Zealand Pharma A/S (ZEAL.CO) Earnings Call Transcript & Summary

I think we'll get going if that works for everyone. I'm Charlie Haywood from the BofA EU Pharma team. My pleasure to be hosting David Kendall today, CMO of Zealand. Obviously, I'd say you haven't got any official introduction, but I guess as a quick 2-minute overview of where we're at, where Zealand is at, how has the year been, et cetera, been an exciting year for you. So that would be a great way to start.

Very good. Thanks, Charlie Haywood, and good morning, everyone. I was teasing Charlie. I live in Southern California. So they're pointing out it's 2:45 in the morning on the clock in the back. So I'll do my best to hang in there. So for those of you I've not met, David Kendall, I've been Chief Medical Officer at Zealand Pharma for the past 3.5 years, been with the company for 5 years. Prior career in the metabolism division of Eli Lilly and started my pharma career at little Amylin Pharmaceuticals and the originators of a lot of the technologies we're talking about today. So in touching on highlights, Charlie, I think front and center is obviously the partnership with Roche, and Thomas just reviewed some of the highlights from their metabolism portfolio and alluded to 2 of those components, obviously, signing that deal in March and kicking off the partnership this summer with rapid progression of the petrelintide asset towards Phase III. As many of you know, we have ongoing Phase II studies with readouts expected in the first half next year and then also with their GLP-1/GIP agonist, the 388 compound, looking for when they can and will share the results of 388 Phase II, so we can initiate the work that is already underway for the fixed-dose combination of petrelintide with 388, and happy to touch on some details of that. I would say that and the advancement of the Phase II program are certainly highlights both financially and from the standpoint of advancing our R&D portfolio. As many of you know, in 2022, we refocused on R&D, not only advancing -- continuing to advance our rare disease assets in congenital hyperinsulinism and in short bowel syndrome, but look to establish ourselves as a key player in the obesity and metabolism space beyond the Zegalogue franchise, the rescue therapy that was out-licensed to Novo Nordisk. And I think for those of you who may have been part of our R&D Day, 2 Decembers ago, where we stepped forward and proudly stated that we believe amylin-based therapies and petrelintide in particular could be a foundational therapy and a stand-alone therapy in management of overweight and obesity. A lot of people scratched their head and said, that's wild, robust and ambitious. But we now see -- and I think this is a highlight of the year that's not solely ours, Charlie, but the interest of players like Novo Nordisk, my former employers at Eli Lilly as well as AbbVie licensing the Gubra asset, and now Pfizer with the Metsera acquisition, championing amylin therapies as one of the cornerstones of weight management. So I think the environment is now telling the story we've been sharing for 3-plus years, and pleased to say that both the advancement of that asset and still what we think are potential best in market or market-leading attributes for that asset and the, I'll call it, the power of the partnership with Roche, both Zealand's inventive and agile R&D environment, but Roche being an established player in the development and commercialization space just further strengthens those efforts. So I'll stop there and let you fire specific questions, Charlie.

Got it. And I think another big picture one, obviously, the obesity market, I think the last year, 1.5 years, we've seen a lot of developments, we've seen shorter stay times on drugs, we've seen the reimbursed market maybe slowing growth, cash market being a lot bigger. I guess within all of that, I appreciate the more R&D side. But where does amylin fit in there? What needs does that address? How do you see that fitting in going forward?

