Welcome, everybody, to this Capital Markets Day for BioArctic. It's actually the first that we've ever done, and we hope that all of you, either here in the room today or listening in, will have just as much fun as we are planning to have. I will soon present to you the—I don't have the clicker, it's over there. I will soon present today's speakers and the agenda, but I just wanted to welcome you first and let you know that if you're interested in the presentation, it is possible to download that from BioArctic's website, either under Congresses or under the Capital Markets Day part of the website. With that, let's look at today's agenda. We have a packed agenda, starting off with more—it's pretty much divided into two halves. The first, before lunch, which will entail presentations by our CEO, our CFO, and our Chief R&D Officer. They will talk about, more on the strategic level, about where the company is today and where we aim to move this company in the future, in the next coming five years. For people here in the room, you will be served lunch after that. Hopefully, people at home can fix their own lunch. Afterwards, you will be invited back with presentations, more specifically on three of our key projects. It's Leqembi, it's the brain transporter, and then finish off with Exidavnemab. We're also super happy today to have Professor Lawrence Honig from Columbia University present here today, who will talk a bit about the clinical experience, real-life setting of Leqembi in the U.S. so far. He's treated a bunch of patients in his clinic, so we're really looking forward to that as well. We will also, obviously, have time for Q&A. For those in the room, you'll be able to ask them here, or you can also do what people online will be doing, and that is sending in their questions via the platform. We will try to manage and take care of all questions. If some questions remain unanswered after this day, then you're more than happy to reach out to the IR Department at BioArctic. Today's speakers, I quickly managed to tell you about the first three, and one in the bottom row. Here, in addition to what I told you, here to present Leqembi is our Chief Commercial Officer, Anna-Kaija Grönblad. We also have Per-Ola Freskgård, who's our Chief Scientific Officer, who will talk about the BrainTransporter technology. Gabrielle Olbert-Hillard, our Chief Medical Officer, will talk about our Exidavnemab program. I think that concludes the introduction. With that, I would like to hand over to our CEO, Gunilla Osswald. Thank you so much, Oskar. A great pleasure to be here today and see so many of you here in the room, and also welcome for those who are online. It is a really exciting day today with our first Capital Markets Day. I am happy to give you an in-depth look at the company and to share it together with several of my management team. I am also really, really happy with Professor Lawrence Honig, who has come all the way from the U.S. to share his experience of Leqembi. Over the past 20 years, we have built a strong foundation for BioArctic, which is based on our founders' vision to create one of the new successful companies in Sweden that will help to treat patients. Today, I can proudly say that we are really a good way on that journey to become one of the next major Swedish pharmaceutical companies. We are now entering into a new era, and we call that the growth era, and we will talk more about that here today. This is built on solid science and innovation, strong finances, and an organization with highly skilled scientists and well-educated personnel, and a value-driven corporate culture. We have the objective of helping patients with severe brain diseases around the world. Today, we hope to give you an in-depth look at our company, where we stand today, where we are heading, and some of our ambitions for five years ahead, 2030. By that, I want to say most welcome, and this is my presentation. We'll have three parts: a little bit of the history, and this is BioArctic. The second part is where we stand today, and the third one is the new era and our ambitions for 2030. As you know, it all started with Professor Lars Lönnfeld and his discoveries, first with the Swedish and then the Arctic mutation of Alzheimer's disease. What he saw was that the Alzheimer patients had increased levels of amyloid that was aggregated and misfolded and toxic in the brain. His idea was, if we can make a very selective antibody that takes away those toxic species while sparing the physiological forms, maybe that could help patients. That's what he found then, the Arctic mutation at the end of, or 1998. He also realized that what he saw in this Arctic family, that is generalizable and exists in all Alzheimer patients. The idea came from a family in the northern part of Sweden. He, Lars Lönnfeld, together with Per-Ola Freskgård, founded BioArctic in 2003. BioArctic generated Leqembi, which now is on the market around the world, helping patients with Alzheimer's disease. I came on board in 2013, and at that time, the company was about 20 people and a very academic private company that has then evolved. We did the IPO and went public in 2017. We have expanded the company with more programs and more projects. It was a very, very special day in 2018 when we saw the phase II-B results of Leqembi. Of course, 2022, when we saw the phase III results, and 2023, when we got the first approval in the U.S. Leqembi was the first fully approved disease-modifying treatment for Alzheimer's disease. That's a huge achievement, and it originates from BioArctic. Today, we are a bit more than 120 employees. We are located here in Stockholm, Sweden, and we have our headquarters and our labs here in Stockholm. We also have small subsidiaries around in the Nordic countries in order to prepare for commercialization in the Nordics, together with our partner Eisai, with regard to Leqembi. We are continuing to heavily invest in R&D. I would say that science, innovation, and research, and R&D will continue to be the heart of BioArctic. We will continue to develop and come up with new innovative treatments for patients with severe brain diseases. Patients are really in our mind all the time. My driving force is I really want to help patients. Our vision is a world where science defeats severe brain diseases. We focus on neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. These are areas where it's a lot of patients who are suffering, and it affects the families and comes with huge costs for society. There is huge unmet medical need, and this is really where we want to help. If we just look at Alzheimer's disease and Parkinson's disease, those are expected to double in number by 2050, exceeding 170 million affected people globally. That is a lot of people who are suffering from these diseases. It's deadly diseases that impose profound physical and emotional challenges on patients and suffering also for the families, of course. It's huge costs for society. Just one example is if we look at the unpaid caregivers in the U.S., they provide 18 billion hours of care annually, and that comes with a cost of about $340 billion. Huge, huge costs for society and suffering from patients and families. If you have seen this close by, you know what the disease is about, and that's why I really want to help. The good news is that there is a huge paradigm shift ongoing, and it's both on the diagnostic part and on the treatment aspect of Alzheimer's disease. The current treatments that were previously for treatment of Alzheimer's disease were mainly symptomatic treatments. What we are developing is disease-modifying treatments affecting the underlying disease, really slowing down the progression of the disease. It shows that the earlier we start treatment, the better effect it seems to be. It is really important to be able to find the patients at an early stage. The diagnosis has been a bit cumbersome, and it is now getting better and better when we see the first blood-based diagnostics. The first one was approved in the U.S. just recently, and I think that is a huge step forward because it makes it so much easier, that together, of course, with the clinical diagnosis, with the symptoms, to identify the right patients. The treatment where we are engaged is to find new, better treatments. Leqembi is the most significant breakthrough in treatment of Alzheimer's disease in 20 years. It is quite a long time since the last symptomatic treatment was approved, and now there are a couple of approved treatments in the U.S. Leqembi was the first disease-modifying treatment with a full approval in the U.S. Now in different parts of the world, we focus on what we say are neurodegenerative disorders that break down parts of the brain. Alzheimer's disease has been a core area and continues to be. We will also talk here today about alpha-synuclein diseases like Parkinson's disease and multiple system atrophy. We are also working on ALS, even though our research there is a little bit earlier, and other neurodegenerative diseases. I'm happy to say that we are among world leaders in two different areas. The first one is to generate highly selective antibodies that are targeting aggregated forms of misfolded toxic proteins. That's where we have, for example, Leqembi and Exidavnemab, and also our TDP-43 program for ALS. We'll hear more about that here today. The other part is the brain transporter platform, which helps to get different biotherapeutics better into the brain. This could lead to even better effect, less safety issues, and lower dose and more convenient for patients. I think this is the next generation of treatments for brain diseases. By combining these two, I think that also helps for the patients to get even better treatments. Since we now have this one, and we'll talk more about that, we are also both a company that generates new treatments, but also a platform company that can work with other companies and re-engineer their different assets to get them better also into the brain. We'll hear more about that also here today. It is, of course, very important what we do, but also how we work and what we do together. I think science, innovation, and high-quality research and R&D is, of course, really important for us. We have got a lot of award-winning science. It is also very important for us with leadership and the soft parts and our company culture. We work quite a lot with those aspects as well. We have a collaboration model. We have a business model where we work closely with partners, and we have a collaboration model, which we have heard is quite unusual and very successful. Just to describe that collaboration model a little bit that we have been prized for, we divided that into five different collaboration principles. This is just normal leadership in a way. What we see is that it is very important to have a vision together and a joint common goal so we know both of us where we are going. To create and develop a clear structure with clear roles and responsibilities, with a clear decision-making process so everyone knows how it works together. Then trust. It is very important to build trust and to continue to nourish trust and to maintain trust. When we work together with our partners, we really try to work as one team. That is what we have done with Eisai, we have done with AbbVie, and we are now doing with Bristol Myers Squibb. Anna-Kaija, you will hear her when she talks about the Nordic organization where they work really as one team together with Eisai. We say that we always strive for happy, happy. That is kind of win-win, but the next level of win-win. That means that we really want to see what is important for our partner. Meanwhile, it's really important for us to speak up with what is important for us. Can we then meet what's important for the partner and what's important for us? If we can meet those, then we can reach the happy, happy stage. I use this, for example, in negotiations. That's quite useful. Try to see, because if you really try to understand what is important for the partner and focus on the right thing, then you can help and also be very clear what's important for you. This model has shown that a very successful collaboration model that we utilize both internally and with different kinds of external partners. I mean, we are a fairly small company, about 120 people. We work, of course, with a lot of contract organizations and so forth, but also with our strategic business partners like Eisai and Bristol Myers Squibb right now. In our business model, it's really important for us to collaborate with Big Pharma. BioArctic has been collaborating with Eisai all the way back since 2005. It's a really long successful collaboration. It started off with a research collaboration that led to a license deal at the end of 2007. A new research collaboration continued, and the second license agreement with Eisai was in 2015. We went into a research collaboration with AbbVie in 2016 that led to a license deal in 2018. We just did the latest agreement, which was a license agreement with Bristol Myers Squibb, which is in Alzheimer's disease and also utilizing the brain transporter for one specific target. The rest of the brain transporter is still BioArctic's asset. I think we will continue to see this approach. It has shown for us to be a very successful approach to reach patients on a global basis, because then we can utilize what's our strength, which is really the innovation part, to come up with new ideas, really work in a very efficient way. We need the Big Pharma with a lot of muscles and a lot of money and a lot of big footprint around the world in order to help to come to access to patients. Where we stand today, we have four corner pillows shaping our position. The first one is the antibody platform that I spoke about. The second one is the brain transporter platform. The third one is financials. I'm really grateful that we have a strong financial situation. The fourth one is leadership and culture. If we start with the antibody platform, then of course it is really important with Leqembi that even though it has now started to come out on different markets, it is really important to continue with the development of Leqembi, which is ongoing with subcutaneous autoinjector, for example, and going even earlier into earlier parts of the disease to see if we can have even better effect. It is really important to continue with life cycle management activities, and that is what our partner Eisai is doing and we are supporting. The Nordic organization to build that and to prepare for launch is a very, very active work, which is ongoing between BioArctic and Eisai together to prepare for all the Nordic countries. Our internal program, Exidavnemab, which is in phase II-A, and Gabrielle will talk more about that here today, our CMO. Here we have opportunities in many different alpha-synuclein diseases. We'll hear more about that. We have other projects that are earlier, like TDP-43, which has opportunities for ALS, but also could have opportunities in other neurodegenerative disorders, including Alzheimer's disease as well. The brain transporter platform, we'll hear Per-Ola Freskgård talk about the brain transporter platform, our CSO. The brain transporter was last year validated in non-human primates. That's when we said all the time, when we have those data and when the patents have come into a certain stage, that's when we will go out and make more external visibility of our brain transporter platform. Per-Ola had his presentation in November at an international congress, PEGS, and there was a lot of interest there. We had quite a lot of interest along the way as well. We then signed a license agreement at the end of last year with Bristol Myers Squibb. It was a bit faster than I would have expected, and there was competition. There are several other big pharmas who are quite disappointed at the moment. There are other opportunities to work with us for them. We will see for the future. We are really happy about this great collaboration also with Bristol Myers Squibb. Our financials, we have a strong financial situation, and we expect to be profitable this year and onwards. We have this year already been entitled to an upfront payment from Bristol Myers Squibb of $100 million. Based on that, the agreement went into execution in February this year. Then two milestones from Eisai, one which was part of the approval of regulatory approval in Europe, and the other one is the first sales milestone. Those two together is EUR 30 million. We are now expecting continuous and increasing royalties quarter by quarter from Eisai. We have the right to 9% royalty on global Leqembi sales, except the Nordics where we have another deal to share. We have some more sales milestones also to expect. The license agreement with Bristol Myers Squibb is also a huge agreement for BioArctic, where in addition to the $100 million that we have got as upfront, we have the right to up to $1.25+ billion double-digit royalties on global product sales if we come all the way to the market. That is another really, really big agreement for such an early program that we have here. Leadership and culture. We focus a lot on working as one company without silos, so we really work close together. It is really great to see how R&D is working close with the commercial organization, how that can go back and forth and cross-fertilize each other. I am really happy about how we are working and also celebrating together. When something is happening in one part of the company, we all celebrate together because everyone has contributed in one way or another. The three leadership principles that we work according to, where the most important one is self-leadership, and everyone is a leader for their own life. Self-leadership is something we talk quite a lot about and is very important because we have so many really great experienced people at BioArctic, and it's really important that they can utilize their own strengths. We have the individual-based, the normal line management leadership, which of course is also important to see that our employees develop and so forth. We have a very important leadership, and that's the project leadership, because I mean, we are there for helping the projects to become products to help patients. The projects are very strong at BioArctic, and I think that's the way it should be. We work a lot with our company value, and we have a great company culture. I'm so happy about that. All of us do what we can to make sure that it continues to be a good company culture. Everyone, when you are at work, you want to focus on the right thing. You can do that if you have a good company culture. We have that, and we will do whatever we can to keep it and evolve it further. A couple of words about our strategic focus and what we're doing. We now are entering the growth era, as we call it, the next chapter for BioArctic. What we are talking about is to accelerate innovation, to work more on business development, and making our science accessible to more patients than ever before. I'll go through those three things step by step. The first one is accelerating innovation. Here we will continue to invest in research and in R&D. BioArctic is a really innovative company and has really highly skilled scientists with a lot of ideas. At the moment, we are looking into what are the new projects that we will be initiating also. There are a lot of great ideas. I think there will be more things coming out of the company. High quality, I mean, that's in the backbone of all our employees. It's really important to deliver with high quality. As I said, we are going to add a couple of projects also quite soon into our portfolio. We will focus, still have the focus in severe brain diseases, but we will expand our portfolio a bit. The brain transporter technology opens up further parts for the company. Both now we have combined it with all our internal different targets, but we see the possibility also to utilize our technology for other companies to take their assets. We will re-engineer their asset with our technology that can help their asset to come better into the brain. That is another part which you will hear Per-Ola talk a bit as well about. Those who have heard me before know how excited I have been about this technology for quite some time. It is really great to see now that we have combined it with all our internal targets and that we have great interest from other companies to also utilize our technology. We are shaping our organization for new partnerships, for also working on other modalities in the future. Our strength at the moment is, of course, antibodies. We are also working on enzymes, and we are also starting to work on antisense and oligos, and also looking into different parts of disease areas. Of course, we can also see that the BrainTransporter technology could be utilized for brain tumors, and we can open up other parts as long as it has to do with the brain. I think that's our key focus. That comes into our second strategic focus area. I work a lot with business development, and I really enjoy that part to work with other companies to see how our asset could benefit also for other companies. Before, those who have heard me talk before know that we have had an open door policy, what we called it previously, where Big Pharma came to us and they could ask. Now we are more proactively also out and talking to different companies about if they would like to use our BrainTransporter technology, for example. I think that unlocks an enormous potential for the company. We need to be very careful about when we select someone to work with. It's like a marriage. We really need to see that we select the right partners. Of course, money is important, but there are more things which are important and have shown to be very important for many years with our collaborators. By this, and also since last autumn, we also hired our first director in business development, and that makes it also possible to work more broadly in this area. I think it opens up further work in working with other modalities in the future and new