Thank you so much. A few follow-up questions from my side. So firstly, on partnership deal updates, just to understand you guys here on the call, is it still the base case to start partnership discussions on clopaclutide during Q2, or is that more Q3 now due to these changes? gathering of the full 24-week interim data on capacity. So will you start the progress with structural partnership progress in Q3 now? Is that fair to assume? Then on CHI, can you just confirm, are you still in partnership discussions? And would, in that case, be fair to assume a potential deal during the second half of this year? Or could it still be earlier? Then I have some follow-ups afterwards. Thank you.

So, let me try to clarify. So, for both CHI and for Clipacrocyte, we have had multiple interactions and we have multiple interests and have discussed discussions at several levels. Regarding moving to the diligence phase and getting into the very detailed discussions, first of all, we are prioritizing to have the data in place. For CHI, that is going to be the case, as you know, very, very soon because we are hopefully soon to submit the MDA. And also, we expect a fast review with the FDA. So a CHI partnership is our first priority this year because we expect to have a partner to launch with potentially already through the top of next year. Another key priority for us is, of course, to, once we have all the data in-house, engage in discussions, in more data and dividend discussions on the faculty time. And whether that's going to start in the second or third quarter, I think it's not something I can comment on. But I can comment on our priorities, and that is basically due to launch timing. That for CHI, it's important for us to have a partner in place before Glibber, because with Glibber, as you know, we expect a 12-month review and only a submission in the second half, so we have more time. And then for BCT, It's a little bit opportunistic to where we just keep dialogues ongoing. So that is my set of priorities. And yeah, I hope that answers your question.

It does. Thank you. Just to follow up then to the CHI sales opportunity. So based on your slides, and you've also previously shown this, it indicates a 400 million total addressable markets or more. Do you think that we underestimate this sales opportunity? And based on the discussions you've had with partners so far, do these partners agree with this? Or is this just, you know, the theoretic sales potential and not what could be the base case?

Yeah, so I would say we have not shared market research yet. So what we have done is we have a pretty good idea about at least as good as you can have for realities which really don't have any good treatments today, how many patients would be available in the key centers. And then when we cook that down to say who are the ones of these patients who we truly could be candidates because they have insufficient responses to current ways of managing the patients, then we get to a number of 800. And that is within the target population of the patients that we would hope to have in a potential label. Having said this, very often for rare diseases and other rare diseases, once you start to have treatment opportunities available, you start to see public patients in centers and smaller clinics. So it could be a higher number, but this is a number which we believe is centered around the key centers, and it doesn't even account for the European opportunity. So it's a number that we are pretty comfortable with, but I could also easily see that number of eligible patients would be higher once we start to, if we have a product that is available to patients. And then I would say another thing that we are looking into when it comes to hydroinsulinism is also if we should start to consider programs for adult patients, because we think there's an opportunity to expand into those as well. So on the value opportunity, we have only, So far, we decided to provide examples of comparable products, which have launched into rare disease, ultra-rare disease markets, and we have not shared any specific market research in our program, but I would say, if we provide sufficient clinical benefits, which we believe our program has demonstrated, but of course, ultimately we'll have to see a potential label, then we think it's good comparison. So I would say later this year we would share more on this. And this is, of course, as you can imagine, also the conversation that we would enter partnership discussions with. This is aligned with some of the ideas that I share here.

Okay. Thanks for taking my questions. Thank you. We will take our next question.

Your next question comes from the line of Mark Purcell from Morgan Stanley. Please go ahead. Your line is open.

Yeah, thanks very much. It's Mark Purcell from Morgan Stanley. I have three. Firstly, on 906, I wonder if you could help us understand the initial impact you see in heart rate with that asset, if you can share that based on the 16-week diabetes data. And is this increase in heart rate a reason why You believe BI is likely to start trials in obesity, but potentially not in type 2 diabetes until further titration work has been done. I note a parallel here to what's going on with Lilly's triple G agonist. The second one on dapaglutide, can you help us understand how much further you're going to likely push the dose in your 13-week dose ascension study versus the investigator-led DREAM study? I'm just wondering which additional benefits you expect you might be able to see as you push up the dose both on the GLP-1 and the GLP-2 component. And then lastly, on the amylin analog 8396, two parts. Have you seen any potential here in CKD? Other companies that are playing in this space have mentioned potential benefits in renal patients. And then part B, when you talk about combination studies, Are those within your own portfolio? So with DAPI, are they potentially with Boehringer? Have they shown any interest in combining Amelin with 906? Or is this already in an early stage looking to seek partners who have complementary assets? Thanks very much.

So I'll start and then I'll hand over to David. Thanks for the question, Sma. So if we just start with the...

I'm very certain that the heart rate observations in the type 2 study has nothing to do with Burner's priorities regarding obesity and NASH. I think it has been the key focus for them all the time. I think it's extremely encouraging to see the very good glucose control the product also provides. As such, diabetes management is more saturated today. There are more treatment choices, whereas in obesity and MS, there's a much, much bigger need for new and novel treatment. So that is the focus for them. And maybe just one more, and Dave, do you want to comment on the heart rate observations?

