All right, good day, everyone. Welcome to day two of Cantor Global Healthcare Conference. For our next session, we are very excited to host Zealand Pharma. R epresenting Zealand is Dr. David Kendall, Chief Medical Officer. David, thank you for joining us.
Pleasure. Thanks.
Lots going on at Zealand these days, but not surprisingly, wanted to start off on amylin given the interest in the space.
Mm-hmm.
Now, amylin has been a target that's been around for a while, but suddenly there is renewed interest in this mechanism for obesity. Even going through some of the EASD presentations, everyone was talking about amylin. What makes amylin an attractive target in obesity right now relative to GLP-1, GIP?
Yeah. Thanks, Prakhar, and I'll tell, for those who aren't familiar with the history, I started my pharma career at Amylin Pharmaceuticals way back when. So I think much of it dates back to the discovery, but then early clinical applications of pramlintide, a very short-acting agent, but seeing in a small obesity phase II study back then a 10-12% weight loss with longer exposure. So that, to me, was the early proof of concept. That's almost 15 years ago now that those data became available. But I think also the unique mechanism by which it works, the incretin-based therapies, as everyone knows, clearly work. They bind to the GLP-1 receptor and other receptors come with certain baggage.
The adverse event profile for a lot of them is quite similar, particularly around GI tolerability. Amylin works through different receptors, different signals, and although decreased appetite is part of this, the sense of fullness, the satiety signal, is the unique one. So I liken it to, you know, waking up, you've had the stomach flu, or you've created a brown bottle flu in yourself, and you just don't feel like eating. That's GLP-1-like effects. Whereas I've gone to the buffet one too many times, I'm full, is the second satiety or fullness signal. Very distinct, and I think that plus the tolerability profile that we're seeing with amylin agonists, much better tolerated. Both frequency, severity, and the nature of the GI tolerability issues we think can be substantially different.
Right. And a lot of amylin drugs in development right now, you clearly have a view that potently activating both amylin and calcitonin receptors is important.
Yes.
Can you just explain why, why do you believe that, and, what, what led to the drug that we know, petrelintide?
Yeah. So, the amylin, calcitonin receptor biology is a complex one and probably still fledgling in our understanding, much like GLP-1 was back in the day. But the GLP-1, or I'm sorry, the amylin receptors, hindbrain and in the hypothalamus, calcitonin receptors expressed in the brain, and in the midbrain in particular. Knockout studies with animals show that the calcitonin receptor is playing a very important role in metabolism, controlling metabolism, controlling satiety. So we believe, you know, receptors don't exist in places where they're not needed. So the central role of calcitonin and the potent amylin activation. So based on an amylin backbone, that's petrelintide. Long-acting agents, it's quite clear, probably have the greatest clinical effect.
We believe petrelintide can achieve GLP-1-like weight loss, 15%-20% with longer exposures, and we strongly believe that calcitonin, amylin receptor binding and biology is critical to the weight-reducing effects in particular.
Got it. And so what are the safety implications of hitting calcitonin? Anything that you are closely watching?
Yeah. Potent activation at the calcitonin receptor, like salmon calcitonin, obviously changes calcium metabolism. Although for the bone, this can stimulate osteoblast activity, makes for stronger bones. It's not the therapy we use routinely for osteoporosis. But the flushing heart rate effects of high levels of calcitonin and potentially effects on calcium metabolism. The good news is, even if you activate the calcitonin receptor, the body is exquisitely sensitive to maintaining serum calcium, so we don't anticipate significant effects on either bone metabolism to the negative or these flushing-like symptoms, tachycardia and the calcium effects with the right balance, which we believe we have from our toxicology studies.
Got it. And previously, you have shown that amylin drugs lead to lower lean muscle mass loss.
Mm-hmm.
There was some data at ADA and EASD as well.
Yeah.
... I believe. So mechanistically, why is that happening?
