Ipsen S.A. ($IPN)

Excellent. Thanks, everyone, for joining and hello. I am pleased to welcome you this afternoon to our corabotase LANTIC Phase II glabellar lines presentation, which will also be found on ipsen.com. Please turn to Slide 2. Please take note of our forward-looking statements, which outlines the routine risks and uncertainties contained within this presentation. Please turn to Slide 3. I am delighted to be joined by Professor Kerscher today, the PI for the global Phase II LANTIC trial, who will present the aesthetic proof-of-concept data. We will both be available to take your questions at the end. I will start by introducing our first-in-class recombinant neuroinhibitor, corabotase. Please turn to Slide 4. The external validation of corabotase is an important milestone for aesthetic innovation. The [ USAN and ANN ] have designated corabotase as a custom-engineered recombinant neuroinhibitor, recognizing the novelty of this first-in-class molecule. If approved, it would be the first therapy in a new botase class, reflecting a differentiated engineered molecule rather than a naturally occurring toxin. It is fully designed, engineered and manufactured in-house at Ipsen, which is critical to quality control and consistency. Built from engineered functional domains of catalytic domain A and binding domain B, every element of its structure has been deliberately optimized to increase receptor affinity, enhance uptake and improve resistance to degradation, reinforcing the scientific milestone reached in this naming designation. Please turn to Slide 6. Corabotase is a precisely engineered recombinant neuroinhibitor developed using advanced protein engineering through Ipsen's proprietary technology platform. It was designed to deliver rapid onset of action, compelling efficacy, sustained duration of effect was prolonged symptom relief. Corabotase draws on insights from nature, but it is not a naturally occurring molecule. It has been purposefully engineered. This approach enables a highly replicable product with minimal variability compared to naturally derived molecules, supported via controlled high-quality and reproducible manufacturing process. Structurally, it combines optimized functional domains: an active catalytic domain A and a binding domain B. The B domain uniquely targets the Syt-II receptor, enabling binding to higher-density neuronal Syt-II receptors and improving binding affinities through amino acid sequence optimization. This engineering is intended to drive higher receptor affinity and a greater probability of receptor engagement, far faster and more efficient cellular uptake and less extra cellular tissue decision. Together, these properties translate into sustained inhibition of neuro transmitter release and a sustained reduction in muscle activity. Please turn to Slide 7. As you can see in our growing neuroscience pipeline, we focus on both development in therapeutic and aesthetic indications. I want to draw your attention to the ongoing Phase III registrational trial for corabotase in aesthetic glabellar lines opened earlier this year and recruiting very well. I will now hand over to Professor Kerscher to run through the LANTIC proof-of-concept data in glabellar line that was presented at the SCALE Symposium in Nashville over the weekend. Please turn to Slide 8. Over to you, Professor Kerscher.