Yeah, Mark, thanks for the question. And as you're probably well aware, virtually across the panel of potent GLP-1 receptor agonists, and I've had exposure to a few of them over the years, particularly as the dose is pushed, that increase in heart rate is a known consequence of these long-acting GLP-1 agonists. But obviously, there are plenty of encouraging data on cardiovascular risk with these same agents in the type 2 diabetes space, reducing cardiovascular risk, likely reducing the risk of progression of renal disease. So despite that, known effects on heart rate. As Adam said, it has been clear to us and made quite clear, we think, by BI that their priorities have been obesity and NASH. But given what is known about the GLP-1 receptor agonism, having a clear understanding of its potential impact in type 2 diabetes and perhaps informing future lifecycle management decisions. But the focus is obviously obesity and NASH for that asset. I'll also address your other two questions on dapaglutide dose escalation. Obviously, the investigator-led study is in great part in the hands of that investigator, and because many of the outcomes are mechanistic, they have a somewhat different dose escalation and maximal dose that we would anticipate will be slightly lower than that planned for our Phase 1b study. As with all of these GLP-1-based therapies, it is really looking to achieve a balance between optimal dose exposure at the highest dose possible, given its tolerabilities, but also having an understanding of what titration scheme will allow you to get there. So our efforts in Phase 1b will be first and foremost to assess safety and efficacy, but also to gain a clearer understanding of what dose scheme, meaning titration and maximal dose, can be used in phase two and beyond. So I hope that gives you some clarification. Finally, to amylin-8396, the combinations, as I alluded to in my remarks, really this opens a number of possibilities. Our assets, as you know, is co-formulatable. We've presented non-clinical data co-formulations with the GLP-1 receptor agonists with our dapiglutide assets as a co-administration. So really, the opportunities to combine with any and all other incretin-based therapies, something we don't see likely with kagrelentide, given how it is being assessed and likely brought forth for submission. But that freestanding or loose combination opportunity, and ultimately, if there is interest, the co-formulation possibility for fixed dose combos really do exist based on what partners may be most interested. Your comment about CKD, obviously any weight loss agent that lowers burden, fat and lean body mass, and also can reduce blood pressure like we've seen with the SGLT2 inhibitors, the GLT1 receptor agonist. So, yes, we are intrigued by that potential opportunity, but first and foremost, as we've said, our focus is will be on assessing our amyloid agonist in the obesity space. But these other value-adds, if you will, will certainly be on our radar as we get into phase two and beyond.

Thank you, David. And just going back to the heart rate increase, if I may. So with Triple D and Masdutide, you're seeing up to 30 beats per minute. With GLP-1s as standalones, it's like six to seven beats per minute. Obviously, it comes down with the Triple G over time and Masdutide over time. but it's something regulators have cited some concerns around. I guess if you look at the altimmune asset, you don't see an increase in heart rate because of the pharmacokinetics. I just wondered with this BI asset, what level of heart rate increase you've seen and whether from your position you think this is something that's going to be important to address through a different dose titration regimen in phase 3.

I think another important aspect here is to recognize that the diabetes study was where they did very fast dose titration. So it was really suboptimal dose titration for our molecule with a lot of nausea and vomiting. So all that adds, we believe, to the observations that was also seen in heart rate. And I think the key difference here is that we have a lot of DLT1 on board, just as David said, some of the other DLT1s. So we don't buy too much into the PK argument for other GLD1 gluogons. We think it's actually more a question of if you have GLD1 on board, then you will observe the same pharmacology as has been seen with other GLD1s. If you don't have GLD1 on board, then you might more see what you would expect from a gluogon. So we think it represents quick and maybe too fast dose escalation in order to get to efficacy readouts. And this is, of course, something, as you also mentioned, when you get into longer-term studies, you can address this and titrate in a more sensible way.

Yeah, and Mark, to add to that, you're right with the long-acting agonists, particularly with the slower titration schemes that have ultimately been brought to market. If you remember back to Juliglutide, Lilly's Trulicity, and I was with Lilly at the time, but these are public domain information. that we actually had an adaptive phase 2-3 design that included both the titration scheme and included heart rate increases as part of that decision tree. To Adam's point, both the total exposure to GLP-1 and the rapidity with which you increase the GLP-1 exposure can have significant impacts on heart rate. So I would not over-read into particularly shorter-term studies that push the dose quickly. And obviously, we'll have, we hope, the data from the obesity population with VI 456906 very soon to get a broader look at a much longer exposure in the 46-week study, which for us is obviously an important piece of data to understand the full safety and efficacy profile.

That's great. Thanks very much for the call. I really appreciate it.

There seems to be no further questions, so I would like to hand back for closing remarks.

Okay. But with that, we would like to thank all the attendants for all the good questions, and we look very much forward to connecting at future announcements and updates. Have a great day.

This concludes today's conference call.

Thank you for participating. You may now disconnect.

The conference will begin shortly. To raise and lower your hand during Q&A, you can dial star 11.

Thank you. you Thank you. Bye. Thank you.

Welcome, and thank you for joining us today to discuss Zealand's full year results for 2022. With me are the following members of Zealand's management team. Adam Steinsberg, President and Chief Executive Officer, Himalaya Davinika, Chief Financial Officer, and David Kendall, Chief Medical Officer. You can find the related company announcement and annual report on our website at zealandpharma.com. As described on slide two, we will be making forward-looking statements that are subject to risks and uncertainties. With that, I will turn the call over to Adam Sainsberg. Adam?

Thank you, Anna, and thanks to everyone for joining today.