disease areas, and it could lead to new revenue streams. The third important aspect is, of course, to make science accessible to patients. I mean, that's our whole goal, to help patients. We will continue to work with a successful commercialization of Leqembi in collaboration with Eisai. I think they are a great partner for us. We will hear Anna-Kaija talk more about how we're building that commercialization in the Nordics. Patients are in the forefront for us, of course, all the time, all the way from innovation. The idea came from patients to BioArctic. Of course, it's important to have them in mind all the way through to commercialization. As I said, it's important for us with business partners and leveraging their global reach to support more patients around the world. We have a lot of ambitions. If we look five years ahead, if we think about 2030, our ambitions are that we are on our way of coming towards the vision of our founders to become one of Sweden's next major biopharma companies. I think that we are really on a good way towards that. We will continue to work on that the coming five years by working on additional successful global partnerships. That is a very important aspect. The second one is, of course, to continue to build our project pipeline to see that we have a balanced and broader pipeline with projects in all stages of development. Of course, Leqembi. We wanted to have a successful launch. Of course, Eisai is in charge together with Biogen around the world. In the Nordics, it's BioArctic together with Eisai, who is working on establishing this as a successful treatment for Alzheimer's disease in the Nordics. We expect to be profitable. In the future, we're hoping for recurring dividends also to give something back to you shareholders. This is our ambitions for the coming five years. I think that was a good segue over to the financial parts. By that, I hand over to our CFO, Anders Martin-Löf, for the financials. Thank you. Thank you, Gunilla. I will try to be brief today. I hope you are all here to listen to our exciting R&D and hearing about the clinical experience from the U.S. with Leqembi. I will not talk too long. I will try to cover what our financial foundation looks like. I'll talk a little bit about what's happening with Leqembi on the market this year and in the coming years. I'll also talk a little bit about what revenue sources we see for the future. Starting out a little bit, this new era, what does it mean from a financial perspective? Actually, BioArctic has been a profitable company for most of the years that it has existed. In the past, the revenues have typically come from milestones, and those are inherently really, really lumpy. We would get, I don't know, SEK 100 million one quarter, and then there would be a number of quarters where we wouldn't have any revenues. That makes it really hard to plan long term. We had to have a little bit more of a short term focus. It also meant that we had to find partnerships as early as possible to sustain this model to be able to make sure that we get new milestone payments. What we have now is that we will continue to have milestones and upfront payments, as you've seen recently. Now we also have the royalties, and they are recurring, coming every quarter. That sort of gives us a base to really start to think long term. That opens also the strategic possibility to really focus on partnering at the right point in time. We do not have to do it as soon as possible anymore. If we find a great deal, we will enter into collaborations as soon as we can. If we do not, then we have the power to run the programs much longer ourselves to really get the most value out of our portfolio. That is really a big change coming with this new era. The first quarter of this year was really a first step in that direction. We made a profit of SEK 1.1 billion in operating profit. Still, most of the revenues came from milestones and upfronts, but the royalties were roughly SEK 100 million in the quarter. You should compare that with the underlying burn rate, if you call it that, but the whole cost for our organization, that was roughly SEK 130 million. We are almost at the point where the royalties cover all of our costs. We are expecting to become sustainably profitable. I do not think it will happen this year. We have guided that the profit for this year will roughly be in line with the first quarter profits. We will lose some money in the coming quarters. During next year, I believe that the royalties will grow so much so they actually start to cover the cost of our organizations. That is when we will turn into a sustainably profitable company. Over then to Leqembi, what's happening there. You know, most of you at least, that it was recently approved in Europe. It took a long time, but it was approved in April. That means that it is now approved in all the major markets. It is approved in 44 countries, where it is awaiting decisions in 12 additional countries. Basically, we are now available or becoming available in all of the major markets. The launch is going fairly well. It is in different phases depending on how long the drug has been approved in the markets. In Japan and the U.S., they have come pretty far. ASI is in the phase that they call the demand expansion phase. China is a little bit behind, we're in the demand creation phase. We're really in the establishment phase in Europe and the rest of Asia. It will take some time before the first patients get the treatment in Europe. It's expected to happen during the second half of this year, starting in Germany and Austria. Anna-Kaija will talk much more about this later on. We're also really happy that we are working on preparing the launch here in the Nordics, and that will probably take place in 2026. If you then look at what's happening with the sales, ASI have issued a forecast that they expect sales to increase from JPY 44.3 billion in their fiscal year 2024 to JPY 76.5 billion in fiscal year 2025. That's roughly going from SEK 3 billion, I should say, to SEK 5 billion. It's a 73% growth. It's growing really fast. As you can see on the right-hand side of the bar there, it's growing at a different pace in different geographies. In the U.S., they're expecting to grow by roughly 50%. That's a little bit lower than the overall growth of 70%. Whoops, I'm sorry. Now it's back. Basically, I think they are expecting strong competition in the U.S. from the only competitor that is out there. Whereas in Japan, you see that they have an even higher growth, 88%. There they have a really strong position being a Japanese company. Also, in the clinical guidelines in Japan, Leqembi is the only product that can be used for the earliest patients. Of course, really strong growth in China as well, over 100%, but they're starting from a lower base. Of course, you should see the highest growth in that region. As Gunilla said, we get 9% royalties. That's correct. We actually get an extra percentage point from Eisai that we then pass on to a partner that is entitled to royalties from us. The recorded royalty that you see in our profit and loss statement is 10% of global sales, roughly. If Eisai then hits this target of JPY 76.5 billion, we will receive roughly SEK 500 million from the second quarter of this year to the first quarter of next year. It's really becoming a large source of revenue for us. We should also recognize, I think, that it's still a fairly complex treatment to get. The patients have to get biweekly intravenous infusions to get their drug. That is what is approved now in 44 countries. Luckily, there are a number of simplifications that will come into effect in the coming year in the U.S. First of all, the maintenance schedule is already approved. Patients that have been on treatment for 18 months can go from biweekly to monthly infusions. That is already good for the patients. What is really going to make a big difference is the subcutaneous version, meaning that instead of getting an infusion, you can get your drug with a pen that you can administer yourself or together with your husband or wife. You can stay at home and not have to travel to the clinic. That is about to be approved in the U.S. for maintenance therapy. That is expected the last of August of this year. It will probably then also be approved for induction therapy. That means all therapy in the U.S. in the first half of next year. This will really make a big difference, moving the drug out from the specialty clinics more towards the primary care clinics. The other important step, and Gunilla already mentioned this, is that there is a revolution ongoing also in the diagnosis field. Today, in the U.S., you need to get a PET scan or take a lumbar puncture to get the diagnosis to really confirm that you have the amyloid pathology. That is also fairly cumbersome and expensive for PET scans. Now there are blood tests. The first blood test has already been approved in the U.S. There are a number of more tests that are on the way out on the market. Gradually, you will start to see a much more simplified way of diagnosing the patients, starting this year, but more and more so in 2026 as well. Another really exciting development is that Eisai is running a study of Leqembi in preclinical patients, that is, patients that still don't have any symptoms, to see whether you can delay the onset of symptoms or maybe delay it indefinitely so that you never get any symptoms. That trial is called AHEAD 3-45. It will be out in 2028. It will still be a number of years. If you ask me what's going to be the case 15, 20 years from now, I think that is the way how we're going to treat this disease. I don't think it will exist as it does today any longer in 20 years from now. With all these developments, Eisai is now engaging in a number of growth expansion initiatives. The first thing is just trying to explain to the general audience what we have learned so far, that the patients that benefit the most are the ones that are the earliest possible in their disease. Everything points in the direction that the earlier you treat, the better. To do that, you need to engage with primary care a lot more than they're doing today. Today, this is primarily a specialty care product and specialty care treatment. You need to reach these patients that are definitely, in most cases, not already diagnosed. You have to get into primary care and educate the primary care practitioners what this is all about and how they should take these blood tests. That is what Eisai is focusing on, targeting about 2,000 primary care practitioners in the first step in the U.S. They are also now starting disease awareness and brand awareness campaigns using direct-to-consumer advertising. Of course, it really helps if the patients understand if you have the earliest symptoms, you should go to your doctor and get a diagnosis as soon as possible to get your treatment as soon as possible. That is something that they have been doing for a while in Japan, and they are starting that in the U.S. now as well. Of course, building that then on the diagnosis process and the more convenient administration that I was talking about on the previous slide. All in all, Eisai, I mean, have issued a sales simulation. It's not a forecast, but they have indicated a little bit what could happen on the market if this comes to fruition. Basically, what they're saying is that they think that the whole market could grow from JPY 44.3 billion in 2024 to JPY 250 billion-JPY 280 billion in three years' time. That's roughly SEK 17 billion-SEK 19 billion in three years' time. That means that they believe that Leqembi will definitely become a blockbuster in the coming three years. What this means for us is, if the sales would be SEK 17 billion-SEK 19 billion on the global market, we would get SEK 1.7 billion-SEK 1.9 billion in royalties that year. It is also expected to become a serious source of revenue for us as well. If we get there to the forecast that they had for 2027, is that the end of the story? No, clearly not. If you start to think, how many patients are there actually? We do not know that today. It is really hard to know because no one has been getting a diagnosis since there has not been a treatment. It has not made any sense to get the diagnosis. There are estimates for how many patients there are. If you look at the bar here, these data are from GlobalData where they have estimated the number of patients with mild cognitive impairment and mild dementia due to Alzheimer's. They estimate that to be roughly 70 million people in the major markets, including China. When I try to calculate, what if Leqembi reaches the revenue simulation that I was talking about, and I add roughly the same amount of patients on [Kisunla], the competing drug, I try to say, let's make sure that I count as many patients as possible, I will still end up at the number that is lower than 500,000 patients towards the end of 2027. If you divide those by each other, basically, you get to the conclusion that less than 1% of the patients that would benefit from this treatment will be on treatment three years from now. That's a ridiculous number if you compare it to any other disease. If you say in cancer, roughly 99% of the patients don't get the treatment. I mean, that doesn't make any sense whatsoever. Over time, that number will increase significantly. Also, the 70 million bar will grow by itself since the population in these countries is getting older and older. The number of patients is getting higher and higher. Dr. Honig will talk about that as well. I think the most important part is that the diagnosis rate will start to increase immensely. It's less than 10% of the patients with mild cognitive impairment actually have a diagnosis to date. The number of diagnosed patients that get a treatment will also increase significantly as the treatment is becoming much more easier to administer to the patients. That's not enough. If the trial that is ongoing, the AHEAD trial where they are testing it on preclinical patients, if that would work out, then it's another 130 million people or so that would actually be eligible for this treatment. The 70 million number could be more than 200 million four or five years from now. This is really, in my view, going to become one of the big drug classes of the world. I often get the question, can we really afford this? This is going to be incredibly expensive. That's true. We are going to spend a significant amount of money on these drugs. The alternative cost is not zero. If you look at what dementia care costs today, I think the updated number from the Alzheimer's Association in the U.S. is $384 billion of dementia care in the U.S. this year. Is that a lot or not? If you compare it to the defense budget in the U.S., it's roughly 50% of what they spend on their military. We think they spend a lot of money on the military in the U.S. $384 billion is a huge amount of money. Actually, $250 billion out of those $384 billion come from the federal budget. More than 3% of the U.S. federal budget is spent on dementia care already today. The only way to control this is to make sure that there are fewer new patients getting dementia so they can stay at home and be healthy to be able to afford this whole challenge. That is why I always say, we cannot afford not to do this. It is the wrong question to ask, how can we afford to do this? I have talked a lot now about Leqembi. We are, of course, much more than Leqembi. We have a number of agreements on top of the Eisai agreement with Leqembi. We have already mentioned the Bristol Myers Squibb Peregrine Program that we entered into in December last year. We have an additional $1.25 billion in potential milestones there and double-digit royalties if that product comes to the market. We also have another agreement with Eisai where they are evaluating our brain transporter-coupled antibody BAN2802. If that evaluation goes well, they will have an option to enter a license agreement regarding that as well. We have a number of exciting future programs, especially the Exidavnemab program, which is really exciting to me. It is currently in phase II. It can really become a blockbuster in a number of different indications. We will hear Gabrielle talk a lot about that this afternoon. We have a number of other preclinical programs, the TDP-43 program for ALS, a program for Gaucher disease, and a number of other programs that could really become important sources of revenue in the coming years. The last part, I think, is also very, very exciting that we can now enter into new types of agreements that Gunilla was talking about, where we couple our brain transporter with a partner's drug so we do not have to develop everything ourselves. We hope to be able to enter into a number of such agreements in the coming years as well. That will be a really interesting way of filling our pipeline. All in all, I hope that you have been able to understand our message that, yes, we are expected to be profitable in 2025, and we expect to remain profitable based on the Leqembi royalties. That means that we have full funding to advance our R&D portfolio at full speed with long-term focus. We also have a number of additional revenue opportunities that we haven't tapped so far. We can now strategically choose if we want to partner our programs or if we want to advance them ourselves. If everything goes according to plan, you can also expect dividends in the coming years. I can't say exactly when. It really depends on what happens with Leqembi. In the next few years, we are planning to start paying dividends. I think that was all from me. I think next on stage is our Chief R&D Officer, Johanna Fälting, who will give you an update on what's happening in the R&D department. Thank you. Thank you so much, Anders. Can you hear me? Yes. Excellent. Thank you all for being here today. Thank you for being on the net as well. I'm going to focus on our science, our innovation, and our collaboration. I'm going to talk more in depth about our platforms that Gunilla mentioned, our technology platforms around antibodies and also around the brain transporter technology. I will talk about how we accelerate innovation in the new era. Looking at the science, innovation, and collaboration, I mean, we at BioArctic, we are working on the brain, the human brain. That is the most complex organ in the whole body. It's about 600 diseases that affect the brain. We have talked about a few of them, but there is much more to do about this. I would say that innovation is something that can't be forced. It's something that happens every day in small and big at BioArctic. It is fostered by a very strong culture of respect, of trust, of challenging each other, and allowing mistakes and learning from those mistakes. That's really important. Also, of course, allow time to test new things. I think maybe the most important thing for innovation at BioArctic is creative teamwork. At BioArctic, our R&D projects and the science are really at the heart and the focus of everything that we do. The project teams are empowered project teams that have the mandate and the budget to drive their project forcefully forward. I think that Gunilla talked a lot about this, that we are one company and we celebrate together. We do not celebrate in silos for one project that makes a success. Everyone is part of that celebration. Because if one project gets a lot of resources and attention, another project maybe had to stand back for that. It is extremely important to have this one company mind, I think. In terms of the research organization, we have a world-class, highly skilled research and development organization with a vast experience across the value chain of R&D, everywhere from ID into research, into clinical development, and to the market. We do continuously invest in R&D, as Gunilla told you, about 68% of our revenues goes into R&D. 70% of the personnel work in the R&D organization, about 90% of those have a PhD. It is a very high educational level. We have about 15 different nationalities. That speaks to, I mean, the kind of creative environment that you can have with this kind of diversity in the company. I think that's extremely important for us. In terms of our technology platforms, Gunilla has mentioned that we are world-leading with two technology platforms in precision neurology. Our antibody platform, where we very selectively develop antibodies targeting what we believe are the toxic species of disease. We have our brain transporter platform that delivers biopharmaceuticals into the brain, not only antibodies. It could be enzymes or any other biologic. When we say that we are world-leading, what do we mean by that? I think Gunilla touched upon this because Lars Lönnfeld, our founder, had an idea already over 20 years ago on what was the toxic forms, whereas many other companies were looking at general antibodies for a specific target. The way we look at it is that a protein can be in a monomeric form, and that is a physiological form. You probably don't want to touch that too much. Then the monomer, for some reason, starts to misfold. It starts to aggregate. These aggregates are the ones that we believe are the toxic forms of the disease. We call them oligomers or protofibrils. They continue to aggregate into mature fibrils and then plaques in Alzheimer's disease or Lewy bodies in Parkinson's disease. For Alzheimer, the protein that accumulates and aggregates is beta-amyloid. In alpha-synuclein disease, such as Parkinson, it's alpha-synuclein. In ALS, we believe the protein is TDP-43. What Lars found when he looked in the clinical picture in the Arctic mutation families that he found up in the north of Sweden was that they had a lot of these soluble aggregates, the oligomers or what we call the protofibrils. He said that what if we develop an antibody that selectively targets these species that are very abundant in the disease state, then we can probably do something to help these patients. You know also from the clinical studies that we are not only affecting the protofibrils, we are also affecting the plaques. We see total plaque