Zealand Pharma A/S

Thank you, operator. Welcome, and thank you for joining us today to discuss Zealand's interim results for the first 6 months of 2023.

With me today are the following members of Zealand's management team. Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, Chief Financial Officer; and David Kendall, Chief Medical Officer.

You can also find the related company announcement and interim report on our website at zealandpharma.com. As described on Slide 2, we will be making forward-looking statements that are subject to risks and uncertainties.

With that, I will turn the call over to Adam Steensberg, President and CEO. Adam?

Thank you, Anna, and thanks to everyone for joining today. I will begin on Slide 3.

I'm very proud of what Zealand has achieved in the first 6 months of '23. With a strong focus on R&D, we have successfully progressed our product candidates within obesity, rare diseases and type 1 diabetes.

Also, we have significantly strengthened our balance sheet to ensure cash runway until mid-'26. Of course, the big news of today is Boehringer Ingelheim's announcement that they are advancing survodutide, co-invented with Zealand Pharma, into 3 global Phase III clinical trials in people living with overweight and obesity.

We are very encouraged by the Phase II results presented at this year's ADA conference in June and certainly share [ bearing ] us excitement about the potential for survodutide and the Phase III trials expected to start in the second half of the year. Also in our obesity portfolio, we presented results from the Phase I single-ascending dose trial at ADA in June, demonstrating profound reduction in body weight after only 1 week of dosing of our long-acting amylin analog.

Then in July, we announced top line results from Part 1 of the Phase I multiple-ascending dose trials, demonstrating improved weight loss after 6 weeks of once-weekly treatment with lower doses of CP-8396. Based on the significant rate reductions and mild adverse-event profile, we have started Part 2 of the multiple-ascending dose trial, assessing both longer duration of treatment and higher doses of ZP8396, and we look very much forward to seeing those data and announcing them in the first half of 2024.

With [ dasiglucagon ], we are excited about the regulatory submissions to the U.S. FDA for the treatment of congenital hyperinsulinism and the regulatory submission to the European Medicines Agency for the treatment of severe hypoglycemia.

Moving to Slide 4. We are well on track to deliver on the strategic objectives that we have had outlined for 2023.

In the second half of the year, we expect to submit the new drug application for the U.S. FDA for glepaglutide for the treatment of short bowel syndrome.

Also, in the second half, we expect to initiate the 13-week dose titration trial with dapiglutide, our dual GLP-1 GLP-2 receptor agonist and complete preclinical activities with ZP6590, our GIP analog. The dialogues with potential partners for our rare disease programs are progressing according to plan, and we aim to enter into a partnership agreement with dasiglucagon in congenital hyperinsulinism in the second half of this year.

Moving to Slide 5. I will now turn over the call to our CMO, David Kendall, to present our R&D pipeline and the recent results from our obesity portfolio.

David?

Thank you, Adam. Today, I will focus my remarks on the most recent results from 2 of our product candidates targeting obesity, namely the Phase II results with the dual glucagon GLP-1 receptor agonist, survodutide, presented at the American Diabetes Association Scientific Sessions in June, and the top line results from Part 1 of the Phase Ib multiple-ascending dose trial with our long-acting amylin analog ZP8396, announced in July.

Turning to Slide 6. Most people living with overweight and obesity, who are candidates for pharmacologic therapy, will benefit from weight loss of between 15% and 25%.

While there are several promising pipeline candidates from a number of companies targeting weight loss in this range, there remains a significant treatment gap and unmet medical need to target the complications of obesity and improved tolerability of treatment. Bringing differentiated anti-obesity treatments to the market that address the different needs of obesity subpopulations and improved tolerability will be critically important.

Please turn your attention to Slide 7. Obesity is a complex disease that is amenable to pharmacologic treatments that target a number of unique metabolic pathways.

We anticipate that the future treatment landscape in obesity will contain several categories of molecules. Today, this is dominated by molecules with a GLP-1 receptor backbone, including dual and triple agonist that target several important metabolic pathways.

