H. Lundbeck A/S (HLUNB) Earnings Call Transcript & Summary

Good afternoon. Welcome to everyone here. And also, I would like to extend a welcome to those who have joined us also on the live stream event today. So it's really a pleasure to be with you today. And of course, also wonderful to see a number of familiar faces that I also met in my first 90 days since I've joined Lundbeck. So let me just briefly introduce myself. I'm Charl van Zyl, who -- I've been with Lundbeck now for about 90 days. And of course, many questions I've often received why have I joined Lundbeck? And it's a very simple answer in a way, it's an answer which is, I've always admired Lundbeck for a company that has maintained itself in terms of its strong purpose to solve complex diseases in neuroscience. One of the few companies that has really remained true to its purpose of addressing these severe diseases in neuroscience. It is, in a sense, also fitting perfectly with my values. How are we thinking about the work we do today that also impacts society in the long term. And so what you'll hear today is very much around how we think about that journey and what we undertake here at Lundbeck to build a long-term future of sustainable growth for the company. During my third quarter interaction with you, we mentioned that we are undertaking a strategic review within the company. And so I know there will be many questions that might want to reveal more of what that means. But I can tell you very clearly that it is essentially building a pathway towards being a very focused innovator for the long term. And we are carefully thinking through this, how we allocate our capital towards 3 areas: the first being securing the growth of our strategic assets in the key markets; the second is being very systematic and purposeful around how we think about a series of M&A activities that will help us for the long term; and thirdly, is really how we continue to think about our capital allocation also towards investing for the long term in R&D. And today is really about that. It's really the focus of that pillar of how we see the long term of the company and how we continue to see the efforts we are undertaking to build a strong innovation focus inside the company. So you'll see, today, programs structured around 2 areas, in a sense, the first part is very much around what has changed, what is the step change we've made inside Lundbeck over the years to build a strong R&D engine. The second part will be where we will put more spotlight on a few of the key programs. So key pillar programs that we believe are important at this stage for you to be aware of. I've had the privilege, of course, in the first 90 days, to work with this R&D organization and get to know it better. And I've, of course, been very impressed with what has happened, and I'm following those footsteps of many others who've worked in this space. But I have to say, I'm very confident, as I stand here today, that we have a very strong R&D organization that can continue to project the company forward with a long-term growth also for the future. So important to say that, of course, I will be joined by the esteemed team. And behind every good R&D organization is really the people that you will meet today, led by Johan Luthman, of course, who you know very well, our Head of R&D. And you will see more of the speakers today as you understand also the depth of the talent and the expertise we bring to the long-term in our R&D organization. At this point, just want to make again the company disclaimer. Of course, what we discuss today is subject to change in the future. And I think this is important that we state that very clearly today. So when we think about certainly the focus of today, it's very much around demonstrating to you what is the long-term potential growth of Lundbeck. And I know that, in many cases, investors would have that question, what is the long-term future, what is the next decade for Lundbeck, and what we will show today is very much that emphasis on how we see that long-term future with the pipeline that we are building and as it evolves into the future. The second component, of course, is that you will hear from the team also the strength of the engine. What have we got behind us? How have we transformed? What is the secret sauce, in a sense, in R&D organization that we believe will give us the confidence for the long term. And the third, of course, in the second part of the program, is really the emphasis around what is novel, what you will see that's first in class, areas that we believe will allow us to be highly differentiated for the long-term future also of Lundbeck. So all of this, of course, we do with the patient in mind. This is our purpose. This is why we exist. This is why we are here. So we continue to think about putting ourselves in the shoes of the patient. What are we trying to solve? We are here to solve severe diseases, chronic diseases in the space of neuroscience for patients that have really these challenging situations in the life. And our purpose ultimately is to provide this environment for patients to be able to live the life that they would like to live. And that's our ultimate goal with everything that we provide in terms of the solution. So you will hear the team sometimes mention that the patients speak, which is really the important component of how we think about everything we do, connecting it to what value do we bring to patients for the long term. There is, of course, the second reason why we think about the space of neuroscience and why you will see in our strategic focus that neuroscience is a core area and will remain a core area for Lundbeck. It's highly attractive. We've seen the science evolve to areas where we have better understanding of the biology. You are seeing clearly an area that will continue to grow. There's a very high unmet need in neuroscience. And of course, also when you see the evidence of some of this capital inflow into the space, but also the number of approvals that we have seen over the years has now increased. So this is an attractive area. We are well positioned in this area, and therefore, also gives us that confidence that we can continue to grow very significantly in this space. So my concluding slide before I hand over to Johan is just to give you a sense of where we are going ultimately. And we think carefully through this in our strategy is how we evolve ourselves to be a very focused innovator in neuroscience, meaning disciplined around our capital allocation, where do we focus our commercial footprint, how we think about innovation across the company in all different aspects of how we operate, and being very focused in that innovator space is where we see the long-term future of the company. And the evidence of today will give you that confidence that we can get there. Of course, we come from a history of psychiatry, and that's a strong area that continues to fund that journey for us. But you'll also see that the pipeline and the focus is shifting to other areas outside of neuropsychiatry, the strength that we're building in severe migraine. There are areas in the rare disease, neurological spaces that we are evolving in as well. So you'll see a diversification in a sense of that pipeline to newer areas of unmet needs in the space of neuroscience. So with all of that, we feel that we have a great position, a foundation of strength and the ability for us to be able to now build on that future with a very strong pipeline that you will see today with the efforts that the team has undertaken. So with that, it's my pleasure to hand over to Johan to take us into more detail of the program. So thank you, Johan.