Yes. So before my R&D days, I was an actual prescribing physician. So I have an interest in how these things actually get to patients and get to the market, and I love the tagline from Roche, doing things now what patients need next. I think it is intoxicating to think this market has evolved to its final state, but we are still in the very early stages of this obesity market. If you said 5 years ago, this is going to be a multibillion-dollar market, people would have scratched their head and said, what are you talking about? There's Saxenda and a few other things. But it has transformed, and all credit to both Novo and Lilly for sort of breaking down those walls. But I think particularly payers, government systems honestly didn't see this coming in the magnitude of the burden of both expense and disease. If you estimate that probably 40% to 50% of the global population will be overweight or obese in the coming decade. That is unlike any other disease state we've seen, and we've seen CBD cancer risk, metabolic diseases like lipid disorders and diabetes, which are dwarfed by the size of this market. I think there are other unique attributes that are still shaping this market and what it will look like in 2026, let alone 29, '30, when a lot of these assets hit the market is tough to predict. But what we're seeing early on in contrast to a lot of other chronic diseases and chronic metabolic diseases, this is patient driven. And I won't say just cash pay patient driven, but there are very few patients in my experience who came in and said, "Hey, doc. I need a diabetes drug. I need a lipid-lowering agent and an antihypertensive." That has flipped the script. And there, it was providers saying, you need better glycemic control, lower blood pressure, management of lipids. Here, we have patient-driven interest in bettering their health through weight management coming in and saying, "I know there are effective weight loss therapies, what would you suggest for me?" So it's almost the reverse of what we've seen in other chronic diseases providers are accommodating to this. And particularly in the U.S. market, which is where I live and spend most of my time, you see that patients are seeking therapy and then sort of backdoor applications for coverage rather than front door applications. I'll only take this if I get coverage. I have a personal example of a close friend who has significant obstructive sleep apnea. He went on 1 of the 2 available agents, lost about 15%, 18% of his body weight. The sleep apnea basically disappeared. So now his sleep doc prescribes his medicine. That's sort of the reverse of what we traditionally think of. So those are some of the dynamics I think we'll be dealing with. Will this be a pure sort of Botox market where there's a cash pay segment that is more driven by patients and their desires versus a medically driven like the migraine side of Botox is where it's reimbursed and for specific indications. I would be only guessing to tell you I know what's going to happen next year or even in 2029. But the market will continue to evolve. And I think having an assortment of assets, not only in our portfolio, but I think with our Roche partners saying, we are a metabolic disease company. We are in the metabolic health business. So we are ready for what comes best we can.

Very clear. And then obviously, the sort of practical standpoint to that is how you look to design your trials, Phase IIIs, whatever, mono, combo. Any -- what are your updated thoughts on any, I guess, novel trial designs if trials will be segmented by BMI, placebo control we still have with this? Where are we at in that whole stage of trial design to -- for how the market may evolve?

Yes. I think two considerations there, Charlie. One is we realize that speed, particularly to U.S. market is primary. So getting too sophisticated, complicated, exclusive with entry criteria, obviously, we'll focus on the obesity and overweight populations, those with overweight and obesity with type 2 diabetes. Given the requirements still in the EU for demonstrating cardiovascular safety, CV safety trial separate from a future potential cardiovascular outcomes trial will be part of the core program. But beyond that and specific to your question, particularly with petrelintide and amylin agonist, we think there is an opportunity for a very distinct and unique experience. We have said all along that we believe petrelintide can achieve incretin-like, GLP-1-like weight loss. And some have asked, is that mid-teens? Is it 15% to 20%? We've said both. I think you can look at the cagrilintide program as sort of just the first indication that mid-teens is feasible. That is a medication that is somewhat dose limited by the injection site reactions, potentially by antibodies. But even in the redefined studies, they got to the maximum dose of what, 80% of the time. So you realize that maximal dose exposure is achievable. So we will obviously look at that, look at the dose response from Phase II and identify what we hope is the simplest dose escalation scheme. We do not want to sacrifice what we think is already a very favorable acceptability profile, not just tolerability, but can I persist on this in the Phase III core program, you know these are literally thousands of patients. Yes, still placebo-controlled because that's what U.S. FDA asked for. But that will only be the first part. And then mechanistic studies, Phase IIIb programs in specific populations, and I won't define them, but you can imagine those specific weight dependent comorbidities like obstructive sleep apnea, because of the unique mechanism by which amylin agonists work considering osteoarthritis. If muscle preservation is clearly an attribute of the amylin agonist, will these be particularly useful in older adults, those with sarcopenia, women in perimenopause where keeping muscle mass along with losing body weight will be the best for bone. This is a population where weight gain and adiposity are a significant concern. Much of that is physiology, not anything else. So those are some of the considerations. So Phase IIIa, as I'll call it, will be straightforward speed to market. Phase IIIb will include all of these things, including the potential to investigate cardiovascular risk reduction.

Got it. Very clear. And then on the combo you alluded to earlier, fixed-dose combos. I guess any updated thoughts on the fixed versus flexible dose combos if you could have multiple fixed-dose combos because we're seeing, I guess, the real-world data suggesting not everyone is on the highest dose of A or B GLP-1. So how do you manage that around the patient versus rather than the specific fixed dose?