We are incredibly excited about the potential for our amylin agonist in the management of overweight and obesity and firmly believe that amylin agonism holds significant potential for offering substantial weight loss and the potential for a better tolerability profile when compared with the GLP-1-based therapies. Amylin is a validated non-incretin mechanism and has been shown to be very effective both as monotherapy and in combination with GLP-1-based treatments.

We also believe that the success of future anti-obesity treatments will be determined by their effects on both body weight and important features of differentiation, including targeting comorbidities, improving tolerability and offering alternatives to these incretin-based mechanisms. On Slide 8, we outline our portfolio of novel and differentiated assets for the potential treatment of overweight and obesity, highlighting the mechanistic rationale behind each molecule.

Our therapeutic approach aims to: one, achieve increased weight loss; and two, provide additional effects to address specific comorbidities; and three, improve tolerability. Each molecule is differentiated through peptide target, design or formulation.

Turning to Slide 9 and recent clinical data. Positive results from the Boehringer Ingelheim-sponsored Phase II dose-finding trial with survodutide, the glucagon GLP-1 receptor dual agonist targeting energy intake and energy expenditure, were presented at the American Diabetes Association Scientific Sessions in San Diego in June of this year.

This study in individuals with overweight or obesity demonstrated significant and dose-dependent reductions in body weight of up to 19% after 46 weeks of treatment. Up to 40% of participants receiving survodutide achieved body weight reductions of more than 20% at the end of study.

As illustrated by the figures, body weight reductions had not yet plateaued at week 46, indicating that further reductions are likely to be observed with longer treatment duration. Please now turn to Slide 10.

In July, we announced additional positive top line results from Part 1 of the Phase Ib multiple-ascending dose trial with our long-acting amylin analog ZP8396, demonstrating mean weight loss of more than 5% in healthy, lean and overweight people, with multiple doses of ZP8396 at both 0.6 and 1.2 milligrams administered once weekly over 6 weeks. These data, compare to the mean weight loss of 2.6%, 3.6% and 4.2%, observed following single-dose administration of 0.7, 1.4 and 2.4 milligrams of ZP8396 administered in the single-ascending dose trial, reported earlier this year.

In the most recent Phase Ib study, ZP8396 was judged to be well tolerated, with no serious or severe adverse events and no withdrawals from the study. Gastrointestinal side effects were the most common adverse event reported, all were mild, and most occurred within 2 days of the initial dose.

We are very encouraged and believe that the weight loss observed are on par with the results reported in initial studies of incretin and GLP-1-based therapies. In addition, we believe that the tolerability of ZP8396 offers the possibility of a considerable improvement over the adverse-event profiles reported with these incretin-based therapies.

We have recently initiated Part 2 of the multiple-ascending dose trial, which is a 16-week study, exploring significantly higher doses of ZP8396, utilizing a dose titration scheme. And these study results are expected in mid-2024.

With these data, our confidence in the potential of our long-acting analog -- amylin analog to achieve substantial weight reduction in people living with overweight and obesity has significantly increased, and we believe that ZP8396 can play an important role as monotherapy to achieve and maintain weight loss and thus provide an alternative to GLP-1-based therapies. In addition, ZP8396 may play an important role in combination with incretin-based therapies in those individuals who will benefit from additional weight loss and help in maintaining that weight loss.

Now turning to Slide 11. My final remarks today are related to our congenital hyperinsulinism program and the new drug application for dasiglucagon, which we are pleased to have submitted to the U.S.

FDA in June of this year. We believe that dasiglucagon, if approved, can be an important and effective treatment option for this rare and devastating disease.

This program represents a significant opportunity for Zealand to address a major unmet medical need for these children and their families. As Adam has mentioned, discussions with potential partners are progressing as planned, and we aim to enter into a partnership agreement for dasiglucagon in congenital hyperinsulinism in the second half of this year.

With that, I would now like to turn the call over to our Chief Financial Officer, Henriette Wennicke, to review our financial results for the first 6 months of 2023. Henriette?

Thank you, David, and hello, everyone. Let's move on to Slide 12 and the income statement.

Revenue for the first 6 months of 2023 was DKK 24 million, which was mainly driven by the license and development agreement with Novo Nordisk for Zegalogue. The submission of the marketing authorization application to the European Medicine Agency in June triggered a milestone payment of DKK 15 million.