Yes. Thanks a lot, Charl. It's really great to have you coming onboard as a leader of our company. He has put a lot of emphasis on innovation. And obviously, that has been extremely important for the industry always. But I think we're living in an era now when innovation is crucially important for success. The political landscape, the regulatory landscape we live in, really require that we are at the front edge of innovation. And we're really trying here to portray how we position now Lundbeck to be that innovator. You will hear through the day how we changed and transformed our organization, and also showcase some examples of programs where we think we have that leading edge, that strong innovation. I have been with Lundbeck for about 4.5 years now. I've been in the industry for many years. I worked in big companies, small companies, very big companies. I've worked in neuroscience, psychiatry, neurology. I also worked in immunology and dermatology for a little while. Working with Lundbeck is coming home. It's really the best place to be. Charl laid out why it is. It's a company that is unique. No one else in the industry has been so dedicated to neuroscience that long with research, development and commercialization of drugs. That is really unique in the industry. And we've been doing well over many years. And I would say we are also going to do extremely well in the future, focusing on neuroscience, because it's a growth area, it's a promising area. What have we done with R&D.? We've done a lot over the last couple of years. We have really a new R&D strategy that we are really delivering upon. We have also retooled competencies fundamentally for our organization. And what is super important also, we have new ways of working. And I will touch upon all those things in more detail later, but a few examples here. When it comes to new R&D strategy, we really have biology-driven research. That may seem trivial, but I will come back to that, because that's the fundament for how we run R&D these days. We work on 4 strategic areas, what I call the SUNRISE biology areas. And Tarek Samad, our Head of Research, will go into a little more detail what that is. We have also applied a very rigorous development process. You will hear things like target engagement, proof of mechanism, proof of principle, proof of concept. We'll really live early development strategy in our company. Many people talk about it, but we actually do it, and you will see examples from our programs, how we do that. Our Head of Development, Johannes Streffer, will give you some examples also how we work in our branded products, but also in the early development space. And he will introduce himself a little later. He's new in the company. We have built a class of programs that are first in class. We have a number of opportunities that are also best-in-class. And Charl alluded to this, we have to be impactful. We cannot just work on me too, that's a no-no these days in the business. We have to have impactful, best-in-class or first-in-class. And you will see from our portfolio, we have first-in-class opportunities. We established ourself, we believe, as a leader in migraine R&D. We have a product on the market, Vyepti, that we have a portfolio behind. So we are one of the strongest players in R&D when it comes to migraine. We are fully fledged by technology company. Biotherapeutics is a fundamental element of the drug platforms one needs to have today, and I will double click on that little later. We have neuroimmunology onboard. That is a new field, but also a very old field, but new field in terms of new indications and we have established ourselves there with development programs already. We expanded our experimental medicine capability. José Luis Molinuevo sits here. He's representing our Experimental Medicine group. He will also present some programs. He's representing that function, but also our thinking around how we really derisk early our assets that we pick should either die in early development or progress with strong biological and data rationale. And in terms of new ways of working, I will talk about our agile methodology that we applied. That was fundamental for us to really change our ways of working at the personal level, how we work together. We had a great platform to build on, but we really needed to be a company that move fast. We have a strong portfolio governance organization. We are very stringent how we progress. Tine Stensbøl is our Head of Product Portfolio Management. She will present a few programs. But she also represent that very stringent view we have on progression on molecules. We have improved our R&D productivity. Well, the proof points eventually is more drugs on the market. And we have shown that actually already this year. But long term, I think we've done a lot in terms of identifying different key performance indicators that will drive the company to increase our productivity. And one very critical element of that productivity is time. That's one of the biggest factors to drive productivity, and we have a laser focus on doing the right things at the right time point. We are delivering already quite a bit. But just to give you some flavor for the shipments we delivered the last 5 years. If you look at our development portfolio, we have 5 new NMEs in the portfolio since last 5 years, that's a 70% change, if you like to do the math on it. There are many new interesting entities and we showcase them, as I said. We can debate whether it's 95% or maybe even 100% new research programs. Tarek has done a tremendous job in reshaping what we do in research. The debate is that we have one program that is -- we have a backup molecule we work on, but we actually worked on the program before 2019. But basically, everything we do in research is new, and everything has best-in-class or first-in-class potential. We have actually 18 programs now since just a few days, not 17. So a lot of good new programs in research. We have had many approvals during the last 5 years, but 13 major approvals during this period. We touched upon a few of those and the clock is ticking. We have actually, today, 64 patent applications that are coming in, which is, of course, very important to drive and document that innovation with strong IP platforms. Yes, this year, it was a pretty good year, I have to say, so far. I've been in this business very long. It's not every year you have 2 FDA approvals with 2 weeks in between. Wonderful year. Also in terms of headline results. The 8 headline results is not every headline results we had. We had quite a bit. But those were major headline results, 8 readouts. And we had 1 positive, I should mention, proof of concept. In this business, you do a lot of proof of concepts, clinical proof of concepts, but the positive ones are not that common. So that's a very, very strong opportunity for us with the PACAP antibody and Tine Stensbøl will talk more about that later. Yes, we had one first in human. We need to put more molecules into man. I'd like to see even more, but that's really where the engine is cooking. And then we have a number of new research programs. As I said, it's ticking a all the time. We're up to 18 new programs overall since 5 years back. So really, really strong performance this year, but the last 5 years has been a tremendous amount of change. We have a rich 18 months ahead of us as well. R&D is all about getting the events coming. Most of them, hopefully, are positive, but there are also negative events, so it's all about keep it coming. We have, in our brand portfolio, a number of bigger important approvals coming up with aripiprazole 2 months, for example, the EU approval; and brexpiprazole, taking that agitation symptom treatment in Alzheimer's further into a new jurisdiction is important. But what is more exciting, I would say, from the longer-term perspective is that we're really moving ahead with some of our early programs. And you may see next year a couple of programs moving into Phase II proof-of-concept trials. And that is really very important for us to build the mid-stage pipeline. We like to have that cooking. One important readout we have, which we'll touch upon later, is the alpha-synuclein antibody readout that we have coming up pretty soon. What we also highlight here, our Phase Ibs, we highlight that for the reason that we are letting the molecule really speak while meeting patients early, and that's why Phase Ib studies are important for us and that's why they count for us very importantly. I'd like you to take you into a more wider perspective. I've been in this business for quite some years. I've been dedicated in neuroscience many years. And sometimes we get the question, why are you in neuroscience? Well, there are some obvious reasons why one is in neuroscience. The medical needs are enormous. Today, 1 in 8 people, that's well over 1 billion people, have a mental disorder. Those are enormous needs. Some of them are more mild, but some are fundamental, really hard, hard mental disorders, like schizophrenia. Neurological diseases is the #1 reason for disability in the world and the second leading cause of death. So I mean this is a big, big medical need. And then if you look at money, more than 1/4 of the global impact, economic impact of disease burden comes from neuroscience. So we have a big task ahead of us. And of course, we are looking forward with that with some confidence. The neuroscience market is expected to grow. We just give you here one number next coming 5, 6 years. We look forward to maybe a 60% growth in neuroscience overall. The disease burden, I alluded to that when it came to the economic impact, but when it's coming to the really disability-adjusted life years, it's big. Neurology diseases are among the top ones, #8, if you look at all diseases and mental disorders, no surprise, it's even more life-affecting by being #6. We're talking about a lot of lost time in people's life. So our dedication is clear here. We need to do something about it. because also the economic impact to be able to do something about it could be fundamental. And here, we have a great value proposition to payers. If we can do something about all those diseases, it could be fundamentally changing health economics in some societies. So a very, very important task ahead of us. Is that easy? No. But it's actually becoming easier and easier. I think this is one of the best periods to be in neuroscience. I always said neuroscience is exciting, but when it comes to technological advances that we've seen in the last years, it's been tremendous. We have a target landscape that is completely reshaping what we're able to do. Tarek has actually no problem finding targets today. 15 years ago, I was sitting there disparaging because we barely had any targets to work on in neuroscience. Very, very few. So we have a completely better understanding about the diseases, mostly in neurology, but we start to also have some glimpses into psychiatry indications. And diseases like migraine, we understand quite well. I shouldn't say we understand it fully, but we have good grips on where to enter those diseases. That's fundamentally changed the last 10, 15 years. What is also interesting to see is that we're bringing the toolbox into this. We have now every drug modality that is used in our industry coming into neuroscience. That was not really believed some years back. We have the good, old small molecules and they're really rejuvenating themselves, Tarek will talk about that. But now we have biotherapeutics as really a major drug class in neuroscience, but also antisense and gene therapies, everything is there. Working with those more advanced modalities require sometimes that you help the molecules to get where they're supposed to be. Often that is in the brain. One technique that has shown immense progress the last years is the so-called brain shuttle technology, blood-brain barrier shuttle technology. We are not leading in this field, but Tarek will show that we have something that looks really very interesting in this field. And that's a very important technological advantage that we have, because we would like to work on the antibodies, we like to work on the advanced therapies, and we like to help those drugs get where they're supposed to be. Something that's also been super important is biomarker field. I spent most of my career as an early drug developer. I love biomarkers, it's fun measuring stuff. And what is fun is also that you can try biomarkers now for early decision-making. All these things we're going to talk about -- target engagement, pharmacodynamic readouts, profile mechanism, that's carried by biomarkers. And we have many, many more of those in neuroscience today. But what is also important is that we have biomarkers that are converted into diagnostics. We are now diagnosing diseases based on objective facts that we can measure. This is a fundamental change. We're not really there yet with many of the psychiatry indications, but there's a lot of things happening there as well, where the digital solutions, to really measure daily life for people with psychiatric diseases. What has also been really very important with biomarkers is that they're now possible to use for drug approvals. We have seen a number of biomarkers now moving ahead, being part of an element of accelerated approvals. Yes, oncology leads the field by far with accelerated approvals, but #2 is neuroscience. And when it comes to orphan drug approvals, yes, still oncology is the big one, but #2 is neuroscience and growing rapidly. We have seen tools like imaging, PET imaging, being the fundamental for accelerated approvals in Alzheimer's disease. Neurofilament light is very important biomarker, we use it a lot in our studies. It's now being approved as an accelerated approval readout for certain indications, but it's expanding rapidly. We also see other biomarkers coming rapidly. Something that can get me going a little bit is something that people don't know, and that neuroscience is actually delivering extremely well when it comes to drug approvals. This is a little bit something people have not recognized. Among the top 3 with FDA, the last 7 years, has been neuroscience. Yes, we're there together with oncology, sometimes dermatology, sometimes infectious diseases, but 7 years in a row, and surely even this year looking at where we are now, neuroscience is among top 3 of drug approvals with FDA. And for the last 5 years, top 3 with EMA. So it's a very productive field. But most importantly, neuroscience is actually delivering. And this is for someone who's been in neuroscience, extremely, extremely exciting to see. We have in the last 5, even I would say, 1 year, seen extreme moments in terms of drug approvals and new drugs coming to the market serving patients. So here I give some examples of the most interesting areas. Neuroimmunology, we are there. We moved into that field. And you may say, well, that's MS, everyone has done MS for a long time. It's so much, much more. First of all, MS itself, there's still major needs in MS. Progressional disease, we cannot do so much about the inflammation, the relapsing, remitting, course of disease, we can do things about. Progression, we just see new drugs coming in that start to do something about it. But neuroimmunology has now been taken into other indications, and there are many neuroimmunology indications. Myasthenia Gravis, just a few years ago there was not much to offer, now we have very, very powerful agents. But we see this going into the little brother of MS, Neuromyelitis Optica, and we'll also see this in other indications like Friedreich's Ataxia. So neuroimmunology is coming strong and expanding very rapidly. Migraine. Well, we are in migraine. Migraine was just 10 years ago, triptans, triptans, triptans. And all of a sudden, with the time frame of 4 years, we got a completely new drug class. And what are we getting out of that drug class? Prevention or migraine. Something we didn't even think about 10 years ago. And I was there. I was sitting there with 2 molecules in another company and we couldn't get our colleagues to move it forward. People didn't see that one coming. And now it's projected to be a big area. It's already growing rapidly. And guess what, monoclonal antibodies made it big here. Those are tools that can provide very long-term prevention of migraine occurring. We have Bjørn Sperling here, who is our lead for migraine. He will participate in the Q&A. But he was part of that journey, working with the Danish Headache Center. And I think he's maybe saw the light, but many people didn't see the light of that whole new therapeutic possibility. Alzheimer's disease. Well, it took a long time, but this year was a big year, 2 full drug approvals with the FDA. One was Lundbeck and Otsuka. We were the first. [indiscernible] we had approval of Rexulti, brexpiprazole, for agitation symptoms in Alzheimer's disease. Johannes will talk a little bit more about it. But that's a breakthrough for 2 reasons. It was 20 years since the last FDA-approved a drug for Alzheimer's disease. Full approval. It's also the first drug for behavioral psychological symptoms in dementia ever approved. So that's a major breakthrough. Then we also had our brothers with the monoclonal antibodies, getting approval a size drug, drug that I actually had the pleasure to work in, in the past. So I'm happy to see 2 drugs in this field getting approved. 2 drugs that I had the pleasure to work on. But I would say Rexulti is an impactful one because it goes for the symptoms. Patients and caregivers can tell when things are happening. Rare diseases are well served by neuroscience today. It's a very, very rapid progression. And here, we have the whole slew of drug modalities. Gene therapies, antisense and also still small molecules. SMA, spinal muscular atrophy, it's famous field, of course, Duchenne's muscular dystrophy, several drugs. We also see drugs now coming in ALS disease, we thought nothing would come. Of course, it's lever of the population, but advanced drug modalities are delivering there. In rare epilepsies and also Rett Syndrome, we see new drugs. We are active in Lundbeck in all these fields. So I would say that we're extremely well positioned in this field. Really feel that's opening up, growing rapidly, not just in terms of science and opportunity, but also in terms of commercial opportunities. There is an unmet need that I described. All of you know that. All of you have some relatives, someone close to you that have a mental disease, that have a neurological disease, I don't need to preach about it. But we are in that space. We like to help in that space. We are well helped by the advancement in technologies and regulatory landscape. And the fundamental for all this is to be a true innovator. We can deliver impactful medicines just through being at the front edge of innovation. That's what we like to show today that we are at that front edge of innovation. How do we operate in this space, how will we be successful? Well, I talked about the changes we've done. And let me talk through that a little bit more. First of all, Charl started with this, I continue this. Lundbeck is unique with our dedication to neuroscience. That helps us tremendously. We're recognized for what we do. Our dedication to neuroscience is not questioned. Other people leave it, we're still there. Strong commitment to research. Yes, everyone would say that maybe. But it's not that simple. Many companies question why they have research, it's a cost, it doesn't really deliver. We have a strong research, retool research, and we see it as a strategic advantage to have a strong research organization. We're actually doubling down on that now, we're going to build more research facilities. And we're also doing something, I think, is quite exciting. We're inviting other companies to come to our facilities in Valby to work with us. We have built what we call an innovation hub, and we have other companies moving in being close to us. We like to have that ecosystem in research, because research should be open and we learn from each other. Tarek will talk more about what we do in research, but obviously, we cannot talk about details. We are not revealing everything we do in research. But I wish we could, because it's very exciting what we do in research. And one very, very important thing with our research effort is that we are so biology-driven. With our biology-driven approach, we need research and we need all that competencies to be successful throughout R&D. We are coming from a different place. I often describe it as that one strategy you could have, which is not bad. Some people do well with it. You start with diseases looking for targets. We are #1 in whatever. In this case, Lundbeck was really doubling down on depression, schizophrenia, Alzheimer's disease and Parkinson. We're still in those areas, but we changed the way we approach it. Because it's hard if you have a disease looking for a target. You may not find it. It may not be delivering the way you want it to deliver, and quite frankly, some of those diseases, we know very little about the biology. So what we did was we turned it around and said let's have strong biology looking for indications. And I'd like to double click on that indications. In R&D, we are not working towards diseases, we work towards indications. We want a strong label, and in the label assess indication. Why is that important? Well, we work in the migraine space. Millions of people have migraine. We work on prevention of migraine with an IV infusion of an antibody, in the Vyepti case. That's an indication. R&D should always be driven what ends up in the label. We drive towards that, and once we got the drug there, we support that label and expand that label and maybe add more labels to it to that brand, like we've done with Rexulti for agitation in Alzheimer's disease. That's how we work. That means that biology can take us in a little different directions. So we're not sitting down saying let's have another drug for schizophrenia. We're actually saying this is a great mechanism. It has potential for schizophrenia, maybe this and that, right? That's how we work. And we take that biology where it tells us to go. We let the biology speak. That means that we end up with various indications, where the biology is strongest, where we can look at the best and where we have biomarkers to lead us. With our circuitry and neuronal biology approach that Tarek will go through, with our protein aggregation approach, with our hormonal neuropeptide approach and with our neuroinflammation, neuroimmunology approach, we have strong biological platforms. SUNRISE biologies that take us towards strong indications. We work on biological psychiatry still when we can, but we also work in pioneering programs in multiple system atrophy, and now we're also in what we call [ neuroadjacency ] indications, where neurobiology plays a role either in the fundamental pathophysiology or in the symptomatology you see. We are building a strong presence still in psychiatry and neurology, and you see that with Rexulti. We're still dedicated to that field. We are in the pioneering part of proteinopathies. Yes, other people do this. Antibodies are popular for neurogenerative diseases these days. But we are pioneering in some areas like multiple system atrophy with a great antibody in alpha-synuclein antibody. We think we have a good position to be a leader in migraine, but overall in headache disorders, Johannes will talk about some interesting data later on that we have in headache disorders beyond migraine and we're investing and growing in neuroimmunology, which we think is a very important field, strategically. How do we do that? Well, as I said, we start from biology and we drive towards an indication. And extremely important in that journey translating biology to an indication, we're looking at attractability. We don't want to bring high risk into late development. We like to have a tractable pathway where we can derisk early. And you will hear me saying that many, many times, and my colleagues do that. That is so important for us to really progress with the most valuable assets. And that's why we're looking -- that's why we're looking for the biology that can lead us in terms of readouts early in man. So we convert that into primarily specialist-treated indications. We like to go where the biggest medical needs, and that is often with the specialists. I already used the term a little bit, but we have kind of 3 things that Tarek will go through with you: Let the biology speak, let the molecule speak and let the patient speak. But it's very important to say that we have one organization that allows the biology to speak, and that is in research primarily. And we have a fully integrated organization in research across 2 sites. Then we take those assets into humans, and letting the molecule speak, where does it want to go. And if it doesn't want to go anywhere, we kill it. And then we're driving as quickly as possible towards robust decisive proof of concepts. We have one example we talk about today anti-PACAP, and we have one coming up with alpha-synuclein. Once we've done that, we should go fast towards developing the molecules to the market with this close eye to what the patients need. I often get the question, what kind of next deal are you going to do? And Charl gets that question often. I just like to say one thing. This is normal business. There is nothing like internal and external, it's all in symbiosis. What you call organically grown, is actually something that the scientist read in a journal about, right? Or sometimes we took it early in research. We collaborate. We do a lot of things with outside partners. An organization -- R&D organization that is entirely homegrown will become sclerotic after a while. You need all that external influence all the time. It's a strong symbiosis. We do that because we think we can also get the best molecules to that way also externally. If you don't have that strong research, if you don't have that strong development for organic growth, you don't make the right decisions for in-licensing and partnerships and acquisitions. So that's a strategic advantage we have to be that strong and have that long legacy in neuroscience. I just put a number here. We looked at this in the neuroscience field, 70% of all molecules that go to approval are not coming from the originator. In my career, I've been involved in quite a few drug development programs, only 2 of them were linear, going from a lab to the market. The truth is that molecules go like this, and they shift hand many times and one day they go to the market. Doesn't diminish the work that each of those parties do. We share this journey together in the industry. Our job is to find the right ones and take them on with our right competence and make sure they deliver. So in my world, it's really not a big deal. This is daily business. You always add things from the outside. Every company does that, unless you're a small startup company. We have done some acquisitions that have been really very important for us. And I'd like to double click a little bit how we look at this. But first of all, I'd like you to look at this curve. This is from 1999, I believe, if I do the right math here, yes, 1999. This is a long period over 20 years, 25 years almost, Lundbeck's growth. You see it's been pretty steady. Over this period, we overcome several loss of exclusivities, including 3 major ones. But it's been a pretty steady journey, and part of that is because we're so good in partnerships. We're good in strategic acquisitions. And let me highlight a few acquisitions that have been really very important for us. Some years back, long before I was in the company. We acquired a company called Ovation. That really built our presence in the U.S., not only commercially, but also with R&D. Later on, we did the Abide acquisition, which was the research side. And also Alder, which gave us biotherapeutics in Seattle. All that created a strong presence in the U.S. that we need to have. We've been really great in partnerships. We have been sharing risk and sharing opportunities in a number of alliances. People are taking our great molecules, like vortioxetine, and took well care of them together us. Takeda did that. And the Otsuka collaboration has been really very important for us. A whole portfolio of different assets that are going forward. Some from Lundbeck, some from Otsuka. Mostly the Otsuka ones were successful, but that's how life is in our business. The other one, which is very, very important for us is the transformation deal acquiring Alder. It's a big acquisition for us, almost USD 2 billion. But it really changed our ability to be in a field we need to be, and that is biotherapeutics. And just to tell you this story, we started with resource collaborations with Genmab a long time ago. Our alpha-synuclein antibody is actually coming out of that collaboration. But we gradually expanded a little carefully. But when we got to the Alder acquisition, we turned it around and became a fully fledged company for biotherapeutics, from research to the market. That transformation is not always easy, but it was super fast. We were behind. We needed to catch up because that's where some of the big therapeutics are in neuroscience. Now we have no problem taking on biotherapeutics in the future. Very important for us. After that, we did one strategic partnership with AprilBio. It actually gave 2 things in biotherapeutics, but also strong asset in neuroimmunology. So with this, I think we're starting to build a really interesting pipeline here. As I said, we'll go through this a little more in detail, but it's well balanced. Some is more high risk, some is less risk. What is important here is that if you look at -- and I think you should look carefully at this one, because we've spent some time making this slide. But it's also important because you see little red stars and little red dots here. This is where we're active right now. If you look at the different fine print here on indications, we're active. Each of the areas we're active in constitute great commercial opportunities. There are big marketplaces and growing marketplaces. We have products in several of these areas. We have also innovation pipeline in several of these areas. We may move. We may come into other areas as well. But we're really well positioned to tap into great value proposition in neuroscience. With this, I'd like to turn over to Tarek Samad. I mentioned his name already a few times. He joined us 2.5 years ago. Been fundamental for our transformational research. He has a strong background from big and small companies, and maybe you can introduce yourself a little further.