Simple answer, we don't know. But it's quite clear that with petrelintide, pramlintide previously, and the data with cagrilintide, it is a fat-specific weight change, at least in the animal models. We'll have to corroborate that in the human clinical trials. I think there are two potential reasons. One, we alluded to in our recent presentation at EASD. Food choices and the approach to food tends to avoid high fat and/or simpler processed carbohydrates, at least in animal models. If you reduce fat, the body will preferentially burn fat, but the more important one, we believe, is amylin's signal to sensitize to leptin, which is our signal of adiposity. So when we all lose five pounds, the body suddenly thinks we're starving. Doesn't matter what our starting weight is, leptin levels fall, sensitivity to leptin falls.
You can then preferentially burn less fat. The body's protecting itself, if you will. By maintaining that amylin signal, still seeing adiposity, we think there is a fat preferential burn. You know, and in the animal models, it's quite clear that that differs from GLP-1-based therapies.
Okay. Got it. Novo's cagrilintide-
Mm-hmm.
Or CagriSema is the furthest along in development. Maybe talk about how petrelintide, which is your lead amylin, differs versus Novo's amylin drug.
Yeah, I mean, I would say at the surface, they are quite similar, so we're very encouraged by CagriSema's clinical effects, the safety profile. They too, I believe, have stated that it binds both to the amylin and calcitonin receptor, and you're seeing pretty substantial additive weight loss. The major differences, we think, are not just biochemical, but that we can formulate petrelintide at a physiologic pH. It is stable, non-fibrillating. Theirs is in an acidic solution, so will always be either two chambers or two injections when used in combination with something like CagriSema. We also believe we have advantages, a longer half-life, greater bioavailability, probably similar potency, but at least in our phase I-B study reported earlier this year, going to higher doses than they've seen with CagriSema.
The other real limitation is, at least with CagriSema, cagrilintide will carry all of the profile of the semaglutide molecule, so the weight loss should be additive, but the potential for additive GI tolerability issues, we think, is also a concern. We've, you know, disenabled or separated the two, so while we believe ultimately they could be used in combination, petrelintide plus a GLP-1, it could be admixed with any other neutral pH compound, and you can titrate each individually.
Right. And no one ever developed their amylin as a monotherapy or so far, not yet. Is there any specific reason for that, and why did you decide to go for a monotherapy route?
Yeah. One, we believed that a standalone therapy that could serve truly as the new backbone of obesity treatment. We realized GLP-1s will have been around for a few decades by the time the effective amylins hit the market, but a better-tolerated GLP-1 like weight loss component to this, we believe can set it apart as a monotherapy. Back to the Novo question, I won't try to answer for them, but I suspect a lot of it was the importance of supporting semaglutide in a very successful franchise. And the other is, I think, you know, as they were doing development, this understanding of we need alternatives, we need approaches other than GLP-1s. Use other metabolic diseases, hypertension, lipid disorders, diabetes.
You almost always use multiple approaches, with one, quote, "backbone approach," a better-tolerated molecule that's as effective can be admixed with anything, such as petrelintide, we think can set it apart. And so we think separating them actually builds even greater value for the assets.
Okay. You presented phase I data recently, in June, I think.
Mm-hmm.
Maybe just help us characterize the efficacy and safety for petrelintide as a monotherapy versus other mechanisms.
Yeah. So for those who haven't reviewed the data recently, this was a 16-week phase I-B with three treatment arms. We call this Part II because we had done a 6-week Part I that showed the lower doses at 0.6 and 1.2 milligram resulted in about a 5% weight loss. In this, what I'll call the mid-high and highest doses, we saw up to an 8.6% weight loss over 16 weeks, and at those highest doses, they had only between six and eight weeks of actual exposure to the maximum dose because of the titration scheme we employed. But to us, that puts the placebo-corrected weight loss approaching 7% above that observed for cagrilintide and for semaglutide, and just slightly less than that seen with tirzepatide.
So, you know, the early data readouts at those higher doses suggest you are on the 15%-20% trajectory for weight loss. Very encouraging safety and tolerability, very limited GI side effects. All but one individual, when they reported them, said they were mild. Only one individual stopped drug of the three treatment groups or 36 subjects for GI tolerability issues related to drug. So to us, confirmation of the safety and tolerability profile and the efficacy that we think will be clearly GLP-1 like.