The operating expenses for the period were DKK 388 million, driven by the progression of the late-stage rare disease [ assets ] 2 submissions and the [ EASE ] programs. Sales and marketing expenses as well as administrative expenses are significantly lower than that result in the same period last year, following the restructuring announced in March 2022.

Almost 80% of OpEx are now allocated to R&D activity and to progress our programs. Net financial items for the period resulted in a loss of DKK 152 million, driven by the final repayment and termination of the loan agreement with Oberland Capital in May this year.

Let's move on to Slide 13 and the cash position. As of June 30, cash, cash equivalent, marketable securities were approximately DKK 1.7 billion.

This significant increase compared to year-end is driven by the capital raise in April of DKK 1.5 billion and partly offset by the cash use for operating activities during the first 6 months of the year and a repayment of the Oberland loan in May. With the revolving credit facility of DKK 350 million, we now have approximately DKK 2 billion in cash, which combined with the near-term upcoming milestones from our existing partners result in a run rate to mid 2026.

I am very satisfied with the fact that we have now managed to [ boost regen ] and clean up our balance sheet in the first 6 months of 2023. We now have a solid foundation to engage in more detailed partnership discussion, ensuring that we maximize the value of our assets.

Let's move on to Slide 14 and our financial guidance. Our guidance is unchanged, and we continue to guide for net operating expenses of between DKK 800 million and DKK 900 million in 2023.

We do not provide guidance on revenue anticipated for [ coming systems ] and potential new license and partnership agreements due to an uncertainty related to a time as well as size of this kind of revenue. That said, we do expect to receive additional milestones from existing partners in the second half of 2023.

And with that, let's move on to Slide15, and I will then turn back the call back to Adam for some concluding remarks.

Thank you, Henriette. So these first 6 months of 2023 has been exceptional for Zealand Pharma.

And looking ahead, I expect an equally exciting next 12 months with several important events and catalysts across the therapeutic areas. Just to name a few, we expect to submit the new drug application for glepaglutide in short bowel syndrome to the U.S.

FDA in the second half of '23. We expect initiation of Phase III trials in obesity with survodutide in the second half of the year, with details of the trials to be disclosed by Boehringer prior to initiation.

In addition, we expect top line results from the Phase II trial in NASH in the first half of '24. In the first half of '24, we also expect top line results from Part 2 of the 16-week Phase I multiple-ascending dose trial with amylin and top line results from the [ investigator-initiated ] Phase II trial with dapiglutide.

Next year, we also expect to initiate first-in-human clinical trials, both with our GIP analog for obesity and with product candidates in the inflammatory space. Turning to Slide 16.

I would like to thank all our employees for their dedicated work towards achieving our strategic priorities. Likewise, we appreciate our partners for the strong collaboration and our current and new shareholders for their continuous support and trust.

Finally, I would like to express my sincere gratitude to those who have participated and are participating in our clinical trials. One final note on Slide 17.

We are planning to host an obesity R&D event in the fourth quarter of 2023, where we look very much forward to elaborate more on our obesity portfolio. Please stay tuned for further information on that.

Thank you all. I will now turn over the call to the operator for questions.

A couple of obesity-related questions. So firstly, an overall strategic consideration here in the wake of the [ V-Go ] SELECT trial.

Is there anything that has sort of made you look differently on your proprietary pipeline in the wake of this top line results? And then just on the amylin, so now you have a number of very interesting data early, maybe also a little bit early to call before we have the 16-week data readout.

But still, is there any way -- do you actually see a potential for a meaningful weight loss with the big clinical and currently available clinical data? And I mean, of course, as potential stand-alone products, so maybe comparable to cure GLP-1.

What do you see here as actually a potential weight loss after 1 year? And then just on dapiglutide.

So sequence derived from GLP-2 peptide backbone, can you maybe just comment -- maybe I've just missed it, but can you comment on the actual bias towards each receptor? So just like you have said with, I think it's 8:1 with ratio with the GLP-1, so those are the BI 45 candidate.

So anything you can disclose here?

Thank you, Thomas. I will start to reply, and then I'll hand over to David for further comments.