Thank you, Johan. Hello, everyone. As Johan said, I'm Tarek Samad, I'm Head of Research at Lundbeck. Very happy to be here. I joined the company a little over 2 years ago today. And I have experience in large pharma, biotech and academia as well, over 20 years. Very happy to be here today and discuss with you the progress we're making on the pipeline. So I will discuss a little bit the discovery portfolio, although, as Johan said, not in a lot of detail, but just enough to give you a peak on why we are so excited. So as you see, this is a fully transformed research pipeline across -- diverse, across a number of indications and biology areas within neuroscience. As you can see, we've got a lot of early, but also advanced, research programs that are progressing. So this is a pipeline that has also a high pace. Just to give an example, by 2024, we expect more than 3 IND-ready development candidate to enter the clinical pipeline. So we'd like to think of this discovery portfolio as an engine for a sustainable, innovative clinical pipeline. So let me talk a little bit more about our strategy in R&D, which starts also in discovery. We -- it's based on 3 major pillars: let the biology speak, let the molecule speak, and let the patient speak. And I will describe these in a little bit more detail, starting with the biology, because those 3 pillars are supported and anchored in human biology and a mechanistic understanding of the unmet need in the human disease, the brain disease. And we have 4 biology area that represent multiple facets of pathophysiology in the nervous system. And I'll go over these in a little bit more detail, but I want to say one thing also about the modality. You've seen a big breakthrough in novel modalities in the field. And we always, when we look at evaluate targets, in discovery, we always select the optimal modality for each specific target, and I'll provide examples over this. So let's move a little bit more into our biology area, the famous for biology clusters, why are we in those biology area? Well, the key word is causality. The science has progressed enough in multiple areas of neuroscience to provide us with enough evidence and causal links between exciting and interesting therapeutic target and the human disease. And that's the reason why we are in those 4 areas for now. Starting with circuitry and neuronal dysfunction. This is a strength, this is a legacy area for us at Lundbeck. Think of circuitry and epilepsy, for example. This is really supported by human biology. Protein aggregation, this is an area we are in. It's high reward area, think synucleinopathies and neurodegenerative diseases. There's a clear causal link. That's why we are active in this area. The transformative impact of CGRP science on the migraine field. Advances in neuropeptide signaling, super important. This is an active area that still holds promise. And of course, one of the newest area we are in, but also progressing quickly, you'll hear about our CD40 ligand program, the role of the immune system in driving pathology. The science has progressed, has unraveled causal links between this function of the immune system and the human disease, we're taking advantage of that to bring value to patients. Another area that has witnessed a lot of progress in neuroscience, but also in drug discovery in general, is the breakthrough in the modality space. The science progressed and provided us with exciting targets, where targets that are linked to the disease. But unfortunately, not all of those therapeutic targets can be drugged via classical drug discovery needs. The field has progressed and has designed additional ways. We can now go after RNA instead of just protein. We can go after nonreceptor proteins. So you see a number of modalities that Lundbeck is actively pursuing. We're part of this journey. You've heard from Johan about the huge expansion that Lundbeck has seen in biotherapeutics. Now we don't just have monoclonal antibodies, but we have also design, this blood-brain barrier shuttle, I'll say something about this. In the small molecule as well, we've got the CLIPPR platform. That's an example of a breakthrough that we had it from our La Jolla site. But we also have small molecule targeting RNA. So you can go after RNA, instead of going after the protein, if the target is not amenable to clear a drug with a small molecule acting on the protein. So we started with small molecules acting on protein, and we're expanding, taking advantage of the progress in the modality field. So this is a powerful way to create value in the pipeline and increase the therapeutic space and impact of Lundbeck portfolio. So one word around the CLIPPR platform. Our La Jolla, Southern California research site brings the CLIPPR, powerful CLIPPR platform. This is a very powerful chemoproteomic approach to pursue targets, as I said earlier, that are not amenable to a classical drug discovery design. It's very powerful because most of the time, science and biology takes us to an interesting target. Unfortunately, it's not just a receptor that you can target on a canonical site. It's a more complex protein. This approach allows us to pursue those targets as well. And we have been pioneers in identifying the advantage of this approach. We started in 2018, and you see now this area is growing. There's a lot of investment. This is a Noble Prize awarded approach a year ago. Multiple companies, lots of investment, multimillion-dollar investment in this. This has helped us identify selective inhibitors for one of our programs in early clinical trial, you'll hear from Tine, monoacylglycerol lipase. That selective inhibitors now. But also allowed us to identify other molecules against other targets that are now progressing in our discovery pipeline in different clusters. So you can see here the space of the target, molecular targets that are opened up by this very powerful approach. Another area where we've seen a breakthrough, I would say, progress, is the abilities as we are in biologics, the ability to target the brain with large molecules. As you know, the blood-brain barrier is there for a protective reason. However, when you're trying to send a large molecule to the brain, it becomes problematic. This is an area that has seen a lot of work and progress. We're not the only ones, as Johan said, in this space. But we do have a shuttle that has unique features and characteristics. The first one is it allows us to increase the brain penetration level by over 50-fold. Think about this for a second. We have 50-fold more large molecules penetrating the brain when we attach them to this shuttle. And this shuttle is based on a camelid antibody. I can go into more details, if there are questions afterwards. But it's also another feature of it is that, it is modular. We can attach different types of cargoes. It can be an antibody. It can be another protein, a peptide, and now we can send them into the brain. So very, very powerful. We're pleased with the progress. It's a very competitive approach. Now let me move to the second pillar of our R&D strategy. Let the molecule speak. Very important. It is about early derisking. Why? In order to ensure early on that we select and pursue the most value creating for patients project we have, not just incremental improvement, but rather transformative impact on unmet need. So to find out early on, whether our early clinical development program, as early as Phase I, have the legs to make that big difference. Now this requires a rigorous development process, focusing on indication with a biology that's well understood. Again, causality, causality, causality. We are biology-driven. It's center to what we do. Second, prioritize projects that are highly supported by biomarkers. And those biomarkers will allow us to find out early on whether there is any clinical and clinically relevant impact on this. So early on, we'll find out. And this is very important for decision making and investing in the right projects in the early clinical pipeline. This approach has allowed us, as it should, to come up with early development decision. As you see a few examples, go, no-go. This is what we are after. Early on, go, no-go, identify those winners and push them forward in the pipeline. The third pillar, and you heard from Charl, it's about patients. That's what we are here for. That's what brings us to work every day. We make sure that patients are at this center always of everything we do. Patient's insight is in everything we do. We innovate in clinical trial design, and we involve patients. As a matter of fact, it's not uncommon for patients to sit on Advisory Board when we look at clinical program. We focus on unmet needs that matter most to patients, and we learned a lot from patients. So it's a symbiotic and synergistic interaction because after all, we're here to serve patients. And I'm very proud to also see that Lundbeck is always cited and ranked among the top in patient appreciation. So we really have the patients at the core of what we do. Now when I move to the next step, which is described and Johan will do this, the R&D organization that we've built, and that is set to deliver. So I'm going to turn it over to Johan.

Yes. Thanks, Tarek. Yes, the patient inside function that we have is really very important. And it may seem trivial, but we have very, very regular seminars with patients coming onboard, talking to our R&D organization, what their needs are. That's where we're driving towards. We have to listen to them very carefully. Clinical trial execution is super important to have the patients and the caregivers on board. If we have protocols that don't speak to them, they will not come to our trials, and we will not have the speed of running trials we're expecting. So that's why all these advisory boards are very important. Well, all these things that Tarek talked about, wouldn't be possible if we didn't strive for also being executional, very strong. We are striving for excellence in execution. Now that's easy said, but we have certain toolboxes here we're trying to apply to be much better in how we execute forward. All these things, let the biology speak, let the molecule speak, let the patient speak would be nothing unless we had a good organization behind it. Some years back, we decided that we're going to go in with agile methodology. Some of you may know what that is. It's a method, but it's also a mindset. So we started to run agile projects. And Tarek is a good example of that. In research, we continuously run standing agile teams. That is a way, a methodology. But at the end, you really like to get into the mindset that people move fast, someone use sometimes the term biotech. I don't know what it is, really. But we try to be someone who can really be quick and go to the key matters and make quick decisions, and we do that in a systematic way. So we rolled out agile several years ago, and it's working well now across the organization. So that's about people and what they do and how they behave. But we also need to deliver, and that's why we have a strong emphasis on productivity as well. We've been systematically rolling out. And I mentioned already that we identified some key performance indicators. We are a reasonably small company, so it takes a while to generate that information. But we are benchmarking now how we do in terms of getting things moving faster. And time is, as I said before, one of the most critical elements here. The other thing is to give the toolbox. And we could spend hours talking about digital. It's the most hot topic in town these days. I will not spend so much time on it, but digital is very fundamental for us as a tool. But we have to be very selective and invest wisely in digital. But let's start to talk about where we are. First of all, we are a global, fully integrated R&D organization. We go all the way from research to medical affairs. We are not big. We have the benefit of being smallish, mid-sized company. We have short pathways to each other and most of us know each other. That's a huge advantage. I told you at the introduction that I worked in very big companies, it's hard to even find the right person to do a job for you. We don't have that problem. We have very clear organization setup and people really know where to go to find a responsible person. We have footprints across the world, because we need to tap into the best talents we can go. But by far, our biggest campus is in Valby outside Copenhagen or part of Copenhagen, where we have a fully integrated research to medical affairs. What is important for that is also that we networked into the rest of the company. We all sit in one campus. But we have, most importantly, also people in Deerfield, Chicago, with development and medical affairs, and we have the research site in La Jolla, San Diego, that Tarek talked about, very important. That research site is very well integrated in what we do in Valby. And then we have our biotherapeutic CMC competency in Seattle. We also have development and pharmacovigilance competencies in Beijing, Tokyo and Singapore. All this is not just that we have a fully integrated global research to medical affairs. We are also fully networked. And let me just expand on this. We sit close to our commercial colleagues. They sit next door. We sit close to our CMC colleagues, they sit down, in the building. We are having the benefit of smallish scale. That makes us reasonably unique because we have all that neuroscience competence. So if we want to understand the commercial situation for something in neuroscience, we just go down the corridor and have that chat. It may seem trivial, but companies struggle with that integration. That makes us quite strong in terms of our organization setup. I just want to double-click on one thing here of all the things mentioned, frontline regulatory strategies. We like to talk to the regulators. Yes, that may seem trivial, but we are very, very proactive in reaching out and talking to the regulators. What you don't ask them, you should not second guess. Again, sounds trivial, but many companies spend a lot of time with consultants second guessing what the agencies say. We go straight to them instead. We have been able to recruit top talent. You see some of them here today, but we have a huge new pool a people coming in. But we also have very, very strong people from our legacy organization. And that's well integrated together. But being the #1 in neuroscience, as I would like to say, makes us an attractive employer. It makes us also an attractive place for people that like to collaborate with us. So we have a strong position and strong name recognition, which helps us. Talking a little bit more about digital. We cannot boil the ocean in digital, and we shouldn't. We should be very smart with our investments. Tarek can talk about this at length, but in research, digital is daily work. We've done that for years. It's nothing fancy -- modeling, simulation, all those tools, we have them. We use them. We badly recognize them as digital. Of course, we try to push the frontiers with target validation, et cetera. We work with people outside. But this, as I said, is daily business. Where digital can be really impactful is how we execute clinical trials. In the clinical arena, we can change a lot. We're actually pretty low tech while we run clinical trials in the industry today. And just by building the ecosystem around clinical trials, we have tools that we introduced some years back like clinical trial tracker, real-time following how we're enrolling patients. That's really very important. Some companies don't even have that yet. We try to build that real-time data together. That's a huge effort, and we benefit from some industry efforts, but we think that's worth while investing in. In the neuroscience space, you probably won't see many fully decentralized clinical trials, but we've already been running a couple of partial or hybrid decentralized clinical trials. And we'll see more of that coming when we have more digital tools for assessment of patient activities. Very important. Real world is also another -- real-world evidence data is another area we invest a lot in digital solutions. Here, we can actually listen to the patients in what they report in. We gather that information systematically. We partner big networks. There is a European network where we're one of the leader in pioneering called EHDEN, where we really try to dock into databases of real-world data. That can give us actually ideas about how our drugs work, our products work, but more importantly, where they may work as another indication. But we also use that information in our innovation pipelines early. So that's an area we think digital could be extremely powerful. And machine learning is a big instrument here to harvest data out of those databases. So that's where we invest. And finally, with the advanced therapies we have, the therapies that may require a completely different interface with prescribers. We're talking about high-end prescribers, specialists, we have to approach them in a different way. Their time is limited. So omnichannel approaches, digital channels to interact with those from medical offices or other interaction points we have, like consultants, KOL meetings, et cetera, is going to be heavily benefited by digital solutions in the future. So those are some examples where we really double click and invest in digital, but we do that carefully. So with this, I think we're very well positioned for success in the growing therapeutic areas. This neuroscience area is really what we call it poised for success. There are breakthroughs here. We are well positioned there. We've been there a long time. We are moving with the most highly likely probability of success in that field. We did this early, as you said -- as we said many times here, and how we pick our indications, as you will see in the next session, is very, very careful. We like to go where no one else is or where we can be the most impactful. We have a global R&D origination, fully integrated. We are really well positioned to be successful in the future. With that, I'd like to hand over to our very, very new, but maybe not very, very young, Head of Development. 3 weeks in the job, I guess. But it's a pleasure to introduce Johannes to you. I know Johannes for many years. He should introduce himself, but he will be a game changer for us in clinical development. So please, Johannes.

Thank you. Actually, I can double the number, it will be 6 weeks at the end of this week. Good afternoon, thanks a lot for joining your time with us. Very much appreciate it. I'm Johannes Streffer. I'm a physician by background. I'm neurologists and psychiatrist. Decided to go into clinical development. And in the industry have been with Janssen, UCB. And before I joined Lundbeck, was CMO at AC Immune. Obviously, the Lundbeck legacy is known to me already as a treating physician. So Lundbeck was a good name, no name. But then when Johan called, it was really what we talked here today, what enthuses me and what drove me to join the Lundbeck family, because I think it's a fantastic portfolio we have the opportunity to work on. Now what I want to talk here is really our strategic brands. And at Lundbeck, we are committed to maximize the value of our strategic brands. What do we mean by that, and I have 4 examples that I would like to go a little bit more in detail with you. You obviously all know and share, hopefully, our enthusiasm around Vyepti. And the treatment, the prevention of episodic and the prevention of chronic migraine. So this is where Vyepti has demonstrated its core value, but now we are moving to understand it better, and where we're looking now is more severity of pain and I will share some new data on cluster headache. Rexulti has demonstrated value in major depressive disorder and schizophrenia. But now as well, we have a new launch, a new approval for Alzheimer's disease and agitation, which I think is a critical syndrome which was underserved at the moment. We have Abilify Maintena, where we initially had 1 month and now moved forward and we can demonstrate that even a 2 monthly treatment is very valuable. And we have demonstrated that with the clinical trials, but we are as well moving that through different regions to make sure that we get the launch wherever we want to serve patients. And last but not least, Brintellix, Trintellix here, where the major advantage was seen with major depressive disorder. But they are co-morbid symptoms, right? The depressive disorder comes with cognitive deficit, it comes with anxiety disorders, and we were able to demonstrate these benefits as well, which then obviously helps physicians and helps patients to use the right treatment for the patients. Rexulti, as Johan said, the AADAD indication, agitation in Alzheimer's disease is very important for us. And I think it's very important for patients. This was the first fully approved new AAD drug in 20 years. Why is that important? Our brand primarily works on inhibition, and that doesn't work in a chronic neurodegenerative disorder like Alzheimer's disease. So these patients lose control, and we see executive controllers, but we as well see more emotional drive. When we talk about agitation, we do not talk a lot, a little bit wondering around. This is the type of agitation that drives patients away from their families. But patients cannot be with their loved one anymore, but have to go into institutionalization. Why is Rexulti a very good drug for that? Rexulti is not only going as antipsychotics into the D2 system, but as well a serotonergic and norepinephrine system. So really in a more holistic way targeting these neurotransmitter systems, and that helps to demonstrate the very good clinical effect. We have a very comprehensive clinical program. And here is just the data from the last Phase III study where we see very strong significant effects over placebo on a scale. Now the scale is what we need to communicate with regulators, what we need to communicate with health care providers. But what's really important for us is what we get as feedback from patients and physicians. And on the right side, you see first impressions from patients, from caregivers, that this is really changing for them. This is a game changer. One of the biggest improvements he had seen, 180 degrees turnaround. No longer verbally abusive. So the person that is agitated in a way that he cannot stay anymore with their patients, we have potentially a tool for physicians that helps them to treat it and give the opportunity for patients to stay with their love ones longer. Eptinezumab, as I said, we do know the prevention part for migraine, episodic and chronic, but we were as well interested how can we move that forward. Now in migraine, we have here in the Phase III trial DELIVER looked as well into the number of migraine days, the severity of headaches. And what you see here in the graph is actually a reduction of severe headache days. So not only prevention, but then for the migraine days there, what is the reduction of severe headache days. And you can see very nicely in the blue and the red, these are the ones that are initially treated with eptinezumab. You see a very fast, strong reduction. And on the green and -- gray, you see the ones that are initially treated with placebo and then rode over into eptinezumab. And you see, as well there, very nicely demonstrated effect and that is a very long and chronic effect. So we see a sustained effect here over 61 to 72 weeks. So that is what we want to have in a chronic treatment for patients with severe medical need. The next thing we did was we went into cluster headache. Cluster headache is a severe headache form with potentially one of the most severe pain forms we know. What cluster headache patients describe to us is a pain that is similar to what women described on the birth. So we talk about a very severe headache form that in clusters comes and these patients have the attacks. Now in the first study here, we looked into chronic cluster headache in an open-label safety study and what could be demonstrated. And you see that on the left side, the reduction in the attack frequency and that was a strong and sustained effect that could be demonstrated here over 12 months. Obviously, in an open-label study. So the primary endpoint was safety. But what is very important that you, on the right side, as well see that, that drives improvement in the patient-reported outcome. You know that the FDA is specifically making a big point about patient report and outcome. But we make a big point out of it because this is what the patients tell us. So we see over these 12 months a sustained effect in the patient reported outcome as well. We then moved forward, and this is actually novel data that we share here today with you. We as well have shared it with investigators, we've shared it with KOLs because this is really important for us to get a good understanding what we see here. On the left side, you see the primary endpoint, which was the change from baseline in the weekly attacks. And there we did not see a significant advantage of Vyepti over placebo. But on the right side, then we start seeing where we see to make an impact, and that is the percentage of patients with reduced attack frequency. What we here look is more than 50% reduction of attack frequency. And that gave us a good indication that there is biologically something happening, and that is as well as confirmed in our discussion with investigators. Now when you look into that, you as well want to see something in reduction in pain severity. And here again, we see a very strong effect on the reduction in pain severity in these patients. I referenced before, this is a headache form with severe pain, very severe pain. So the pain severity is potentially something that is meaningful to patient very much. And you see that on the right, began with an improvement in this patient-reported outcome score, where the patients tell us, yes, I do feel better. This is the treatment I want. And obviously, we have Bjorn Sperling with us, our best expert in headache. He's leading the migraine group in the development, and he will be able to answer questions later on that. But the feedback we're getting from the physicians is we need this treatment. This is a very good opportunity for these patients with severe headache. With that, I would like to conclude this part on our strategic brands. Obviously, we try to leverage the potential of these brands and provide solutions for multiple important unmet medical needs, the strong understanding of the signs and the mode of actions enable us to maximize these opportunities from our strategic marketed brands, and we do continue to have significant R&D investment to support the expansion of these brands. With that, I would like to hand over back to Johan.