Yes. I think a lot of learnings from the CagriSema program where doses were tied together and sort of high, high was the goal. We're chasing the biggest weight loss number, it was clearly part of what they at least put forth. They may have fallen a little short of their own expectations. But I think we have the opportunity to do something slightly different. And the current thinking is how can you maximize what we believe is the better tolerated petrelintide component of a fixed-dose combo and then more or less optimize, not necessarily maximize the GLP-1 component. What you see in the CagriSema program is the tolerability of cagri, which conservatively has 1/2 the rates of nausea and vomiting, 1/4 of the rates -- I'm sorry, 1/4 of the rates of vomiting, lower rates of diarrhea, constipation. But once you add cagri at full dose, you sort of aggregate all of that advantage. So can we go to a lowest feasible, lowest effective dose of a GLP-1/GIP, the 388 compound, or is it a mid-dose, high, high is really there only if you need the sort of the biggest hammer for that nail. But instead of, as we describe it, playing the weight loss Olympics game to get the biggest number, can we preserve all of the attributes of tolerability and then leverage the known benefits, glycemic control, additional weight loss, likely cardiovascular protection of the GLP-1 component. So we will be more flexible in Phase II. Obviously, we need to see the Phase II data from each individual program. before we go there. But that's our current thinking, it is not a race to the top because the vast majority of people, based on our own work and others, want to lose 10% to 20% of their body weight. They're not looking for 25%, 28%, 30%. That is reserved for the most significantly affected morbidly obese with major complications. I think it's the NHS where a BMI of 40, and I said kiddingly 56 comorbidities are required to get some of the drugs covered. But that is an exceedingly small minority of the population seeking weight management. So where can we find that spot that meets the majority of need.

Got it. And then I wanted to come on to your petre Phase IIb data, obviously, we'll get the full read next year. I guess the blinded interim is soon, but I'm sure it has been clear that is blinded and you won't see the data. Remind us on the main differences versus your Phase Ib because I think we've seen other competitor data, which we'll get on to in the sector coming through this year. A lot is going to weigh on that Phase IIb data. So what are the main differences? How are you thinking about that read? What are the expectations?

Yes. I mean quite a bit of learning from Phase Ib and probably the simplest one, and this comes to the competitors. We want to leverage the tolerability to as great a degree as possible and lower starting doses with monthly dose escalations because weight management is not a rapid sprint. Yes, patients want to see results, but that dose escalation scheme. And then obviously, seeking to identify, is there a true dose separation at the higher end. When we did the Part 1, Part 2 of the original study, you remember there was sort of the low 0.6 milligram, 1.2 milligram dose cohorts all the way up to 9 milligrams. Some purported similarities between the higher doses, do they actually separate. The other very important part of that is, obviously, we've got a longer follow-up interval, 28 out to then 42 weeks for the primary endpoints. And in contrast to our Phase Ib, 80% males, lower BMI, we have a much more representative population. We reported that at our last quarterly call, BMIs of around 37 on average, roughly balanced for male and female. Those are 2 key components because higher preponderance of females tend to increase weight loss because of the inherent natural adiposity in larger trials lose, 3% to 4% more body weight than males. On higher BMI, the same sort of 2% to 3% plus difference, meaning greater weight loss. So we wanted to be representative. Beyond that, obviously, we're doing this 28-week interim to enable regulatory interactions, the 42-week to make full decisions. But obviously, preparations right now for Phase III doses, ultimately, device and the large Phase III program are ongoing pending that. So not major differences other than the balanced gender, higher BMI, much more representative. And then the second study, including a small cohort with type 2 diabetes, where we think weight-losing effects can be virtually similar in those with or without diabetes, something that does not occur with GLP-1 agonist where you sacrifice some of the weight loss components because of the potent insulin stimulatory effect of GLP-1s.