Maybe just first on dapiglutide on the balance between GLP-1 and GLP-2. We have not presented that.

We have just disclosed the general principle here [ seen ] when we have GLP-1 in our molecules, we have designed them towards GLP-1 activity and less activity on the, you can say, second receptor. So that you can at least -- that is also the case for this molecule, but we have not yet released the actual balance.

So -- and then maybe on your question on SELECT, let me start on this one first. And I would say we were, of course, pleasantly -- we're really happy to see the outcome of that study.

I think it really underscores the potential. And I would also say what we have been pursuing all the time with these medications that we have in development, that is, of course, far more than just weight loss, it's about clinical outcomes and, of course, very importantly, cardiovascular outcomes that we are trying to address in our pipeline.

So I would say, it does not change our approach or how we have been thinking about these things, but it underscores how important it is to actually be active in this space. And before I hand over to you, David, I would just mention with amylin, I think this is -- as David also highlighted today in the call, and I think something we'll talk much more about at our R&D day later in Q4, we do think there is a significant potential as amylin as a monotherapy.

And if you compare across trials, you will see that early data, both from our program, but perhaps also from other long-acting amylin analog, suggests that you should be able to get into GLP-1 like weight loss medications and perhaps with a more benign profile when it comes to tolerability. It's something we will elaborate further on but -- at our R&D day.

But maybe, David, do you want to put some more thoughts into both the question on SELECT and amylin?

Yes. And thank you, Thomas.

I'll reiterate what Adam shared. Certainly, the SELECT trial results are, in our way of thinking, a significant positive for the overweight obesity pharmacologic environment and the approach to treatment and not surprising in some ways, given the known benefit of GLP-1-based therapies on cardiovascular risk in the diabetes population.

But I think this opens the door in a very important way to target not just body weight as a number, but in fact, target those with overweight and obesity to improve outcomes and in this case, very important outcomes, cardiovascular risk of events and cardiovascular death. And I think it will have significant implications on how clinicians, prescribers engage patients in those conversations about the potential benefits of therapy.

And we will wait to see how this affects the reimbursement environment, but I see it only as a positive and very positive move forward with regards to making these therapies available to those at highest risk. Adam also said it hasn't changed our perspective on the portfolio.

We believe both the survodutide program and our own dapiglutide program, which have a strong GLP-1 receptor agonist component, are, in great part, designed on the assumptions that GLP-1-based therapies couldn't and wouldn't have these beneficial effects. And finally, with Amylin, I think for those of us who have grown up through the oral anti-obesity medication era, expecting single-digit weight loss, we're now in a phase with the incretin-based therapies and as Adam suggested, early and mid-stage data with amylin agonist that suggest that they do have the potential to achieve incretin-like weight loss, and there, we're talking double digits of weight loss.

And while it would be premature to project, I think looking back at the early clinical trials, both with cagrilintide and many in the GLP-1 agonists that achieved mid-teens to close to 20% early results that were on par with what we've seen with our amylin program. So we are very encouraged by that potential.

Great. And maybe if I just may sneak in one additional question just on BI 45, so the Phase III, are you able to give us any color on the design?

Just if there's anything that sort of materially differ from what we have seen with the [ V-Go ] and [ peptide ] and also in relation to whether there are some issues with the [ glepaglutide ] part, any special requests from the FDA that you are aware of?

So we are not aware of any special issues, if you will. We can share that we see that Boehringer is extremely excited, and they're extremely committed to put this molecule into Phase III and excited about the potential for this molecule to address both weight loss.

And the benefits we have just discussed here, that was also evident with the SELECT study, but also in the [ forms ] in the NASH space. On the specific design of the Phase III program, we cannot share more beyond the fact that they -- Boehringer have released now that we are talking about 3 Phase III trials that they are working on, but they do expect to present further details on the trials before they initiate them later this year.

So we will have to stay tune there. Sorry for that.

Just firstly, a quick clarification. I think I missed it in the prepared remarks.

The cash run rate to mid-2026, does that include any anticipated milestones and/or use of the credit facility available to you? .