Yes. Hello, everyone, absolutely excited to present here again the data we have shown last week at SCALE meeting in Nashville. Well, it is the first data that has been obtained in subjects with glabellar lines, the proof of concept data. Next slide, please. And you have been already introduced to corabotase. For us, as aesthetic physicians and dermatologists, it's really important because aesthetic injections of botulinum toxin are worldwide since decades the most often performed procedure in aesthetics. So seeing something new on the horizon is quite important for us. And corabotase from a scientific point of view is absolutely interesting as it is the first recombinant neuroinhibitor, combining the binding domain of botulinum neurotoxin type B and the catalytic domain of botulinum neurotoxin type A. And through amino-acid modifications, this neuroinhibitor binds to the synaptotagmin receptors at the nerves, and this means they are more abundant there than, for example, the receptors conventional neurotoxins bind to. And this means that we have enhanced binding and uptake and then, after internalization, the catalytic domain of botulinum neurotoxin type A within corabotase causes muscle relaxation. At the conference, I had the chance to first report the data from the LANTIC trial. Please, next slide. And the LANTIC trial has really a very complex study design. It is a 3-stage study design including or starting first in patients with glabellar lines and then moving up to treating also horizontal for headlines and lateral counter canthal. And this study is still ongoing and is conducted at 9 sites in France and Germany. We, at the University of Hamburg, are one study site from the very beginning. And the LANTIC study is a study that evaluates safety, on the one hand side, and efficacy of corabotase. Next slide, please. And I'm now reporting the data from stage 1 step 3. This means data that has been obtained in a study setting that assesses different doses. So it was a dose-finding trial, and it has been assessed versus placebo, just injection of saline solution and versus abobotulinum neurotoxin type A. And it has been done in a double-blind study design, was randomized and placebo and gold standard control. We included in this clinical trial adult patients from 18 to 65 years, all having moderate and severe glabellar lines, and all patients or subjects in the clinical trials being dissatisfied with their glabellar lines. Next slide, please. The primary endpoint of this clinical trial has been the response to treatment at week 4. And this response to treatment has to be measured as a so-called composite response of at least 2 great improvement. This means if someone started, for example, with moderate glabellar lines, a 2-point grade improvement means no glabellar lines in the end. For sure, not only the primary endpoint has been assessed, but a lot of other endpoints, including composite response at the other time points up to week 24 and longer than treatment response. This means an investigator life assessment, the ILA, with none or mild and subject satisfaction that's really important in daily clinics and time to onset of response, and this has been evaluated through a patient's diary. Safety endpoints included treatment emergent adverse events, serious adverse events and adverse events of special interest during the whole period of the clinical trial. Next slide, please. We directly walk now through the results. And first, we have to look at the participant or subject characteristics, subjects that have been included in this clinical trial. And these characteristics were, in general, absolutely consistent with those in prior studies in subjects with glabellar lines. So mostly female subjects, 82.5%, with a mean age of 46.8 years. It's quite important to also look at the investigator life assessment score at baseline because due to the study protocol, patients with moderate and severe glabellar lines could be included. And as you can see here for the corabotase group, 1/3 had moderate glabellar lines while 2/3 came with severe glabellar lines. Next slide, please. And now the response rate at the primary endpoint. This means the response rate at week 4. As you can see here in the columns, 66% of subjects that have been treated with 15-nanogram of corabotase showed an at least 2 great improvement as composite response as compared to 0% with placebo and 54.3% with abobotulinum toxin A. This is a high percentage of patients responding to treatment using the specific endpoint of at least 2 great improvement. Next slide, please. Let's now have a look at the response to treatment at week 24, and this is quite important criterion because this reflects duration of treatment effect. And as we can see here on the columns or also on the graph on the right-hand side is that almost 61% of patients or subjects treated with corabotase 15-nanogram had a clinically meaningful response at week 24, here assessed as investigator life assessment as a treatment response of non or mild. And this comes again in daily clinics because patients are satisfied if they have no glabellar lines at all or just mild glabellar lines. And again, this treatment response is really clinically meaningful, and it is absolutely high also as compared, for example, to the group that has been treated with abobotulinum toxin A and has a treatment response that is lower, just 36.75. Next slide, please. Quite important especially for patient is also the onset of effect. And as you can see on the left-hand side, median onset of effect with corabotase is less than 1 day, 0.84 days as compared, for example, to onset of effect with abobotulinum toxin A that is 1 day longer. For me, the most important result of this clinical trial so far is we have a look at patient satisfaction or subject satisfaction. This is the linear graph on the right-hand side. And here, we can see that the patient, they are really satisfied or satisfied over a plateau of almost 32 weeks. This means that subject satisfaction is higher and takes longer than the treatment effect. And if you compare the orange line versus the green line, we see that treatment satisfaction gradually decreases with treatment, for example, with abobotulinum toxin A, while it remains on a very high level, up to week 32. And this is really an interesting and clinically very meaningful treatment response to corabotase. Next slide, please. Subject safety is always quite important, especially as soon as new drugs come on the aesthetic market because we have to have in mind, we are treating in general healthy patients that are dissatisfied with some aesthetic factor with some lines and wrinkles in their face. But in general, they are healthy. So we are not treating a disease. We are treating just a skin condition that dissatisfies our patients. But in this clinical trial so far, corabotase was very much tolerated, absolutely no safety concerns with any of the evaluated doses. Next slide, please. So so far, we can conclude that stage 1 step 3 of the LANTIC trial achieved very good clinically meaningful results for corabotase in glabellar lines. Data so far support an onset of action, less than 1 day, a peak effect that is consistent or least consistent, even better with one with abobotulinum toxin A and a sustained duration of effect with the majority observed to have a line severity score of none or mild at week 24 and to report it being satisfied or very satisfied with the treatment. The safety profile of corabotase was consistent with that observed for marketed botulinum toxin A products so far. And this first aesthetic data certainly support the initiation of Phase III trials in glabellar lines, and the first patients have already been enrolled in February this year. Next slide, please. So in my opinion, corabotase is really important, scientifically absolutely interesting molecule within the always emerging market of botulinum toxins and neuroinhibitors. Thank you so much for your attention.