I'll begin on slide three. 2022 was a transformative year for Sealand, and I'm proud of the progress our team has made since announcing the change in strategy to prioritize investments in peptide therapeutics R&D. we achieved key milestones across our clinical pipeline, reporting positive phase three results for both our assets targeting rare diseases, for basic work on the newborns and children with congenital hyperinsulinism, and for people living with short-life syndrome. We also advanced our portfolio of peptides targeting obesity. Following our decision to scale back commercial operations, We executed two partnerships for our marketed products. We sold the Vigo insulin delivery device to Mankind Corporation, and we entered into a partnership with Novo Nordisk to commercialize SeekerLock. Finally, despite the challenging financial markets, we were able to strengthen our balance sheet through equity raises and extend our cash runway into mid-2024. Continuing this momentum, 2023 looks to be a very exciting year for Sealand. Turning to slide four, we have three key strategic objectives aimed at maximizing the value potential of our portfolio. Our first objective is to progress our rare disease assets, Static Luergon and Lipaglutide towards regulatory submissions. Our second objective is to advance our BVC portfolio. Through GLD-1 dual agonist BI-456906, Berner is planning to share the results of the Phase 2 obesity trial with the scientific community in the coming months. Berner has also informed us that in parallel they are engaging with health authorities to discuss plans for Phase 3 for people living with an overweight and obesity. Regarding our wholly owned assets in obesity, we expect to present data from the amylin phase 1 program during the year and initiate new clinical studies with all three assets. Finally, our third key objective is to engage in partnership discussions in alignment with our change in strategy. As we evaluate future partnerships, we will seek to continue to participate in the programs across the value chain, leveraging our strengths and capabilities to maximize the value of the asset. In addition to these three key objectives, we are also focused on activities that support our programs in type 1 diabetes management. This includes submitting a marketing application application to the European Medical Agency for Zika lock, which we are responsible for under the global agreement with Novo Nordisk. I would like to spend a few minutes on our classic program in children with congenital hyperinsulinism, or CHI, as we are approaching the NDA submission in the first half of this year, and we believe it represents significant opportunity for C-Land to address a major unmet medical need for children and their families. Moving to slide five, CHI is a rare disease that affects babies and children. A defect in the pancreatic beta cell results in an overproduction of insulin, leading to frequent episodes of severe hyperglycemia that may result in brain damage. Care for patients with CHI is complex, and more than half may be suboptimally treated with current therapies. We've completed a phase three program, demonstrating the clinical potential of dasyclurgan administered as a continuous subcutaneous infusion We have a viable pump. If approved, we expect to utilize the DECA infusion pump to provide DASIC-GluA1 to patients. Shown on slide 6, we estimate that there are up to 800 children with diffuse CHI that may be eligible for DASIC-GluA1 treatment in the U.S. Most of these children are treated or closely followed by a pediatric endocrinologist in a few centers of excellence. To the right of the slide, we present examples of other products targeting ultra-rare diseases with high clinical burden that command premium pricing in the U.S. And if approved, we do believe that Dashing Low On has the potential to provide comparable clinical value, thus also representing a significant opportunity for C-Land. Advancing to slide seven, I will now turn over the call to our Chief Medical Officer, David Kendall, to discuss the risks of the RMP pipeline. David.