And secondly, you mentioned about the potential in NASH, and we talked about the ratio of GLP-1 to glucagon. And I guess, given the importance of glucagon activity for the liver effects, how do you kind of expect results in NASH to fare versus the competitive assets with kind of -- with greater activity on the glucagon side of things?

And then finally, on the artificial pancreas timings, I've seen the report, still expect the trial to start this year. Is that based on any new information?

Or is that just the maintenance of the prior commentary?

Thank you, Lucy. I will again start by addressing your questions.

Then I hand over to both Henriette and David. On the artificial pancreas, there's no change in guidance.

We -- as you know, we are dependent on Beta Bionics. Moving forward here, and it is our belief that they will move forward based on conversations with them.

So -- but we are -- it's not a new belief or anything. So we -- it's just retaining [ there ], keeping the guidance.

When it comes to the cash runway, I will let Henriette elaborate on that.

Thanks for the question. So the cash run rate to mid-'26 [ cause ] our current cash position, including securities, and then it also includes near-term milestones from existing partners.

So not for new partners, but existing partners, where we expect all of those in the second half of this year.

And then before I will hand over to you, David, on the relative balance of GLP-1 glucagon, where we do have an 8:1, I think it's extremely important to remember that in order to get meaningful weight loss with the GLP-1-based therapies, we know we need to have very, very high exposure and also higher exposures than what you would need in a type 2 setting, for instance. And therefore, of course, with the profile that we have and the very high exposure to GLP-1 we achieved in the program, we would expect that the glucagon component will be sufficient to also drive effects on the liver, despite the fact of the balance, actually.

That's why we designed it that way to be able to push GLP-1 to those highest doses while getting meaningful glucagon exposure. But David, I will -- will you elaborate a little bit more also compared to data that we have seen from other studies and so on and why we are so encouraged?

Yes. Thank you, Lucy.

And Adam, agree that clearly, one of the greatest impacts on NASH and NASH progression has been demonstrated with bariatric surgery and the weight loss associated. So having a potent GLP-1 component, we have deemed and our partners have deemed that, that is a critical piece to achieve weight loss that in the obesity studies was up to 19%.

And I think the glucagon component and the effects on metabolism and liver fat trafficking is important, and we believe we have dialed in an appropriate amount. Remember, too, that many patients with fatty liver disease and/or NASH also have coexisting glucose intolerance.

So excess glucagon agonism would be expected to have less beneficial effect on glucose metabolism and as a consequence, free fatty acid metabolism. Obviously, with the BI compound, the survodutide data in type 2 diabetes, clearly an effective glucose-lowering agent.

So not any evidence of excess glucagon impairing the glycemic response. So importantly, the Phase II data, which we'll read out in the first half of next year, will be biopsy-based primary endpoint data in that NASH trial.

And I think we'll answer your questions well beyond the speculation that I or Adam can answer, but we have great confidence in the balance of the 2-receptor agonists in this molecule.

It's Michael from Nordea. A couple of questions.

So first of all, trying to dig down a bit further into the Phase III plans. I know -- I respect that you can't say that much, but is it fair to speculate that there will be also a dedicated cardiovascular outcomes trial related to survodutide because cardiovascular outcome trial is not a registrational requirement?

So could it be fair to assume that they do 3 registrational trials and then, on top of that, a cardiovascular outcomes trial? And then secondly, on the NASH sort of release timing, would you mind sort of speculating when this could be?

I think we have the European liver meeting in May of -- or late May, early June next year. So should we expect sort of the same progression in releases from Boehringer Ingelheim you think, as they did on the obesity data, so spring-wise and then presentation during the summer?

And also timing wise, do you expect -- or is it fair to assume that there will be data at ADA on both the [ peptide ] and also ZP8396? Then I have a follow-up.

But let's take the first three ones.

I mean thanks for the questions, Michael. And I'm really -- we cannot comment more on these things.

We really have to honor also the relationship with BI, and they do expect to present the details of the programs before they start the Phase III program. .

I think a lot of the considerations you shared are good considerations, but it's not something we can comment on. I'm sorry for that.

And with regard to data presentation for our own, both the amylin and [ obesity ], I think we are, right now, comfortable guiding that we expect results in the first half next year. When we will present the data, we will have to wait just a little bit longer before we can commit to specific conferences.