Yes. Thanks a lot, Johannes. Yes. It's really interesting data we've seen in cluster headache. The chronic data, of course, open label, but the episodic data is quite convincing, but we're happy to talk more about it. Yes, you saw this slide before from Charl. I think it's important to see how our journey now is transforming Lundbeck. We have a strong footprint in psychiatry. We have done a lot there. We're taking psychiatry and neurology, first one ever. And we had transformed our basic research. We've transformed the way just how we work in development. And we would like to show, after the break, how innovative we are in terms of also building the future based on the footprint we now established with changed ways of working and changed research platforms. We are well poised to set up for breakthrough in the future. The 6 programs you will hear from, I will just give you a little glimpse how we position them before the Q&A. First of all, we have the alpha-synuclein and there is no secret, there's high risk in that field. So of course, on the access are likelihood would reaching the market, it's on the lower end. But of course, if it makes it, it's a big game changer. That's how we balance that with other assets, but you will also hear from our early MAGlipase platform, more symptomatic treatments. We have a very strong biological understanding of what's going on. But we're still letting the molecule speak, and Tine will go into more detail what we do in that program. Then we have 4 assets that are much more on the right side and you may say, well, those are early guys, but you will see from the data after the break that we have strong data already from those programs. Our dopamine agonist program for Parkinson. Our CD40 neuroimmunology program, our anti-ACTH for neurohormonal signaling. And of course, our anti-PACAP, which already passed the proof of concept and has a strong likelihood of reaching the market. With that, we should sit here for some Q&A before we take the break. Yes, hands are up already, but can we get the panel here.

So let me say, we will go through the program. So please hold your fire on those 6 programs. So primarily, we may able to focus here on our strategy and what we're trying to reshape here in terms of our R&D. Yes?

Yes. Martin Parkhøi from SEB. Then 2 questions because if we look at the size of Lundbeck being a leading neuroscience company, the size of the market, then you're still a fairly small company. And I don't know, we normally should not mention the attrition rates in the CNS business because then your blood pressure is going up. So why do you think that there is no -- if this is such an attractive area, why can the leading company be so small compared to the market? Why are there not other specialized companies with a similar size or even bigger? Why is that? And then secondly, you speak about the biological speak and maybe we speak about money speak. So when are you putting in the commercial part in your business when deciding on which indication to use, because they can be different in pricing, whatever indication, which are approved first? So when are you pulling in commercial part of Lundbeck also?

Thank you very much. Some really good questions here. Let me try to remember all of them. But let me start with -- there are kind of 2 there, but it was probably more. Let me start with why should you trust us when we are still a small player, right, basically. Well, the rapid changes in neuroscience, as I talked about, there are things we can do today we couldn't do just 5 years ago, 10 years ago. So this is a well positioned place to be in. Our business in R&D is to do everything right, have the right people, have the right assets, make the right decisions. And then we are really preparing the way for breakthroughs. In the meantime, we deliver the bread and butter, right? We have to keep the company going. We do very well with brand support. We progress assets and hopefully, now and then we deliver a drug to the market, and we do deals, right? We are now at a higher, higher probability to have some breakthrough, because we're in the right space and we're doing the right things. It's also, quite frankly, a benefit to be our size. And I tried to portray that. Sometimes too big and too much money is a problem to be effective. And I think we have shown that we can get a lot out of the investment we're doing in R&D. It's not a massive amount of money we put into, our CFO may have a different opinion about that. But in terms of comparing to our peers. We don't put massive amounts, but we get out of this, we actually looked at it. Our productivity is really high. And among those top 3 neuroscience approvals, we have been playing in that space and we're actually one of the top 5 companies in number of drug approvals. So we get quite a bit out of it. Are we hitting the jackpot with a big brand? No, not yet. The other question was...

Yes. Sure. So maybe I can touch on that. As Johan had mentioned, a lot of our focus is on finding the indication of the subpopulation. So I think when you look at scale, we are not needing to be large in commercial footprint. It's really about high-value patient in a very clear defined patient population, where the differentiation is high. That's what we really aim for. So we don't see scale as a factor in terms of commercial to succeed. If I think that's a little bit of your question. Of course, we decide more at the proof-of-concept stage where we can take the patient population, define that very well. But our selection is very much around where can we differentiate, what is the subpopulation, how does that sit with the payer value proposition to make that differentiated view and certainly scale for us is not the limitation in the sense. So we want to make sure that we be very clear and focused there.

Quickly, 2 more things. Let the money speak. Yes, well, I think when I came into Lundbeck, I saw there were some biologies that really look promising. They're not yet on the market. They're just about there. I think getting something like Vyepti is probably going to let the money speak too. Of course, most primarily, it's helping patients, right? But that's an enormous impactful therapeutic. If you look in the class, this is a leading drug in it's class and we have many, many years with that asset. So we think from a commercial perspective, I think the money will also speak. We have things behind it, and you will hear more about how we're doubling down and building a much stronger position in migraine, where we think we -- people overlooked it for years, as I tried to allude to before. We are now in a good position to exploit that very, very high medical need there that remains. Just since you turn on my cylinders. Oncology is worse than neuroscience in terms of success rate. If you put the molecule into man, it's a wise bet in neuroscience than oncology. No one ask the Head of R&D, why they do oncology, I think they should.

I think you also ask why aren't others in neuroscience, bigger companies. The answer is there are many companies in the neuroscience that really -- yes...

Yes. I think we should go to the next question.

Michael Novod from Nordea. Two questions as well. So to the capital allocation, I saw on one of the slides also you say that the life cycle management for Trintellix is sort of done, I guess for Rexulti. How much have you spent during the last 5 years of your R&D spend on life cycle management? And how does that sort of free up money for capital allocation into real innovation in the next 5 years?

Let me start. I think Charl should answer that one, too. But I can say, being -- there are lots of blessing being our size. I try to portray that. There's one less blessing, if I may put it that way. You're kind of a little victim of your own successes. You have to invest behind the brands, and there is kind of a minimum amount you need to invest. My job is to move that investment as fast and efficient as possible. We try to do that with Vyepti. Vortioxetine, we did some very crucial studies, but quite frankly, we should maybe have done them earlier and get that out of the door, because the impact comes earlier. So we just have to learn how to maneuver that money. We're actually in a really good position now because now we're actually going down in our brand support, which is big for our size of company. We have been public with it. It's sometimes over 50% R&D money going into brand support. That's our license to operate, but also expanding and living well with life cycle management. That is going down quickly now because we have some big commitments done. We put our money behind Vyepti, primarily now.

Yes. I mean, Michael, I think what we can say, of course, it's going through cycles and in a sort of a later stage pipeline, it can often be 50% of your R&D that sits in the life cycle side. No, we are not in that situation anymore. It shifted more too early. So we haven't been forced in a sense to make a clear choice yet early on because we are fostering a lot of the programs. Of course, in a full success scenario, if these all develop towards Phase III, then we cannot -- we will need to think then about partnering. But I think that's a nice problem to have when we get to that point. So for today, I think our focus is very much on reallocation fast towards the early stage to build that breadth of the pipeline. But as things mature, we will need to find other sources that might not come from within, but through partnerships is at least one of our strategies.

And as the follow-up, when does that sort of start to come into the discussions that you need to find partners? When in sort of the development...

I think that's an interesting point because it is sort of where is the most value creation point. And is it at the proof-of-concept stage where you can clearly demonstrate that you have an asset that has an effect, I think that's the sweet spot in a sense to extract the most value to seek a partner, to find that you have clear proof of concept. So I think that's at least our ingoing approaches to try and develop the assets to that point, and then make an important choice, do we go alone or do we partner. Okay.

[indiscernible] from Danske Bank. So just following up a little bit on the capital allocation. So the target landscape that you highlighted earlier on in the presentation. So I think much is pointing towards sort of an disease-modifying approach here, and in CNS that costs a lot of money. So can you maybe elaborate a little bit on how much you're actually willing to spend? And are you moving into earlier stages? So in the clinic, so are you going to partnerships early on or are still committed to go beyond, for example, proof of concept? And then second question, just to confirm the -- sorry, the platform, you highlighted the -- let me see, the shuttle platform on the blood brain barrier, is that proprietary? And secondly, those exposure levels that you highlighted, I think it was about 50x for antibody. Is that -- how do we compare to shuttle platforms in the industry? And also maybe add a little bit color on -- you have some nanobody fragment antibodies, so how does these compare to the shuttle platform? .

Very good questions. I'd like Tine to answer a little bit also what we do in terms of progressing and, of course, Tarek about the BBB. But just very quickly on -- yes, there are some big monsters in this space when it comes to neuroprotection disease-modifying therapies. And the biggest one is Alzheimer's disease. We're not active there. There are other big areas, of course. We pick wisely where we go in terms of disease modification. But I'd like to emphasize that even with our antibody therapies, we do things like migraine and headache space, which is relatively speaking, not so expensive. And the nice thing is symptomatic readouts that are fairly quick readouts. So if you're smart about your indication selections, you kind of manage that. We are steering away from the big, big investments in high, high-risk disease modification. Tine, you're there? Yes, can you come up?

Yes, we will -- we have -- obviously, we have a variety of programs in our portfolio, early and exploratory clinical and some of them will go via the disease modification area and some will be symptomatic. I think we don't shy away from partnering. We have done that tremendously well over the years. And we will do that, continue to do that once we are satisfied with that we have something that we believe that we need a partner for. Eptinezumab is a very good example. You will hear Jose Luis talk about that later. And he -- and what we've chosen there is to do a proof of concept in a smaller indication, MSA, that we will be able to do ourselves. Obviously, if we go to a big indication, it's another matter. We will have to seek other ways of funding those big neurological diseases.

And on that text, there is obviously, if you work on highly attractive programs, people are knocking on our doors, and that is happening already, right? So we have the options all the time to find partners. Tarek?

Absolutely. Before going to the shuttle and your questions, so progress in biology, both in symptomatology but also in disease modification, so biology is progressing on both fronts. To go back to the blood-brain barrier shuttles, to answer your question, the first one is, yes, it is a Lundbeck proprietary shuttle. And for those of us who are aficionados in biologics, this is based on a camelid, to be more specific, Llama-based VHH. So it's a Lundbeck proprietary, very interesting approach. It's no secret to go to the second question that this is a hot field and a lot of players are there. And the data you've seen is preclinical. But when we compare head-to-head preclinically, we don't see the others reaching more than fifty-fold increase in the amount of biologics that you're sending to the brain. We've got a very nice coverage across the brain with our shuttles. So we're particularly excited about it and we have multiple discovery programs. Some of them are attaching to their point antibodies. Some of them are attaching peptides and proteins and enzymes to go into enzyme replacement therapy. So it prevents significant advantage we're excited about, and hopefully, you'll see this in the clinic in the coming years.

Yes. I think...

We better wrap up. We have a longer Q&A session at the end, but at least I need a break.

Yes. And we probably need here, too, so we're coming back here at what time point?

2:15.

2:15, we're starting for those online, we are then 15 minutes behind in our schedule so 2:15. [Break]

Welcome back. So now we're going to go through these 6 programs that I mentioned that we like to showcase or have spotlights on. And we're going to go through them one at a time, of course. And we're starting with Tine Stensbøl, who will talk about to our assets. Tine has a very strong background in research and development, was the key leader behind some major brands for Lundbeck and been part of Lundbeck for many years but you can introduce yourself a little more in detail.