Thank you, Professor Kerscher. Please turn to Slide 22. And let me tell you a little bit more about the LAURITE registrational trial. The Phase III program is underway, marking an important step as we move from the Phase II learnings into late-stage development. As shown on this slide, these studies are designed to confirm efficacy and safety and to support potential future filings. Please turn to Slide 23. Over the next 3 years, we expect multiple readouts from across our neuroscience programs in both aesthetics and therapeutic indications, including the beyond migraine program for Dysport and further Phase II and Phase III data in aesthetics as well as key proof-of-concept readout in 3 therapeutic indications for corabotase. Please turn to Slide 24. To conclude this presentation, we are continuing to maximize the potential of our portfolio of botulinum toxins while exploring the full potential of our purposefully designed first-in-class recombinant neuroinhibitor, creating a truly unique opportunity in Ipsen's neuroscience pipeline. With that, we are pleased to take your questions.

[Operator Instructions] First question we have is from Victor Floch.

Maybe starting with a question on Dysport, which seemed to have bode well in the trial, especially at 6 months on treatment response and despite less favorable baseline mix. So what do you think drove that result? And could it also have influenced corabotase outcomes? And my second question, maybe more for Professor Kerscher. Can you discuss the feedback from your peers on the data? And which aspect was most positively received, was it onset of action or durability?

Maybe I'll start addressing this question. So the first one is a question regarding abobotulinum A in our trial. So I'd like to start by saying it's not really possible to compare data from the Phase III registrational trial run with Dysport in 2007, where they were 100 patients treated with our active comparator arm in a Phase II proof of concept. So there are many differences between those two studies. And one key is the number of patients, but also the treatment paradigm was very different at the time of Dysport's registrational trial. And I'd like to bring Professor Kerscher in this time to maybe comment on the difference of injection paradigm.

Yes, absolutely right. And thank you for this question. It's really important from a medical point of view, and it has already been explained. 20 years ago, we had completely different injection protocols. If you have a look in the publications, then you might see that the 5 injector points in the glabellar area 20 years ago were injected in a V shape. So this means from our knowledge by today that we injected the corrugator point, the lateral corrugator points more within the frontalis muscle and not within the corrugator muscle, and the corrugator muscle has to be relaxed for getting rid of the glabellar frown lines. And this reduces the outcome, especially if we compare and have a look on the duration of effect because if you have a look at week 4, week 4, have a high consideration of neuroinhibitor in the area around the synopses is also in the corrugator muscles. So this effect doesn't show up. However, as soon as the molecules were needed at the synopses less molecules are present at the corrugator muscle if we inject in a V shape and not directly over the bony orbital rim. This is mostly due to the development of new injection protocols nowadays. On the other hand, I think we also have [indiscernible] injector volumes, but it's mainly to our now to the knowledge of anatomy.

Thank you for this complementary answer, Professor Kerscher. To the other part of your question regarding the duration of action, I would say the detailed comparison at isolated late time points should really be interpreted with caution. The study was not powered for that level of granularity and the sample size are limited. The more meaningful comparison is across the duration window, where we see a very clear and consistent signal, particularly at the week 24.