I can not be more precise.

But -- and then just a follow-up in terms of partner discussions. So you described potential partner discussions and also signing something for dasiglucagon in CHI this half year.

. Regards to glepaglutide, how dependent is sort of the timing of the deal going into the first half of next year on the Ironwood and VectivBio glepaglutide data?

I mean, in terms of sort of how competitive will the process be with negative data for Ironwood and Vectiv -- Ironwood versus sort of very positive data? How do you see that playing into a potential attractiveness of the deal and timing of the deal for your asset?

Yes. So first of all, with regard to CHI, then, as you know, we submitted the NDA in June, and we could then have an approval first half next year.

That, of course, also, that is a good timing for us to establish the partnership this second half of the year, which has been part of the plan all the time. And as we're announcing with this call, confirming with this call, then we are in good discussions and progressing according to plan with that one.

With regard to glepaglutide for short bowel syndrome, we have also been very clear on the fact that we're going to have our pre-NDA meeting or we will have a pre-NDA meeting in this second half and also expect to submit the NDA in the second half of the year. We have not started confidential discussions with partners for glepa yet, but we do expect to start that very soon and also start to open up [ data rooms ].

So that also means that we have not had the confidential discussions or disclosed or shared confidential data with any party until now. Whether there will be -- regarding the readout of the Phase III program for [ glepaglutide ], whether that will impact our timelines, it's not something I can comment on right now.

We believe we have a very, very competitive profile with our product having been developed in an auto-injector, very simple injection and some very compelling clinical data that we have presented at clinical conferences throughout the first half of the year. So we think we have a product that is very competitive.

And that, of course, has to be confirmed also in future discussions. But of course, ultimately, if [indiscernible] reads out positive in the Phase III study, we will see that as a competitor in this [ business ] another long-acting GLP-1 -- sorry, GLP-2.

But still, I would argue that we have a very competitive profile of our product and actually see the potential for a market leader with glepaglutide.

I've got a couple [ or two ]. So firstly, on survodutide, there's obviously been some concern in the market on the drug's tolerability post the Phase II data that we saw ADA specifically on the discontinuation.

Could you just help to put that into context for us? And I realize that you don't lead development of the drug and you're not leading the Phase III, but I guess, in theory, what could practically be done to reduce those discontinuations in the Phase III trial?

And then similarly, just kind of coming out of ADA again, there was obviously data from Lilly's [ triple G ]. Could you just talk about how you think about survodutide type's competitiveness and your wider portfolio's competitiveness relative to that?

And then I just got a follow-up on complement, but maybe you could take those first.

Thanks for the question. I would just -- and I will start by addressing the competitive landscape, maybe a little bit and then hand over to you, David, to also address the continuation and how we believe that Boehringer can handle that in Phase III.

I think it's, as David also alluded to in his remarks on one of our slides, then first of all, obesity and obesity-related comorbidities are a very complicated area of treatment, and there will be the need for many different approaches in the future. And I think that's extremely important to note, there will be some patients who will need 30% weight loss.

Others might benefit more from a 15% weight loss or a 25% weight loss. And you can say the relative balance to also where you then see effects and comorbidities and so on, the balance between tolerability effect, side effects, how do we work, how do we affect heart rate, how do we affect other aspects, all those things ultimately will play into how these future medications will be used in the landscape.

So we can just say with what we have seen with this service so far, it looks like a very competitive product also compared to the programs that we're releasing early data at ADA this year from competitors. And we are, you can say, of course, close to BI, and we know they feel the same way.

So we see that [ survodutide ] has a very strong profile. The data that was presented from competitors at ADA doesn't change that picture.

I think we have moved beyond just looking at who can give you the most weight loss. It's really about how can you differentiate, how can you address specific patient needs.

And I think that is where the conversation will go in the coming period, also in this field, in general. But David, I will hand over to you to also address discontinuations and perhaps provide further considerations on that.

Yes. Thank you, Adam.

And I'll add one more comment on [ triple-G ]. As Adam said, the relatively high rates of GI intolerance in that study, the heart rate concerns that were raised by some.