Right. And I guess one question that we got when the data was released was around the dose response.
Mm-hmm.
You certainly believe that there will be dose response in longer trials, so maybe talk about why, why you're confident on that.
Yeah, and the full data for this study will be reported at ObesityWeek upcoming. I think a lot of people surmised that before it was even official for us. The dose separation between the two highest doses, while the clinical result was comparable, shorter exposure, and there was a pattern in at least the mid-high dose group, where they seemed to lose an excessive amount of weight on the same doses early. So the separation and the trajectory of the lines later suggests that at least at that mid-high and highest dose, we have the potential to go to at least, you know, 2-4+ the doses you're seeing for tirzepatide.
Okay, and when you present the detailed data at ObesityWeek-
Mm-hmm.
What should investors be focusing on?
Yeah, I think, more detail on the individual responses. Again, in that study, every individual exposed to the active study drug lost weight at some point, through the trial. The average was, you know, between 5 and 8.6%, for the three treatment groups. But then obviously giving a little bit more granularity to what the tolerability profile means, other safety parameters, none of which raised it, for us, any level of, limitation or concern for progressing to phase II-B, which will, be in the coming months.
Okay. And you said that amylin could be a more tolerable drug than GLP-1.
Mm-hmm.
Any details on that could be provided, maybe on the frequency of GI events, the time course?
Yeah, we don't have direct comparative data, so we're making sort of qualitative discussions. But, you know, we are seeing, at least in the early components of the trial where the titration is usually the most rapid, probably rates, particularly vomiting, diarrhea, that are half of that, or less than observed with GLP-1s. I would say it's similar for nausea, that we're seeing it at half the rate as you see in GLP-1 trials, at least early. The other thing we're seeing is, if you remember the earlier phase I studies, all the GI side effects were mild. We had this one episode on the patient in the highest dose cohort, but both a lesser frequency, a lesser incidence, and ultimately these data would suggest less intense, and perhaps shorter duration.
We did not see substantial increase as we stepped up the doses, for example. It was with first exposure. So those sorts of things will be part of the discussion.
Okay. And longer term, you have highlighted that you would like to see 15%-20% weight loss as a monotherapy. What's driving that confidence?
Yeah. I think it's both, some preliminary modeling now that we have the phase I-B data, looking at the trajectory, knowing what we know from pramlintide and cagrilintide, what the slope of those curves looks like beyond, you know, just 14-16 weeks of exposure. So, you know, that and the comparative trial data that say this actually exceeds what we saw with semaglutide in their phase II, phase I and phase II studies, and is approaching that we see with tirzepatide. So the trajectory will tell the story, obviously, but we believe, a continued downward trend up through, you know, 48 weeks at least.
Okay. And, talk about the phase II design, potentially what doses, titration schedule, anything that you can provide right now?
Yeah, an additional detail on that will likely come with the disclosure of the phase I-B data in full, but it'll be a multi-arm study. We've described, you know, approximately four, maybe five treatment arms with a placebo control group. We anticipate titrating up to the highest dose that they have exposure in phase I-B. That was part of the intent of the phase I-B is to reach our sort of tox limits and NOEL limits, and have done so safely. So that protocol is pretty much signed off and ready for initiation, but multiple arms, as we've talked about, I think, publicly, at 28 weeks, we'll do a cut for regulatory purposes only.
But to take that for dose ranging to design the phase IIIs as early as possible, but the full duration of the trial will be more than 40 weeks of exposure. So we'll have one small, unblinded team that gets the regulatory work done, and the rest of us will be still awaiting the full one-year exposure.
Okay, got it.
Yeah.
Longer term, is there a reason to believe that amylin monotherapy could have a different shape of the weight loss curve, compared to a GLP-1 monotherapy?