Got it. And then 2 questions on the design differences. I guess, I don't know if you see them as risk or whatever into your Phase IIb, but obviously, the first one has a higher female proportion of patients, which obviously, from the data we've seen so far on GLP-1s has been mostly female patients, you obviously have a much higher ratio, which you think could bring more weight loss. But is there a risk that the higher female patients also bring worse tolerability? And I guess, do you have any data on that? I don't think we've seen anything from cagri. And then sort of on that is, is there a risk of higher BMI patients bring worse tolerability? So 2 parts.

I think I mean, our position is because tolerability has been so good thus far, we don't see a great risk. And interestingly, and this has been some work done both in animal models and in real humans, no offense to the rest of the men out here, but we tend to be less tolerant than females in response to many adverse effects. There is some evidence that actually signaling of some of the neuronal pathways, GLP-1/GIP, amylin are programmed differently in females, perhaps as a consequence of the high levels of human placental lactogen they'll see during pregnancy. Morning sickness is driven in part by hPL. So quite the opposite. I would think that a female population, instead of us winding males complaining about adverse events, maybe no more likely and potentially less likely we'll see. We don't see that as a significant concern nor do we think body weight will be a profound concern. Interestingly, and this goes back to pramlintide years ago. The more overweight populations who are amylin replete, meaning they're hyperscreening insulin, hyperscreening their own amylin tend to be the most tolerant to amylin agonists. Those with type 1 diabetes who have wiped out their beta cells have no endogenous amylin are the most sensitive to the GI side effects. So as you go from type 1 diabetes to type 2 diabetes to plain obesity in the absence of diabetes, those that tolerate amylin the best, amylin agonist the best are the overweight and obese population.

Very clear. Any questions from the audience on petre specific before I'll get on some broader amylin? All good. Lots of evolution in the space in the last 12 months, as you've mentioned already, a few deals, et cetera. Remind us where you think petre stacks up versus competition? Yes, big picture, we'll start with that.

Yes. I mean I'll start with saying we have great confidence in the program, not just because it's ours and we own it. But I think looking at the Phase I single ascending dose and particularly the multiple ascending dose, the consistency of response to petrelintide, meaning every patient who's been exposed to reasonable doses, meaning above 0.6 milligrams, has lost some weight. And that's a 100% response rate. I don't expect that in larger long-term studies, but it is a very consistent weight loss pattern in those exposed to higher doses. We have been quite clear that particularly around the receptor biology, what is balanced agonism across calcitonin and the 2 key amylin receptors, amylin-1 and amylin-3, we believe is ultimately the most advantageous for both weight loss and tolerability, and I'll give some specifics around that. Many of you know that calcitonin receptors exist in the midbrain and hindbrain, likely there for a reason. They are closely tied to the amylin receptors. They are closely related to the leptin receptor. So all of these homeostatic systems that control ingested behavior, homeostatic behaviors that control body weight are tied to all 3 receptors, and I always sort of say tongue in cheek. The body doesn't put receptors where it doesn't need them. So these calcitonin receptors clearly have some role, at least homeostatic. If you wipe out calcitonin receptors in the midbrain of rats, they become metabolically disadvantaged, greater adiposity, greater weight gain, more dysglycemia, things like that. So we believe calcitonin agonism is not a hindrance, but actually a benefit. The only pure amylin agonist that I would argue exists is pramlintide, short-acting, very difficult to assess compared to some of the longer-acting compounds. And the adverse event profile for pure amylin agonists or those that are biased towards amylin are at least emerging in some of the early studies as being slightly different. Cagri in that large Phase III program with CagriSema we think derisks petrelintide. Those are very similar molecules from the standpoint of receptor biology. With petrelintide, one of the reasons we believe it is a better-in-class, you get higher milligram dose exposures that are possible. So we can get 5 milligram, 7 milligram, 8 milligram, 9 milligram exposures. They are limited at 2.4 milligram, probably for a variety of reasons, the acidic preparation, antibody formation that they've seen. Similarly, bioavailability with petrelintide is about 80%, about 30% for cagrilintide. So while that program and its safety profile, we think, derisk petrelintide's safety program, we think higher total dose exposure is likely. So that sort of sets the floor for what we would anticipate we could see in a large Phase III trial. So our mid-teens up to 20%, we believe, is supported both by that and our own modeling. The other assets in the space, eloralintide got a lot of attention, both at the ADA meeting and the recent Japanese study that they reported. I would say it's still a very limited data set in my mind. The mid-doses, which seem to be well tolerated to me appear quite similar to cagri, petre and others. They do get one high, high dose, I'll call it, that gets a more exuberant response over a shorter period of time, I think, up to 11%. I think both the tolerability there and sort of the overlap in the mid-doses tells me I don't have enough data yet to say, is it better, worse, no different. I would expect similar results with something like eloralintide. The difference we're seeing, just like with pramlintide, they've reported more headache, they reported some of these neuropsychiatric adverse events, which I don't know that they're related. Headache appears to be actually from the old pramlintide days. If you have a person at risk for migraine and you provoke with pramlintide, probably from profound activation of the amylin receptors, not CGRP, you can induce migraine. So although we think eloralintide has some calcitonin receptor activity, you see acute lowering of calcium, it, in their mind, is amylin predominant. Does that contribute to headache as an adverse effect? I think we've seen so little data from that. Metsera talks about its monthly dosing, and now Pfizer and they are lined up to put forth monthly dosing of that and their GLP-1/GIP agonist. We have not yet seen data that convince us that the half-life of this or any other asset can readily be given once monthly. One of the risks with longer dose intervals is we know with GLP-1 agonist, amylin agonist, that trough to peak variation between doses is what contributes to the potential for particularly GI adverse events, meaning the more variation, and we did this with lixisenatide and pramlintide in the day because they were so short acting. But if you have a relatively moderate half-life and you see even with a monthly injection that rise and fall, I think that certainly doesn't abrogate the risks for tolerability and may actually amplify them a bit. The half-life that we've seen in our hands, we have a 10-day half-life with petrelintide, that could be given monthly, but we think we would sacrifice those same things. I'm not yet convinced that the Metsera compound is readily or fully amenable to monthly dosing. We'll see in the data. And I think the MariTide data taught us a bit of a lesson on monthly dosing, what happens with variation. And I think in the Metsera, Pfizer studies going forward, they're going to do weekly and then go to monthly or transition to monthly. That's what they've reported, which may abrogate that, I don't know. But again, we are still confident that the pan-receptor activation, the higher dose exposure, the consistent Phase Ib data and hopefully Phase II data that we have with petrelintide sets us up as a better -- certainly better or best-in-class.