clearance in the Alzheimer patients treated with Leqembi. We believe that is due to a shift in the equilibrium because, first of all, we target what we believe are the new toxic species and the soluble aggregates. You can shift that equilibrium by. I think that this is really unique for BioArctic. We have a unique competence in finding antibodies that selectively target the soluble species. It comes to our deep knowledge about the biochemistry around the antibodies, the assays to test them, but also to be able to, in a test tube, make all of these different forms of aggregates and select the antibodies that specifically bind to the toxic forms. This is what we have done with Leqembi. This is now what we are trying to do in the other alpha-synuclein disorders, such as alpha-synuclein diseases and TDP-43 for ALS. Alzheimer's disease is, of course, our core. As a result of this deep and unmatched experience, I would say, in protein science, Leqembi was the first fully approved disease-modifying treatment for Alzheimer's disease in the world. It is directed against these harmful, toxic, soluble species. This is a disease with a huge unmet medical need. Both Gunilla and Anders have mentioned this. Actually, you have changes in the brain maybe 10-20 years before you go to the clinician and have the symptoms. You can imagine that there has been a lot of damage already going on before you actually get your diagnosis and you start treating these patients. It is extremely important with the early diagnosis and then the studies that Anders alluded to that Eisai is now running in early patients. These are large unmet medical needs. There is now a new standard of care for treating these being established by introducing these new medicines. What you see in the bottom here is a PET image of the brain of an Alzheimer patient before treatment and after 18 months on Leqembi. What it lights up in green, that is the amyloid load. You can see how it reduces with time. As I said, our antibodies have a unique profile. We really believe that the targets matter. You can't hit all amyloid. You need to hit the thing that is actually toxic. These amyloid antibodies are built on a very strong genetic and pathological rationale. Lars looked in the clinical picture, and he saw the aggregates there. He directed the treatment towards those. The unique and targeted binding profile is really key. What I should say in Alzheimer's is that we have several opportunities. Of course, Leqembi is the first fully approved disease-modifying treatment. We also have these PyroGlu antibodies. The truncated Aβ or PyroGlu, this project is focused on novel antibodies that target PyroGlutamated -Aβ. That is a species that is a bit shorter, and it's truncated in the beginning. These monomers are much more prone to aggregates. They can lead to the formation of these harmful A beta aggregates. We have that program as well that is now licensed to Bristol Myers Squibb. We talked about the blood-based biomarker that will be extremely important for the treatment of these patients. There is, of course, combinational opportunities here with other symptomatic treatments. I think that there will also be a need for better symptomatic treatments in Alzheimer's and other disease-modifying treatments hitting other targets, such as tau maybe or targets within neuroinflammation. I think that this was the first project that really unlocks synergies across disease areas. We have learned a lot from Alzheimer's disease that we are now capitalizing on when it comes to our other diseases, such as the alpha-synuclein disease, where Parkinson is the most well-known one. Gabrielle will talk more about this in the afternoon. Here we have two projects, Exidavnemab, currently in phase II-A, and then we have a brain transporter coupled variant called ND-BT3814. These are also disease-modifying therapies. There is a huge unmet medical need for these treatments. No existing disease-modifying treatments today. For Parkinson, there is actually quite good symptomatic treatment. Even though you get this symptomatic treatment, the brain continues to deteriorate. We think it is really important to also do something for the underlying pathology and not only the symptoms of the disease. This is a younger patient population, many of them still at working age. There are several diseases here. Parkinson maybe is the most famous one. There is Lewy body dementia and MSA, multiple system atrophy, which is an orphan indication. We have a really unique binding profile of our antibodies that we have generated. They are built on genetic and pathological rationale. I would say that we have the most selective alpha-synuclein antibody that is currently in clinical development with an over 100,000 selectivity, sparing the physiological monomer and binding to what we believe are the toxic species. We have an excellent pharmacokinetic profile for this one as well in humans. Gabrielle will talk more about this. There are several opportunities for these alpha-synuclein antibodies with Parkinson, with DLB, with a later form of Parkinson, Parkinson's disease with dementia, and also MSA. Recently, we have received an orphan drug designation for MSA in the U.S. and the EU. That will make it a little bit easier for us from a regulatory perspective when getting these drugs through clinical development. We have the potential to be both first in class and best in class as a disease-modifying treatment for these diseases. Here as well, new biomarkers are being developed both for the diagnosis and to follow disease progression. It is extremely important because there is quite sparse pathology in these diseases. You really need to find good biomarkers to demonstrate an efficacy on disease modification. We have an excellent patent life for Leqembi up to 2046, including extensions. There will be a lot of time on the market when this is approved, when and if. ALS is still a research program for us, but it is also a devastating disease with very, very high unmet medical need. Here we have two programs, ND3014 and a brain transport coupled variant called ND-BT3814. These are disease-modifying therapies targeting a protein called TDP-43. They have an opportunity to reach the majority of all ALS patients because about 97% of all ALS patients have this protein in the brain. There are other companies targeting the genetic forms, but they are quite low, actually. For example, the SOD1 mutations, it is less than 10% maybe of the ALS populations that have these. Again, there is a huge unmet medical need. This is the most common adult-onset mutant neuron disease. The mean survival rate after five years is about 10%. It is a very, very bad disease. The sporadic ALS constitutes a major class, like I said, and the familial are quite uncommon, 5%-10% maybe. Very, very high cost for society and a global prevalence of about 223,000 in 2005. It is expected to grow. Again, this is a target that is built on a strong genetic and pathological rationale where you have mutations in the TDP-43 gene that will lead to ALS. You can see these aggregates in the brain. We have developed antibodies with highly selective targets for the aggregates, again, sparing the physiological monomer, which we believe is extremely important. For these antibodies, there are also other opportunities because actually in Alzheimer's disease, you also have about 50% of TDP-43% or 50% of the patients have TDP-43 inclusions in the brain. That is also true for frontotemporal lobe dementia. There might be a secondary indication here as well. Looking at our antibody portfolio, of course, Leqembi in all variants has been our main focus for many years, but we are much more than Leqembi. We have Leqembi infusion that is now on the market, the subQ that Anders talked about, and the presymptomatic treatments, which I also believe is going to be extremely interesting to follow. We have a backup program with Eisai. We have now the pyroglutamated antibodies together with Bristol Myers Squibb. We have our alpha-synuclein diseases with exidavnemab, the alpha-synuclein target for ALS, TDP-43. We have other CNS diseases as well for Leqembi because we have out-licensed Leqembi to Eisai for Alzheimer's, but other indications we own by ourselves so that we can drive internally. I think that we have a rich and well-balanced portfolio focused on brain disorders and with both partnered projects and projects of our own. In terms of CNS drug development, and especially for immunotherapies, one of the areas that will increase substantially is improved brain delivery. Per will talk much more about this in the afternoon. We know that we have clinical benefit from the antibodies such as Leqembi. It has been achieved, but it is a quite high dose. It requires quite high doses to reach the target into the brain. Maybe 0.1% or even more of the actual drug that you give enters into the brain. That is a real challenge for us. We are now working with a brain transporter platform where we have developed antibodies that can be actively transported over the blood-brain barrier. The blood-brain barrier is there to protect the brain from harmful things that should not get into the brain. Here we hijack or we capitalize on a transporter called a transferrin receptor, which transports iron into the brain. By capitalizing on this transport system, we can actually achieve much, much higher levels of antibodies into the brain by coupling them to a small modality that will bind to the transferrin receptor, thereby hijacking it. Like I said, there are more than 600 diseases affecting the brain. This BrainTransporter technology in non-human primate studies that we have performed has shown that we can increase the brain exposure about 70-fold of an antibody. That, of course, unlocks new targets to be reached into deeper structures of the brain and potentially also new diseases. What is more interesting is that these transporters, they are also on the surface of cells. You can not only transport things into the brain, but also into cells. That opens up a new target space for us as well. It unlocks partnerships across new disease areas and also with new modalities. This is not unique to antibodies. You can use it for enzymes. You can use it for peptides. You can use it for antisense or other things. In terms of our BrainTransporter portfolio, we have the PyroGlutamated-Aβ antibody that we have partnered now with Bristol Myers Squibb. We have an undisclosed Alzheimer target with Eisai. We have the alpha-synuclein program that we have also coupled to this BrainTransporter or ALS program. We have an enzyme program called Gaucher disease or GD-BT6822. This is a very uncommon disease that is a multi-organ disease. It affects all kinds of things. There are actually quite good enzyme replacement therapies already out there on the market. They only affect the peripheral symptoms because they do not get into the brain. If we can make this enzyme and facilitate the transport into the brain, we can also get to the central symptoms that are quite severe for this disease. That's a really interesting program. We are now expanding our technology, not only working with antibodies, but also working with enzyme replacement, which I think is a huge area. Of course, the platform by itself that Per will talk about, where we develop potentially new ways of transporting things depending on which target or modality it is. Looking at our whole portfolio, it's a combination, as I said, of fully funded projects run in partnership with global pharmaceutical companies and a very innovative in-house project with significant market or out-licensing potential. We are now combining these two platforms, our antibody platform, where we can selectively make very selective antibodies against different aggregated proteins with the brain transporter programs. What do we do to further accelerate innovation? I think we talk a lot about precision neurology here and what that means. It's our own science, but it's also innovation outside of BioArctic. One of the things that is moving really fast now is the biomarker and diagnosis of different diseases. For example, imaging, the PET imaging that we have talked about earlier, but also MRI as techniques of looking at the brain and really seeing where you have the pathological species. The biomarkers in CSF, that's in Sweden, it's quite easy to get the patient to give a lumbar puncture and you do a CSF test. In the U.S., it's not the same. The willingness to give these kinds of tests is not that high, actually. Even though it's a very good test and you can measure different things depending on the disease, really where we need to be is the blood biomarkers that is now approved in the U.S. We're so happy about that, that the amyloid biomarkers is now getting to be approved in the U.S. because now this kind of treatment or this kind of diagnosis might be able to go out to the primary care. Also, there's a lot of biomarker development going on with digital biomarkers, such as if you have a smartwatch or something. Especially for motor symptoms, such as in Parkinson, it's something that you easily can measure actually with this kind of device. You can get the continuous measurement of what's going on. I think the biomarker development, it is extremely important for us. It needs to go hand in hand with drug discovery and drug development. We need it to identify the right patient, to put the right diagnosis, prognosis, also to follow disease progression in our clinical trials and monitor the treatment effects. We know that for some of the early Alzheimer trials, about 30% of the patients were actually misdiagnosed because you had not done your homework looking at that they really had the amyloid pathology there. This is extremely important. What will we do further in terms of growth strategy? I think that this for us, the growth area is, of course, built on solid science and innovation, strong finances like Anders talked about, and then also an organization that is well-educated and a very value-driven corporate culture, I would say, that helps us to combat these kinds of diseases. We are looking into new projects built on our current experience around the antibody platforms, around neurodegenerative diseases, the brain transporter platform. We are also broadening our portfolio right now. We are looking into broadening our scope in severe brain disorders. We are evolving our competence to expand also the target space into new modalities. In the past, we worked on antibodies. We have an enzyme program. Now we are also learning more about peptides on other proteins and also on antisense. I'm trained at AstraZeneca. At that time, we used to talk about five Rs, which is really important, I think, as success factors for precision neurology. It all came down to the right target, the right patient, the right dose, the right study design, and the right safety. We have actually added two more here at BioArctic. One of them is the right modality because I think that there are many good targets out there, but there might be other modalities that we can actually use to catch these targets even in a better way. Right collaborations, that's extremely important for us for BioArctic. We are really skilled in collaboration, I would say, internally with external partners. I talk about academic partners, about CROs, and also, of course, with big pharma. We have been prized for that kind of collaborations. I think we are really skilled in working with many of the CROs. You should remember that we are a fairly small company. We talk a lot about how do you become a prioritized customer when you're a small company. That is maybe by sharing a lot of information and making the partner or the CRO feel committed to the project that we have. We go there and we talk about our project and our science and what we want to achieve together. That's part of it. We are also shaping our organization for this new era. We have a diversified recruitment base, I would say. Sometimes I get the question, are you able to recruit good people to a small country like Sweden? The answer is yes. We have recruited top scientists from Roche, from Denali, from Genentech, really the life science engineers' hubs, I would say, innovation hubs out there. We are also now expanding our competence in line with this pipeline expansion. We have this innovation group that Gunilla talked about, where we are looking into new potential disease areas or targets that we can work on and even new modalities. I think that in Sweden, we really hold top-ranking universities. There is a good recruitment base in Sweden as well. We are also able to recruit talent globally. Really important is the projects. The projects are in focus of everything that we do. The project teams are really empowered to make their own decisions. They have the budget to make their own decisions. We do not want to build deliberately. We have tried not to build a too strong line organization. It is extremely important that we have empowered project teams and empowered project leaders. I think that is extremely important. We have also developed a specialist career for people that are scientists. We have the line career, of course, but you can also be a specialist in science. That is just as important as the line career at BioArctic, if not even more important. I think it is extremely important with the project in the focus. We do have a strong competence across the whole value chain of R&D, all the way from the research to the market. We have the possibility to advance programs and expand the portfolio to really maximize value. Like Anders said, we have the finances to partner or not partner. We can choose when we do that, when we get a good deal. We are really skilled at research. We are really skilled at CMC development, at clinical development. One thing that we have said that we are not going to do, at least not now, is CMC manufacture because that is a whole nother game. That is something that we are not investing in, even though we are sponsors for the production of drug. It is not something that we will invest in. We keep to what we are good at. Then we find partners that we can collaborate with on other things. I think that part of our sustainable organization is this very strong company culture that really fosters an innovation spirit in the company. We are an attractive employer. We have less than 1% staff turnover. We have this specialist career, which I think is extremely important for the scientists, highly educated personnel that may be not always suitable to go into a line career, but actually can be specialists and can do the best thing in terms of the science. We have a successful track record of successful collaborations. That is really important. Gunilla mentioned the five collaboration principles that we have. What is, I think, super interesting with those is that it is not a product that management came up with. Actually, we sat down with all the people in the organization and we said, what is it that we do that makes us so successful in the collaborations? From that, the collaboration principles came down. We just wrote down how we actually worked. It is not a product from management. It is from the organization. That comes down to our core values as well. We have done the same thing. Yes. The key takeaways is that we are developing best-in-class disease-modifying treatments with several opportunities in neurological indications. We have two world-leading platforms, our antibody platform and the brain transporter platform in precision neurology. We are combining these with our internal programs, with external programs. Like Gunilla said, if there is someone from an external company that has a good target that they want to get into the brain, we can help them to deliver that. It does not have to be in our core areas. It could be anything, basically. We are expanding our scope in several different disease areas. I think that we have really an attractive portfolio that has reached a lot of external interest for potential partners. We need to decide also upon which is the best partner for us to work with. We have a highly skilled organization with vast experience across the value chain. We are supported by great collaborations in both ACI and BMS right now. Yes, that was my last slide. Thank you, Johanna. Thank you, Gunilla and Anders. Maybe I can invite the three of you all up on stage to do a bit of a Q&A before we head for lunch. I think there will be opportunities to ask questions here in the do we have a mic in the room for if somebody wants to ask questions? I am looking at the guys in the back of the room here handling we have a mic here. If anybody wants to ask questions in the room, we have a mic here. You can ask questions. I can start with a question that we received online for now. Then we can add questions from the room. Okay, let me see. Okay, they're dropping in here. Let me try to focus on one. There are a couple of questions here. Maybe this is more for Johanna, maybe Gunilla, Anders too. Yeah, because we're all involved, right, in the management team. It's about artificial intelligence, AI, right? That's a very hot topic now. How do we work with that? Do we see any limitations? Do we already include it in what we do? Is that something that we view as maybe a threat or an opportunity for the future? If either of you could allude to that. Gunilla, do you want to start? I can just start. Then I'm sure Anders and Johanna want to add. I mean, I think AI, I mean, it is here to stay. It is just something we need to embrace. We have started. We have been using different kinds of technologies for quite some time. I mean, you also need to make sure that you are doing it in the right way. Of course, we are using AI. We are looking into how we can benefit from that in a good way and in a safe way for our environment. We have built our own parts and then utilized that technology. I think definitely it is an area where everyone can be more efficient and use with the benefit, but with some care. If I may add on to that, I think that, I mean, in research, there is enormous potential in this. I think it