Yeah, I think two answers to that question, Prakhar. One is for amylin alone, we believe, given this leptin sensitizing capacity and the overall effectiveness, that you could see a more stable plateau. Now, that could be driven by adherence, tolerability, acceptability as well, which would be perfectly fine with us if people can take it. The toughest drug to use is the one you won't take. And, you know, the significant proportion of people who stop GLP-1 therapy, we think will be helped. So we believe this will be as good or potentially better in terms of weight maintenance. The other question that begs is, well, you lose a lot of weight on a GLP-1, you don't feel that great. Can you then either convert or cover with an amylin agonist that's being better tolerated as effective for weight maintenance?
We think that leptin signal component, even though it sounds like a basic science, may be very important for weight loss and weight maintenance.
Okay. And, you're all obviously focused on monotherapy right now with amylin, but combination strategy, what kind of combination mechanisms may be most attractive, and when do we hear more about that?
Yeah. We anticipate, first and foremost, that if these tolerability and efficacy data hold up, people will think of amylin first, not just GLP-1, although we'll be fighting a few years of history. But combination studies we know will be important. So early, safety studies in combination with GLP-1s to look at the additivity, the impact on adverse events, just as they've done with CagriSema, will be part of our planning, and then what combinations we take into phase III. Do we do an amylin SGLT2? Do we do an amylin GLP-1? Do you do it sequentially as follow-on or for maintenance? A lot of phase III and phase III-B planning to that, but all those possibilities, we believe, will be important to ultimately enhance the value of the amylin, asset and pramlintide in particular.
Novo's CagriSema phase III trials will start reading out soon.
Mm-hmm.
So is that something that could guide your combination strategy as well in terms of the efficacy and safety that you would see from that product in a larger sample level?
Absolutely, and I think it could move us either way. If this looks, you know, exuberant, then combination studies undoubtedly will be higher priority. If it looks like as we postulate, there's really a bit of baggage that comes with the high dose GLP-1, 'cause remember, you can only titrate to the highest semaglutide dose or the highest cagrilintide dose if you get to the highest sema glutide dose, 'cause it's a paired administration. So I think you could see limitations in effectiveness based on titratability, not so much because of the amylin component, but the GLP-1 component. But I think, you know, it will reaffirm efficacy, which we've seen in phase II. I would be interested in the cagrilintide-only arm just for tolerability.
It's not, in my mind, adequate for a separate indication for cagrilintide alone, but I think it'll teach us a lot about where the adverse events in the trial are coming from.
Got it. And GLP-1 monotherapy drugs obviously have the benefit of showing outcomes data.
Mm-hmm.
What gives you confidence that amylin could replicate that?
Yeah, I think for us, that's a critically important part of the life cycle and the development of this compound. GLP-1s have salutary effects on lots of things, the heart, now we see the liver with glucagon agonism adding more. But amylins, one, if you can't take a GLP-1, you're not getting the benefit. So if it's 70%-80% of people who are off a GLP-1 after a year, what do you do for that group? Amylin agonism, data from Cagri, our preliminary data from phase I, and the animal data does not increase heart rate, lowers blood pressure, appears to lower markers of vascular inflammation. Now, there are no amylin receptors on cardiomyocytes that we're aware of, but those other effects, combined with reduced body weight, we think can and will have a salutary effect on comorbidities.
Will we beat a GLP-1 in cardiovascular outcomes? I'm not sure that's the point. Cardiovascular safety and demonstrating these, but cardiovascular outcomes would, I think, nail that for the life cycle of assets like petrelintide.
Okay. Any plans to test amylin in diabetes as a monotherapy or combination?
So our current phase II plans will include a separate study for weight reduction in a type two diabetes population. As many of you know, when you give a GLP-1 to population with diabetes, they lose less weight than those without diabetes because GLP-1 is an effective glucose-lowering therapy, stimulates insulin, so you store at the same time you're losing weight. We believe that amylin in the diabetes population can actually preserve the weight reduction, so weight reduction in those without and with diabetes should be similar.
Right.