Got it. And then I guess, I mean looking at least timelines, it feels like cagri is going to be there first as the mono, probably Lilly and then probably you, I guess, a bit of a mix. So how do you assess the potential -- I'm happy to underwrite amylin versus GLP-1s and potential differentiation on tolerability. But how do you assess potential differentiation within the amylin class even of a slightly worse amylin, but is it amylin and amylin? Or do you think -- how much differentiation do you think it will evolve how the GLP-1s do? Any thoughts on that?

I mean I think I've already alluded to where I think cagri and petrelintide may differ, getting higher dose exposure, potentially greater weight loss with that dose exposure without sacrificing tolerability. So the tolerability profile of cagri, I think, is quite good compared to GLP-1s in particular. And as I already alluded to, I think that derisks some of the potential safety signals with very similar receptor biology. As I've also alluded to, eloralintide just has a different character of the adverse event profile. It's very limited data, so I can't judge better, worse, no different. But I think a couple of things about our asset. One is it both for us and for Roche is being put forth as a foundational therapy, stand-alone monotherapy. And yes, the others will go with monotherapy. They also have very important GLP-1 franchises to protect. So how will they put that forth and still protect what are very important, both clinical and financial platforms for them. I think we have the opportunity with Roche to say, let's put this front and center. 388 is an excellent compound in my mind, but will it be part of the sort of additive portfolio. The fixed-dose combo, I think, as I've said, we can maximize petrelintide, optimize 388, and maybe make this the better option for the big number chasers that are out there. So Phase II data and Phase III data for all, I think, will ultimately allow us, are they more similar than different? Are we in a space that is like dulaglutide and semaglutide, where they were quite similar in clinical efficacy? Or will we see a step change? The differences between tirzepatide and some of the first and second-generation GLP-1s I think showed us that improvements can still be made, first-in-class. If you remember, semaglutide was what, seventh-in-class. Dulaglutide was fifth-in-class. So first-in-class doesn't always mean best-in-class. But I think those to me are sort of the 3 leading candidates at this point, Charlie.