all much started in looking at pictures, for example, and trying to do a better analysis of different pictures from immunohistochemistry or brain, for example, and stuff like that. We are now switching into doing more protein engineering. In the past, we did a lot of, we employed a lot of neuroscience, maybe. Now we're doing more protein engineering. In that space, there is really a lot of things that you can do with AI in terms of structures, modeling, docking different proteins, and trying to build new kinds of proteins. I think that's a really interesting area within the research. Then for clinical, for example, and I don't know if Gabrielle is going to talk about this, but we talk about digital twins, for example, in clinical trials. You might be able to reduce the number of patients in a clinical trial by including a digital twin. I think that's really an exciting area as well. All of these biomarkers that relate to the smartwatches and that, I think that's part of an AI evolution as well. There are enormous potential here. We just need to know what we're going to do with it and to do it safely, of course. Good. We've got a question in the back there. Hello. Thank you for this great presentation so far. My name is Suzanna Queckbörner. I'm from Handelsbanken. I have a question regarding the brain transporter platform. The combination with the PyroGlutamated- Aβ antibody is the most advanced, but out licensed to Bristol Myers Squibb. I was wondering, do you have any insight in terms of at what point to expect it to be in the clinic? First of all, something, a question more about the timeline. As a follow-up also, is that a limitation for further deals going forward, you needing that clinical data before more actually come on board? Two excellent questions. I'll start by saying, I mean, we are really happy about the collaboration with Bristol Myers Squibb. It's now them who are driving our program forward. It's called BAN2803, the one which is combining PyroGlutamated-Aβ together with the BrainTransporter. I can't really say exactly when they will go into clinic. It has passed the stage when we normally would say about two years to clinic. It's really them who are driving it. It is some more work which is needed before you can take it into the first clinical studies. I think they are really committed. What I see is a fantastic company doing a really, really great piece of work for that asset. We will follow that eagerly. Your other question is really important. I mean, as I said, the BrainTransporter technology is really something that we can utilize for many different parts. What we have out licensed to Bristol Myers Squibb is to utilize the BrainTransporter for PyroGlutamated-Aβ only for that target. We cannot do another deal with another company on PyroGlutamated-Aβ. We can do many other deals for many other targets and so forth. The platform is ours. We have several patents and are working on more patents and evolving this technology even further. I think that we can in the future see several new deals coming in this area, many collaborations in the future. If I may add to that, you asked about the clinic, if we need to go into the clinic before we can find new patents. I would say, or partners, I would say no, because this target is already validated by Roche and the brain shuttle that they have developed. I mean, the transferrin receptor as a transport modality in the brain is validated. The pyroglutamate as a target is validated by Donanemab. I think this is a match made in heaven, this project. I think it's going to be low risk. You should never say that, but still. I don't think that we need to wait for clinical data before going in. It's quite low risk. Thank you. We've got a question just there. Great. Thank you for taking some questions. [Johanna Nils] Redeye perhaps should already know this. But anyway, please give an insight. This opportunity to start Alzheimer treatment earlier than typically diagnosed is, of course, super interesting. And you will have some provide some results. Was it 2028? Could you remind us about the baseline of these patients and what time and duration they will have been given your treatment at that stage? Because if you start earlier before typically diagnosed, it will also presumably take a bit longer in order to see the results. Excellent question again. I'm sure that we'll hear more about Leqembi after lunch. There is an ongoing phase three trial, which is called AHEAD 3-45, where this is individuals who before they have symptoms, they have elevated levels of amyloid deposits in the brain. Depending on how much amyloid deposits there are in the brain, they come into either a study which is called A3 or the sister study A45. If they then have the level of amyloid deposits in the brain that they are in the A45 study, then the primary readout is a composite score called PAC5. Also, of course, you will look at how you take away amyloid deposits in the brain and so forth. It is a treatment which is four years. The last patient was included in October last year. Now Alzheimer Clinical Trial Consortium in the U.S., who is in charge of this study together with ACI, they are driving it mainly in the U.S., but also in other parts of the world. We are eagerly waiting 2028 when there has been a four-year treatment. All the data that we have seen from the phase three trial in early Alzheimer's disease alludes towards that the earlier you start to treat, the more benefit it looks like you can have of these kinds of treatments. I'm really excited about this new avenue when you, if you, so if you could push the symptoms even further ahead, that could really help patients have a better quality of life for a longer time. Very interesting. Another thing, I think you mentioned that on the brain barrier platform could also include tumor opportunities and collaboration, presumably. Yeah. This is an area, and I don't know if Per will come into this a little bit maybe in the afternoon. We see so many different opportunities for the BrainTransporter technology. I mean, of course, we started to combine it with our own targets. We have done that with all our internal targets. Now we are also discussing with different partners their different modalities and the targets. I mean, there is a lot of opportunities, including, but when we talk to big pharma, there is often the neurology department and then the oncology is separate. There are different parts of big pharma that we need to talk to. We see different opportunities for the future. That is also a very important area. Thank you. Got another question here in the—there you go. Tuck, Elsa. Hi, Joseph Heden, Arc Securities. ISO put a fair amount of emphasis on the blood test diagnostic as a driver for sales of Leqembi in the future. I'm just wondering, what do you expect the timeline to be for that to become, I mean, it's great to see it's been approved, the first one. What do you expect the timeline to be for that to be broadly commercially available, reimbursed, and to start to see the potential effect that that has on U.S. sales? Yeah. I think I'm sure we'll come back to this after lunch. I see this as a major breakthrough that the blood-based biomarkers are now starting to be approved and come out on the market. We saw the first one being approved recently. We expect one more to be approved later this year and then others to come. I think it's good that there are different alternatives. For Leqembi, I mean, it doesn't matter which one as long as it's a good one. I think that really opens up the opportunity. I think realistically, I mean, you are changing the approach that the diagnosis is being used currently. Normally, it takes a little bit of time to get the uptake. I think next year will be, I mean, where we would see more dramatic change starting this year. Also, I mean, it's being utilized for quite some time also in research. That's where we have learned about this. I think Sweden has also been part both in Skåne and in the Gothenburg area with really skilled scientists who have also helped to evolve this area. Now there are many different companies who are coming forward with their different tests. I think that US is, again, in the lead. Other parts of the world will also follow. I think China is also quite interesting because they started to commercialize and find the patients through blood tests and digital approaches. I think there are different parts of the world. Already, it's being used quite a lot for triaging, where you find those who have a clear difference in the blood test. You know that it's high likely that it's Alzheimer's disease. If you have a very low level, then it's something else. If you are intermediate, then that's when you need to confirm it with amyloid PET, for example, or CSF samples. Now, I mean, the first confirmatory test has been approved in the U.S. The short answer to my long answer was probably next year and onwards. Okay. Thank you. Perhaps one more. You talk about moving into your growth era with such a robust financial position. How does business development fit in? Are there any near-term priorities? I mean, our near-term priority is to find the right collaboration partners and right partners for the BrainTransporter technology as the first thing. For example, Exidavnemab, if we find the right partner, we will partner. If we do not find the right partner right now, we will have the opportunity to continue. We are in a very strong position, just like we were for the PyroGlutamated-Aβ program. We said that we could drive that further. We got such a good collaboration offer from Bristol Myers Squibb. We did partner. We have the same kind of strength position for Exidavnemab. We could partner or not. We will see. For the brain transporter, that is where we have our short-term, more active approach, finding some really good collaborations to help other assets to come better into the brain. It would be excellent if we can learn from others with other modalities, for example, combining it with our brain transporter. We can have a happy, happy, really, in that kind of collaboration if we can learn about oligos or peptides or anything, combining it with their knowledge and our knowledge. We can expand upon those. I think that would be a dream for me. Thank you. Mattias here. Thanks much. Mattias here from Handelsbanken. Late this year, we will have the results from two phase trials investigating the use of oral semaglutide GLP-1 in a population with mild disease using the same primary endpoints. There are some of the boxes as was used in Clarida AD. In a scenario where we have positive results, how should we think about the sequence of treatment, assuming both an oral GLP-1 and subcutaneous Leqembi is available over time? Two completely different mechanisms of actions. Linked to this, would the company be contemplating sponsoring a combination trial since access and reimbursement could be a challenge for two innovative medicines, proving that the combination may be favorable? Thanks so much. I'm sure we'll come back more to this in the afternoon as well. I think, I mean, I think Alzheimer's disease is a devastating disease. I really welcome different approaches. I think the best thing for the patients is, of course, if there is a possibility to combine different approaches. I really hope they will also be successful. That gives more opportunities for the patients. I think then, I mean, combination of different, maybe we'll see something with like amyloid targets like we do. Even if we target amyloid, we also have an effect on tau neurodegeneration, different kinds of neurodegeneration aspects, and neuroinflammation. We can also have an effect on GFAP, for example, in our Clarida AD study. I think that it's really good if we could combine with different targets for the future. I think we are just in the beginning of a new treatment paradigm shift for Alzheimer's disease. I really hope that more different targets will be positive, also helping patients in different ways. I really would like this question to come more in the afternoon when we have the true experts on stage. Any more questions in the room? We have one more there by Frederik. We have a couple here online as well that we should manage before we take lunch. Yes. Hello, and thank you. I was wondering when do you expect, if ever, competition from biosimilars for Leqembi? Will data exclusivity also be a barrier to entry? At that time, when you potentially get competition, how many other programs do you expect to have on the market? Thank you. Excellent question again. For Leqembi, lecanemab, the patent life, including five years extension, is 2032. That is for the bigger markets like the U.S., Europe, Japan, and so forth. What we have to think about is, of course, the patent life. We also have the regulatory and the market exclusivity part, which also adds. That is like 10 up to 12 years for different markets. I think that we have a really, really good coverage for quite some time ahead. There could be some smaller markets where it could be coming earlier. For the major markets, I think that's really, and of course, 2032 is something we're looking towards. That's why it's so important that we invest now so we have other new projects, programs coming, products to help to build for the long-term future as well. We'll come back to the patent life for Exidavnemab is up to 2036. Forty-six. Forty-six. Thank you. Oh, forty-six. Thank you. I mean, and we work actively on patents all the time. We have a really good patent strategy, thinking both about the target and also then to the substance and how we can prolong patent lives in different ways. That is an active strategy that we have for each and every project. Okay. I see no more hands in the room. We have a couple more questions here online. Some of them are regarding the BrainTransporter technology. I will save those questions for this afternoon when we have Per on stage. There is one here. This is maybe more for the AGM and the board. I will let Anders have a stab at it. It is from Luisa at Kempen. She is asking, what level of profitability would you expect to reach before you start distributing dividends? Is there anything we can say there? Yeah. Obviously, this is not my decision. It is a decision for the board. If I would recommend the board, I would say that I would recommend them to wait until we see that we are sustainably profitable from the royalties. That could happen already in the beginning of next year. It could take a little bit longer. We just do not know. I would hope to be able to give the board that recommendation within a year or two. Thank you. Any more questions in the room? Not that I can see now. I think we have all earned a lunch. We will see you back here at 1:00 P.M. Thank you so much for this session. Welcome back to this second part of BioArctic's Capital Markets Day. After a very interesting start of the day, more focusing on the strategics, we are going to make a bit of a deep dive into the business this afternoon. Just before we do that, and before I present my colleague, I was told also I forgot to introduce myself before the start of the first half. I will start with that. My name is Oskar Bosson. I'm the Head of Investor Relations and Communications at BioArctic. Enough focus on me. I think let's now hand it over to our Chief Commercial Officer, Anna-Kaija Grönblad, who will introduce this first section, which is about Leqembi, where we will also have, as we've said before, Professor Lawrence Honig, and that will be followed by a Q&A. Until then, it's your floor. Thank you, Oskar, and good afternoon, everyone. I hope you enjoyed a nice lunch, maybe some fresh air. I'm going to continue speaking about Leqembi, even though we had a lot of interesting questions in the morning session. I have 20 minutes of my time before I hand over to Professor Honig, and we're all very excited to hear about the clinical experience in the U.S. There's going to be a little bit of repetition or some overlap. I'm just going to say a few words about Alzheimer's disease as such before I move on to Leqembi and what is the status also on the global and European level. Then I'm going to speak a few words about the preparations for the Nordic launch. That is the plan. Just to start off again, I mean, I think you've all heard this, and I think everyone can relate to this disease of dementia. I mean, on a global level, Alzheimer's and other sorts of dementia is estimated to affect over 50 million people worldwide. If you think about it, in only 25 years, this number is predicted to more than triple in 2050. In America, I read, there is about 7 million Americans living with Alzheimer's disease. Here in Sweden, it might be 120,000 patients. It's quite difficult to estimate how many have MCI, mild cognitive impairment, also due to the lack of diagnostics, but there's a lot of people also having MCI due to AD. This is a very common disease, but it's also important to say it's also a chronic and a fatal disease. As we live longer, and maybe some of the cancers that we have in life today, I mean, they're becoming more and more chronic. Actually, in high-income countries, Alzheimer's disease is actually the second leading cause of death. Maybe that's not something that you think about all the time. Of course, this means a heavy burden for the patients and their caregivers and a massive cost for the society. Anders mentioned the cost for Alzheimer's in the U.S., more than $380 billion. Here in Sweden, there is a report saying that dementia costs about SEK 80 billion per year for society. A majority, around 80%, is affecting the municipalities. This is for the cost for nursing homes and home care, for instance. Only 2% is about drugs or healthcare. Very often, this disease is diagnosed too late. There is a lot of stigma, so a lot of patients do not seek help, but it is diagnosed too late. In the Swedish Dementia Register, for instance, 60% of the newly diagnosed patients are already in the moderate or severe stage of the disease. There is plenty to do here. This we have already talked about. I mean, the indication for Leqembi is here where you have early Alzheimer's disease, MCI due to Alzheimer's disease or mild AD. This is where actually the patients start to see some cognitive impairment or some implications in their activities of daily life. As mentioned before, you can actually see increasing amounts of abnormal values in a number of biomarkers such as A-beta-42 and p-tau, for instance. This is the so-called preclinical AD where the AHEAD 3-45 study is being performed, as Gunilla Osswald mentioned. When you think about it, this phase of early Alzheimer's disease is maybe around, you stay in that phase for maybe 10 years or so. Clarity AD, our phase III study, was done during 18 months and somewhere in this phase. It means a lot if you can keep patients in a milder form of Alzheimer's disease for longer so they can stay more independent. You can hopefully also avoid some of the costs then mainly coming from the moderate or severe stage of the disease. I think this is a nice graph just to show how the disease progresses. It is really exciting times, I think, for the Alzheimer's disease area, both in research but also for patients. Being able to launch Leqembi is really exciting times and will come also to the development of the blood-based biomarkers. Just to say a few words about the results, and as Gunilla already mentioned, this is not a symptomatic treatment. This is actually affecting the underlying disease. This has been shown by decreasing the amyloid burden, but it has also been shown in a number of downstream biomarkers. Here in the left-hand side, I kind of, I'm showing the effect on the CDR-SB in the EU population where you're excluding the homozygous. That's meaning that you don't, so you're excluding the patients that have the risk risk gene of ApoE4 from both your parents. You show a 31% slowing of the disease progression versus the placebo arm. That's what the CDR-SB shows, how the cognitive and the functional parameters are changing along the way. Possible side effects are infusion-related reactions or headaches or something also called ARIA, which is imaging abnormalities that you can see on the MRI. It could be either an edema or it could be a microhemorrhage, for instance. These things happen, but the majority of these ARIA occur quite soon within the first seven doses of the treatment. About 2% are symptomatic. Of course, some can be serious, and that's the kind of the meaning of having the MRI examinations early on through the treatment. Also, what I would like to show is a couple of sub-analyses from this full Clarity AD study. On the left-hand side, and what Gunilla talked about earlier about that, we have some clear indications that the earlier you start treatment, the better. On the left-hand side, they have pulled out a patient population with no or low Tau population. Actually here, you can see there are patients after both 18 months of treatment and in the open label extension arm up until 36 months of treatment, around 51% of the patients are actually getting better. I know this is a very small sample size, but it's really interesting to see these data. Then also on the right-hand side, when you look at another way of identifying early patients, those having amyloid burden of less than 60 centiloids, also here you can see an even better effect on the CDR-SB, around 51% versus the placebo arm. This is also continuing when you continue treatment up until 36 months. This is really interesting to follow. During the AAIC Congress in July later this year, Eisai will be presenting data up until four years. It will be interesting to see. Where are we? Anders mentioned that Leqembi is now approved in 44 countries. It has been on the market in the U.S. with full reimbursement for two years and in Japan for one and a half years. The majority of the sales is coming from the U.S. What happened most recently in the U.S. Is that Eisai have received an FDA approval for the IV maintenance dosing. That was early this year. What can be, what is fair to say is that it's been a lot of