Thank you, Adam. Today I will focus my remarks on our obesity portfolio, but first I would like to provide a brief update on glpaglutide, our long-acting GLP-2 analog that is being developed for the treatment of short bowel syndrome and intestinal failure. Please turn to slide eight. As many of you know, in September of 2022, we reported positive top-line data from the EASE-1 Phase III trial, which demonstrated that glopaglutide treatment given twice weekly when compared to placebo significantly reduced parenteral support volume required in individuals living with SPS and intestinal failure. In addition, we observed that approximately one in eight patients treated with glopaglutide in EASE 24 weeks, achieving so-called enteral autonomy, while no placebo-treated patients were able to achieve this enteral autonomy, a feature we believe is differentiating from current treatments. We look forward to presenting the results of EASE-1 at upcoming scientific congresses in the coming months, including data on the response in specific subgroups. A total of 96 patients who completed EASE-1 enrolled in EASE-2, the first of two long-term safety and efficacy extension studies. Interim data from these extension trials, as well as from the EASE-4 study assessing long-term effects of glopaglutide on intestinal fluid and energy uptake, will all be a part of the regulatory package for glopaglutide. We had previously anticipated interim results from EASE-2 before the end of 2022 and from EASE-3 in the first quarter of 2023. However, having the positive results of EASE-1 in hand, we made a decision to extend the interim analysis to include 24-week data from all individuals enrolled into EASE-2. This will include data from patients who were on placebo in EASE-1, and thus, this will allow us to hopefully expand our understanding of the potential for glupaglutide as we observed in EASE 1. As such, the interim results from EASE 2, 3, and full results of EASE 4 are now anticipated in the first half of this year. Importantly, extending the follow-up period for EASE 2 and 3 will not impact the timing for a potential regulatory submission, which we anticipate in the second half of 2023. Advancing to slide 9 and focusing on our obesity portfolio, There is little doubt that obesity represents one of the most significant healthcare challenges of our time, and we are excited to have a rich and differentiated pipeline of novel assets for the potential treatment of obesity. Obesity is a complex disease that can be treated pharmacologically by targeting a number of unique metabolic pathways. While single modality therapies have shown significant to achieve even greater degrees of weight loss comparable to that seen following bariatric surgery. We are using two specific approaches at Zeeland, dual pharmacology to target two receptors with one peptide and potent and differentiated single receptor agonist that can be used alone or in combination with other peptides as loose combination or in co-formulations. Please turn to slide 10. In this figure, we present a representation of our differentiated peptide molecules targeting obesity. Each peptide in our portfolio has been designed to target important neurohormonal pathways that are important in the regulation of body weight, including food intake, energy expenditure, food composition, and satiety, any one of which can play important roles in achieving weight loss. Our therapeutic approach aims, one, to achieve increased weight loss, and two, to provide additional effects to address specific needs or co-morbidities of obese or overweight individuals. Our novel dual hormone candidates are designed with GLP-1 receptor agonism as a foundation to provide weight loss through reduced food intake and delayed gastric emptying, and to offer the potential to improve glycemic control while adding agonism to a second receptor for complementary effects. With each of these molecules, we are targeting weight loss that can exceed that observed for GLP-1 receptor agonism alone, with the potential, based on non-clinical and clinical observations to date, to be on par with other dual hormone candidates currently in development. Turning our attention to BI-456906, an asset co-invented with Berger Ingelheim, where the additional effects of glucagon receptor agonism are designed to complement GLP-1 agonism and are postulated to stimulate energy expenditure and improve the trafficking of fat, with the potential to further improve weight loss and target disorders of liver fat. BI-456906 is in active clinical development with our Beringer Ingelheim partners for the management of obesity and NASH. In 2022, very encouraging data on both glycemic control and weight loss in patients with type 2 diabetes were reported following only 16 weeks of treatment. We very much look forward to having BI share the results from the 46-week phase 2 trial of BI-456906 in overweight and obese individuals at a scientific congress in the coming months. Dapiglutide is a first-in-class dual GLP-1, GLP-2 receptor agonist, leveraging the effects of GLP-2 agonism, a peptide hormone that is co-secreted with GLP-1 following meals. The rationale driving use of dapiglutide is the potential to provide weight loss through potent GLP-1 receptor agonist activity, combined with the known effects of GLP-2 agonism on intestinal barrier function. It is postulated that improvements in intestinal barrier function can improve gut function and target the low-grade inflammation that is associated with syndromes of obesity. We are actively investigating a number of these mechanisms through an investigator-led clinical study due to start in the coming days. We also believe, based on data from clinical studies, that GLP-2 receptor agonism can also contribute to improved tolerability of the associated GLP-1 agon. And in closing, we note that our portfolio also includes two single receptor agonists. The islet hormone amylin is known to play an important metabolic role and is a validated target for the potential treatment of obesity. Amylin treatment results in weight loss by reducing food intake by increasing satiety, and amylin is known to restore leptin sensitivity, which may contribute to more lasting weight loss effects. We believe amylin agonism can play an important role both as a standalone treatment for obesity, serving patients who may not tolerate or adequately respond to GLP-1-based therapies, and amylin as a non-incretin hormone can be used in combination with other incretin-based treatments to provide additional weight loss. Zeeland's novel long-acting amylin analog is specifically designed to allow for once-weekly administration and for co-formulation or co-administration with other peptide-based therapies. We are currently advancing our amylin analog, ZP8396, through phase one multiple ascending dose studies and plan to share clinical data from this program this year. Finally, we are planning to bring our unique standalone GIP receptor agonist into clinical studies in the second half of 2023. We are both excited and encouraged by the strong momentum across our development pipeline in rare diseases and obesity and look forward to providing additional updates as we advance our programs in 2023. I will now turn the call over to our CFO, Henrietta Benecke, to review the full year financial results for 2022. Henrietta?

Thanks, David, and hello, everyone. Let's move to slide 11 and the income statement. Revenue for 2022 was 104 million DKK driven by the development agreement with elections and the partnership agreement made in Q2 2022 with Novo Nordisk. CEDAN received an upfront payment of 25 million DKK from Novo. The operating expenses for the period were 941 million DKK within our guidance for 2022. This is slightly above last year when comparing the continued operations. The increase is driven by the progression of our research and development activities, especially our late-stage clinical programs. The sales and marketing expenses decreased compared to last year, following their announced restructuring in March 2022. Other operating items increased due to restructuring costs related to continued operations and costs related to the U.S. NASDAQ delisting in September 2022. Net financial items for the period resulted in a loss of 135 million DKK compared to 25 million DKK for the same period in 2021. These costs are primarily driven by the loan agreement with Oberland. As a result of the amount restructuring, all income and expenses related to commercial efforts related to VIGO and SIGA law are accounted for at this continued operation. Net result for this discontinued raise in 2022 was a loss of 237 million CKK. Let's move on to slide 12 and the cash position. In 2022, we were able to strengthen our balance sheet with gross proceeds worth more than 1 billion CKK, despite very challenging financial markets. We also pay down half of the sustainability in the Oberland and make significant investments in progressing our pipeline. At year-end 2022, cash equivalents and marketable securities were approximately 1.2 billion DKK. With this, we have a cash runway to mid-2024, which allows us to continue investments in progressing our R&D pipeline in 2023. Talking about 2023, let's move on to size 13 and the financial guidance for the year. As Adam said, 2023 looks to be a very exciting year for TNN. We will invest in progressing our rarest seed assets towards regulatory submission in 2023, while at the same time investing in our BTT portfolio. Consequently, in 2023, we guide for net operating expenses of between 800 to 900 million DKK. This is somewhat lower than recent year's expense level and do reflect the restructuring initiative implemented last year. In 2023, we will also engage in partnership discussions, as Adam mentioned, aligned with our changes strategy. However, we will not provide guidance on revenue anticipated from existence and new license and partnership agreements due to uncertainty related to the timing as well as the size of such revenue. And with that, I will turn the call back to Adam.