Thank you, Johan, and welcome back from the break. I hope you're all energized. Now we go into the real stuff, the pipeline programs so I hope you will find this session enjoyable. My name is, as you have said, Tine Stensbøl. I've been with Lundbeck for more than 2 decades. I started as a bench scientist and I worked on the project that gave birth to Brintellix, as you all know, a key brand for us. And then I transitioned after 13 years, I transitioned to development, to the dark side, as I say. And then now I spend my time on project and portfolio management. So I will be kicking off the session by talking about how we're expanding in our migraine and headache space and disorders. And I just want to remind you how migraine is -- remains a huge challenge not only for society and patients that live with it or the patients that live with it but also for society. It is the #2 cause of disability in the world and there is still significant unmet medical need associated to it. Patients that live with migraine still do not have enough treatment options. And this is why we are committed to stay in this area. It also has a large economic impact on our society and accounts for approximately USD 36 billion in U.S. alone in lost productivity. As I said, there is a need for new treatment options for patients. We need increased efficacy, but we also need medication that's tailor-made for individual patient populations. Our lead into this migraine field was our acquisition of Alder that came with, of course, Vyepti and a portfolio of compounds. Vyepti, as you know, is currently being rolled out throughout the world and we are very proud with how it's doing. I will be diving into our anti-PACAP program in a minute. But in addition to those 2 programs, we are, of course, looking at combination approaches. It goes without saying with our proof of concept earlier this year on PACAP, of course, we are looking to find a way to combine anti-CGRP and PACAP but also other neuropeptide antibodies to give new treatment -- additional treatment options for patients. Tarek alluded to it. We are continuing our quest for novel targets outside neuropeptides but that are all built on solid biology. So let's dive into our anti-PACAP program. Now migraine is initiated in cerebral blood vessels and transmitted through the trigeminal nucleus, whereby signaling transport is transported to cortical areas and the sensation of pain occurs. PACAP is present in or in areas that are essential for the pathophysiology of migraine and pain in headache disorders. And it sits on nerve terminals in the trigeminal nucleus where it stimulates downstream processes. In addition to sitting on these neuro terminals, it's also present on mast cells. And upon stimulation of these mast cells, they degranulate and they can be stimulated by a number of different neuropeptides. One is PACAP, another is CGRP, but massive amounts of PACAP is released from these mast cells and triggers downstream events that then gives migraine or headache attacks. So there is no doubt that PACAP is essential in the pathophysiology of migraine and headache disorders. Our antibody targets PACAP in the peptide PACAP. Now you're probably sitting wondering, "Okay, when is she going to tell me something about how is this different from anti-CGRPs?" I told you about the mast cells where -- from where PACAP is released. But we have clinical studies and clinical evidence that point to that PACAP and CGRP can both provoke a migraine attack or a headache in healthy volunteers and migraine patients. What we see with headaches or migraine attacks that are provoked by PACAP, they also come with a lot of premonitory symptoms, prodromal symptoms such as mood swings, flushing and a number of other symptoms. In addition to that, PACAP-elicited migraine is also more delayed in nature, so clearly differentiating the pathophysiology that's dictated by CGRP and PACAP in migraine and headache disorders. That's what really makes these 2 neuropeptides very interesting in -- one by one but also in different combinations. This is a study -- clinical study in migraine patients, where migraine patients were infused with a dose of PACAP. And what you can see here is the sensation of pain experienced by the patients. You see that each and every patient had a different experience with -- of the pain when given PACAP. But what is interesting is that 11 out of 12 patients that received PACAP actually experienced a headache, and more than half of them experienced this as a migraine-like attack, speaking to the importance of PACAP in migraine. Now we know there will be data coming soon, published. There will be data published soon. That speaks to -- or that describes a study, where patients that are treated with anti-CGRPs can get a migraine if they're provoked with PACAP. Also telling you that the patients that respond to CGRP do not necessarily -- are not necessarily free of a PACAP-induced migraine attack. So super important biological understanding of the mechanism of PACAP that's driven by PACAP and the mechanism that's driven by CGRP. Tarek and Johan spoke about this earlier, how diligently we assess the biology, the pharmacology before we put drugs into clinical development. This has become a key component of our derisking strategy. And on this slide, I show 3 different pieces of evidence where you see that our antibody 222 clearly demonstrates a potential to work in migraine and headache disorders. On the first panel on the left, you see how our 222 antibody inhibits, completely blocks a light sensitivity that is induced by PACAP, so giving a very strong proof of mechanism. And then on the middle panel, you see how our antibody does dependently reverses pain evoked by NTG, which is also a nitroglycerin. On the third panel, you see that linkback to our -- the mast cell degranulation and the potential of our antibody inhibiting degranulation in -- this is in a cell-based model but you will also see that if you test it in vivo. So very clear in pharmacological data that convinced us that this was a biology that we wanted to investigate further in humans. We took it into -- we -- once we were satisfied with the technical qualities of our antibody, we took it into and we tested it in regular single-ascending dose studies, multiple-ascending dose studies. But what we obviously wanted was also to have a proof of the mechanism that this drug actually worked in humans on the mechanisms that we were supposed to do. So we challenged patient -- healthy volunteers with an injection of -- an IV injection of PACAP and looked at the vessel dilation evoked by that PACAP injection. And what you can -- you can see that by the red line, where you can see the artery diameter that is dilated and that is completely blocked by our antibody. Once all of that was done, we took it to our Phase II study. And this is the moment, the pivotal moment for any researcher, I have to say, when you get that first data on -- of a new mode of action that shows you that here, you've got something with the potential to really, really do a difference for patients. Earlier this year, we presented these data that we had done a proof of concept in 240 patients, 2 doses testing a high and a low dose. And what you see is that we hit our primary endpoint quite markedly. And I have to say, when we are sharing this data with KOLs that Bjorn also alluded to, there is no doubt that they're very impressed with the data they see. These are the data that -- these data show you the effect from week 1 to week 4. However, we also have data going beyond week 4, where the drug works. And in addition to that, we have a 12-week safety follow-up where we saw a very nice safety profile of the compound. So all in all, we are very happy with the results of this powerful and very clear proof of concept that we got. I should say that one of the things that really intrigued us about this study was that we put in an extra dose, the low dose just to check what would that look like. And what you see up here is that, that lower dose actually worked as well as the high dose. And the number of patients that was in that group was actually quite low compared to the others. So it really tells you that we have 2 working doses in our proof of concept. And this is also why we now need to move on to do a proper dose-finding study because obviously, we want to go into our pivotal program with the lowest possible dose. And in addition to that, we are also shifting from an IV dosing that you saw in the previous slide to do an SC dosing in our pivotal program. Why do we want to do SC dosing in our pivotal program? Well, we actually believe that this is going to be a drug for many, so the convenience is, of course, an issue or a thing here. But we also want to make sure that we have the optionality of having both an SC and an IV ready once we hit the market. So all in all, what this slide shows you is that we firmly believe that we have a highly differentiated compound in our hands. There is no doubt that PACAP, the pathophysiology of PACAP in migraine or that is induced by PACAP in migraine is different from that with CGRPs. And therefore, it's important to have that treatment option for patients. In addition to that, the premonitory symptoms that are associated with migraine is still a high unmet medical need for patients. And we believe that PACAP has the potential to actually treat some of these unmet medical needs. So we are very excited about this molecule and taking it forward. And it's great to be in the front of migraine research as a research organization. This is where we want to be. So we will, as I said, go into a dose-finding study next year and then start our pivotal program early in '26 and hope to hit the market by '29. Just a reminder that how big an opportunity this is for Lundbeck and also for patients suffering from migraine. There is no doubt that this market, migraine market, will continue to grow over the next decade or so. And there are a lot of patients that still have -- still are not well served with the standard of care and the CGRPs. So we believe that PACAP and our anti-PACAP program has a role -- a big role to play in that market space. So let me summarize by saying that we have the first anti-PACAP antibody that has a strong proof of concept in the clinic. We believe that this is a highly differentiated approach. And we have -- we are committed to taking this forward into migraine and headache disorders. And moving from our late innovation pipeline to our early innovation pipeline, I'll now discuss our MAGL program, where we are exploring new mode of action. So our monoacylglycerol lipase program, which we like to call our MAGL program because it's just much easier, deals with a number of compounds. And what does this program do? Well, basically, when we inhibit the enzyme that transform 2-AG into a arachidonic acid and a number of other compounds, then we increase the levels of 2-AG. And 2-AG is a powerful agonist of CB1 and CB2 receptors, and you will probably have heard them as the part of the endocannabinoid system. Powerful break on our excessive neurotransmission and neuro-inflammation. So this mode of action really holds a great potential of being an important player in a number of different diseases, both in the central nervous system and also in the periphery because this enzyme is present both in the CNS and also in the periphery. We have already explored a couple of indications in this with some of our compounds here but have now chosen to focus on 2 areas that we find very promising. One is pain and the other one is epilepsy, and I'll come back to that in a minute. When Johan and Tarek spoke about letting the molecule speak, letting the biology speak, this is a very good example of where we have taken the time to really explore what can these compounds actually do, how do they work and do we actually believe in their potential. This is an example from a clinical trial that we did an exploratory trial, where we wanted to make sure that this mode of action actually did what it was supposed to do, increase levels of 2-AG in the periphery or not only in the periphery but this study was done in the periphery. And what you could see here is that we get a very clear dose-dependent increase in 2-AG levels after MAGL inhibition. So 2-AG, which is the compound we want to increase is actually also serving as our biomarker. In addition to that, we also have another powerful tool in our hands, and we can actually measure the presence of the drug in the brain with PET scans. We have a pit ligand that we can use. And what you can see here is on the panel on your left. The middle row shows you before you get a treatment with our MAGL compound, and then you completely displace the radioligand with our compound. So really showing you that this drug -- one of these drugs does go into the brain. Now we have a very, very good and solid understanding of how is that plasma -- or how are plasma levels associated to blood -- to brain occupancy. So we have the full toolbox in this program. So I said we are following 2 paths or 2 indications with this pool of compounds that we have. One is pain. We all know that pain is still an area where there is a significant unmet medical need. And there is really a need for novel mode of actions that play a truly different role compared to opioid receptors. We believe that with this mechanism where we target both the neurotransmission but also neuro-inflammation, we have a great opportunity to find something that can be superior to standard of care in the field of pain. In addition to that, epilepsy is another field where we are very interested to investigate the potential of this drug. Epilepsy, the mechanism that we have, we have very, very good data, I should say, from our preclinical work from Torex Group, where we show -- we have clear indication that this drug has the potential to work in epilepsy. And we are following that path. And we actually believe that the mode of action could potentially be disease-modifying in epilepsy as it works on both neuro-inflammation but also neurotransmission. So it's going to be interesting to follow these molecules to see what they bring in our experimental medicine early clinical development. We are exploring these 2 indications, as I said a couple of times. We've just initiated 1 compound in first in main and another compound, we've just started an invoked pain trial from where we will get some data sometime next year. And then we hope to initiate our program -- our pivotal program in epilepsy sometime in the mid of the '20s. This is a new molecule. It's a new mode of action. It's -- it has great potential. It's beginning to unfold and the biology and the molecules are beginning to speak to us. We're doing -- making a very rigorous process where we're looking at what is the potential of these compounds. And we will take them forward in the most promising indications that we see in our early clinical development program. And with that, I think I will hand it over to my colleague, Johannes Streffer, who will talk about 2 other programs.