focus in these countries really to set up the infrastructure for these new patients. I mean, the new patient journey that is happening. It's been a lot about reimbursement both for Leqembi, but also for PETs, for instance, but also on securing capacity when it comes to infusions and MRIs and also nurses and maybe neuroradiologists that are going to look at the MRI scans. As Anders mentioned, now they're focusing even more on the demand stimulation and expansion phase. As said, I mean, having knowing that a lot of the patients are in the primary care, they might not seek help and they are not referred to specialty clinic. Here, there's a big need of education and disease awareness and coordinating those networks between primary care and neurologists. Also, what is interesting is to collect real-world data on Leqembi, and we're going to hear a little bit about that from Dr. Honig and to kind of share that experience across sites. In Japan, Eisai has had a good benefit of being in the field for many years and launching Aricept more than 20 years ago. They have also been very successful in introducing a very more centralized patient journey. What they are doing now is, they have some sites that are introducing treatment for patients while other sites are following up on the patients, which kind of frees up capacity in those hospitals. If we talk about Europe, as you heard, I mean, we just recently got the European Commission approval finally, I would say. ASA is aiming to launch primarily in Germany and Austria later this year, and then in the coming countries or next year in 2026 in the other countries in the EU. What happens now is that there are some risk minimization measures, for instance, the PASS registry, which is the post-approval safety study, and a controlled access program that needs to be implemented. This is in dialogue with the European authorities and the national authorities. Sometime later this year, a launch is expected in Germany and Austria. In the U.K., there are some out-of-pocket sales while they're waiting for a decision from NICE on the reimbursement and as well as the NHS. Also in the U.K., ASA has submitted the maintenance dosing to the MHRA, the regulatory bodies in the United Kingdom. Hopefully that will come out later this year. Exciting times ahead for Leqembi. As already mentioned, I mean, the introduction of hopefully the subcutaneous autoinjector for the maintenance treatment with the PDUFA date in August will really help to potentially free up some bottlenecks in the healthcare, but of course also give a lot more freedom for the patients to be able to inject themselves at home or with the help of their caregiver. Then later in 2026, they're expecting also to have the initiation treatment approved for this subcutaneous autoinjector. As well as potential new expanded indications, we are, as Gunilla mentioned, the AHEAD 3-45 study in the preclinical Alzheimer's disease is fully recruited as of the end of last year, and the results are expected in late 2028. A lot of things happening. We have already talked about the blood-based biomarkers, and we discussed, Professor Honig and I during lunch, how is this, if he has any experience from this in his clinic in New York, it was obviously a little bit different that you will come back to. Maybe not the access has not been that great in New York so far, but it has been tested, for instance, here in Sweden in Lund by Dr. Palmqvist and Professor Oskar Hansson. Clearly, I mean, this will save time and resources for the healthcare going forward. It has the similar accuracy in detecting Alzheimer's disease, just like CSF, for instance. Probably it is not going to be used in the primary care centers immediately. Probably they are going to start in the specialized clinics, specialty clinics, memory clinics, but in the future, to be used as a triaging tool will be very valuable. What has also been mentioned is that since we do not have maybe enough specialists in the future, this could be used as a very efficient way of sending the right patients from primary care to the specialty clinic, because there might be patients, of course, that have cognitive problems due to other reasons, and they should not be sent to the memory clinic. I think there is a big opportunity here going forward with these blood-based biomarkers. Finally, to say a few words about the Nordic launch. I must say I am really, really excited to be part of this journey. I have been with BioArctic for four years, and finally, as I said, we have the approval for Europe. What we have done now is that we have built a really, really strong team with a lot of experience and competence, and not the least the motivation to drive this mission towards the patient to prepare for this launch internally and externally, and also to be part of the founder's vision to help develop BioArctic as a company. I mean, I must say this is the most exciting launch in the industry, I must say. As Gunilla mentioned, we have subsidiaries in the other countries, and now we're about more than 20 people at BioArctic preparing for this launch together with ASA. It's a 50/50 agreement, and we're really working as one team towards the healthcare. They are going to shift some of their people from epilepsy into Alzheimer's disease. We're going to increase gradually but responsibly the team here in the Nordics. I also must say that, I mean, since BioArctic has been around for more than 20 years and collaborating with academia and healthcare, we have an excellent foundation for a launch in the Nordics. I mean, since Sweden and other Nordic countries have a history of Alzheimer's disease and blood-based biomarkers, I think the foundation is there for a good launch in the Nordics. What is it that we're doing right now? I mean, we have been preparing for this launch for a couple of years or so, and together with Eisai, we are supporting them when it comes to the market access. What usually happens already a couple of years before is that we have these horizon scanning meetings, and we're meeting payers and decision makers explaining the drug and how the patient journey works and what is to be expected. Of course, they have questions about how many patients are really in scope for these treatments and so on. Now we have submitted or are about to submit, or Eisai has also to the authorities when it comes to the health economic evaluations that need to take place for the price and reimbursement topic. That is happening. I also want to stress that we have been in dialogue with a lot of sites across the Nordic countries to discuss this patient journey and what it means when it comes to resources that are expected. Some neurologists might have some experience from MS drugs, for instance, whereas some memory clinics have not used these innovative biologics previously. There is a lot of dialogue ongoing now, which is of course now intensifying since the European Commission approval. Now we can also talk proactively about the drug and its safety and efficacy and so forth. What is clear is that some clinics are there. They're very well informed and educated, but there's a lot of sites that are not really there when it comes to the knowledge and disease awareness. We are investing a lot in a new educational platform, I mean, digital education, and also to create a yearly Alzheimer's disease symposia, Nordic educational symposia, which is going to happen after summer. This is a really, really big investment that we need to drive as well. Finally, I mean, what is important is to engage in very high-quality collaborations to continue that collaboration with the academia and the healthcare providers. I just put down a couple of them, PROMINENT and REAL AD, you can Google if you want, but it's about precision neurology to try to identify, diagnose, and to treat and follow up patients in a very structured way. This is PROMINENT, this European kind of public-private partnership that is led by Linus Jönsson here in Stockholm. The REAL AD study is driven by Dr. Mikael Schöll in the Gothenburg area, where they're also kind of validating these cognitive tests, digital cognitive tests, but also blood-based biomarkers in the population. Have a look there. These kind of collaborations are also very key for us to continue on the path forward. Twenty minutes has gone. This is my last slide. I felt like I was speeding up, but I think you've got the message now that Alzheimer's disease is a chronic, deadly, and costly disease. Now finally, we have some hope to give these patients. It is a high unmet medical need out there, and we're looking forward to launching also in the Nordics in 2026. This is really the start of the paradigm shift as we have been talking about, and the global launch is progressing well. We are ready also here in the Nordics for a launch in 2026. That was my slides for now, my 20 minutes on time. I'm going to hand over to Professor Honig from Columbia University in New York, and you can give us some real-world experience. Thank you. Thank you so much. It's a pleasure to be here in SVAIA. I guess the next slide is my title slide. Good. Very, very good technology. Nordic technology. I think as was often the case with several speakers, you'll hear a little bit of duplicativeness, but that's good. Always good to hear something more than once, I think, anyway. Of course, if you have Alzheimer's disease, it's a necessity. I did include the Swedish flag just to remind myself where I was, but I also included a little flag at the bottom. In the present climate, I thought I would include the New York State flag, which you may not be familiar with, rather than the other flag. In case you're wondering about these two ladies at the bottom who flank the symbol, that is liberty and justice, two qualities perhaps not quite as in good supply as we would like some of the time. I like to present my disclosures just so you do know that I do consult for BioArctic and other companies, as well as receive research funding from a large number of companies, many of whom do make monoclonal antibodies and other treatments for Alzheimer's disease and related disorders. I'm going to actually step back for a moment. You've been hearing a lot about the exciting work that started out here in the Stockholm area in BioArctic for many years. I would like to go and just put it a little bit in context. I'm going to speed through a few little slides. I hope it's not too boring to most of you, just about how did we get to where we are. The first thing, the question I get in the clinic so often, and that investors ask and that others ask is, what's the difference between dementia and Alzheimer's disease? Dementia is a deterioration in intellectual capacity that affects one's activities and ability to do things. It's just a syndrome. Alzheimer's disease, of course, is a specific medical diagnosis and something which we can now treat after a century of knowing about this disease. This disease, as you've heard before in a variety of other graphs this morning and this afternoon, is increasing. It's increasing in the United States. It's increasing in Europe, and it's increasing throughout the world. It is common, but it's not universal. Not every single one of the people in this room is going to get Alzheimer's disease. If you live to your 90s, you unfortunately have a significant chance, which is why we think it's so amazing that we have these therapies, these monoclonal antibodies that can slow down the progression of disease. Just not to leave Sweden out of it. This is a recent paper from the past year showing the prevalence of dementia in Sweden and just sort of accentuates some of the figures that Anna mentioned, which is that it does occur throughout Sweden and occurs in those born inside and outside, dare I say, as well as dementia, of course, occurs, but so does cognitive impairment that doesn't yet quite reach the boundary that we set to call something dementia. I'll discuss that a little bit more. What other kinds of dementia are there? Alzheimer's disease is far and away the most common dementia of the elderly, not in 20-year-olds, where dementia is very, very rare, but Alzheimer's would not be common at all. Lewy body dementia, which I think you'll hear about later this afternoon from Gabrielle, is the second most common cause of dementia. If those of you have been reading old medical texts that said vascular diseases, those are not correct. The frontotemporal dementias, which are unfortunately also a little bit more prevalent here in the northern regions of Europe, are also a prominent cause of dementia, and vascular causes and other causes are much less common. How does this relate to biology? It's key to think about the proteins involved. Alzheimer's disease is primarily, and at least starting out, a condition in which amyloid is not normal. There's more amyloid than there should be in the brain, and it's aggregated. You heard about that, and you heard about Lars Lönnfeld, the founder of BioArctic's amazing work in looking at that in the 1990s and since. The second most common protein is synuclein, and that's the primary protein that's involved in Lewy body disease, which you'll hear about later on. Tau is involved in a number of brain diseases, but in particular is involved in Alzheimer's disease and is a reasonable target as well. Amyloid is the primary target because it is the upstream and earliest feature of Alzheimer's disease, as you saw in the very nice curves derived from Clifford Jack in the prior talk. This is kind of the way it works. For those of you who wanted a little refresher, you start with amyloid. The amyloid brings tau changes. The tau changes seem to bring neurodegeneration or loss of nerve cells and their connections. There is brain reaction or astrogliosis or inflammatory changes. There are co-pathologies. That is, the synuclein pathology in particular can occur together with the amyloid pathology. In those situations, we have to decide what to do. I'll mention that later. There is a spectrum of affliction, if you will. There are people who think they have something wrong and may or may not have something wrong. There are people who think they have something wrong and definitely have something wrong. They have the beginnings of Alzheimer's disease, but it's just not diagnosed as dementia. There are people who clearly have dementia. Then, as you heard, even those, only a fraction of them go to their doctor early on, and a significant fraction may not appear until they no longer can take care of themselves, which is unfortunately a little bit late for some of the therapies we have. It is great that we have the ability to diagnose it more definitively earlier on. I will not talk too much about that today because I am talking mostly about treatment, but I will touch on that a few times, as you heard also in the prior talk. To summarize, diagnosis and treatment, where we are at is that Alzheimer's disease can be diagnosed, as you heard, with either PET or spinal fluid, and now with blood. Future of Bio has released the first FDA-approved blood test in the United States. Diagnosis is particularly important because we now have treatments. Previously, people would say, "Why would I want to know?" Now the reason why you'd want to know is because we have something we might give you. That is important. It is a big difference. As you heard before, lecanemab is now approved not only by the Food and Drug Administration in the U.S., not only by the European authorities, but also by authorities throughout a variety of Asian and Middle Eastern countries, not to neglect Mexico and a few others. I am going to talk a little bit about how we got to lecanemab and then talk about the real-world use of lecanemab. The therapeutic strategies, as you might imagine, given that amyloid is the beginnings of Alzheimer's disease, some of the most important strategies have involved manipulating amyloid. There are ideas of bothering tau protein and bothering other aspects of the neurodegenerative process. It is really the amyloid strategy that is the only one that has worked so far, although we have a number of very interesting agents in development, we as in the community at large, for other molecules and other aspects of the process. The first trials were of active immunization, then a passive immunization. You can see then at the bottom, the three drugs that have been approved in the United States, aducanumab, lecanemab, and donanemab, the first one no longer on the market, all are based on the strategy of impacting amyloid. Where did it start? It started in 1999-ish when there was this amazing Nature paper that you could immunize mice against amyloid. These are mice that are destined to get Alzheimer's disease as much as a mouse can, and they would not get as bad or as much Alzheimer's disease. It was quite amazing. Their brains were better, and they swam better in the maze. You see the maze on the left. Do I have a laser here? I do have a laser, yes. That is a mouse swimming in a maze. Okay. That is from Wikipedia. I figured I would be neutral. That went amazingly fast into an active immunization trial, which failed because of side effects, and then a passive immunization trial with the antibody bapanoezumab. That antibody clearly did clear plaques to some extent, and I won't go into the details of it, but it didn't also cause impressive side effects that were unknown to us neurologists and did not, however, influence clinical course over an 18-month pair of phase three trials. It was a sort of a first starter, and that was followed by some other antibodies, most notably lecanemab, otherwise known as BAN2401 for BioArctic, the BA. In the phase II trial that you heard a little bit about earlier, it was really quite impressive for a phase II trial in the sense that there was a dose-dependent marked clearance of amyloid from the brain, a marked improvement in biomarkers, and a dose-dependent improvement on a variety of clinical measures. That phase II study was only a phase II study, but it was a very large one and impressive in the dose dependence of the drug. It also had side effects, but we'll talk about side effects a fair bit later on. It was followed by a phase three study, which you've heard probably quite a bit about today already, the phase three Clarity AD trial, which I was involved in and still am involved in the extension phase of. There it was clear that no matter how you looked at it, lecanemab was an efficacious drug for Alzheimer's disease. There were a lot of naysayers who did not think that this strategy would ever work because of bapineuzumab and some of the other drugs that preceded it, including some that I was also very key involved in, such as solanezumab and other antibodies, crenezumab, and gantenerumab, and a few others. Leqembi worked, and it was not equivocal at all. It cleared amyloid on PET scan very substantially, and it caused a clinical benefit no matter what scale one looked at. Whether one looked at functional scales, cognitive scales, or biomarkers, there was an improvement in patient status. There were also adverse events. We should never neglect that. That has been really the thing that has caused, as far as I'm concerned, slowness in, for example, European regulatory approval, dare I say, here in Europe, but also in the uptake, even in the United States, because of fear and mystification of the use of this drug because of the fact that there is a small incidence of significant brain side effects. Here we are trying to improve people's brain, and we can have brain side effects. This is probably too small for you to see, so I think we'll go on. We will have some more slides on adverse events. Before we do that, the drug, in the meantime, aducanumab had very similar results, although the clinical efficacy was less clear because the drug study was terminated prematurely. Donanemab had a phase II trial, and it also showed very similar curves, as you can see here, and very similar degree of clinical efficacy and amyloid clearing. Their phase three trial, again, matched their phase II trial. I should say that in the Alzheimer's world, it's not always true that phase three trials replicate phase II trials. The impressive thing about these anti-amyloid drugs, for both lecanemab and donanemab, was that the phase three trials and the phase II trials matched each other very well, again, lending credence to the strength of the effect of these drugs. In terms of hazards, as you've heard, there are these hazards called ARIA, or amyloid-related imaging abnormality, and they occur principally in the first half year of therapy, whether we're talking about donanemab or aducanumab or lecanemab. We're going to talk more about them. They relate very much to the ApoE genotype. As you know, all of us are either non-carriers, carriers, or homozygous carriers on both sides for ApoE for allele. The side effects vary between the drugs, and I'm going to show you this slide again later on. The basic bottom line is that, as currently administered in the phase II and phase three trials, the incidence of ARIA-E and ARIA-H was lowest for lecanemab compared to aducanumab and donanemab. We'll talk a little bit more about those side effects later on. The current state is that in the U.S., the FDA-approved anti-amyloid therapies include these three; it did include these three drugs, aducanumab, lecanemab, and donanemab. Aducanumab is no longer on the market for marketing reasons, and a little bit more complicated than that. Two of the drugs are on the market, and lecanemab in particular has been on the market since January of 2023 and approved by our Medicare National Elderly Insurance since July of 2023. We have had a fair bit of time to go and deliver these drugs, and I will tell you about what our experience has been like in New York. The clinical trials clearly show that these drugs were clinically efficacious, that they were biomarker efficacious, and that there were side effects and are side effects, including this brain edema and brain hemorrhage, but that these are manageable. I think this slide pretty much says what I just said, which is that the