Thank you, Henriette.

2022 was a year of significant evolution for our company. And through our strong clinical progress and successful partnering efforts, we are well positioned to achieve our strategic priorities in 2023 and beyond. We look forward to NDA submissions for our rare disease programs and significant progress for our clinical programs targeting obesity while striving to be the world's best peptide drug discovery and development company. Thank you all, and I will now turn it over to the operator for questions.

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

Yes, thank you very much. A couple of questions here from my side. So to just kick off, we're kicking off here with the BI45. So you comment in the report that the BI is currently engaging with health authorities to discuss the phase three plan. So could you maybe just add a bit of color on the advancements made by BI recently and also the reason for you to now be able to communicate what seems like quite material increased certainty that this candidate will go into phase three. And secondly, just on this being, you could say, devil's advocate here, so that phase three planning comment you made, I guess that's, of course, related to obesity and not just interactions for type 2 diabetes, obviously, just to rule out any misunderstandings here. And then my last question relates to CHI, so of course the partner situation. I noticed you have raised your peak sales expectations due to, of course, all the drug pricing strategy and then after some payer feedback. But so what does this actually leave you regarding the outlicensing, the partnering situation? I sort of sense a change of mind here. So can you maybe just elaborate what's your plan A and plan B, so to say? So anything that could, first of all, materialize pre-NDA or pre-approval, and also if you actually end up going alone here, is this actually something that maybe could even also have some impact on your OPEX guidance for 2023? Yeah, I think that was basically it. Thank you.

Thank you, Thomas, for your question. And I will start out, and you

I may hand over also to David at one point. But if we just start with CHI as a first thing, it is with the new strategy we have, it is our clear ambition to have a commercial partner for CHI. And as we approach an NDA submission in this first half year, and we would hope to see a fast review round of six to eight months with the FDA, it is of course important to have a partner on board this year in order to pursue those timelines. So it is clearly our plan A to have a partner. And as we also have shared, we have had very good interactions and are making good progression on these discussions. But we've also been clear that we wanted to get the NDA file in place before we truly activated these discussions, because it is more simple to have a dialogue with multiple parties if you have the full data set in an NDA format. So we feel very confident on this path and that is our strategy. Having said that, as we also shared and I shared here in our prepared remarks, then it is our ambition to play a role in these strategic partnerships. We are not just looking for strategic opportunities on paper. It is our ambition to continue to play a role but to collaborate with companies who have rare disease commercial infrastructure in place so we will not have to build that meaning sealant will still play a role there. But of course, that also depends on the discussions as they progress. And I would also say all the commercial activities needed this year for pre-launch activities, they are built into our budget, so there should be no impact here. When considering our glucagon GLD1, the Bi456906 molecule that Boehringer is developing, We have been very clear for a long time and of course it's based on our own review of the early data that the product looks extremely strong and we have also communicated and based on feedback from Boehringer that they have a lot of confidence in the molecule. You are right that now they actually allowed us and informed us that first of all they expect to share the data in the coming months from the obesity phase 2 study and that they are having parallel discussions on Phase 3 planning for overweight to obese individuals with health authorities. In our mind, that's, of course, stronger messaging than what we have done before, but it's in line. It's a step forward in the messaging, and it just underscores the confidence we believe that Beringer have in the program and also have towards the opportunity to move into Phase 3. As you know, I cannot comment further on these details because we have not seen the phase two data yet. And it is up to Berner to provide the further details to the program. But we sense a lot of confidence in the program and also confidence towards the opportunity to move towards phase three.

That's great. Thank you very much.

Thank you. We will take our next question. Your next question comes from the line of Brian Bolshin from Jefferies. Please go ahead. Your line is open.

Hey, it's Brian from Jefferies. Just a quick clarification on BI-906 and obesity. Is there a potential milestone associated with the initiation of that phase three?

Thanks for that question, Brian. We only guide on the, you can say, outstanding milestones and royalties, and we have around €350 million in outstanding milestones and high single to low double-digit royalties to the program. I think it's fair to assume that it's a classical preclinical deal that we made, and we have received milestones, as you can see in our earlier reports when we initiated phase two, which was around €20 million. So I think it's fair to assume that we would get something also when we pass specific development steps and also with regulatory and commercial. But we do not guide on this specific value. So that is back to what Henrietta said. Those will only come once we know them.

Got it. Thanks very much.

Thank you. We will take our next question. Our next question comes from the line of Michael Novud from Nordea. Please go ahead. Your line is open.

Thank you very much.