So the next question is from Ben Jackson.

I got two questions from my side, please. Could you perhaps just provide a little bit more information about the dosing of Dysport that was used in the actual trial and how that differs or perhaps differs from how it's used in the real world? And then also on your own dosing of corabotase, it's obviously been noted that it's, I think, at 50 nanograms. It seems slightly bigger than what we typically reduce for a neurotoxin. So perhaps you could talk us through what it is within the profile of corabotase that allows you to do that and whether that could increase importance of longer term and reinjection data to improve the knowledge around that. And then secondly, can I just also ask if you've looked at the subject live assessment at all in the study and how this perhaps differs from the investigator responses that you were looking at? And is one more important than the other in the real world when it comes to decisions around with product is given to which patient?

Thank you, Ben, for this question. I'll start with the dosing question, then we'll hand over to Professor Kerscher to talk about dose used in the study and assessment. So Ben, we actually cannot compare at all the doses in the sense that natural occurring toxins are dosed by units and those are units of activities. We have engineered a fully recombinant protein and our doses are expressed in nanogram, but they are not comparable to whatever equivalent you're thinking of with the natural toxin. So we really cannot draw any conclusion from this. Professor Kerscher, would you like to comment on the choice of dose for abobotulinum toxin A in our study and also the assessment?

Yes. Thank you very much for discussion absolutely important. And I think the 50 nanogram has already been explained. This is due to the fact that it's a completely different molecule. For abobotulinum toxin A, 50 stable units have been used, and this is exactly the dose that is recommended for treatment of glabellar lines. Then I think if there is nothing open about this point, the second part of your question was the subject life assessment in comparison to the investigator life assessment. And I think this is a phenomenon that we observed in all the clinical trials that are performed in patients with glabellar lines, also horizontal forehead headlines and periorbital lines although in nasolabial patients to a different assessment if they have to have a look for their own wrinkles. And they tend to see them a lot milder than the physicians rate the wrinkles. And this means that subject life assessment often is, for example, if you as a physician, see it's severe or maybe even very severe, patients sometimes even think it is mild for them. And as a physician, you are not allowed to explain and you are not allowed to communicate to the study subject how you as a physician rate the wrinkles. Even if patients ask, I cannot tell them anything. So they are just alone to rate their own wrinkles, and then they have a tendency to do this in a more positive way. And this is although the fact that this composite evaluation often has very low percentages. Even if we are happy with the 66% response in general and as physicians, we might see a more than 90% response because we see that the patient perfectly responds to the treatment. But having in mind that then the subject may be just improves in the own decision from a 2 to a 1, this then is lost for a treatment response.

So the next question comes from the line of Xian Deng. Xian?

So two, please. First one for Professor Kerscher. Just wondering, I mean, of course, this is Phase II data, very small sample size and everything. So just wondering, given the data so far, how do you generally feel about corabotase versus [indiscernible]? That's the first question. The second one is specifically for this data. So just wondering, the chart where you actually show the response to treatment at week 24, so the 2 curves, I think, between corabotase and Dysport has a bit of separation but there's a lot of overlaps with [indiscernible]. Of course, this is a small sample size. These 2 lines doesn't seem to have much separation. But then the next slide, the subject satisfaction, there is a very kind of quite a significant separation of the 2 curves. So just wondering what do you see as the reason that contributes to a better satisfaction for corabotase versus Dysport.