Thanks a lot, Tine. The next 2 programs are very critical in our ambition to be a leader in neuroscience. One of them is targeting a pathology projecting from the brain out and the other is targeting a pathology from the outside in. And I would like to go into detail a little bit now. The first is our anti-ACTH antibody. ACTH is a critical part of the so-called hypothalamus, pituitary adrenal access, HPC access. This is a critical access that is important for the maintenance of body systems like blood pressure, glucose levels, but it's as well very important in stress control. Chronic deregulation and chronic stress leads to a desensitization of this mechanism and to chronic diseases, but there are as well 2 diseases that I would like to highlight where there is a relatively acute and strong dysregulation or chronic dysregulation of this mechanism that leads to acute symptoms. Our anti-ACTH1-clonal antibody, 909 has a powerful mechanism and very well-described biology and the potential to be active in this circuitry to reduce the symptoms of the patients. Here, we have in the circuitry from the hypothalamus, the CRH with as well as sometimes referenced as CRF. That leads to a production of ACTH from the pituitary gland, which then stimulates the adrenal glands. And while feedback mechanism cortisol going back into the pituitary gland which should normally inhibit. So any dysregulation of that can lead to overproduction or under-production, which is important in the 2 diseases. First disease I would like to highlight is congenital adrenal hyperplasia, CAH. This is a disease where due to an enzyme defect in the adrenals, we see a lower production of cortisol. This is a genetic disorder with a very strong mobility and as well access mortality. These individuals, because the cortisol does not feedback anymore into the hypothalamus, have an overproduction of ACTH. So the primary pathology is really driven by the overproduction of ACTH, but in itself, in the adrenals where normally the cortisol should be produced due to the enzyme effect, if not, they have an overproduction of androgens. So these are really the 2 key drivers of the pathology in these patients. The interesting aspect for us going in with a very potent biology like a monoclonal antibody against ACTH, there is nearly no safety risk for them because the ACTH has more or less lost the physiological function and is really an overdrive. So for us, this is a very good indication to go in with this very new potent biology. And we do hope that with this, we can have a very strong and good impact on the symptoms of these patients, which, for instance, is the dysregulation due to the cortisol level on the blood pressure, blood sugar energy, but more importantly, prevent adrenal crisis. The other disease I would like to highlight is Cushing's disease, not to be misunderstood with Cushing's syndrome. For instance, individuals with CAH, they are treated with steroids. They can get Cushing's syndrome. In Cushing's disease, we have a benign tumor of the pituitary gland, hypothalamus. This benign tumor is overproducing ACTH and that ACTH drives the circuit. So in these individuals, the standard of care treatment actually, surgery, radiation or inhibition of this glucocorticoid synthesis. The symptoms for the patients are very much driven, as you see here a depiction of a person with a very strong obesity but they as well have fragile skin. They have osteoporosis. What they as well have are very strong neuropsychiatric symptoms. They get a dysregulation that, for instance, can drive symptoms like emotional incontinence. So these individuals are as well very strongly affected in the neuropsychiatric area, which leads to a fact that we obviously are experts in these arenas. And these are patients that are very close to our heart. So here, as I said, in the pathology out of the brain, affecting the body with the ACTH overproduction. What do we do with our monoclonal antibody, 909. And these are actually data from Tarek's idea where it's been demonstrated to be very powerful. On the left side, you see a very strong dose-dependent reduction of the corticosterone in red. And on the right side, in the nonhuman primate model, even after 2 injections, we see a very long and sustained reduction of the cortisol levels in these nonhuman primates, which obviously is a very good indicator of the success of the program. From the preclinical, nonclinical data at the moment, we do believe that this should be a very safe, chronically to be administered program. So we hope to have a very good tolerability with optimal beneficial effect for the patients. This is novel data. We are just in the first in-human study with our new compound. And what you see here in the graph is aggregate data from the first 3, so first lowest doses into the program, first 3 patients in the program where we already see this very strong reduction of the biomarker 17-OHP. Actually really interesting program to what we all discussed with biological psychiatry, early derisking. This again is a program where we have early biomarkers that will help us guide the program so we will not only be able to have an early proof of mechanism, proof of the efficacy. We will as well be able to do dose-finding and modeling for proof of concept and pivotal studies but as well as this is a disease where regulators accept biomarkers for registration. So this will be a very biology-driven program where we are in a fast and informed way move forward to help patients. This obviously is not an area where we are allowed. You do know that the CRF antagonists are currently on the run. In a way, we think that's very good for us because we see ourselves here as a fast follower. We do think that our monoclonal antibody will have a stronger effect because it's actually downstream from the CRF, CRH. And we, as we do think that we will have a more sustained effect for these patients. So in that sense, we do believe that the follow-up position in this situation is really good for us. On the other side, for the Cushing's disease, there is really nothing else that currently could target the key pathology of the ACTH and overdrive. So here, we do believe that this treatment will be first and best-in-class for individuals with Cushing's disease and therefore, be a real game changer, certainly will as well for CAH, but in Cushing's disease potentially even stronger a game changer in this disease moving forward. Where are we in our development program? As I just referenced, we are in the first-in-human study. We have first results. Everything is moving smoothly. We do believe that we can as well initiate next year a Phase Ib study in Cushing disease. At the moment, we are in CAH. We then hope to have the first pivotal dose in '25 and early '30s to launch this program. What does that mean? Is the opportunity? Obviously, it's a huge opportunity for patients. We as well do think that this is a good commercial opportunity for us. Both indications have an overall market of about $1 billion. And we do think that a best-in-class or a first and best-in-class molecule will be very well suited and successful in these 2 markets. So in summary, 909 is a first-in-class antibody with what we hope favorable safety profile targeting ATCH, the main driver of cortisol production. We do expect better efficacy compared to the CRS antagonism in CAH and potential to treat both neurohormonal dysfunction and psychiatric symptomatology in Cushing's disease. With that, I would like to turn towards neuroimmunology. Neuroimmunology is obviously a very strong developing field and you all have seen the anti-CDH-ligand antibodies. We do believe that our anti-CDH-ligand binder has the potential to be a best-in-class in this field. And obviously, Tarek has already demonstrated it with his team in the nonclinical space, but we are quite confident that we can demonstrate the same as well in the clinic. Why do we believe CD40 is such a very valuable target? CD40 actually in this inflammatory spectrum targets the both 2 big axes. So we have the innate and the adaptive immune response. We have the B cell and the T cell system. And the CD40 is a key link between these 2. So we have both CD40 ligand cell-bound, and we have CD40-ligand receptors but we as well have soluble CD40 ligand. And that not only drives auto antibodies, but it as well drives a pool of different T cells that then can elicit negative effects in these patients with immunological disease. We have referenced here, for instance, killer T cells, helper T cells, suppressor T cells, memory T cells, regulatory T cells. These are all systems that are individual driven as well by the CD40 system. What does that mean for patients? Obviously, that means that we have with our antibody against CD-40 -- with our anti-CD40 ligand binder, the potential to go both on a number of different diseases. We can reduce auto antibodies. We can block immune response. We can reduce inflammation, increase regulatory T cells and reduce cytokine release. Now obviously, that puts us into a little problem because we have a wide variety of biology that we can target. And we did a very thorough investigation, a prioritization exercise where we looked on clinical feasibility, clinical relevance, medical need but as well on the biology, where is the best biological score, which of these diseases can best benefit from a CD40 approach? Now we have decided to start our exercise with TED, and I will explain that in the next slide as a starting indication that obviously is a neuro adjacency, but we think it is a very nice disease to start with this new powerful molecule. We as well realize that MS has just proven to be very amendable as well to CD40. And we do believe that there is a huge opportunity as well potentially for a CD40-ligand binder in MS, and we are exploring that actively. So coming to thyroid eye disease, TED. This is a disease where actually the biology has proven both on the B and the T cell side. So this is driven by auto antibodies but then as well leads to a pathological swelling of the fat tissue behind the eye, which is driven by the over-activation and the CD40 system is obviously relevant in both of these features. What happens to the patients? The patients get dry eyes, they get painful eyes and that can go up to blindness. What as well happens, you get a proof of ptosis, so the eyeball is moved forward, which, as much as a very bad sign for the patients is a very nice symptom for clinical trials. So a very objective measure that we can early on in the trials use to demonstrate clinical effect. Currently, standard of care are steroids and orbital radiotherapy, but we do believe that the CD40 ligand binder can be here really a disease-modifying treatment for these patients and normalize the situation. Why do we believe multiple sclerosis is a very good opportunity? Obviously, we could stop here and say it has just been proven. But we know, obviously, that CD40 is, on the one side, genetically involved. It's a risk factor. But we as well know that both the B cell and the T cell system are critically important in the developing of the MS. And I think what he is very important to realize, a lot of the current MS treatments are going against the relaxing [indiscernible]. What is really underserved today is the progression of MS. We do believe that CD40 with the effect on both T cell and B cell system will be able to as well go to the underlying disease progression, and we see a real value here. What is our molecule? And this, I think, Tarek, would be better for you to explain the molecule to you. And the clinician I can tell you and you all know that there has been monoclonal antibodies against CD40, and there were significant safety problems in the first generations. They have been solved. We have understood that the Fc receptor involvement is really not the right thing we would like to have here. So that has been reduced, and there has been a lot of learnings in this. We do believe that our molecule with the suffer technology can both improve the exposure to have. So the efficacy for the patient, but as well comes with a better safety profile for patients. So we do believe that here, we have an opportunity to be best-in-class. And our compound 515 could be that best-in-class molecule for CD40. Where are we in the program? This is actually data out of the clinical program. As you see on the left side, the pharmacology, so the exposure. We have a very nice dose-dependent exposure increase on the different doses. On the right side, actually, more importantly, you look at the soluble CD40 ligand so our real target. This is target engagement where we think we're really going to the biology. And you see here after the injection, a very nice, long sustained dose-dependent reduction of the CD40 ligand. So we have proof of activity already, and we think we can move quickly now into the proof-of-concept clinical trials. Now the potential benefits in MS, as already slightly alluded to, MS is a disease with T cell and B cell involvement. So CD40 is potentially a very important new treatment modality for these patients. We do believe that, that obviously minimizes the risk for patients in contrast to immune suppressive diseases. Our compound as the last-generation CD40 antibodies has no risk of the embolism that was eliminated. But obviously, we do believe that by the properties that 515 has with a very nice pharmacokinetic and safety profile could be best-in-class in this. So in that sense, what is our reason to believe for TED? Obviously, this is a molecule that very nicely can target the both features, T and B cells and therefore be a best-in-class for T in the molecule. But we as well think that, that proof of concept in TED can very well move forward in our franchise for this. Where are we in the 515 program? So TED, obviously, we have the first dose already. The first pivotal dose could already be in '25, if we can demonstrate the clinical efficacy as quick as we are targeting, and that would be a market entry before '20 -- around 2030. What is that as an opportunity? TED itself is a very significant opportunity so the market for TED would be more than [ EUR 6 billion ]. And I think this is where you've seen it on Johan's graph. If we look one step further right, and we look at the opportunity to MS, then we obviously would have gone out of that chart. So that is a much bigger commercial opportunity in the MS market. But we, as a reference here on the right side are other promising indications. This is neuroinflammation. So neuroimmunology and neuroinflammation is really underserved. We do not yet have a very good handle on that. And if we will be able to demonstrate with our CD40 ligand binder that this is a new avenue into neuroinflammation, then we have a very powerful tool here. So in conclusion, we think that 515 is a best-in-class differentiated CD40 ligand binder. It provides immunomodulation, bringing superior safety profile compared to more aggressive immunosuppressive treatments. And the dual inhibition of B and T cell activation holds strong promise in autoimmune-related disorders like TED and MS. And with that, I would like to hand over to José Luis.

Thank you, Johannes. So my name is José Luis Molinuevo. I'm heading Experimental Medicine. Experimental Medicine, among other tasks, is in charge in early development but also in the biomarker strategy and execution. So we are heavily involved in letting molecules speak. Previous to joining Lundbeck, I'm a neurologist by training so I was leading a research department, taking care of Parkinson and Alzheimer's disease patient. So for me, it's really a pleasure to be able to be here and introduce 2 programs that are related with movement disorders. Beyond that, these 2 programs are a good example of our research strategy. One of them is focused on the symptomatic effect, the D1/D2 agonist, but also, as Charl mentioned at the very beginning, we are not only targeting Parkinson's disease, we are targeting an unmet need in Parkinson's disease, which is motor complications. The other program is on disease modification and is targeting a rare devastating disease, and I will come back to that later. So let me now dive into our D1/D2 agonist program, which is an innovative and derisked oral treatment for motor complications in Parkinson's disease. So you probably know, Parkinson's disease is characterized by the loss of the neurons from the substantia nigra pars compacta. In physiological conditions, dopamine activates D1/D2 receptors, which results in activation of the direct and indirect pathway that are heavily involved in how the basal ganglia work. Lack of dopamine means lack of activation of these pathways, which results in the classical symptomatology of Parkinson's disease patients, bradykinesia, resting tremor and rigidity, which is heavily invalidating. Initial treatment with levodopa usually solves the problem and they are symptom-free for some time. That's what we call the honeymoon period. But as every honeymoon, it finishes. And most of them suffer after that from motor complications. So up to 60% of them, at some point in their disease progression, suffer from motor complications. And that's where the unmet need is there. And why do we have an unmet need? We don't have efficacy. Current treatments, for example, D2 agonists do not have sufficient efficacy. That's the agonist that you are usually exposed to, or if we have a treatment like apomorphine that is -- can bring efficacy because it is D1/D2 receptors, we have to supplement it subcutaneous with a continuous pump. So very huge unmet need for Parkinson's disease patients. Let me explain a little bit more about our motor complications. Motor complications is a term that we use to define the period of time that Parkinson's disease patients are either in off, means symptoms reappear or in on time with big-dose dyskinesia, meaning that even if they are on, the abnormal movements preclude them for having a normal life. And as you can see in the graph, the amount of time that they spend in good on-time keeps decreasing over time. I can share with you that 25 years ago, I was launching one of the initial DBS, deep brain stimulation, programs in Barcelona at the time. So we were doing DBS into the subthalamic nucleus. We have a waiting list, huge waiting list. So we had to attend those patients with motor complications. We were suffering in front of them because we really could offer them nothing. That has not changed nowadays. With patients with motor complications, either you go to DBS or you go to [indiscernible] which is extremely invasive, as you know, or you use apomorphine subcutaneously with a pump. Well, we don't have a solution for that yet. So that's where we are coming in. We are coming in with an innovative oral drug whose active metabolite activates D1/D2 receptors, both of them. That's an important point. We are not only hitting D2. We are hitting D1/D2 receptors. On the other hand, it's oral as well. So this comes with 3 benefits: increased efficacy compared to D2, increased tolerability since we are hitting D1/D2. Levodopa can be reduced dyskinesia disappear or at least are heavily reduced. And it's oral, which is a huge advantage with the current treatments, as I have already explained. You probably are wondering, how can be an oral compound provide a continuous stimulation? Well, this is a fascinating slide, I have to say. Because the reason is this is metabolized into an active metabolite. That active metabolite hits D1/D2 receptors. Then it is metabolized into nonactive one, but these ones are back-converted into the active one. So the active one reaches a steady state of plasma levels. And this is not just theoretical. You can see the graphs below there. Let me point them out. These graphs are based on real data. So as you can see, apomorphine, plasma levels come down and stay at the floor level. Levodopa goes up, comes down right away. Our active metabolite, when it rises, remains in a steady state with stable plasma levels. And that correlates with the activity that we see in [indiscernible]. So this is a validated model of continuous oral stimulation. Further to that, we early derisk, let the molecule speak. We have profiled and we are hitting D1/D2 receptor similar to apomorphine. And when we went into monkeys, nonhuman primates, we see that we provide an effect, they are in on-time for a longer time compared with levodopa. But even more exciting than that, our initial preliminary Phase Ib data is also speaking. Patients are relieved of the symptomatology they are on. They can't reduce levodopa, some of them up to 100% reduction, so levodopa-free and they still feel completely well. So this is very early on but it's telling us that the molecule is doing what we are expecting to do. So with all I have said, obviously, I'm quite excited and I can see that we can be really competitive. We are hitting D1/D2 receptors. We have -- we provide continuous dopamine stimulation. We have effect on motor fluctuations. We have seen already that in our Phase Ib. And that potentially will have an effect on dyskinesia. So we are providing an oral solution that will be like an apomorphine-like but oral hitting D1/D2. Where are we right now? We are running our Phase Ib. We hope to start our Phase II next year. And from there, we move into the pivotal. Hopefully, entry, early 2030, the market. I have insisted this is a strong unmet need. And again, I will link that to our strategy somehow. We are not just going for Parkinson's disease. We are going for Parkinson's motor complication, which is really relevant. And there is a huge market potential here as well. As you know, the estimated total market size by 2031 in the U.S. is up to $4.5 billion, and estimated total market size in Europe and Japan is up to $3 billion. So to summarize on our D1/D2 agonist. We have an innovative prodrug that provides continuous receptor stimulation and prolonged therapeutic action, good on time. We are hitting D1/D2 receptors, which is something extremely important to keep in mind. And it's oral, so really improved tolerability compared with the current treatment paradigm. Let me now move to our anti-alpha-synuclein antibody. As I said, this is quite balanced when we are approaching movement disorders. Symptomatic before, now we are going to disease modification. And we are going into a rare disease. And I will come back later on why multiple system atrophy. So this is potentially the first disease-modifying treatment for multiple system atrophy. Why do we believe that we should target alpha-synuclein? And why should we target alpha-synuclein in the context of multiple system atrophy? Well, alpha-synuclein, there is evidence that is related with neuronal death. How does that happen? Alpha-synuclein aggregates from monomers, goes into oligomers, fibrils and through several intracellular mechanism that leads to neuronal death. After that, after -- aggregated alpha-synuclein is released, and that is taken up by oligodendrocytes. The oligodendrocytes became also dysfunctional, and that also generates a dysfunctional neuronal function that also contributes to this negative feedback loop that leads to neuronal death. So when we are using our IgG1 antibody, we are targeting these fibrils. So that stopped the seeding of the fibrils. And further to that, the Fc component stimulates microglia that also helps in the clearance of this aggregated alpha-synuclein. Why MSA, multiple system atrophy? Another key message that Charl gave at the beginning, we are committed to treat devastating neurological diseases. This is one of them. This disease, the name itself, when we say multisystem, it means that it really attacks 3 different neurological system. Patients suffer dysautonomia, Parkinsonism, and they have cerebellar dysfunction. So it's really debilitating diseases. But even more than that, it is extremely fast-progressing disease. Patients in 3 years, 50% need a walking aid. In 5 years, 60% of them cannot walk. And some of them really do not live beyond 7, 8 years. So very rapidly progressing disease that currently has no treatment. Why do we believe that we can treat MSA? Well, I have given you before the theoretical, hypothetical mechanism. But we already are letting the molecule speak, and Tarek in his lab already has shown that we can bind MSA fibrils with our IgG1 antibody. And those fibrils were coming from brain extracts from MSA patients. But we are not only binding to the fibrils. We stopped the seeding. So the hypothesis behind the mechanism has been tested, and very early on, we move into patients. So our SAD study was not only on healthy volunteers, was also in Parkinson's disease patients. We decide on Parkinson's disease for the SAD study because, obviously, Parkinson's disease is way more prevalent. It is another alpha-synucleinopathy. And potentially, it can give us also a signal where we can go after with our IgG1 antibody. So this is on healthy volunteers, this is slide. But you can see how free alpha-synuclein is reduced as a function of the dose that we give of our antibody. This was confirmed on PD patients. On the left, you see the effect on plasma. But more important than that, on the right, you see the effect of CSF. So this is proof of central mechanism of our antibody in PD patients. With all of this, we really believe we can be competitive. We are capturing the fibrils. We are stopping the seeding. We have clinical proof of central mechanism in PD patients. And we can be the first to go into market to modify a terrible disease such as multiple system atrophy. We are finishing our Phase II study that is being conducted in the U.S. and Japan. Japan was very strategic because thanks to that, now we have what we call SAKIGAKE. So that is like an orphan state in development in Japan. So that will obviously help us very much. We are planning with our first pivotal dose in '25 and into the market in '29. We are expecting orphan pricing, as I have said. Already in Europe, we have orphan status. And we have SAKIGAKE in Japan. In the U.S. market, the estimated total market size can be up to $2 billion and in European Union, the 5, and Japan, up to $1 billion. So let me summarize. First-in-class antibody that binds to all major forms of alpha-synuclein and prevents aggregation, clinical proof of mechanism, central proof of mechanism in Parkinson's disease patients, and we are probably the first in our development in multiple system atrophy. And with this, I hand back to Johan.