But I also think in that retatrutide data, there is confirmation of GLP-1 and glucagon in a single molecule, which, to us, add strength to the cornerstone that survodutide has established back to the discontinuation rate. A couple of very important things to consider, and we have with our partners, looked at this in detail.

This was a very rapid titration scheme by GLP-1 and incretin-based therapy standards. Going every other week to relatively high doses and maintaining them there, there were some unique components of the protocol that allowed patients to hold at a lower dose, which we think may have limited the capacity to understand the higher doses.

But that fast titration over 2 weeks with the GLP-1-based therapy is one that not only our BI colleagues, but others in this space, have learned is likely quicker than need be. And remember, across these trials, some allow use of antiemetics, antinausea therapies, some do not, and not allowing that may resulting in slightly higher discontinuation rates in the clinical trial program.

But overall, I would say qualitatively, and we have looked at other Phase II programs, both the rates of nausea and discontinuation, we assessed to be qualitatively quite similar. And we believe that in the Phase III program, the consideration of a much slower titration scheme to maximal dose and assuring that the efforts are taken to enable tolerability can and will be part of the program to both minimize the impact of the potential GI side effects and understand just how high adherence and persistence can be.

Perfect. And then just a follow-up on complement inhibitor.

So in terms of kind of the preclinical activities you're expecting by the end of the year, the data that's been generated to Alexion or I guess, [ AstraZeneca ] now have ongoing visibility onto that, and have they sort of indicated that they expect to progress development? And if so, would there be a milestone to Zealand with that?

Yes. So it's been a collaboration where we have been responsible for most activities until now.

And once we deliver, you can see the Phase I-ready package, Alexion or AstraZeneca will take over most of the development efforts, but we will continue to contribute in a few areas. So they are very [ kept ], have been very engaged.

And our assessment is that they, like we -- I mean, they share the same excitement about the lead molecule that we have now progressed and will soon give over to them, so they can progress it into clinical testing. So of course, we don't have all insights into the executive rooms, but we see a lot of excitement, and we anticipate to hand over the program to them quite soon, and then they will take it from there.

So that's our clear ambition that they will also expect -- expectation that they will push this into Phase I.

Firstly, as follow-up to the question on the partnership status on glepaglutide. So trying to ask in a different way, has Ironwood's Phase III data delay to March '24 instead of late '23, has that sort of changed to interim timelines because I guess that may drag discussions out a bit versus previously?

And then just on the partnership timeline from here, can you just help us prepare the market how you intend to communicate on the partnership process in the coming quarters on how you progress and whether there's any progress at all? And then just a question on the R&D event, just to preview this.

Will this simply be an educational event? Or will there be any incremental updates?

And then just on timing, why already in Q4, is there any particular reason? Or is that just because you are excited to share some stuff?

So just on the big R&D day, it will, of course, be hopefully a very educational day, where we'll also try to put all our data a little bit more in context into where the field is moving. So we do not plan to announce significant new data updates that would normally be in a press release since it is so, you can say, defining for our activities right now.

. With regard to the 3 months or so delay in data readout from the [ APRA ] Phase III that was announced by Ironwood, it has not changed anything to -- as we have also said, communicated, we have, all the time, thought there was a little bit of a stretch to have data and late this year since the studies were not completed.

So this is probably more in line with what we had thought all the time. And we do not see a specific connection to our partnership discussions.

But again, that is, of course, up to partners. We think they have a very competitive profile.

We are looking for a collaboration, where we'll continue to contribute. We have a lot of confidence in glepa.

So it's -- and so we believe partners will have once we get to partnership discussions. And as I said, we have not gone to the confidential or data sharing-level yet.

It's Charlie Mabbutt from Morgan Stanley. So I guess, firstly, on dapiglutide, one of the major benefits cited has been on [ leaky gap].

And post the SELECT data, this may perhaps be even more interesting, given the potential effects on inflammation. So I was just wondering what evidence you'll be able to gather on the dapiglutide's utility here, given the short length of the current programs?

And if there's anything you sort of expect to see in these in these studies that may support that? And then secondly, I was wondering if you could provide a little bit more color on the new Phase I, the ion channel blocker, if there's any insight into the indication being targeted?