That's our postulate. So we also want to include them in the phase III program. While there's been some outside interest in developing it for a separate diabetes indication, we think its primary indication must and will remain obesity and weight management.
Got it. And amylin space is getting very competitive-
Mm-hmm.
-with more options coming, similar to what we have seen with GLP-1, so maybe-
Mm-hmm.
Lay out the landscape as you see right now with some of your competitors. You have AstraZeneca going with their amylin, Lilly has their amylin, Gubra has an amylin readout coming. So just lay out the landscape for us and how you will differentiate.
Yeah. I think, one, we're relatively farther advanced. Eloralintide, the Lilly molecule, we know very little about other than its structure. Pure amylin agonism differs from our amylin calcitonin balanced approach. One, we think it's more efficacious. If you have both, amylin receptors alone have only part of the metabolic effect, predominantly on glucagon secretion and probably satiety, not just food intake. But we feel confident that, you know, we are positioned to be best- in- class, duration of action, the early clinical data, the rodent and safety data we've seen throughout give us great confidence. You know, selfishly, we like to say we were there first talking about this as a standalone therapy, and now others are sort of singing our tune, which is, you know, maybe a form of compliment.
I think the other limitation, particularly for cagrilintide, is you're not gonna have cagrilintide available to you as an individual therapy. So if amylins work as we believe they do, we should be amongst the first, and we believe best in that category.
Okay. Moving on to some of your other assets.
Mm-hmm.
We can probably talk about amylin for a while, but you have dapiglutide as well.
Yeah.
The GLP-1, GLP-2, which has started to show more encouraging weight loss data. So maybe you mechanistically talk about what does GLP-2 add-
Mm-hmm.
on top of GLP-1s, and what are you trying to achieve with this asset?
Yeah, and from the recent data, you and others may have seen, we are seeing GLP-1 like weight loss with the higher doses, and we're continuing to even higher dose exposures now that we have the tox coverage, doses up to 26 mg out at 28 weeks. So we'll have a little longer exposure in that fourth cohort. But GLP-2 specifically has tissue preservative, tissue restorative effects, and these are not just limited to the lining of the gut, but that, for us, is one of the important potential mechanisms by which this little bit of GLP-2 that we think we've dialed in will have protecting the gut barrier, which is a source of inflammation in visceral adipose tissue .
And in the liver there are GLP-2 receptors on the stellate cells in the liver that give rise to some of the inflammatory components of MASH, so we think direct effects, potentially on the liver, and in really encouraging data around vascular inflammation and neural inflammation, and whether that will translate to reduced cardiovascular risk above the GLP-1 alone, effects on neurodegenerative diseases like Alzheimer's, maybe Parkinson's. All of these, we think are clear ways to differentiate a GLP-1, GLP-2 from the myriad other GLP-1 based therapies.
Good. And so for this asset, is the differentiation more about inflammation, or could the GLP-2 also improve the weight loss and improve the tolerability profile of a GLP-1 asset?
Yeah, I mean, there's preliminary evidence that GLP-2 can make GLP-1 infusions better tolerated. I think some of that has been abrogated by longer, more potent GLP-1 receptor agonists, like we believe dapiglutide is. So I wouldn't predict or anticipate significant reductions in GI tolerability, but if they occur, it will likely be that we can get to higher doses than other GLP-1s. And it's where the GIP-containing molecules have taken us as well, is to slightly higher doses that the other mechanisms are, we think, focused on those tissue restorative and anti-inflammatory. So we don't expect a lot of other value add, except potentially higher dose.
Got it. And so you had some weight loss data with higher doses that were disclosed recently. So maybe just talk about that, what you saw with the higher doses, and what are you hoping to achieve?
Yeah
In terms of the profile for this drug on weight loss?
Yeah, I think, depending on who you ask in our core teams, but those data certainly make this look like a GLP-1-like asset, and if we can further double and triple that dose exposure, then, you know, we would anticipate weight reduction that is in the high end of the dual agonist category. If you ask our CEO, Adam, he'll tell you, you know, somewhere in excess of 20%. My core team and the modelers say, you know, 15%-25% is clearly achievable. We believe when you get to high teens and now around 20%, you know, talking 1% or 2% difference there probably means less to the clinical population than it does to us and to the investment community to prove you have what you'd say you have.