drugs have clinical efficacy, biomarker efficacy, and adverse events. Let us go into the details a little bit. In the clinical trials, and part again of making this a bit mystifying is that in clinical trials, of course, we have very strict eligibility rules often, and for good reason. We want homogeneity of patients, and we want to make certain that our study results aren't confused by extraneous events such as heart attacks or cancers or unexplained falls or deaths or things like that that might interfere with our interpretation of the drug effect. In the clinical trials of lecanemab, for example, there was a defined age range. There was defined body range. Many of you may know people; I see a lot of them on the street here in Sweden with body mass index less than 17 who are perfectly healthy. Doesn't mean you're about to die because you're thin. Likewise, the other direction. There are plenty of people who have more weight than they might like, but who are not in danger of acute danger from that. In clinical trials, we also had strict MRI criteria and strict criteria about other diseases that would exclude people from being considered for this clinical trial. In clinical practice, of course, things are much more broad, right? People can be younger, people can be older, people can be thin, people can be larger, people can have mild AD dementia, but test very poorly, so they might not meet the clinical entry criteria. The neurologist can look at them and say, "You're mild. Just because you can't talk well doesn't mean you're very demented. Some people have the language centers, for example, affected very prominently early in the course and have a great deal of difficulty coming out with words, something I hope you don't accuse me of. There can be various brain lesions on MRI, which can be puzzling and peculiar and might have excluded one from a clinical trial, but aren't necessarily relevant to usage of an anti-Alzheimer's therapy. There can be various medical conditions, various implants, various pacemakers, other things, various other drugs. All of these might have excluded one from a clinical trial, but not necessarily exclude one from being treated in real life. Finally, I think Anna briefly addressed this and even Gunilla earlier also, the question about what are people at other ends of the spectrum in terms of disease severity? What about people who know they have Alzheimer's disease? Now that we have these good biomarkers, we unfortunately can test people who are clinically normal: CEOs, CFOs, sorry, lawyers, politicians. Let's not be—we can test them and say, "You have Alzheimer's disease," just like we say you have diabetes when your hemoglobin A1C is elevated, but you may not know it, right? You may be completely normal clinically, and those are the so-called pre-symptomatic patients. We do not know quite what to do with them because the drugs are not labeled for treating those patients. You heard about the 8345 or AHEAD study where we are hoping to be able to answer that question, although it is not a sure thing that the study will answer the question. You heard it's an arduous study, four years, but we are hoping that it might answer the question as to the value of treatment of pre-symptomatic patients. I bet many of you are thinking that you'd want the drug anyway, right? That you're probably thinking that if you were pre-symptomatic or a family member was, you might be very interested in thinking about a therapy, even if it wasn't proven until you had symptoms, kind of like some people's actions based on BRCA or something and some famous actresses. What do they do when they have a BRCA mutation? What about moderately affected patients? There, it's a less clear, a much less clear scenario. We've never tested these drugs in people who are moderate or severe. We have reason to believe that the efficacy might not be as good. The disease process is more advanced. We also have reason to believe, unfortunately, that the side effects might be more severe because they have a higher amyloid load, and the side effects seem to relate to the amyloid load. Whereas you hear me being somewhat optimistic about the idea of treating pre-symptomatic patients, I am less optimistic that these particular therapies will help our moderately affected patients. What is the real-world use? The real-world use, of course, is guided in part, and maybe in Europe in totality, but in America, we have off-label use by package inserts. The FDA package insert is really rather broad for lecanemab. It says you have to have early AD, which is either MCI due to Alzheimer's disease or mild Alzheimer's disease dementia. You have to have amyloid confirmation. You have to prove it's Alzheimer's disease, and you have to have a baseline MRI that looks okay by various measures. The FDA also encourages but does not mandate ApoE genetic testing so that people can go and be aware of what their risk of side effects might be. I guess I didn't say it in detail, but in general, the ARIA risks for carriers and non-carriers, as long as you're not a homozygote, are not that different, maybe a factor of two different. Whereas your risk of ARIA from being a homozygote is much higher, perhaps five- or six-fold higher, perhaps even eight-fold higher than if you're a carrier or a heterozygote carrier or a non-carrier. The European Union was a little bit paternalistic about this, if you don't mind my saying, or maybe maternalistic, and did decide that they would not approve the use of these drugs, well, of this drug, lecanemab, for persons who have ApoE4 homozygosity. That excludes about 16%-17% of the Western European or American Alzheimer's population. In other words, roughly 80%-83% of the Alzheimer's population is not a homozygote and would still be eligible on that basis alone. The European Union also excluded anticoagulation, certain MRI findings indicative of cerebral amyloid angiopathy, including superficial sclerosis. The EU did put into place a little bit more of a rigorous monitoring and controlled access program that we don't have in the U.S. Although we have something similar, we do have to have everyone registered in the United States, which I'm fond of saying takes three minutes to do on the form. It does. The major concerns, what have been the reasons for this controlled access and this mystification a little bit? The concerns are brain side effects. Pretty scary, the idea that you're giving a person a drug that's supposed to slow down their brain disease, but that there's a chance of ARIA, brain edema or effusions, and ARIA-H, microhemorrhages, superficial sclerosis, or macrohemorrhages. I know you're not all physicians here in this room. What do these all mean? Edema is swelling, so basically, and that can be symptomatic. It's symptomatic about a quarter of the time. About three-quarters of the cases of edema are asymptomatic. Microhemorrhages or microbleeds, this is something we detect on MRI, but otherwise people are completely unaware of it. We can't even detect it on CT scan, CAT scan, computerized tomography. Superficial sclerosis, likewise, is something we can detect on MRI, which is sort of like microbleeding on the surface of the brain, and again, undetectable by any technique except special MRI sequences. Macrohemorrhages, of course, are large bleeds, those we can detect with cerebral computer tomography and are more often symptomatic, but not always symptomatic either. Macrohemorrhages means a hemorrhage greater than 1 cm. They can also be asymptomatic, but are more likely to be symptomatic and can occasionally result in severe morbidity or death. Fortunately, macrohemorrhages are extremely rare, less than 1%, but these other findings all occur. In general, microhemorrhages are asymptomatic. People usually don't know when they get it. Even though patients and their physicians and practitioners are worried about them and it sounds scary to them, the fact is we do not really know their clinical significance, and at least for any given microhemorrhage, it is exceedingly unlikely that a person would be symptomatic from it, that they would notice it. In our center, we have treated over 230 patients in the last two years, and we have a risk discussion with the patients, but we do not put in any special barriers, and we just follow the package insert, which in the U.S., as you heard, is fairly broad. There are about 10 providers in my group, but a significant fraction of these patients are under my direct purview, but a significant over half are not. We do simple procedures. We do not feel like there is a need to have an enormous degree of infrastructure or superstructure. The key feature, as far as we're concerned, is that when we treat patients, we do do MRI monitoring as indicated by the package insert, and that we don't treat somebody until their MRI has been cleared. That's really the only key safety issue, which is that we think that if you did have the side effect, then we should, in general, as I'll go through in some of the next slides, pause or discontinue therapy and not necessarily treat through it. For that reason, we don't want people to continue getting their therapy without being monitored adequately. It's a little bit different from, let's say, the high blood pressure pill you get from your doctor, who may give you a year's worth of supply and say, "Go home and take your drug," right? It's a little bit different here. We have to do three MRIs for lecanemab after the initiation of treatment. One MRI after the first four infusions, that is about two months after the initiation of treatment, a second MRI after the next two infusions or after the third month of treatment, and a third MRI during the seventh month of treatment. Over the first seven months, we do three MRIs, and we only prescribe the medication to the point that they get their next MRI. The idea being is they're not allowed to get that one year's prescription. That's the key feature, and I think that's really the only thing that you really have to do. Other than that, of course, you ask patients to report to you if they have a side effect. You want to hear about it right away, but that goes with any medical practice. What's different about this drug? What's different about this drug is they have to have the MRI monitoring. There's no blood monitoring. There's no urine monitoring. Of course, there's clinical monitoring. You want to hear about anything the patient experiences. Some people may get NICH. Some people may get something else. You never know. It may or may not be related to the medication, but we want to hear about it as a good medical practice. We have treated people. Another question I often get is, "Where are the patients treated?" We treat them all over. In the U.S., we have freestanding infusion centers, and just like pharmacies, just like I don't run a pharmacy or my institution doesn't, my institution does actually run an infusion center, but only a fraction of our patients are treated at our own institutional infusion center. The majority of them are treated at a variety of freestanding infusion centers, just like the majority of patients get their medications from various pharmacies around what we call the tri-state area, the New York metropolitan area. Some patients have pacemakers. That makes it a little bit more hard to MRI them, but that's the only problem. It's just we have to go and have cardiac supervision of their MRI. Some patients are on anticoagulation, and we discuss the possible increased risks of being on anticoagulation, which aren't so clear, but we discuss the data as it is. Some patients have had strokes and other problems. Certainly, some patients are on other monoclonal antibodies for their bones or their skin or for other things, and we don't exclude them from treatment. It's a drug, after all, not a way of life. Who have we treated? I mean, the average age is in the 70s, and as young as in the 30s, and as old as in the 90s, mostly women, because most Alzheimer's patients are slightly the majority are women because they live longer. A variety of ApoE genotypes. As you can see, in our population, there is a mild underrepresentation of E4. I told you that was 16% or 17%. It turns out that after full discussion, only 12% of our patients are E4E4. This isn't relevant to Europe because it's not part of the package insert or part of the established EU policy that these patients are not allowed to be treated in Europe. In terms of ethnicity, we treated people with a variety of ethnicities, which I see here in Stockholm as well. Global CDR is either 0.5 or 1, which is mild cognitive impairment or mild dementia as per package insert. However, the range of some of the boxes that score you saw in our outcome measures on the Clarity trial ranges pretty significantly from very minimal to significant. The MMSE score, which is a 0-30 score, in general, people scored in the low 20s on average, and likewise on the functional activities thing. Just to show you the age distribution, you can sort of see that here. There are a few people who are younger, but the majority of people are in their 70s or 80s. How do we decide who to treat? How did we go and we did amyloid confirmation, of course. This was before any blood-based biomarkers were available that were FDA-approved and before any were really available in New York. Regardless, most people had CSF, like in Sweden, a common, and some people had PET as PET became approved by the regulatory, the insurer, CMS, Medicare in the U.S. The range of, for those of you who are knowledgeable about the range of CSF values, the interesting thing about this is that there were some people who did not have a CSF that was that extraordinarily indicative of Alzheimer's disease, but they did have a PET, and some vice versa. For people who had 12% of people had both, and the reason why they had both usually is because one was more uncertain. It is valuable. Even with having the best techniques like CSF and PET, sometimes we have a little bit of difficulty saying that something is Alzheimer's disease and whether it warrants treatment or not, whether it is true amyloid confirmation. How about our MRI experience and our infusion experience? We have infused people over 25 months. Even though the drug was approved in January, it did not really get active until the spring of 2023. We have done over 4,000 infusions in our practice, and the average number of infusions is about 17, up to 48 infusions for some people. That is one infusion every two weeks for 24 months. We have had infusion reactions, and infusion reactions have been somewhat similar in incidence to that experienced in the phase II and phase three trials of lecanemab, mostly chills, mild fever or feeling hot, headaches, fatigue, sometimes weirder things like nausea or even diarrhea, though we do not really understand that, but it does appear to be real. These things can happen. They are infrequent, and they tend to only happen in the first few infusions, the first month or two of therapy. We've done lots of MRI scans, as you can imagine, because we follow the product label, and only a few unscheduled MRI scans because someone said, "Oh, they have a headache," and we couldn't be certain whether they might be experiencing ARIA, for example, or not. Sometimes we do unscheduled MRI scans. We've had to pause or discontinue therapy in roughly 10% of patients, and this has principally been done for ARIA. When people have had ARIA, even relatively minor ARIA, in general, the therapy has been paused. In general, it's also been resumed without problem later on, but we have had at least two cases of significant symptomatic ARIA out of 200 patients, 200+ patients, including one of those two who did die, which corresponds pretty much to the experience in the clinical trials that the death rate from ARIA is less than 1%, something over 0.1%, but not that much over. I thought you'd be interested in seeing a little bit, hearing and seeing a little bit more about the side effects since that looms so large in both the regulatory authority's view of these drugs and in practitioners' acceptance, and for that matter, in patients' acceptance. I think the thing to emphasize is that prescription depends very much on practitioners. I think perhaps more so here in Europe, where patients are very bound to their practitioner and want to hear what their practitioner has to say. Perhaps in the U.S., they're more bound to the internet and know what they want to get and just telling you what to give them. That's one issue. The other issue is risk aversion, and that really varies enormously between patients, right? There are some people who say to me, "I don't want my ApoE genotype. I don't care. I know I want this drug. I don't care if the risk is 10% or 1% of a side effect. I want it either way." That's a reasonable attitude that they would tolerate a 10% risk regardless of whether they know it or not. Everyone's different. As you know, the European Union decided not to tolerate labeling the drug for people who had as much as a 10% risk of symptomatic ARIA. This is what ARIA looks like, just to show you, give you an idea. I think even to a layperson, you can see that there is something big and white in the brain here, and that is ARIA. It goes away over time, and you can see that by three months, it is gone. These are just two different ways of doing the sequence. This shows you the edema. Not uncommonly, the edema is associated with microhemorrhages. That is these little black spots that show up in this bottom sequence. This is the same brain here and here, and basically what you are seeing is that there are little black spots that appear in the area of the edema. Now, one of the interesting things is the RAE goes away, and if it has side effects, they go away too. Of course, 75% of them do not even have side effects. They look just like this, and they do not know it. They say, "I do not know why you are stopping the drug, doctor. I want to keep going." Rules are rules, and safety is always paramount. The RAH does not go away. That accumulates, and that basically, for the most part, those little black signs on our MRI are areas of what we call hemosiderin deposition or microhemorrhage, and those retain their signature over time. Here is another example, not quite as dramatic, but quite white, quite impressive. Again, it goes away over three months, sometimes much shorter, but may again leave microhemorrhages. I do not want to give you the impression that you always have microhemorrhages when you have edema. Sometimes you do, and sometimes you do not. Of course, microhemorrhages can occur without the edema, but it is not uncommon to have microhemorrhages when there is edema. Sometimes it is much more subtle. In this lighting from you, you may not see anything at all, but there is something here that is not there pre-infusion, and it goes away over time. Sometimes it is even more subtle. Probably many radiologists would have missed this one. There is something subtle going on here, but it is very subtle, and again, it goes away. What about the ApoE4 distribution, the risk? Just to show you. For us, actually, the last time I, this is not the full 230 patients, but this is a set of people who are genotyped at this time, and you can see that actually the risk in our particular group was actually a little bit higher for non-carriers than carriers. Regardless, in the studies, it was at most twofold higher. We are talking about not a very large difference between RA in carriers of the E4 allele and non-carriers such as E3E3. For people who are E4E4, there is clearly an increased risk of RAE and RAH, and particularly an increased risk of drug-associated RAE. That is why your package label on this side of the Atlantic differs from ours. There are ways of classifying this RA, so it is not just all words. We can call it mild, moderate, or severe in terms of radiological. This is straight from the FDA package insert in the U.S. There is a whole algorithm we say what to do in terms about whether we should pause it or continue dosing or suspend dosing or permanently suspend dosing, depending on the severity and the symptomaticity of the ARIA. That is something that it might be hard for primary care practitioners to manage, but on the other hand, that is the only issue is when the ARIA does happen. To summarize the ARIA concerns or ARIA situation, bleeding sounds worse than swelling, but in reality, the swelling is much more likely to be symptomatic. Bleeding can rarely be catastrophic when it does occur and can result in seizures or even death. In general, that is very, very low incidence. As I mentioned earlier, RAH is asymptomatic generally, and RAE can be symptomatic, but 75% of it is asymptomatic. The patients are walking around. They say there's nothing wrong with them. You call them up after you've seen their MRI, and they say, "Huh." They have no idea why you're bothering them because they feel completely normal, and their family thinks they're completely normal. 