Well, thank you for these questions. I start off with the first part of your questions, meaning corabotase versus relabotulinum toxin A. So as this study was a double-blind study, as injector and physician involved in the trial, I didn't know whether a patient had corabotase or abobotulinum toxin. So I just could assume over the period of time. But you also have to have in mind, in some phases of this clinical trial, we also had different doses of db. So clinically, I have no idea how it behaves in comparison to relabotulinum toxin A, because study setting is completely different. What we have seen in the clinical trial with corabotase is that we had a percentage of patients showing really long-lasting clinical effects and even -- and I'm still completely blinded, so I can just assume that this has been the group of subjects that have been treated with 50 nanograms of corabotase. So clinically, so far, it is not on the market, so no chance to compare it in a direct clinical setting with relabotulinum toxin A. And then the response at week 24 concerning patient satisfaction with corabotase, well, I think here, patients even if they don't rate their wrinkles in a way we as physicians with and have a tendency to rate their own wrinkles a bit milder than they are in real life. Concerning their satisfaction, patients have clearly shown that they are satisfied over a long period of time, and this was what they told us, at least some of the patients we have treated. We also had patients with placebo being very disappointed. But the others told us, whatever you gave me, as soon as this is on the market, I would like to have it because I'm absolutely satisfied. And injection has been 6 months ago, and still I have a much better outcome and mood as I did before. This explains why patient satisfaction is on a high level over a long period of time.

So apologies, everyone, just been informed that the Zoom meeting will actually be cutting in 4 minutes. Sorry for this technical error. But if it cuts, can we just all call back into the same link and we should be back online. But the next question is from Simon Baker.

I'll be quick. Two questions, if I may, please. Firstly, for both of you, I was just wondering if you could give us perspectives on the translation of Phase II results into Phase III studies typically for neurotoxins. And then secondly, one for Professor Kerscher. I'm just wondering if you could give us the considerations that you make as a clinician in deciding what neurotoxin to use for a given patient and also the role of the patient in deciding that. Is this something where it is principally clinician-led? Or is it determined more by the request of the patient/consumer?

Thank you, Simon. So maybe I'll start with the Phase II, Phase III question and then hand over to Professor Kerscher. So this Phase II LANTIC stage I step III has actually delivered exactly what we were looking for, which is proof of concept that corabotase is fast-acting, has sustained efficacy and show really strong patient satisfaction. So based on those results, we're really encouraged and have started 2 parallel Phase III trials. And those trials will further establish efficacy and safety. So we're very encouraged from this proof of concept data. Now I'm going to hand over to Professor Kerscher to comment on the second part of the question.

Thank you. I think the second part of the question especially deals with the fact which neurotoxin or which neuroinhibitor to choose for our patients in a clinical setting. Having in mind that all the different drugs are approved, then for me, the most important thing is safety. So safety comes always first even over efficacy and duration because we have to have in mind, we are treating young patients. We are treating healthy patients. So we see from worldwide statistics that the average age on which patients start with their botulinum injections, it decreases more and more. So we have young patients who is 23, 25 years, having the toxin. And then we have to have in mind that the might need this neuroinhibitor over decades. And in later life, they also might need it for a therapeutic indication. So safety is really important. And among safety, it's mostly immunogenicity that counts, especially for me. So it's absolutely important that we just have the pure 150-kilodalton protein within the corabotase, and this gives us more patient safety than having a conventional neurotoxin with the [indiscernible] and complexing proteins.

Thank you very much. I think we've lost it now. So if you could all dial back in. Sincere apologies for this technical glitch. [Technical Difficulty] Apologies for the technical glitch. Christelle, I see we have you back.

I am indeed, and I can hear you.

I know we had a question from Yihan. [Operator Instructions] Victor has another question. So maybe we can go to Victor's question while we wait for Yihan to rejoin.

Maybe just a follow-up because I think in my 2 questions I've asked, I've asked about like physician feedback. I'm not sure I got that. But if ever Professor Kerscher can just discuss what was the feedback from your peers on data will be quite useful. And as well, maybe just a quick follow-up on dosage, and I do understand that it's maybe tricky to compare the 15-nanogram to what we've seen from Dysport and like more classic type A toxin to in the past. But I was just wondering whether we can discuss the potential implication in terms of immunogenicity. I mean, for now, data looks pretty reassuring. But with this kind of toxin loads over the longer term, I mean, more or with the frequency of dosing and everything, do you think it's something that you begin to have to follow up closely in the future? Are you like worried about this? Or I mean, just how should we think about like immunogenicity causing the toxin load.