I would say well in excess of 15% and likely in excess of 20% weight loss.
Got it. And when do we see the data presentation from dapiglutide? And when, whenever you present the data, will we get data on inflammation markers as well, which is a key-
Yeah
... differentiation for this asset?
Yeah, it just came into our hands a couple of weeks ago, so you saw the top lines, and thank you, Anna, for putting that out into the world. And, you know, once we have the full clinical study report, which, as you know, takes a few weeks, couple of months, and then we anticipate disclosure at a scientific congress in the first part of next year, seems the most likely. And that will, like the petrelintide data, you know, include more granular data on the weight loss, the titration scheme, and the adverse event profile. Remembering that this 28-week cohort four is still going to be ongoing. We hope some of that can be included in the presentation, but it will wrap up about the time many important abstracts are due, so there's always that game.
Okay. Moving on to the third asset that you have, which is partnered with BI, survodutide.
Yeah.
There's a perception out there that the survodutide tolerability is not good based on what we have seen in the phase II. Could you talk about why that's not the case in your view and-
Yeah
... why the tolerability for obesity and MASH should improve in phase III?
Yeah. I mean, I think the theoretical reasons supporting this could be different, as glucagon is known to have some GI tolerability or adverse effect profile. But given, again, their titration scheme, what they're now doing in phase III, going to the highest dose, higher than we saw even in some of the phase II studies, but clearly, for example, in the diabetes study where they dosed twice weekly to very high dose, it is, you know, clearly our estimation and the pattern of adverse events seen in those who continued the therapy in phase II, clearly put it, for us, on par with GLP-1-based therapies, depending on the trial, the population. Interestingly, the tolerability profile in the MASH study was slightly better than what was observed in the obesity studies.
May have been titration scheme, may have been stability at the top doses. Interestingly, in their F4 presentation, there was no worse, and in fact, maybe even better tolerability in those with the worst liver function. So I think there's lots of now associated evidence that say this will be GLP-1 like, not better, not worse. And all of the data point that. Obviously, phase III will tell the story.
Okay, and so what's the status of the phase III trials in obesity and MASH?
Yeah, so the obesity trials are rapidly progressing to completion. And I think clinicaltrials.gov has the final completion of the 78-week exposure, end of 2025, with full study. I think was listed in January of 26. So those are moving on schedule. That will trigger their likely submission for the obesity indication. The MASH trials, we are awaiting word from the partner as they control development, as to when and how those studies will be initiated, but we fully expect, given their public statements, that BI will initiate the MASH phase III program, which may not be a 78-week, year-and-a-half trial because it's a different indication independent of obesity. But the negotiations around biopsy, non-biopsy endpoints, all those things, but we anticipate initiation of that soon.
Okay, and last question from me. You have some early-stage obesity assets as well that you're working on. Which assets are you most excited about?
You know, we haven't disclosed the details around this, but we have a program we ourselves call Obesity Plus, which, as you can imagine, includes amylin plus, which is petrelintide and other molecules. So if the amylin signal is, as we think, potent, efficacious, well-tolerated, can we leverage that with other, you know, either common peptide signals? The issue of adding, for example, an activin or myostatin, because you have natural lean mass preservation, we don't think it's necessary. Leveraging, for example, program that Amylin Pharmaceuticals and Takeda had, where they added human metreleptin to amylin, looking to get synergistic weight loss, 'cause leptin alone does nothing. Are there leptin ligands, fragments of that, that could be manufactured? So these are, you know, ideas that we are generating.
So I would say if there is another peptide signal, tolerated or not, then we will be investigating that in early clinical trials and trying to optimize peptides to bring into the clinic.
Okay.
Yeah.
That's all the time we have today, but thank you to the Zealand Pharma team for joining us.
Perfect. Thanks, Prakhar. Thanks, everyone.