So a couple of questions from my side as well. First on the pigletite, would you expect that it's possible to have the initial results available sort of by year end 2023 or early 2024 from the investigator sponsored phase two trial? And secondly, on BI 456906, given sort of traditional timelines, would then be fair to assume that data will be out at ADA, and secondly also that at that point in time, Beringham will have likely clarifications of the ongoing discussions regarding Phase III plans with the regulatory authorities, i.e. that they would also like to be able to communicate around ADA. whether it's a go or no go decision to start the phase three. It definitely sounds like a go decision, but we just need the firm announcement and the timing of that. And then lastly, maybe just sort of a, of course, a smaller question to Segalog. Now it's in the hands of NOVA. We haven't seen any sort of notable traction thus far. When would you expect that we start to see something on Segalog? I know it's not a key question, drug for you guys, but still, it would be nice to see that it gains some traction in the US. Thank you very much.

Thank you, Michael, for good questions. If I just start on Zika, you can say we handed this product over to Novo Nordisk in the second half of last year, and of course, we would expect to see some traction coming into the year once they get their hands around it. But as we have also all the time said, it is not the most important part of our value or equity story to see that it's an incredibly important product for patients. And we are extremely happy to see that it's in the hands of Novo Nordisk. But of course, we would expect to see traction and also that the product starts to provide some contributions to our revenue in the future. And one of the activities that we are focused on this year is the marketing authorization application. So we could also potentially get the product into the European market. Berner collaboration 906 and assumptions around when BI will make decisions and so on. I'm really sorry that I cannot make more comments. I think we have gone as fast as we can go right now in the commenting. But as I said before, we feel very confident that BI is confident in how to move this product forward. And I think it's also clear that they see it as a very important potential product in pipeline so so i cannot comment further on this um that those speculations i will have to leave with you guys uh on that we are just about to start the study as david said and maybe david you can share a little bit more light on what we intend to achieve here but but i think it's more likely early to

Michael, thanks for the questions around DAPI. The investigator-led trial, we have successfully navigated the requirements now in Europe for CCA, CCIS. And as I said, we anticipate the initiation of the first patient within the coming days. The timing of the final data availability and disclosure to Adam's point is very likely to fall right around the change in years. So we would anticipate that in early 2024, we would have those data. And obviously, we ourselves are planning progression to the dose ranging and titration study phase 1B. So all of that is in play for this calendar year, and we look forward to more comprehensive data availability from the investigator-led trial in our own programs in the first part of next year.

Okay, great. Maybe I can just throw in one additional follow-up question to sort of the partnering preferences, because you're getting phase one data for YAML and analog during the year. You're getting depicted data during sort of turn of the year or into early 2024, what would be sort of the partnering preferences? Is it to do a potential larger strategic collaboration where you sort of also play a smaller role? Or would you rather prefer to do individual partnerings on these projects like the Amelin, the Piclotype, and also the GIP?

That's a very good question, Michael. And I would say we are open to both scenarios. I think the most important part for us is we believe, especially for the three preparatory assets where we have all rights, we believe this represents a very, very significant value potential for the company. And we are in a unique situation here. It's actually not that often that biotech companies find themselves in a situation where even though it's still early clinical programs, they are quite mature when you compare across the industry, if you look outside the end of the world. And we know there is a large farmer, a group of companies who you would normally expect to be in this space, but they do not have the richness of the pipeline you would expect. So we are in a very, very unique situation. And we also, as we have said today, fully committed to continue investing and putting all the effort into these programs as needed in the next couple of years. Before we end the phase three, it would be very logical to have a partner involved. And I would say also, of course, it could also be logical to have a partner on board earlier for these programs because of the potential value they carry. But our focus is perhaps not so much if it's one partner for all three assets or even stuff we have in the preclinical pipeline or the individual partnerships. The most important part for us is that it's the right partnership. It's a 100% committed large pharma company, and we have the opportunity to continue to contribute and thereby also retain more of the value for these programs because of the value potential we see with them.

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

Thank you. We will take our next question. Your next question comes from the line of Susila Hernandez from Van Lanshot. Please go ahead. Your line is open.

Yes, thank you for taking my question. So for the MLN analog single ascending and multiple ascending dose data set that is coming out in H1 and H2 respectively, can you provide some context on what we should expect in terms of number of subjects and metrics and biomarkers? And what is, in your view, key to show in this study? And also a second question on the partnership. So could you further elaborate on your plans for Where are the discussions now versus late last year, and what do you look for in a partnership, and what should we expect in terms of timing? Thank you.

Thank you. I'll start, and then I'll hand over to David. On partnerships of the PacLutide, it's a little bit of a similar situation as we have with CHI. We really like to have all our data in place before we open up data rooms, but having said that, we have multiple interested parties, as with CHI, and we have progressed dialogues, but we do not anticipate to open up data rooms until we have all data in place. Basically, it makes it too complicated if we have half-baked data stories. So that will give you a little bit of an idea on the timeline for that. And I would say for Glebe, it's a little bit the same type of partnership as with CHI. Perhaps you can say for Glebe, you need organizations who have a little bit stronger commercial footprints Because it is going to be a competitive situation, whereas for CHI, we are going to be potentially the first that can introduce something for these patients. So there, it's enough just to have the Radices infrastructure to support the products get to the market. On the timelines and the data and studies on amylin, because it is one of our key ability assets, I will ask David to just comment a little bit on that.