Yes. I would agree. And then I guess, how -- it sounds like -- just remind us in terms of any signals you've seen on the CNS side, Lilly on the CNS side. What have you seen in your profile? Are you confident you've not seen anything along similar lines?

Yes. We really have seen no neuropsychiatric side effects. We had one episode of jitteriness, another of a change in libido, which we report as neuropsychiatric. And in fact, the rates in our Phase Ib study of headache were lower than placebo. So quite the opposite of what some have reported where the rates are higher. The cagri program, I think, also supports that neuropsychiatric side effects despite some mumblings to that effect really did not show a significant change. Higher dose amylin agonism, if you do rodent studies, looking at signs or symptoms of depression are actually antidepressant or should be antidepressant. Pramlintide was actually being investigated as such in animal studies. So I think there is, in fact, more than likely to be no effect or a beneficial effect, but that's based on nonclinical data, not on clinical outcomes, but nothing in our portfolio or the profile thus far with petrelintide that suggests any of either neuropsychiatric or headache-related events.

Got it. We'll have a look for the early data coming soon, I believe. And then on -- and obviously, we saw with the Gubra compound, adrenomedullin backbone, and then elora suggested to be more amylin specific, that turns out. I think your sort of previous commentary is actually in vitro, it looks to also have some effect on calcitonin. So it sounds like mechanistically, there's one side and then actually in the clinic, they seem to be all looking a bit more similar than expected. Is that a fair assumption? Or what are you -- how are you feeling about that?

Yes. I think receptor biology studies, for those who know them maybe even better than I, and I have to be careful, my wife works for AbbVie, Allergan, so I have to be kind to Gubra and their asset. But the receptor biology studies where you overexpress receptors in an artificial way in a cell line really is just mechanistic. Does it bind the receptor, does it generate cyclic AMP at a specific rate, and what's the affinity and potency of that receptor activation. That's very distinct from what happens in clinical studies, and I alluded to the fact that calcitonin receptor agonism with virtually all of the DACRAs or pan receptor activators, what you see is a transient but acute and short-lived drop in serum calcium that is the consequence of peripheral calcitonin receptor activation that is not long-lived. In our hands and in other people's hands, Novo alluded to this in a presentation at the diabetes meetings this year, you see an acute drop in serum calcium with eloralintide, which suggests that while it may be amylin predominant, it is not purely amylin specific. The only one, to my knowledge, that doesn't see this to any great extent, although there's some minimal cross-reactivity, is pramlintide, the old SYMLIN molecule. The others, I think clinical data will tell you much more ultimately than the receptor biology studies.

Very clear. And I will -- unless any other questions on competition.

It's Ben Yeoh from RBC Global Asset Management. I was wondering on the regulatory pathways as the sort of current drugs are pass through. Do you think the regulators will potentially raise the bar for classes and things coming through versus where we've seen? Or do you think as it is currently, we can expect that because sometimes they kind of do raise the bar on some of these things. And obviously, chats with the regulators have been a shifting landscape. So I was interested in your interactions so far. You kind of feel as trials are designed as of now, it's likely, obviously, they're clean and things like that, that will pass through.

Yes. I think, I mean the "most recent guidance," which is a bit older now than recent, but there were changes, but in the bar itself, not profound differences as we read it and as we interact with the regulators. I think the old 5% threshold, which was sort of, can we get an oral of some type across the line is sort of in the rearview mirror. We know clinically now that double-digit weight loss ultimately is probably where people will target therapies and virtually, all the therapies in active late-stage development are going to get there one way or another. The real interest to me is categorically, even though we've had a few efforts to push for the highest number, the metabolic advantages of weight loss, some of the effects on comorbidities actually don't require 25% weight loss. Diabetes prevention is probably optimized at 10% or more. Most of the effects on blood pressure and lipids and lipid trafficking occur in that 10% to 15% range. So I think as it relates to comorbidity, there may emerge some requirements if you're going to make that claim that you have to achieve a certain threshold that's much higher than the traditional threshold. I think there are a few components of the guidance. For example, all this talk of muscle mass, without actually showing functional differences, 6-minute walk grip strength, something else in a sarcopenic population. It's fine to talk about it in theory, and overfed rodents do really well with amylin agonist as an example, but showing functional changes in muscle mass or functioning, which is alluded to in the guidance. It's not enough to just do DEXA or MRI or something like that. So I think some of those secondary claims, if you will, or label language that we may see will be the ones where there's still a bit of an unknown.