25% of them are symptomatic. Let's not neglect that. Generally, you can resume therapy, and most of them want to resume therapy once the RA resolves. What sort of challenges do we have? There are treatment eligibility decisions. How are we doing time-wise? I can't really see where the timer is. Are we okay? Maybe a couple more minutes. Okay. Okay. Yeah, I think we're almost there. A lot of considerations. We talked earlier about eligibility, question of degree of symptomaticity of how mild the person is, question of borderline or ambiguous spinal fluid or PET scan or blood results. A big question is people who have concomitant disorders. They seem to have Lewy body and Alzheimer's. Could they benefit from an anti-Alzheimer's therapy? There is a big question about all these MRI findings that I've just shown you. How many microhemorrhages is dangerous to a person, if any, and should one stop when one gets over 10 microhemorrhages, for example? These are unknowns, and I'm not sure we'll know them for sure, but at the moment, as we increase the clinical practice, we'll have more information on these aspects. There is the issue of appropriate and inappropriate use. Some of my colleagues in the U.S. have gotten together and written what they think you should do, which they call appropriate use, a couple of self-elected overlapping committees. We have great amusement at conferences, my saying that what they think is appropriate may not be the only thing that's appropriate, and what they think is inappropriate may not be inappropriate and may be completely safe. Again, in general, what they've done is say that anyone who wouldn't have met his clinical trial criteria shouldn't be allowed to get clinical treatment, but that's patently not the case. Certainly, our experience to date shows that the package label, which is broader than the clinical trial criteria, allows for perfectly safe and manageable use. We talked briefly about off-label use, and the fact that there the biggest question is people who are asymptomatic. As you can imagine, practitioners such as myself get people coming in, say, "I did a blood test. I know I have Alzheimer's disease. I want treatment. I'm completely normal. What do we do with those folks?" Okay. There are issues that come up a little bit: MRI availability, PET availability, infusion center availability, payer interest in paying, and duration of treatment. We can talk a little bit about this in question and answer, maybe. I will end with this sort of summary that you can use lecanemab safely in a U.S. practice, and one does not have to obey any appropriate use criteria, and that the rates of ARIA and side effects that we see in clinical practice are much the same as we are seeing in the phase II and phase three studies, and that serious or lethal ARIA can occur even with the very best monitoring, as in most disorders. Many of you may know people who have been treated for cancer, and despite the best treatment, expired from their treatment or with their treatment. Patients and families have very high acceptance of infusions. They do not want to stop the drug, even when we tell them maybe they should stop, and they very strongly wish to continue with therapy often. Thank you. Thank you. I know that you got to rush to your flight back, but I hope we'll have time for a few questions and answers before. Absolutely. I'll be able to stay here for another hour or so, but I know the questions are only 15 minutes, 12 minutes at this point. Super. Thank you so much. We have questions online. Is there anybody in here that wants to start first? Yeah, we got Suzanna there. Hi. Thank you, Professor Honig. I have a question regarding the confounding morbidities. What population of your patients who come to you would you exclude based on anticoagulants or stroke risk? If you could just give me one number. I think there are two slightly related questions. I mean, one is true comorbidities, like they come to me, and I think they honest to goodness have Lewy body disease and Alzheimer's disease, or Alzheimer's disease and hydrocephalus, or something like that, or Alzheimer's disease and multiple sclerosis, which has come up because people do have multiple sclerosis. It does not mean they cannot get Alzheimer's disease. In those cases, I believe the best strategy is to go in for the clinician to decide on the basis of all the evidence they have, clinical examination, testing, and biomarkers, what is most likely responsible for the predominance of their symptoms. If we feel that Alzheimer's is a strong contributor, then I think it is reasonable to treat, and I would not exclude them on the basis of a comorbid condition. In terms of the other things, like strokes, there I do not think it is even an issue. I think there is no reason to exclude them whatsoever. There is no reason to believe that having had a stroke would put you at greater risk of side effects given that you have Alzheimer's disease. That is the key thing that I think some people miss. The question really is, is there a safety hazard from treating people who are on anticoagulation or who have had strokes or who have had brain contusion? They fell off a motorcycle when they were 25 or have minus venous or vascular anomalies. There are a lot of things out here. In a room this size, basically over a third of you have something in your brain that is not exactly normal, I am sorry to say. It doesn't mean it's causing you any problems or that it will ever cause you any problems in your entire life, but it's just the way things work. Just like we all have moles and skin things, we have things in our brain. One shouldn't exclude people for things in their brain unless there's any reason to believe that that thing in their brain would be a danger to them during the therapy. Sorry, just to follow up then. Of the 70+ year-old who you treat, would you say then that practically all are eligible or just to put a number on it? Yeah. I have tried to do this. It is a little bit hard. I should say that I have permission from our institutional review board to do this registry of people who are on therapy, but of course, I do not necessarily review every single patient in the entire practice and say who enters. I would say that the vast, but I have, obviously, it is an important question. The majority of people who are not eligible are not eligible because of severity. It is that figure that Anna mentioned that here in Sweden, 60% present at moderate to severe dementia. They are not eligible because they are not eligible according to the package insert and because we do not think it might work and because we think they might have higher side effects. That leaves the other 40% in Sweden and maybe 80% in New York because people present early in New York. They present before they have anything at all or even when they do not have anything at all. Just kidding. I am not entirely kidding. That leaves all those folks. In terms of medical contraindications, exceedingly rare. Anticoagulation and the ApoE status, those are things that we just discuss with them and say, "Look, this is your risk based on the phase three data, what we know, and are you comfortable with that?" If you are comfortable with that, I say, "I am comfortable with it because I am." Another practitioner might not be. If they are not comfortable with it, then they should not embark on that therapy. They want to slow down their Alzheimer's disease, but they may have an 8% risk of symptomatic ARIA, for example, if they're in E4, as opposed to a 1% or 2% chance. That would be something that they have to take into account. Still, 92% chance they're not going to. Everyone looks at that differently, right? It's like going to the casino. Thank you. I have a follow-up on that, actually, online, which I may just sneak in in between here. Out of your pot of eligible patients, how many would you say are on treatment? I mean, again, it's a little bit of a hard question to answer, but I think that basically when people are eligible, they're usually, I mean, by definition, if I think they're eligible and they're willing to take it, then they take it. I would say that particularly in E4 homozygous, there are a number of people who decline it because of the risk. Not that many because we still have 12% that have homozygosity, but there are people who do decline therapy or because they don't want to go to infusion center every two weeks or whatever, but they're in the minority. The majority of people want it. I think I turn away more people because I think they're not eligible. For example, they're too severe, then people turn away the offer because they decline the treatment hearing the pluses and minuses. Thanks. I have a question. Yep. Hi. Yeah, I guess you partly answered my question there in terms of how much is the current administration frequency a barrier to the people who are eligible? The majority are kind of taking up the treatment if they're eligible. Yeah. I mean, I tell them it's like going to the hairdresser or going to the grocery store. I mean, most people go to the grocery store more than once every two weeks, right? It probably takes you less time to get the infusion than it takes to go to the grocery store. This is for your health. I do not think that's really, I mean, sure, it may sound like a lot, "Oh, I have to go and get an infusion every two weeks," but the fact is to some people that's a barrier, but I think only two or three people out of, I know, stopped it because they basically did not like going out of the 233, I think. It is uncommon to be a barrier. Obviously, some people would prefer four weeks to two weeks. Of course, we now have the maintenance therapy to offer them, and we offer them that for the future, that at 18 months, we may be able to offer you every four weeks. I have to say that the converse also occurs. I have people who have reached the 18-month period, and I say, "Mrs. Jones, Mrs. So-and-so, I think it might be reasonable for us to go to four weeks." They say, "Oh, no, I want to continue every two weeks." Again, they get used to it. It's like going to your hairdresser, right? Yeah. That was my next question. I mean, you've been treating some patients for 25 months, so most patients surely would switch, but. No, not well. There are different considerations. We are not mandated to switch them to every four weeks. We are allowed to, and that has only come up relatively recently during this past year that the FDA has made that decision, appropriate decision to allow us to go to every four weeks based on modeling data. Is it your preference to switch where possible? I mean, you're happy with the data which has satisfied an approval, so. I think I'm reasonable about switching to every four weeks just as per the allowance in the product label, but I don't think it's unreasonable if somebody wants to continue every two weeks. It's not completely unreasonable. It's hard to know what the considerations are in that regard because we just don't have good enough data. For example, you might argue that if there was complete amyloid clearance from the brain that you couldn't detect it on PET scan whatsoever after 18 months, that you might be less inclined to do intense therapy every two weeks. Whereas if there was incomplete clearance and there were still some little remnants of amyloid, as there sometimes is in a proportion of people, that those people you might be more inclined to continue the intense therapy for a further period of time and not go to the less intense maintenance therapy. You could argue that that would be a deciding factor, but it's not clear that that's data-driven. That's just an idea, right? We don't have clear evidence of that. Thank you. And then last one. I appreciate it's not been available for as long, but donanemab's now available to you as well. I mean, how do you balance what to offer patients? Are there certain aspects that are appropriate for different patients, or is there just a clear preference or what are your thoughts? I knew this question would come up, and it's always a tricky one. We always like to have more than one drug available and to have things available, options available. The differences between lecanemab and donanemab, in addition to the more recent availability of donanemab and the every four weeks versus every two-week initial therapy, is that donanemab has a slightly higher rate of ARIA-E and ARIA-H, particularly in homozygotes, but in general, and even with the modified dosing titration strategy that I believe they probably submitted to the FDA that they talked about in meetings. The other large difference, which is one that is very hard, which is that every reason to believe, according to the PACC insert and the makers of donanemab, that the drug may not work once amyloid's cleared from the brain, that the target for the drug, which is the pyroglutamated modified aggregated amyloid, is no longer available. So there's no target for the drug. That's a problem because, as we know, Alzheimer's disease doesn't stop when you remove the amyloid from the brain in the form of plaques. There's an ongoing continued, as there has been the prior 20 years, as you saw in those graphs, ongoing continued generation and imbalance of amyloid in the brain. In particular, we believe those toxic intermediaries, the protofibrils and oligomers, are building up, and we can see the biomarker consequences of that both on PET and CSF and even blood. There is the argument that lecanemab has the ability to continue treatment for years and presumably still be efficacious so that we do not have placebo-controlled data after 18 months, whereas donanemab, the PACC insert actually says the opposite. They usually consider stopping it. What do the poor Alzheimer's patients do? Some of them come to me and I say, "We can put you on lecanemab," and that is certainly an option. This gets to be an area of clinical unknowns because we just do not have trials that tell us what is going on there. It is a feature. I think most people would like a drug that continues to treat them. Okay. Thank you very much. Maybe a follow-up from the online people here on that question right now. We also heard Anna-Kaija and I think Gunilla has also mentioned the subcutaneous version of lecanemab. Is that something that you see will be important? How do you view that in your setting up for patients, et cetera? Right. Of course, initially, when we hadn't, except in the guise of research trials, except in the form of research trials, had not been treating people with intravenous medications who had Alzheimer's disease, there was a lot of reluctance and concern about whether infusions every two weeks or every four weeks were going to be tolerated. In fact, as we've discussed, they're tolerated exceedingly well to the point that people don't want to stop them. That being said, I think many people still would prefer to do subcutaneous than intravenous. Certainly, in the research sphere, we've had not complete uptake where the same thing has been offered them. In the extension portions of CLARITY trial, it's been offered to patients to have switched to subcutaneous or to continue on intravenous. There's been a mixture. Not everyone immediately went to subcutaneous. Nonetheless, I do think that a lot of people will want to do subcutaneous, and I think there's a lot of reasons in terms of health utilization. It's certainly cheaper. We don't have to deal with a nurse, an infusion center, IV apparatus, visit to an infusion center, more of a barrier here in Europe. I think it'll be a big plus, the availability of subcutaneous, assuming the FDA agrees to allow the use of those autoinjectors, which we've been using in the research sphere, but have not been using clinically. I think it'll be a definite advantage to have a different dosing regimen available, and I think it'll be helpful. Certainly, people are used to using autoinjectors for a whole variety of things. Thank you. We've got another question here, Ms. Suzanna I was also wondering how familiar are you with the BrainTransporter technology, and how does that make you think about, I mean, first of all, the target amyloid beta and how little, I guess, crossed the blood-brain barrier before, and now the potential with that? Yeah. I mean, I think I wanted to tell you most about the experience with lecanemab, and as you heard, I did not talk much about donanemab or aducanumab. Of course, there is a whole bunch of anti-amyloid antibodies. It is not just those three. There is [saburnatug], remternatug, and a whole bunch of others. There is a bunch of antibodies against amyloid and [trentenumab], the one going into phase three with transporter, and others that are under discussion. I think that it is important to have trials and to develop new drugs. I am quite certain that we will not have only two anti-amyloid agents on the market, that we will have others on the market. Some of those may well include ones with brain transporter technology or other technologies that reduce the risk of ARIA, which would be advantageous. The things that have been mooted or the ideas that have come up in the preliminary trials so far are that BrainTransporter technology might allow a lower dose of drug. That's really neither here nor there, of course. At least I can say that I'm not the sponsor. Mentors are good at making antibodies. The other thing it does is perhaps sometimes clear amyloid faster. Again, I'm not sure that's necessarily here or there. I'm not sure speed is the issue here. I think the issue is longevity, and we talked about that a little bit with regard to the other agents. The third issue is ARIA, and there, of course, that is an issue. We would definitely like to have improved safety. To the extent that the transporter did the third thing, which was affected safety or reduced the incidence of RAE or RAH, that would clearly be a plus for such a drug. To the extent that it caused faster clearance or a lower dose of milligrams per kilogram, it's not so clear that patients or practitioners should feel as certain that that's a big issue. Could I ask one more follow-up? In terms of the general Alzheimer pipeline, are there any other candidates or, for example, the TREM2 agonist, anything you're particularly interested in at the moment beyond amyloid beta? Yeah. As I say, and again, I keep leaving things out, right? Indeed, in addition to lecanemab and aducanumab and donanemab, there are other anti-amyloid agents in clinical development, some entering in phase three already or entering phase three. In addition, there are a number of other agents in phase II, anti-Tau agents, as you mentioned, TREM2-active agents, and other agents. I think we just do not know. We need to go and see phase three trials to know. I think many of us believe that just like high blood pressure, HIV treatment, or other treatments, it is quite likely that a decade from now or maybe even earlier, we will be treating Alzheimer's patients with not only an anti-amyloid agent, but some other agent as well. Just what that agent might be, whether it's a Tau or relating to the immune system, is not clear because we need phase three trials to inform us as to clinical efficacy and safety. I think Max. Is it possible to say anything on the efficacy, what you've seen so far from patients and relatives, et cetera? Yeah. Another question I expected. Thank you. A good question. That is, of course, a very hard one. Of course, the patients ask us that every—some patients more than others, but it is a reasonable question. How do I know if this drug is working for me, doctor? Right? The answer, of course, is that it is very different from a drug, let's say, for diabetes or high blood pressure or even cancer in the sense that the idea is that it is slowing down progression. We do know that people do progress despite treatment. The issue is that the phase three trials have shown that people progress at somewhere between 26%-37% and maybe as high as 50%-60% slower in the milder stages, maybe in the low Tau stages, low amyloid stages, maybe as high as 56% slowing with drug versus placebo. In any given individual who's in front of me, I can't tell them too much. I can tell them if the drug has cleared the plaques from the brain by amyloid scan, and that's an indication that at least that drug achieved its target aim or at least a manifestation of its target aim in the brain of that particular individual. Other than that, it's hard to tell them that, "Yeah, I think you're doing twice as good as you would have been doing." I mean, how would I know, right? I mean, how would I know how they would have done if I didn't give them the drug, right? I think the counterpoint to that question is when they have ARIA is, do they do worse? Because that came up. That's how questions come up. There we have pretty good data that the people who had RA and then the treatment resumed did not do worse than the people who did not have RA. We have pretty good data, at least for lecanemab, that the counterpoint that they did not do worse from the treatment in certain circumstances. I mean, obviously, overall, they did better. The question is, did some subsegment do worse? The answer is, best as we can tell, no. Yes. We've seen already 18 months' data that is promising, sort of preclinical or pretypical diagnostic, and we will get four-year data rather soon. Presumably, that could be rather promising. What's the risk of backlash? Because there will be mildly rich and mildly confused people, and there will be more off-label, gray-label use, and some of these people will, of course, hit side effects before they see any benefits. That's a few questions wrapped up into one. Thank you. In terms of the data, I should point out, so there's only 18-month data, is the phase three data for both lecanemab and for that from aducanumab, shows that 18-month is randomized control versus placebo. We already have three-year data that's been shown, phase three extension data, and now four-year that will be coming up. What that shows, however, is not placebo control after 18 months. It simply shows that it's safe and that the benefit's maintained, if you will, but doesn't show that there's increasing benefit, for example. If there was decreasing benefit, we would see it because we would see the two curves flatten out onto each other, right? There's historical data that suggests the benefits may be increasing, but that's tricky. In terms of your gray zone question, I mean, this happens in everything. I don't know if you know about even in Europe, it happens, but certainly in the U.S., the number of people who are on antidepressant drugs without meeting the criteria is enormous. The number of people who are on memantine, a drug that's only FDA-labeled for moderate and severe dementia. The number of people with psychiatric diagnoses who are getting memantine is far greater than the number of people who are getting it for Alzheimer's disease. It's amazing. People come in to me all the time on memantine or even on cholinesterase inhibitors, such as donepezil, without an indication for it. It's never been proven to be efficacious in MCI, for example. There is a lot of off-label use in the U.S., and I wouldn't be surprised if there's off-label use of the anti-amyloid