Yeah, thanks for the question. And yeah, phase one, as you well know, is not always the space for the most creative study designs, but safety and tolerability and ensuring we have adequate exposure to our aminal analog that will inform dosing for phase two is obviously key to those studies. But as we have reported, we've completed the single ascending dose study and those data, we believe, will give us the first glimpse at the potential impacts on body weight, much, as you may recall, for our dapiglutide asset. Despite relatively short exposure, one gets an early perspective on the potential for its impact on body weight, and Phase 1b will give us even greater insights into dosing, dose escalation, and longer exposure that will allow an even more granular look at the potential clinical impact, specific in terms of body weight loss targeting this asset for obesity. So I won't overpromise from a Phase 1B set of studies. But much as we've seen with other assets in the obesity space, I think we can get significant insights as to their clinical effect, even in the safety tolerability and dose finding studies.

Thank you.

Thank you so much.

Thank you. We will take our next question. Your next question comes from the line of Jasper Nielsen from Carnegie. Please go ahead. Your line is open.

Thank you so much. A few follow-up questions from my side. So firstly, on partnership deal updates, just to understand you guys here on the call, is it still the base case to start partnership discussions on clopaclutide during Q2, or is that more Q3 now due to these gathering of the full 24-week interim data on capacity. So will you start the progress with structural partnership progress in Q3 now? Is that fair to assume? Then on CHI, can you just confirm, are you still in partnership discussions? And would, in that case, be fair to assume a potential deal during the second half of this year? Or could it still be earlier? Then I have some follow-ups afterwards. Thank you.

Thank you. So, let me try to clarify. So, for both CHI and for clifactotide, we have had multiple interactions and we have multiple interests and have discussed discussions at several levels. Regarding moving to the diligence phase and getting into the very detailed discussions, we have, first of all, we are prioritizing to have the data in place. For CHI, that is going to be the case, as you know, very, very soon, because we are hopefully soon to submit the MDA. And also, we expect a fast review with the FDA. So a PHI partnership is our first priority this year because we expect to have a partner to launch with potentially already through the top of next year. Another key priority for us is, of course, to, once we have all the data in-house, engage in discussions, in more data and dividend discussions on the practical type. And whether that's going to start in the second or third quarter, I think it's not something I can comment on. But I can comment on our priorities, and that is basically due to launch timing. That for CHI, it's important for us to have a partner in place before Glibber, because with Glibber, as you know, we expect a 12-month review and only a submission in the second half, so we have more time. And then for BCT, it's a little bit opportunistic to where we just keep dialogues ongoing. So that is my set of priorities and yeah, I hope that answers your question.

It does, thank you. Just to follow up then to the CHI sales opportunity. So based on your slides and you've also previously shown this, it indicates a 400 million total addressable markets or more. Do you think that we underestimate this sales opportunity? And based on the discussions you've had with partners so far, do these partners agree with this? Or is this just, you know, the theoretical sales potential and not what could be the base case?

Yeah, so I would say we have not shared market research yet. So what we have done is we have a pretty good idea about at least as good as you can have for realities which really don't have any good treatments today, how many patients would be available in the key centers. And then when we cook that down to say, who are the ones of these patients who we truly could be candidates because they have insufficient responses to current ways of managing the patients, then we get to a number of 800. And that is within the target population of the patients that we would hope to have in a potential label. Having said this, very often for rare diseases and other rare diseases, once you start to have treatment opportunities available, you will start to see public patients in centers and smaller clinics. So it could be a higher number, but this is a number which we believe is centered around the key centers, and it doesn't even account for the European opportunity. So it's a number that we are pretty comfortable with, but I could also easily see that number of eligible patients would be higher once we start to, if we have a product that is available to patients. And then I would say another thing that we are looking into when it comes to hyperinsulinism is also if we should start to consider programs for adult patients, because we think there's an opportunity to expand into those as well. So on the value opportunity, we have only So far, we decided to provide examples of comparable products, which have known into rare disease, ultra-rare disease markets, and we have not shared any specific market research in our program. But I would say, if we provide sufficient clinical benefits, which we believe our program has demonstrated, but of course, ultimately we have to see a potential label, then we think it's good comparison. So I would say later this year we would share more on this. And this is, of course, as you can imagine, also the conversation that we would enter partnership discussions with. This is aligned with some of the ideas that I share here.

Okay. Thanks for taking my questions. Thank you.

We will take our next question. Your next question comes from the line of Mark Purcell from Morgan Stanley. Please go ahead. Your line is open.

Yeah, thanks very much. It's Mark Purcell from Morgan Stanley. I have three. Firstly, on 906, I wonder if you could help us understand the initial impact you see in heart rate with that asset, if you can share that based on the 16-week diabetes data. And is this increase in heart rate a reason why You believe BI is likely to start trials in obesity, but potentially not in type 2 diabetes until further titration work has been done. I note a parallel here to what's going on with Lilly's triple G agonist. The second one on dapaglutide, can you help us understand how much further you're going to likely push the dose in your 13-week dose ascension study versus the investigator-led DREAM study? I'm just wondering which additional benefits you expect you might be able to see as you push up the dose both on the GLP-1 and the GLP-2 component. And then lastly, on the amylin analog 8396, two parts. Have you seen any potential here in CKD? Other companies that are playing in this space have mentioned potential benefits in renal patients. And then part B, when you talk about combination studies, Are those within your own portfolio? So with DAPI, are they potentially with Boehringer? Have they shown any interest in combining Amelin with 906? Or is this already in an early stage looking to seek partners who have complementary assets? Thanks very much.