Thanks a lot, Jose Luis. So I'd like to wrap up just a little bit by saying what I said before. If you want to be successful in any R&D endeavor, you have to have the right assets. And we showcased 6 assets here. We also talked about our strong brands. We think we're well positioned with those strong assets. We have the right assets. Of course, as head of R&D, I'd like to have more. But you're showed 6 good cases that we have done also the right decisions about. That's the second element. Right assets and right decisions. We are carefully derisking. We are not progressing until we have proof of biology, proof of the molecule working in humans, that engage the target that the mechanism works and then moving ahead. You need to have the right decisions really to move ahead into the next step. We have now a number of good assets that look very promising and most likely would enter into Phase II already next year. The third element you need to have is the right people. You've seen an example here of 5 people from our organization. They are the right people, obviously, but they represent a group of about 800 people that are really a top-notch organization. And I talked about how we work together. Our size is a benefit. Our way we collaborate is a benefit. Our global organization that utilize talents across the world is a benefit. So with these 2 elements, I'm confident that we will be able to successfully move forward and move some of these assets into the marketplace in very, very promising indications where the medical need is, of course, enormous. So we have exciting opportunities with anti-PACAP. You saw what Tine presented. We have a solid program moving forward. You saw what Jose Luis presented with our anti-alpha-synuclein antibody. That is, of course, a high-risk program. No doubt about it. But you're also showed about a fabulous effect we have in clearing alpha-synuclein aggregates in blood and in CSF. So we've done the right thing. We're going to test that concept, and the results will come soon. We are moving some really interesting strong assets in the new adjacency area, the CD40 and ACTH forward. We picked our indications. You saw the potential of those molecules. We are also well positioned with our strong R&D organization to take on other assets in the future. With that, I'd like to hand over to Charl to wrap it up.

Thank you, Johan. So first of all, I wanted to just to leave you with a few closing remarks. And first of all, thank you for investing the time with us this afternoon to learn more about what we have in the engine. I also want to take a moment to thank the team, in a sense, people who are here today. As Johan said, you're seeing a sample of many people working behind the scenes to deliver what you have seen today in terms of potential. And I think you've got a sense of a future Lundbeck. That is Lundbeck that has a different engine. It's a reboot of R&D. It's one with a lot of potential. And it's there to, in a sense, address the long-term potential of the company. And I think that's the #1 question I hear from you often, is what is the long-term view of Lundbeck. What is the next decade going to bring? And I can reassure you that as a management team and as we think can reflect on our strategy, that is the #1 area of focus as we think about capital allocation and the discipline we will place in the company to ensure that we succeed in the long term. And of course, pivotal for that will be R&D, as you've seen today, as one of the key areas that will determine the long-term growth of the company, in addition, of course, to a very focused M&A approach and, of course, securing that we achieve the growth that we've set aside also for the strategic assets we have in our hands. So with that, I would like to invite the panel up for questions. We have some good time now for questions. So really for those even questions you could not answer earlier, since the time was a bit short, I really invite you for more questions. So let's get the panel here.

James Gordon from JPMorgan. Two questions, please. One was about R&D and just the extent that you mentioned the R&D reboot in terms of whether you're going to need to spend more on R&D. And if that does happen, is that more in 2025 when you get Phase III initiations or 2024 when it sounds like there's more Phase Ib and Phase II kicking off? And just do you still think you can do the medium-term EBITDA target, which I think was 30% to 32%, even financing all the interesting things you've been talking about? So that was the first one, please. The second one was M&A. So for the 2 things that are going to be in Phase III, it sounds like they could launch in 2029, but not before, and everything else will be later. So why isn't there a bit more urgency, unless I'm just missing the urgency, to refill with more M&A? Because it feels like if those 2 don't work, and even if they do work, they're not going to be in time to replace Rexulti. And if you buy anything else, it's going to have to be a Phase III that someone else has already kicked off or it's going to be an asset that's so far so early. It's not going to be in time. So is there like a big urgency to get something done in the next 12 months? Or is it fine that maybe earnings does go down in 2030, and then you sort of return to growth later?

Yes. So let me answer multiple questions because it is the core also of our strategic focus, of course. First thing to say is that, yes, the -- with a success scenario in this pipeline, of course, there will be an increase in an R&D view that we would need to take, of course, beyond the sort of '25 window, as you would have seen in the milestones. If we achieve that success scenario, of course, there will be a question of can we fund all of this ourselves. And I think the answer is probably not. We would have to look at partnerships as a way to enhance that pipeline going forward. And I think that's quite normal for companies like us and quite standard also in our industry, of course. Our current guidance remains intact. Of course, our current guidance is without any M&A baked in at this point. So if M&A is, of course, a key lever for us, then we will have to think about that target differently and, of course, communicate that very clearly as well. But as things stand today, we do not see a change in the midterm targets. When we think about our current strategic assets, we have Vyepti, on a constant basis, growing 81%. We have Rexulti at 19%. That sort of growth momentum we see, we feel confident that, that can carry us at least in the midterm growth -- from a growth perspective across the sort of midterm range and then focus our efforts really on solving the long-term challenge of the company, which is, as you've seen today, part of that's in the pipeline. And then I come to your question on M&A, which is in M&A, it's not -- we are certainly taking that as a sense of urgency. We see it as a series of deals rather than one single deal. And we will start already as of '24 because we want to, in a sense, be in a position together with the pipeline as well as a series of M&A to allow us to get into that growth bridge as we get towards the end of the decade. So we will look more at assets that are either clearly proven themselves in Phase II and entering into Phase III or later. And we clearly look at those more in the space of a series of deals, could be with a peak sales potential each of $500 million to $600 million or more. But it's really what is also digestible for us with firepower and makes sense for a company like us to focus on a series of deals. So it's high on the agenda, but it's in a systematic, programmatic way that we think we can address it going forward. Okay?

If I just may add to the first part of your question, I always say I like to be in the positive problem of choice. So when it comes to R&D investment, it's great to have options, right? And we -- through having options, we're always going to progress the most promising ones. And we have now several promising programs. So it's maybe harder to choose between them. But there are so many opportunities, partnerships, et cetera, as Charl talked about. So I don't see a problem having a strong R&D portfolio, quite frankly. I think that's my job to create that. And then we make the right decisions with it.

Charlie Mabbutt from Morgan Stanley. So firstly, a couple of regulatory questions. So on cluster headache, could you just tell us a bit more about the path forward there? And then secondly, given the unmet need in MSA, is there any opportunity for accelerated approval post Phase II? And then on R&D technology more broadly, you showed a slide with RNA, and you've talked about gene therapy before. Are those areas where you'd be interested in adding technology versus what you have internally? Any insights that would be interesting.

Three great questions. I think we'll start with Bjorn Mogensen.

Thank you. And just a little bit about myself, neurologist by training out of Copenhagen. And Johan alluded to seeing the light. I think that's maybe a very strong word. I was helping turning on the light, being part of the team that first demonstrated vasodilation in migraine during migraine attack and reversal during the early treatment days and then later induce migraine attacks with CGRP together with the group from the Danish Headache Center. So this is a core area, close to my heart, that I was happily getting into. As for cluster headache, you just saw on the slide very strong efficacy in the sense of proportion of patients that respond well to treatment, even quite early. And you saw the change in patients' global impression of change from baseline that heavily support a benefit that we also heard from the investigators and not the least patients that desperately wanted more. We have presented these data to key international specialists. They also believe that there is efficacy seen in these trials, and we are looking to bring this drug to patients and finding a path forward to that.

Just to comment, this is a very, very new field with enormous medical needs. So I mean we have something that you saw works. So there is a space in some way for it. Maybe Jose Luis, you can talk about alpha-synuclein and possible path forward?

Yes. So definitely, I would say that there is room. We already have had a very interesting conversation with Japan, and they seem to be very positive. That's why we have the SAKIGAKE, and that can lead to very fast approval. We are having conversations with the FDA, and we will have more conversation when we finish our Phase II. We do have some biomarkers included in our Phase II as well. So there will be room for discussion with the FDA.

And as I showed, there is a great movement now with accelerated approval based on biomarkers, et cetera. We have, of course, decorated the trial with good biomarkers like neurofilament light. So -- and that can continue maybe in late development. Tarek, can you handle the next one?

Sure. I think one of the question was around the modality. And you mentioned RNA and also gene therapy. For RNA, we opted to go for a small molecule that interacts with RNA. So it keeps all the characteristic and the feature of orally bioavailable small molecule that targets RNA. So we believe this is a good way to get around some of the inconveniences that you see with other nucleic acid approaches, intrathecal and fairly invasive administration. So we opted for this one. You mentioned also gene therapy. We're not yet in gene therapy. I don't think we have plans in the near future to go in gene therapy, as much as I can say. Great. Charl?

Yes, yes. Gene therapy, we can do a lot of stuff in our rather limited R&D organization [ antisense ] we could do if we wanted. We have an alternative, as you heard with the SMiRNAs, which is probably better suited in many ways. Gene therapy is a big beast though. And that's as big, at least as going into biotherapeutics. But we can partner, and we can work with other people, if you think. I think we had a question up there, right? Yes.

Thank you. Xian Deng from UBS. Two, please, on the specific assets. So the first one is on PACAP. So Johan previously mentioned that the Phase IIb trial designs would have multiple access, might have various time for readout. Just wondering if you could elaborate a bit more in terms of the Phase II trial design for the PACAP program. And sort of what are the time points can we see some of the data and might actually give us a sense of where this might go? And so in addition to that is that do you think -- for the pivotal trial, do you think you can actually run the trials in biologic-naive patients? Or do you think you might have the run initially for refractory, CGRP refractory patients? So that's the first part on PACAP. And second one on CD40L for TED. Just wondering, what do you think about the competitive landscape? Because by the time you initiate Phase III, which sounds like post 2025, there will be at least 2 FcRns that might have read out by that time, people to read out. And not to mention that TEPEZZA may or may not have depleted some of the accurate patient pool, but chronic seems to be a bit subpar. So just wondering, what do you think about the competitive landscape there? And do you think when you run Phase III, you have to actually beat FcRn at this stage?

Very good questions. I actually like to pass them on. Should we start with the PACAP one, Tine?

Yes, as I said, we are starting the Phase IIb. We will do a classical Phase IIb design with multiple doses, and it will run until the end. We will not stop the trial for efficacy at -- so that is not planned that we will stop the trial for efficacy until we have the final readout. So we will do a very cautious dose-finding study because it is important for us to find that pivotal dose that we want to take to Phase III. That was the first part of the question on PACAP. And what was the -- oh, then you had a second part, whether we are looking into CGRP nonresponders. The trial that we're doing is -- includes patients that have been treated with 2 to 3, 4 different -- or fails 2 to 4 treatment options. And some of these patients will, of course, also have tried anti-CGRPs. However, it's only a part of the trial that we include. And the whole differentiation part around PACAP will start to take form in that Phase IIb where we are including scales, and Bjorn can maybe speak more to that, to look for these premonitory symptoms, signs or signals of differentiation in the premonitory symptoms. I think you will see the differentiation unfolding in -- as we progress in Phase III. But we really want to get that dose right so we can move swiftly into Phase III. We know how to run these migraine trials now. So we will run that very efficiently, I'm sure, once we get to Phase III.

I'm sure Bjorn like to comment, but I have a little bit of a hiccup when it comes to dose setting. I mean, many people go to -- fast to Phase III and pick the wrong dose. So I think it's very crucial we do the right thing here. You can spend a lot of time in Phase III, trying to figure out a dose, but that's not my appetite. But Bjorn, maybe you can talk more about the potential differentiation.

Yes. I think Tine was stating it correctly. This will unfold. Now whether this is a late line or even earlier line, we will have to see over time. I think it's important that the leading experts we have discussed these results with see this to be a drug that can be used across the spectrum of migraine patients. We will have to see how it unfolds. It's not a certainty that is where it goes in the failures.

Yes. And then we had CD40. Maybe, Johannes, you can start. And then maybe I can -- yes.

Thanks a lot. I mean obviously, the FC targeted therapies are very strong. And we are very much looking to see those results, and they will as well help us in trial design. But as I alluded to, our CD40 ligand binder has the opportunity to be B cell and T cell, right? So we go significantly beyond that. If I look at the biology, we are targeting -- and the way we are targeting it with the CD40 ligand binder, that it should be superior. So I'm very convinced that for the current ongoing trial that we have, we will not have a problem of competition. And it will be important for us to demonstrate the sustained safety and efficacy profile that then will as well put us into a lead position. Overall, it would be great for patients, but I don't really see that there would be a depletion of patients in this quite prevalent disease.

Yes. Just to underline, the mechanism is much broader than the FcRn, right? Because here, we go for both innate and adaptive, and part of the fibrotic tissue growing is probably macrophages and other things going in, right? So that is fundamentally different mechanistically. So yes, it's hand waving at this stage because it's just theoretical, but it carries a great potential for being much powerful. So efficacy, I think, is something they're going to look for. Competing for patients in a small area, yes, that's a problem. But if you have a good offering, they probably like to try that.

Just to add on that, Johan, it is known that fibroblast have the CD40 receptor, so -- the CD40L receptor, so we will be targeting that locally as well. So that's clearly another mechanism that we believe can bring additional efficacy.

Did we cover all your questions? Good.

Lucy Codrington from Jefferies. So just a couple for me. Just on the brain shuttle technology in terms of when that might be first getting to market. And is the plan to apply that to your existing pipeline? Or is that for as yet undisclosed assets? And then just on the alpha-synuclein, given that that's also an intracellular pathology, is an antibody the best approach here? And what can be taken from experience to date with anti-tau antibodies. I'm thinking, Johan, of your experience at AC Immune. And what can we take from that in terms of optimizing the development here?