And then also, I guess, where your other preclinical efforts are now being focused? That would be helpful.

Thanks for your question, Charlie, I'll start, and then I'll hand over to you, David. So on the Kv1.3 ion channel inhibitor, we do expect to initiate Phase I development next year, and we are extremely excited about the potential.

If you look through the literature, it actually has potential in a number of inflammatory conditions, severe chronic conditions. We are not at a stage yet where we will announce where we will take it, but there are many avenues as you will see.

And we have, of course, ideas, but we will wait with sharing that those, so until we are a little bit closer to Phase I initiation. On dapiglutide, I completely concur with you that the SELECT data, of course, underscores the potential with this molecule.

And with the low-grade inflammation, we know, has been a -- is a major driver of cardiovascular disease. And also, if we look into NASH and the NASH space, there basically, we believe, to be two things that are causing mass to develop in the obese -- metabolic data, and that is excessive fat on nutrition and inflammation.

And [ with one glove ] we address the excessive fat with [ dapiglutide ]. With [ dapi ] we address the inflammation.

So we also, we believe, has potential opportunities in [ NASH-less ] molecule. But maybe, David, you can elaborate a little bit more on what we could expect to see from the Phase II study that we have ongoing.

Yes. Thanks, Charlie, and I'll reiterate what Adam said, I think the SELECT data and the implications for high-risk cardiovascular disease populations, not now just diabetes, but diabetes and obesity.

And to your point, the effects of GLP-2, both on gut barrier health, but also the -- more broadly, the inflammatory environment, many know that those at highest risk for heart disease have markers of inflammation, [ HSCRP ], but how one modifies that inflammatory environment beyond statin therapy and blood pressure lowering. We will, in the current investigator-led Phase II study, have, what we believe is, a broad brush look at a number of critical inflammatory disease markers or markers of systemic inflammation, both those that primarily affect the liver and vascular bed.

And we believe that will, at a minimum, give us insights about the potential anti-inflammatory effects. Obviously, the ultimate test of this is a cardiovascular outcomes trial, and we're a wave's away from that, just starting Phase IIa.

But suffice it to say that we are aligned with your perspective that the leaky gut improving gut health, perhaps the gut microbiome and affecting these markers of systemic inflammation can be critically important in both cardiovascular disease and NASH.

Great. And also just as a follow-up, I was just wondering on your initial perspectives on whether you think amylin could add cardiovascular benefit?

Again, this is going to be an important topic for our R&D Day coming up in October, but I think there's already now a substantial evidence in the literature that if you treat with a long-acting amylin analog, then you will see very significant reductions in cardiovascular risk factors, such as decrease in blood pressure, neutral to actually decrease in heart rate, which is in contrast to what you see with the GLP-1, significant effects on C-reactive protein, which is a known driver of cardiovascular risk. And then importantly, study is also demonstrating very beneficial effects on VLDL, triglycerides and then increases in HDL, which is a good cholestrol.

So if you put all those data together, you will actually see an incredible strong profile when considering amylin as an agent that cannot only induce weight loss, but it could also be very, very strong when it comes to cardiovascular benefits, perhaps even beyond the weight loss that you see with these molecules.

This is Luisa dialing in for Suzana. I have one single question.

So regarding glepa, could you provide us with some more -- sorry, not glepa dasi. Could you give us a better understanding on what are you looking here for in a partnership in CHI?

Thanks for your question, Luisa. And we are looking for a partner who have commercial rare disease infrastructure, either you can say just regional, so U.S., Europe or other regions; or global infrastructure.

So that is the -- that's what we don't have. We have the capacity to manage manufacturing and thus supply finished product.

We can support on the medical aspects. We have very deep ties into the community, both the patient communities and the patient prescriber -- potential future prescriber communities and deeper insights into the disease area.

So we can [ help ] there. So we are looking for true collaborations, but we are looking for a company with rare disease commercial infrastructure, and those are the companies that we are discussing with right now.

Thank you. And with that, we would like to thank all of you for attending and for the questions, and we look very much forward to connecting at our obesity R&D event in the fourth quarter and to view future announcement and updates.

So thanks a lot, and have a good day.