So I'll start and then I'll hand over to David. Thanks for the question, Sma.

So if we just start with the... I'm very certain that the heart rate observations in the type 2 study has nothing to do with Burner's priorities regarding obesity and NASH. I think it has been the key focus for them all the time. I think it's extremely encouraging to see the very good glucose control the product also provides. Diabetes management is more saturated today. There are more treatment choices, whereas in obesity and MS, there's a much, much bigger need for new and novel treatments. So that is the focus for them. And maybe just one more, do you want to comment on the heart rate observations?

Mark, thanks for the question. And as you're probably well aware, virtually across the panel of potent GLP-1 receptor agonists, and I've had exposure to a few of them over the years, particularly as the dose is pushed, that increase in heart rate is a known consequence of these long-acting GLP-1 agonists. But obviously, there are plenty of encouraging data on cardiovascular risk with these same agents in the type 2 diabetes space, reducing cardiovascular risk, likely reducing the risk of progression of renal disease. So despite that, known effects on heart rate. As Adam said, it has been clear to us and made quite clear, we think, by VI that their priorities have been obesity and NASH. But given what is known about the GLP-1 receptor agonism, having a clear understanding of its potential impact in type 2 diabetes and perhaps informing future lifecycle management decisions. But the focus is obviously obesity and NASH for that asset. I'll also address your other two questions on dapaglutide dose escalation. Obviously, the investigator-led study is in great part in the hands of that investigator, and because many of the outcomes are mechanistic, they have a somewhat different dose escalation and maximal dose that we would anticipate will be slightly lower than that planned for our Phase 1b study. As with all of these GLP-1-based therapies, it is really looking to achieve a balance between optimal dose exposure at the highest dose possible given its tolerabilities, but also having an understanding of what titration scheme will allow you to get there. So our efforts in Phase 1b will be first and foremost to assess safety and efficacy, but also to gain a clearer understanding of what dose scheme, meaning titration and maximal dose, can be used in phase two and beyond. So I hope that gives you some clarification. Finally, to amylin-8396, the combinations, as I alluded to in my remarks, really this opens a number of possibilities. Our assets, as you know, is co-formulatable. We've presented non-clinical data co-formulations with the GLP-1 receptor agonists, with our dapiglutide assets as a co-administration. So really, the opportunities to combine with any and all other incretin-based therapies, something we don't see likely with kagrelentide, given how it is being assessed and likely brought forth for submission. But that freestanding or loose combination opportunity, and ultimately if there is interest, the co-formulation possibility for fixed dose combos really do exist based on what partners may be most interested. Your comment about CKD, obviously, any weight loss agent that lowers burden, fat and lean body mass, and also can reduce blood pressure like we've seen with the SGLT2 inhibitors, the GLP-1 receptor agonists. So, yes, we are intrigued by that potential opportunity, but first and foremost, as we've said, our focus is will be on assessing our amyloid agonist in the obesity space. But these other value-adds, if you will, will certainly be on our radar as we get into phase two and beyond.

Thank you, David. And just going back to the heart rate increase, if I may. So with triple D and masdutide, you're seeing up to 30 beats per minute. With GLP-1s as standalones, it's like six to seven beats per minute. Obviously, it comes down with a triple G over time and masdutide over time. but it's something regulators have cited some concerns around. I guess if you look at the altimmune acid, you don't see an increase in heart rate because of the pharmacokinetics. I just wondered with this BI acid, what level of heart rate increase you've seen and whether from your position you think this is something that's going to be important to address through a different dose titration regimen in phase three.

I think it's another important aspect here to recognize that the diabetes study was where they did very fast dose titration. So it was really suboptimal dose titration for our molecule with a lot of nausea and vomiting. So all that adds, we believe, to the observations that was also seen on heart rate. And I think the key difference here is that we have a lot of TLD1 on board, just as David said, some of the other TLD1s. So we don't buy too much into the PK argument. for other GLD1 gluobons. We think it's actually more a question of if you have GLD1 on board, then you will observe the same pharmacology as has been seen with other GLD1s. If you don't have GLD1 on board, then you might more see what you would expect from a gluobon. So we think it represents quick and maybe too fast dose escalation in order to get to And this is, of course, something, as you also mentioned, when you get into longer-term studies, you can address this and titrate in a more sensible way.

Yeah, and Mark, to add to that, you're right with the long-acting agonists, particularly with the slower titration schemes that have ultimately been brought to market. If you remember back to Juliglutide, Lilly's Trulicity, and I was with Lilly at the time, but these are public domain information. that they actually, we actually had an adaptive Phase 2-3 design that included both the titration scheme and included heart rate increases as part of that decision tree. At Adam's point, both the total exposure to GLP-1 and the rapidity with which you increase the GLP-1 exposure can have significant impacts on heart rate, so I would not over-read into particularly shorter-term studies that push the dose quickly. And obviously, we'll have, we hope, the data from the obesity population with BI 456906 very soon to get a broader look at a much longer exposure in the 46-week study, which for us is obviously an important piece of data to understand the full safety and efficacy profile.

That's great. Thanks very much for the call. Really appreciate it.

There seems to be no further questions, so I would like to hand back for closing remarks.

Okay. But with that, we would like to thank all the attendants for all the good questions, and we look very much forward to connecting at future announcements and updates. Have a great day.