Well, super good questions. Tarek, have a go at that.

Maybe I can start with the shuttle. To answer the first part of the question, are we applying this to existing assets and the discovery pipeline, attaching them to the shuttle, the answer is yes, we're looking at this. We're looking at opportunity to see whether we can benefit from an enhanced brain penetration for some of our assets. We've got activity in discovery. But we're also open to attaching other cargoes to the shuttle. So it serves multi-purposes. I wouldn't want to speculate too much on market entry because we're still in discovery. So I mean I'd probably remain cautious in throwing dates and numbers on that one.

Yes. One of the proof points is, of course, we like to get this into man quickly and show that it really delivers that value in humans. Strong animal data. We are not lifting the lid entirely yet on what we're doing, but we have some pretty advanced thinking there. So we have advanced programs in that field. Let's see now the -- yes. So it's probably in your shop.

Yes, yes. So I would say here, we are obviously targeting the spreading, and we are also targeting the oligodendrocyte contributing to the pathophysiology. Beyond that, we know that oligomers also have other impacts in the disease at many different levels. So I personally -- and this is personally. I do believe that we are targeting clearly the pathophysiology of the disease at different levels.

Yes. You alluded to anti-tau as well, right, if I heard you right. Was that part of your question, right? So maybe you can comment on that also. Yes. There are kind of similarities here because you're doing intracellular stuff. That's, I guess, what you're after, right?

Yes. So anti-tau, I mean, when you look at the data that has been shown in trials -- and you are probably very aware of the trials, right? I mean there are some that have been done in very early disease. They were really flat. There were others done a little bit late on the disease. And there -- for many people, paradoxically, there was a signal in episodic memory. So that is the other mechanism I'm alluding to. Oligomers have an impact on the synapse function. And that is my personal view. I have to disclose. But I think that has an impact also on the disease pathophysiology. So I do believe that our -- with our anti-alpha-synuclein antibody, we are really targeting different pathophysiological pathways in this case in multiple system atrophy.

Yes. Not so many years ago, everyone had an anti-tau. We also had one [indiscernible]. It's not listed in our portfolio anymore. That's one of the choices we make. We're happy that other people explore the biology. We still think we have the best-in-class, but it was theoretical best-in-class. So we're careful with that, and we basically paused our alpha -- our anti-tau and instead doubled down on alpha-synuclein. We also has -- where we have also the strong target engagement data. So we really was -- we're leaving ourselves also showing that the molecule works, right?

Is it fair to say for MAGL that you consider pain more high risk than epilepsy? And also, why is there a lag in initiating the epilepsy trial after the pain? Is it your waiting to see something first? Or what's the rationale there?

I think it's premature to say what's higher risk in that -- those programs. I think both have a great potential. I think we have from a -- what we have some preclinical evidence, I wouldn't speculate as to which is higher risk. The reason we have a lag is that we're taking a different molecule into the epilepsy part. So it's 2 different molecules because there are some of the technical qualities around the 2 compounds that we believe have to be different, targeting one indication space compared to the other. So that's the reason for the lag.

Michael from Nordea. Two questions. First on MSA, can you try to sort of explain to us what is seen as a successful outcome of the headline data we're going to see in Q1? Is that some ranging from sort of a signal to highly statistically significant? Just so we get a feeling of where is sort of the range for what we could expect. And secondly, on the half-life of 515, the actual half-life potential, administration frequency, et cetera, what are we looking at? .

Yes. So let me start with what you should fill in. But in our business, I really like what I call red or green readouts. We like to do a proof of concept when we walk away and say we tested it. It didn't work. When we tested it, it worked. That's not always the case. We're exploring the frontiers of biology here. So we can get something that is in between, and that's a range of scenarios that maybe you can talk about. But I just mentioned we have clinical and biomarker readout. So...

So exactly, Johan. I mean so we have several biomarkers that can also help us to understand the underlying impact not only on the pathology or on the pathophysiology but also then the patients that have the right underlying pathology because as you know, traditional with many of these diseases, the diagnosis is more phenotypic. So PIs look at patients that fulfill the criteria, and they go in the trials. But right now, we have biomarkers that can tell us if they really have the underlying pathology. So with that, where I'm going is that we can have a readout, a general readout of the trial, but we can also have post-hoc analysis diving into those that we know that have the pathology. So I think we'll be facing -- we are facing a small trial. So I wouldn't focus on the P value. That is for sure. I will focus on the signal that we get and a signal that has to be meaningful taking into account all the different biomarker scenarios.

I'd like to add that this is the kind of program 10 years ago, everyone would do a big, big trial, putting a lot of money at risk. We spend a lot of time thinking through. Can we do this with a very small trial? And it is small, and we thought we can. We will know when we have the readouts. So of course, we went fast. We did the right thing. We have loaded with readouts. We are not putting the family farm at risk here, which could have been the case, and particularly if we have would gone in parallel with Parkinson or anything like that. I think we're going with the aggressive little brother of Parkinson's, which is a really very high medical need. So we also picked the right one for signal detection, quite frankly, because they're rapidly progressing. So I think we did exactly what one should do today in neurogenerative diseases, chronic ones when you're looking at disease-modifying treatments. You can do smaller trials to find out. And hopefully, we'll find that. Yes, yes, 515. Yes.

So that's our CD40L binder that you are referring to. No, no, no. That's why -- you want to answer? So I mean half-life is right now, I think, around 15 days, something like that. But beyond that, we are seeing target engagement that goes way beyond those 15 days. And that is related with the second part of your question because that will be an exercise that we'll have to do at some point to try to understand what is the right dose and the timing of the doses because maybe with these kind of compounds, you can dose way more sparse than with other kind of compounds.

Charles Pitman from Barclays. Just first on PACAP. I'm just wondering to what degree you're hoping in the future there's an opportunity to partner your PACAP with potential other CGRPs in the market and kind of benefit from the broad reach of other products in the market. And to what degree do you think that you might be able to identify patients that would benefit more from a CGRP or a PACAP in the future? And then just secondly, on the D1/D2 agonist. What are the implications of your expected dosing if concentrations are expected to remain high for the longer period? Can you give us kind of any idea of what this could mean for the longer on time it could generate?

Yes. So your first part, it's probably a little more for Charl to discuss what we do with a great asset like this. But I'd just like to emphasize, we have, as I said repeatedly, a very strong position right now in R&D but also with the drug on the market in migraine. We are one of the few that really see the light here, and there is a lot of medical need, and we know how to operate. So there are pluses and minuses finding a partner, but it also depends on capital allocation and other things, right?

Yes. I mean I think, Charles, here, our -- maybe our bias here is that we're building quite a strong position in severe migraine. So if there's any way we can protect the full path and develop this asset ourselves and commercialize them, that would be probably our preference. If we have strong data, of course, then we could certainly explore geographic partnering and so on. But I think it's not our first choice today. I think maybe your question was also maybe on combination use, which is probably where you're going. So I think -- maybe we can get some comments more on the combinations. Yes.

Yes, absolutely. So we heard before about refractory CGRP patients. I think we should think about this slightly differently. So you have truly refractory. It's a small population. But then you have a lot of unmet need still in those that are treated with CGRP. So we do see a potential for a combination of the 2. It doesn't mean you have to go first or last. That will really unfold over the trial. I do think the anti-PACAP mechanism of action is encompassing a broader aspect of what migraine is. And remember, today, the migraine field and prevention of migraine is really in its early stages of development. We are counting migraine days and talking response rates. This is a disease that impacts the patients throughout the whole month. There's a lot of intellectual burden, premonitory symptoms that Tine talked about. So I do think there's a lot of space for a new mechanism of action here.

Question was on the D1/D2. I don't forget. So I think it's a little bit early to answer that question. And I'm not avoiding it. It's just that we are still running our Phase Ib trial. What I can say is that we have a powerful compound, and that will have an impact on the dose and that we probably will go BID. So that's where we are heading, but it's still early. But those 2 things are powerful very clearly to me.

Suzanna Queckbörner, Handselbanken. I'd like to ask some more strategy questions. So first of all, we've seen some companies that, like Roche, within neurology really focused on digital endpoints. And you did mention there would be some small investments in this space. So digital endpoints could be more objective, and given that we see strong placebo effect in some of these indications, how are you thinking about that? That would be my first question. And then a follow-up on previous comments regarding partnerships. So it seems like the sweet spot for partnering is sometime around proof of concept in terms of value creation. But looking at your pipeline, both ways for you to partner but also for partners to start considering your assets. At what point is this attractive? And how can you make value -- or maximize value creation if you're already later on in the journey?

Yes. I can start with your last question maybe as you think about this. Clearly, there is a value inflection point at the sort of proof-of-concept stage. So that's often the best position to be in from a partnering value creation also for Lundbeck. I think it might be different in the space of neuro-inflammation when you look at the broad range of potential patient populations that you could go to. And so I think there, you might want to consider even earlier access to discussions around who could potentially develop in other indications where we cannot invest today. And I think that's an interesting area of discussion we should continue to look at because as we know, that space, maybe you could have a pipeline inside a molecule scenario there, and we need to be open to look at partnering earlier there.

Yes. And to your digital question, it's a really great one. We hope a lot when it comes to digital. We think that may change the landscape, particularly in psychiatry, I would say. We really need to turn that simple readout when we ask how do you feel today to something that is objective. And you can do that. There are a lot of interesting things going on, measuring things like quality of life measures. Have you been cooking today? How many times did you do your hobbies this week, et cetera? Those may seem simple, but they actually convert something that is very subjective to something that's objective. Actigraphy is already used in other things, right? So there are a lot of very, very promising digital biomarkers that will also have an impact in neurology, for sure. We use digital readouts today. We have e-sourcing, our data that Bjorn can talk at length about what we do in migraine with these things, right? It's the digital infrastructure around it also that's important. There is an element here that is a big hurdle -- actually 2 elements here. And I've been part of this journey for quite some time. And one is really how you build enough data for regulatory acceptance. And the regulators are very open to this. But they have a lot of scale validation people that like to see a lot of data because they have -- they are used to see certain data. So you cannot just switch from the Montgomery-Asberg scale or something else. You have to bridge and show that it bridges. And they are very, very obsessed about clinical meaningfulness. It's just not significance. And one of my experience is in the cognition space. Just to remember one more word on a word list on a computerized test won't help you, right? You really have to show that is clinically meaningful for patient clinically. So patient reported outcomes will be part of this journey. So there is quite a big journey to really convert this to primary endpoints as secondary, at least supportive, maybe not key. It's coming strongly. The other thing that is actually something we start to be able to deal with is those devices change all the time. It's a quick, quick, quick progression in the technical solutions. And if you spend 5 years validating one method, it will be obsolete when you're ready. Now the regulators and people in this field have been smarter. They say it's not really the device. It's not really the classical device development. You're doing -- you're actually developing a particular way of reading things out. And if you can't -- take a simple example, step measurement, right, actigraphy. Yes, it's not -- if you use an iPhone or use something on your arm, whatever it is, if you're really measuring steps that you have to prove. So you don't need to validate your device so much any longer, but that was a big hurdle we're dealing with. So I think that is gradually disappearing, but it has to still be a lockdown device that you're using, meaning it's not changing over time meaningfully. Otherwise, you need to read, but it's going to change. But we have big hopes that this will be the dramatic shift. I'm not so sure about that. Anyone else?

Just to add one comment, sort of from a strategic perspective. I think the -- when you look at the landscape, the sort of health tech and biotech, there will be more of an interface of this going forward, this sort of advance of wearables, ability to measure real-world data. So we need to be very open to be there. Of course, not developing these inside but partnering with companies who can develop this for us. So I do see us continuing to move towards more. Also, when you think about commercial models, how do you address maybe total care for patients? And we provide the drug solution, but there are other elements to digital therapeutics, for example. So I think being open to see how you look at sort of total patient care is a piece of our strategic reflection we should make in the company.

Yes. Thank you, Charl. I talked about our real-world evidence stuff. That's really where you can use it a lot. And it's a little more acceptance how you validate those scales. So that's a field where we are doubling down. We talked about that. But maybe -- I don't know if someone likes to...

I can add something. We do have a team that looks into digital health technologies. But beyond that, what is the potential context of use, what is the usefulness, et cetera, et cetera, because that is where the field is changing. I mean the digital health technologies are there, but they are -- they don't have the face validity yet for some context of use. And that's where we are really carefully looking into that, too. If they come up, then we will be there ready to include them in our studies.

And maybe I could also add from the field of migraine where this is absolutely also a relevant question. So I will say 2 things. So we are working together with FDA on developing a new scale, [indiscernible], that is an FDA initiative recognizing that we didn't have sufficiently good outcomes. Our PACAP program is part of validating that scale. Let's see where that takes us. Hopefully, for key secondary endpoints, not only secondary endpoints. At the same time, we are also taking a step further than step counters because what really matters for patients is that they are out and about, able to participate in life. And we are trying to find digital ways, and we'll be testing it in the program to measure being out and about.

Great. Maybe just a follow up on that. So specifically with migraine and the data we saw from Tine on PACAP, there wasn't a clear dose response between the low dose and the high dose. And so I was wondering, in terms of second-generation migraine drugs because now given that the CGRPs are in place, do you think that clinical trial design will change, in which case, how are you thinking about that in more later-stage trials and especially where the placebo is so high?

Can I start?

Yes, you can start.

So I think Tine already explained why we do a dose-finding study very solidly. So you're addressing exactly that. We don't know how low we can go with this drug. At the same time, I will say our specialists, our advisers are saying, please bring us a drug that is treating it sufficiently well. So think about going to the market with one dose that is sufficient. So there are several parts in that development, but doing a very proper Phase IIb dose-finding study is part of getting there to what you're asking for.

I think it also is because we're shifting from IV to SC. So we wanted to do a classical dose response -- dose-finding study. But what I think you're also alluding to is, are we using -- are we planning on using Bayesian designs, other designs that will inform us earlier in our clinical trials. And yes, we are, when it's suitable. So we will do that, and we've actually discussed it quite intensely with this particular trial, I can say, whether we wanted to go down that route. But we decided not to because it was very important for us to get the dose right and test multiple doses.

And solidly document doses that are not working here.

I'm a big aficionado of Bayesian. So that's why she's smiling a little bit. I think it can be quite helpful, and we've seen Alzheimer drugs getting approved or accelerated approval based on a single Bayesian adaptive design. So it's really coming strongly. It's best suited to find a signal, those kind of designs. When you really like to tease out a dose response relationship, then frequentist designs are a little better suited. And that's where we landed. But we did pressure test that even for pickup, but this is a design that's coming strongly for more chronic neurodegenerative diseases.

For our alpha-synuclein, should we be lucky and go forward, of course, then it will be something that we will be looking at.

How are we doing? We have time for 1 or 2 questions? One question more. Last chance. Okay. Good Yes. Thank you for coming.

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