So I didn't know if Professor Kerscher has rejoined yet. I can start by addressing your question regarding immunogenicity. So first of all, I think Professor Kerscher mentioned, one of the key advantage of our fully recombinant neuroinhibitor is that it is a 150-kilodalton protein, just one protein, while every naturally occurring toxin is actually purified from a bacterial [indiscernible] and comes often in complex with other proteins, complex that is difficult to fully control. So that is one first advantage is that we know exactly what protein is produced. Second is in repeaters in preclinical studies in NHPs, we have not seen any sign of immunogenicity. Second, we are, of course, running repeat dosing and that is important. And should there be any signal, that's where we would see them. But so far, we have already conducted repeat dosing in Phase II. There are no signals to date. And again, the dose cannot be compared and 50 nanogram is not a large dose in terms of what we're injecting. We also, of course, as you can imagine, optimize the sequence to minimize immunogenicity risks within the boundaries of what is known in protein engineering. But we have taken this into account. And so far, there are no signals. So we don't have a particular concern. Professor Kerscher, have you rejoined.

I think she might be having issues rejoining. In the absence of that, we can go to the next question from Yihan Li.

Yihan Li from Barclays. So two from me, I guess. So the first one is on the data baseline. So it seems like -- I know it is like a very small sample size, but it seems like the prior Dysport exposure was around 25% in the corabotase arm versus over 50% in Dysport size. I'm just curious, like could prior toxin exposure potentially affect patient reported onset or satisfication or any response rates? So that's my first question. And the second one, I think it is just like a follow-up question. Just curious, like what -- it seems like corabotase have a pretty good combination of [ sub-1 day ] median on site of action and also the sustained 24 weeks response. Just from a clinician perspective, how should we think about its profile versus other non-acting toxin such has [indiscernible]? Yes. And what kind of data we should see in this rate to be competitive or potentially differentiated?

So maybe I'll take the first half of the question and then I'll hand over to Professor Kerscher. So in terms of pretreatment or not, this is a Phase II. And in a Phase II proof of concept, we did not stratify our patients. So I can really not speculate on this at present. There is no data within this study that would support any kind of speculation. So I won't. I'd like to hand over to Professor Kerscher to maybe comment on how to think about the administration action?

Professor Kerscher, I'm just trying to unmute your line again. Please unmute. I think we've lost Professor Kerscher. So maybe we can try to come back to that later on. If we come to another question from Ben Jackson. Ben?

I also dropped out briefly. So apologies if I'm asking again. Feel free to skip it if I am. But just two further from me. Could you just remind us about how prior toxin use can impact aesthetic results in this context? Obviously, it differs by arm, but more interested to think about repeat dosing over time. Does it become more difficult to build a response? Or does it improve with the frequency of prior botulinum toxin use? And then secondly, can you just remind us about diffusion around injection sites, specifically for corabotase? What do patients and physicians want in terms of diffusion? And how can corabotase be positioned to actually build on that, too?

So I don't know if Professor Kerscher has rejoined. Again, Ben, thank you for that question. I won't speculate on whether pretreatment or not has had any impact on the Phase II results because we did not stratify our population. In practice, I'd like Professor Kerscher's opinion on this question. Obviously, she is a treating physician. In terms of tissue diffusion, so we have engineered corabotase so that it has a very high affinity binding to the CIP2 receptor, and that allows us to do two things. One is to bind very tightly and to internalize fast. And these properties really allow to have less local tissue diffusion, something we measured in preclinical settings. And this is in order to give us a good therapeutic index. So it was engineered so that it really gets in the cell rapidly and it does not diffuse. So those are the properties that were built in. I wonder if Professor Kerscher has rejoined us and can address the other part of the question.

We seem to have lost her. We're still trying connect her. Okay. [Operator Instructions] At the moment, there are no outstanding questions. Unless, Ben, you have another question?

I'm okay from my side.

Okay. It looks like we have no further questions. Sincere apologies for the technical glitch today. And we will come back to you on those other questions through my team and Professor Kerscher if possible. Thank you very much for participating today, and apologies again.

Thank you very much, everyone. Have a good rest of the day.