Yes, thanks, Ben. And I guess sort of on that similar more big picture topic, orals, not something you have currently in your portfolio. I mean, yes, I guess, interested in bigger picture perspective of them. Is it something -- again, we see a lot of hype around it. Just interested in your view whether that we assume at some point.

Yes. I mean we keep our eyes and ears open for potential oral options. I think oral delivery of peptides remains a significant challenge even with the RYBELSUS asset and the soon-to-come obesity preparation, just cost of goods, the amount of drug substance that's required with peptide-based therapies. I think orfo and related compounds, the Roche compound from Carmot have changed the conversation that these oral GLP-1 agonists in particular, maybe the oral amylin agonists like that from structure and others can play a role. I think my own bias and I think our company position is while in other spaces, the diabetes space, for example, orals took 80%, 20% were left to the injectables, we see sort of the opposite here, monthly injectables, semaglutide now the tirzepatide franchise, the emerging longer-acting incretin agents and amylin agents really have become sort of the status quo, the standard. If orals were to compete profoundly, I think they have to meet the same bar in efficacy and the same bar in tolerability. What I see in the orfo data, even in the complexity of taking an oral semaglutide is they do not achieve the same bar in terms of weight loss, at least in some populations and tolerability is no better, and in some cases, maybe slightly worse when it comes to GI adverse effects from the oral GLP-1s. That makes sense to me sort of teleologically because you're taking an oral daily with a short half-life. And as I talked about earlier, trough to peak variation in exposure. And if you miss a dose, now you're taking another dose a day delayed from that decay. So while you can achieve steady state, I think if orals have met or exceeded the bar of injectables, the weekly injectables, but for those of you who know people or have yourself taken these weekly injectables with auto-injectors or multi-dose pens, it is becoming a sort of ridiculously simple approach. And I think the efficacy is there. We understand the tolerability, dose titration, managing adverse effects. So if you were to ask me, and I think our sort of corporate position, this is still going to be an 80 parenteral, 20 oral market. There will be very important things about the orals, no cold chain. So you can get it there. Cost of goods is very likely to be lower. Certain markets that may wish to take orals versus injectables, some East Asian populations much prefer orals to injectables. I think in the West, with both sema and tirzepatide, we've seen a significant lowering of the resistance bar to injectables. But if a good oral makes its way known to us and we can develop it, by all means, we will. But like I said, it has to meet those tolerability and efficacy bars for us.

Very clear. And then just in the last minute, obviously, we've seen another GLP-1s reading out with some data in Alzheimer's fairly soon. You've got a GLP-1, GLP-2 both on the inflammatory side of that. So what do you want to see from the competitor read for you to get excited for your own asset to maybe move into that space or tangential spaces?

Yes. I mean I think I credit Novo for the work on evoke and evoke+. I think there is plenty of suggestive evidence. I mean we've known this for years that weight reduction, probably some improvement in glycemic control is likely associated with the lower risk of progression. I think there are a couple of risks here. These early cognitive changes are tough to discriminate. So how will the treatment effect sort of emerge? Is it big enough to convince us to go forward? The second is the dose exposure is relatively low, which makes sense. This is not a population that needs to lose lots of weight or significantly improve glycemia. I do think if there is even a numeric shift in -- towards benefit, that will raise the interest in the community. And whether GLP-1/GIP, its effects on oligodendrocytes, GLP-1, GLP-2, which also targets the potential inflammatory component of neurodegenerative diseases, I think you will see a significant amount of enthusiasm if this is even directionally positive, whether it is statistically significant, clinically significant. If you can measure it, but it makes no difference functionally, how important is that versus something that truly transforms the rate of progression of disease. So I won't try to predict the results. I think the risks are low dose in a relatively early stage of neurodegenerative change. The benefits are -- I think any evidence of benefit will go a long way to keeping people excited about that area.

Perfect. Well, we're up on time. Much appreciate the time. Always very insightful. Thank you all for joining.

Thank you very much, Charlie.