agents. The one thing I would say is to address your last question, which is the safety consideration. There it's very interesting because those people are precisely the people for whom the risk of side effect is the absolute lowest. If you have no amyloid in your brain, it's a waste of the drug, for sure. It's a waste of the IV nurse's time. It's a waste of the practitioner's time. It's a waste of the patient's time because they don't have amyloid in the brain. Are they going to get side effects from it? Virtually impossible. How are they going to get ARIA if they don't have amyloid in the brain? The amyloid antibody is not going to have anything to touch, right? It's like water off a duck's back. It's not going to be. That's the one thing, the amusing thing is that those people who are less and less symptomatic have perhaps the most to gain but also have the least to lose. Sorry. I think we have to sort of cut off there. There are a couple of questions left on the digital space, but I think we also need to run on with the schedule. We'll follow up with those questions directly to the people that sent them in. I want to thank Professor Honig for taking the time to travel all the way to Sweden. I'm happy that we could offer you some good weather because we haven't had a lot of that this year so far. I wish you a good trip back home as well. Thank you so much. Thank you so much. With that, I would like to enter into the next and final session of this day, which is no, but focusing specifically on two projects I was about to say. Thank you for keeping me straight, Per-Ola. You're the smart guy, so. We'll start that off with the BrainTransporter technology by Per-Ola Freskgård, our Chief Scientific Officer, and then we will round off with exidavnemab and the ongoing project there. Per-Ola, the floor is yours. Thank you, Oskar. Good afternoon. My name is Per-Ola Freskgård, and I'm the CSO at BioArctic. I started in the company five years ago and have been in the field of neuroscience and drug delivery for almost 25 years. I have some history even in this area before I joined BioArctic. What I will try to show you today is how the BrainTransporter platform actually works. Going to be a little bit on high level and also a little bit on the details so you get the feeling on how this works and what we think about it and how we think we can evolve this further. I should also mention that this type of technology, we strongly believe that we will change the way we develop and make medicines for brain disorders because it's opened up the door basically for a lot of different types of drug types or modalities. I will just start with a few slides why we need the BrainTransporter technology. That's quite obvious. We have heard that already, obviously, but I will go into a little bit more detail. A few on the progress we have made and a few achievements. In the end, I will give you a flavor on how we think we can sort of unlock or develop the platform further into other areas and into other drug types or modalities. Hopefully, as Johanna said, we can find a pair of the target and modalities that we hope can create the medicines with the best clinical effect. I'll start with the need of the brain transporter. I don't think I need to state this again, but we know that the human brain is the most complex organ in the body. It's affected with 600 diseases. We don't have all these diseases, all of us, of course, but some people have one disease and another person has another one. It's a lot of diseases, and the medical need is huge. I think the brain transporter technology explains some of it, maybe the major part where we haven't been so successful so far. If we can solve this now and open the door to the brain, so to speak, I think we can do much better than we have done the last 30-40 years or something like that. This is the challenge, and it has already been mentioned today. We know that very, very little of the antibodies get into the brain. I should state that antibody gets into the brain. The reason for that is that they have a very long half-life in the blood. They're circulating for a long, long time. Over time, we get exposure. If you think about other modalities like enzyme, antisense oligo, we do not see any exposure if we do intravenous or subcutaneous administration. Most of the work in other modalities, which does not have a long half-life in the brain or in the blood, you need to have other types of administration routes, like intrathecal, for example, or directly injected in the brain. This is now what we try to do. This is just a number of a preclinical study in non-human primates, probably the most relevant data that has been generated. About 0.03% over two weeks can be measured by a standard antibody in the brain inside behind the blood-brain barrier. It is very, very low. Of course, due to the long half-life and you inject for a long time, you start to see exposure, obviously. Antibodies, we know, work. We have talked about that, but for other modalities, it might be even more important. The brain is highly protected. The reason for that is the neurons on the other glial cells or the brain cells need a very stable environment to function. It is sort of a very restricted environment in the body that we have. There is no other organ that is as tight as this. What is defending, so to speak, the brain is the blood-brain barrier. Here are a few statements. First of all, the brain is the most perfused organ in the body. Actually, 50% of what the heart is pumping out in blood volume goes directly up to the brain, even though the brain is quite small compared to the rest of the body. The demand of blood and energy for the brain is quite high. There you see how extensive this blood-brain barrier is. This is actually from a human where they use a special technique just to sort of restore or make sure that the capillaries and the vessels are restored even when you take away the brain. It is actually 600 km long. It is really amazing. What we used to say, we who work in this field, is that each neuron has its own capillary. If you are able to transport across the blood-brain barrier, you will have a neuron next to it. It is a fantastic way of getting in. That is why nature evolved this, obviously. It is patrolling everything that is sort of in the bloodstream and very, very little, as I mentioned, is in the brain. Another important aspect, this is scalable. When the brain is getting bigger and bigger from mice to non-human primates to humans, this scales also. It becomes more and more useful for a bigger brain compared to a small brain. That's probably why we see this fantastic data now in clinic. It actually seems to work better in humans than in small mice models. Okay. As I mentioned, this huge brain capillary network that we have would be the perfect delivery system if we could cross it somehow. That is what nature is doing when it's transporting energy and other things that the brain is needed. One way to do this is using something that Johanna already mentioned. This is quite an old concept. It's actually a concept back from the 1990s. There were some researchers who sort of discovered that one particular receptor, the transferrin receptor, is highly, highly expressed on the blood-brain barrier. You have the blood side on this side, and then you have what we call the blood-brain barrier. You have the brain side where you obviously would like to be with your drug. What we are using, we're using the receptor-mediated transport, which is an active transport, which is very important. A normal antibody is slowly, slowly diffusing into the brain compartment. I will come back to that. We're using what Jan also mentioned, binding modules. We'll come back to that. It's a small part of an antibody. What is unique for our system is we're using a very, very specific novel binding site on the transferrin receptor. That's really what differentiates us from our competitors, we think. I should also mention when we started this five years ago, around five years ago, we actually sat down and made sure that we have all these requirements that we hopefully in the end could incorporate in the BrainTransporter platform. When this binding module was diffused, in this case, to the antibody, it's sort of been transported together with the transferrin receptor and the endogenous ligand transferrin that normally transports iron. It's actually following it through the blood-brain barrier, which is a very, very complex structure with at least three different cell types. On the inside, it's released, and then it has access to the brain cells. Depending on the target, we target different cells or even the extracellular space. The cargo is the antibody, the binding module. We've used that in the back of the antibody. This is sort of the basic concept of how the receptor-mediated transport works. Other companies as well are using this receptor. The key for us is how we have designed both where we bind to the transferrin receptor and how we position our cargoes. I will come back to that. If we can do this and some of these things are obvious, of course, we are going to increase the brain exposure because it is an active transport. We get a very, very nice broad brain distribution, completely different. I have a picture on that as well. We reach the deep structure of the brain. We reach all the pathology where we need to make sure that we engage with the target that we are interested in. Another thing is this is a very, very fast process. It takes hours, days to get very, very high concentration in the brain compared to maybe a standard antibody, which needs weeks or months and higher doses, obviously. All these together, we know based on preclinical data. Now some clinical data are also coming together that if we reach a very high target engagement and complete access to the target population, we can address all the pathology in the different areas of the brain. We are not restricted to passive diffusion. For a biotech company or a pharma company, convenience is, of course, very, very important. Lower dose, lower injection, and the route administration is for all our programs for the BT is subcutaneous. The goal is to have subcutaneous administration because of the low dose and volume. Safety, we already mentioned that. I will come back to that. But in general, you can say that you're using reduced total drug load. Maybe in other areas outside Alzheimer's, this could also be beneficial. For Alzheimer's, the ARIA issue that we discussed, we might be able to get around that as well due to the very unique way how we enter the brain. All right. Yeah. This was how we set up the program from the beginning. We did a lot of screening. Let's see if this is working now. No. Maybe I need some help up there. Yeah. This is just a few examples. Here I probably need to explain a little bit. This is the transferrin receptor. It has three different domains. The helical domain, which dimerizes the receptor. This is a homodimer receptor. We have the apical domain in green, and we have the protease-like domain in orange. We spent a lot of time initially screening for binders. This is what we call the binding modules. We have three examples here. We determined the structure of these because we used the structure in the design of the BT platform. We actually selected this binding module. It sits on the side of the transferrin receptor at the protease-like domain. It preserved the normal function of the transferrin receptor. We do not interfere with the normal hemostasis of the transferrin receptor because if you do that, you will have issues with the iron-related function in the body. Maybe also very important is that we could position our therapeutic antibody or other modalities now on top of the TFR because we bind to a very unique site. We have the structure. We actually have four different attachment points on this small molecule. I will come back to that. Let's see if this can roll. Can you? Yeah. Super. This again, just to show you how it works. You have the transferrin receptor. It binds on the side. I should also mention that the transferrin ligand is here. I do not have it in the picture. It does not interfere with the binding module. We are done using the apical domain where the epitope, at least, is for the ferritin, which is a second potentially very important iron transporter for the receptor. We call this BAT-007. This is how we actually differentiate ourselves from competitors. Unique site. We have the structural data. We can use that to position our cargo in a very, very precise manner. All right. Now I will go into yeah. I probably need some help here as well. Here I will show you how a standard antibody, a standard A-beta antibody. This is a mouse brain. Here we image the complete brain. It is a very specific, unique technology that you can use. You inject your antibody, 10 mg per kilo for 72 hours. It is a double transgenic animal that we have generated. What is very interesting, at least for us who are working with this, is that after three days of injection and circulating in the blood, we do not see in this experiment any what we call parenchyma exposure. We do not see anything behind the blood-brain barrier. All the antibody are actually accumulated in the ventricles in the corpuscus. What happens with the standard antibody is actually not passing or crossing the blood-brain barrier. It's actually filtrated through this corpuscus system that most of our blood-borne proteins that normally are filtrated in the CSF. This is a very nice structure, which is the corpuscus. This is where the antibody starts. In the beginning, if you do multiple injections over months, they will start to penetrate. I will come back to that, how it actually works. If we compare that with the standard antibody, maybe I need to click or yeah. You see this huge difference between the standard antibody. This should also actually rotate. This maybe is maybe no. Can we get this one to rotate as well? It should be yeah. The same antibody, the same dose, the same time. You see this huge difference. The green part is the antibody. It's detected in the same way. Same antibody. The only difference is that we have added this binding module that binds specifically to this unique epitope on the transferrin receptor. This is what we see now in mice models, which is really astonishing, I must say, because all this green is sitting on the plaques in the brain. Black. Yeah. You did the same, right? It is a huge difference both in exposure, target engagement, and you see also this fantastic brain distribution. This was really encouraging to see initially when we developed this technology. This just showed the correlation between the brain exposure. In this graph, have we actually measured the exact concentration? Have we measured the whole brain? If you remember, for the standard antibody, we measure this. This is not inside the brain. This is 24 hours, 48 hours, or 72 hours. Yeah. What you see there is actually not real brain exposure. It's in the ventricles and in corpuscles. For that one, here you see really how fast this process is. This is 24 hours. This is 72 hours. If we do it even earlier, after six hours, we start to see a little bit lower, obviously, than this one. We're talking about hours and days to really saturate the target compared to a normal antibody. Just to show that this is translatable to primates. What we do in the industry, we normally make sure that our data are translatable into the closest species we have before we enter human trials. Here again, we're comparing an antibody, the same antibody. The only difference is that we have fused the binding module. This is what we see. We measure in different brain regions, but this is three important brain regions, I would say, for certain diseases. This is 24 hours after injection, the same dose. You can see for our BT, A-beta antibody, we have 58-fold higher concentration behind the blood-brain barrier compared to the standard antibody. Here, it was actually really hard to measure anything. Hippocampus, around 40-fold, and striatum is up to 70-fold. Very, very fast, a very, very high exposure rate, obviously. We also see this broad, nice. This was key data to validate the BrainTransporter technology, not only for this antibody, but as a platform, a validation. In summary, for this, is that we think we have a faster, broader, and deeper penetration of our antibody using the BrainTransporter platform. Up to 70-fold increase in amyloid beta antibody in the brain. That number comes from the striatum. Up to that, of course, we have to do more injection over time. We have also done that in other programs, and it looks good. Okay. This is what I mentioned in the beginning. We have found a very nice epitope, and we have found a very nice binding module. It is doing what it is supposed to do. We get the antibody into the brain much more efficiently, and it has all these nice properties. What we did, we looked at the competitors. This is the binding module. As I mentioned, there are four different attachment points where you can link up your antibody in the back of the antibody. This one is this one, and it is fused to the antibody. What we did, we looked at our competitors. Most of our competitors are using the apical domain, so the outer part of the transferrin receptor, as far as you can come from the cell membrane. We did not take that approach. We actually focused on the lower area, and we call it the hidden space. By using what we call NVL, that is the site here. If we fuse the antibody through that, we can position the antibody very close to the plasma membrane. That has a very, very important function for it. Because when the antibody is injected, the transferrin receptor is, of course, expressed in the blood. It is expressed on the blood-brain barrier side, on the blood side. There are other cell types, like reticulocytes, that have the transferrin receptor. It is crucial that we make sure that the cargo or the antibody is immune silent when it binds to the transferrin receptor. That was also part of the engineering, not only that we have a novel site, but we could also position our antibody in a silent way before it enters into the parenchyma. In the parenchyma, I do not show you the data, the antibody becomes active because then it starts to bind to the Fab region. The effect of function sits in this, what we call the FC. This was very important for us. The key experiment to test this is that there are blood cells that express a high level of the transferrin receptor. If you have antibodies that are exposed and you have effect of function in your antibody, you will see that the reticulocytes, and the reticulocytes are the precursor to the blood cells, are killed. You see a very, very strong drop in reticulocyte reduction. We tested this, obviously. We started with mouse data. This, again, is in our human or in a transferrin receptor model. This is typically 10 mg per kg, 24 hours. If you have issue, you will see reticulocyte reduction. Here you see we do not see any effect on reticulocyte levels and% of reticulocytes. Importantly, we do not have any issues with hematological parameters. This was really encouraging. Of course, we did the same thing in non-human primates, the same thing. Here you see if it is on the dotted line here, there is some difference between pretreated and treated. They are collected around the dotted line. This is if you have problems, you see very, very low levels of reticulocytes. Again, the hematological parameters look very good. We hope that this hidden space approach that we have taken holds up. Of course, you have to do a chronic study, and that is ongoing. Okay. This is, in my view, extremely interesting. We mentioned we have a faster route into the brain. What we actually do, we're bypassing the brain area. This is what we discussed during the lunch. If you inject a standard antibody in the blood, it has to go through the corpuscular filtration. It goes into the CSF compartment. This is the corpuscular area. You even see the fourth ventricle down here. Then through the perivascular diffusion into the brain. That is why you have all, I will not say all, but a lot of amyloid deposit in the vessels. That is what we think drives the ARIA issue. The antibody attacks the amyloid beta that sits in the vessel, makes them leaky, and then you get the issue. Of course, over time, you will be able to diffuse into your target in the parenchyma. For a BT map, we completely jump over this. We enter the blood, we cross the BBB, and then we reach the target. Maybe this actually explains why we see much, much less ARIA in the clinical trials so far from a competitor. In summary here, we have a unique transferrin receptor binding mode, and we have a direct pathway into the brain. I think that's key also for this. The BT map is silent when it binds to the transferrin receptor in the blood compartment, and we bypass brain areas that could mitigate safety issues for this A beta antibody, for example. All right. We've mentioned this a little bit, or there was a question around this, I think. The first BT candidate will not only validate the BT candidate per se. It will also validate, obviously, the BrainTransporter technology. We will see which one will be tested first in clinic. There are a few which is possible. BMS, as Gunilla mentioned, might be the first one. We do not know so far. This is what we are heading towards now. In my view, as I have worked with this for some time now, I think the pre-clinical data for the BrainTransporter is so strong now, based on all the data we have in different species pre-clinically. You can never be 100% sure. I think the transferrin receptor transport mechanism in humans has also been sort of validated. Hopefully that also translates for our system. A little bit short. I do not know how much on time, Ali. You have been moving along quite well. Maybe three or four minutes more. Okay, perfect. Of course, we have worked a lot with antibodies. We have a program, Johanna mentioned that, on enzyme. We think this delivery machine, if you like, could be used for other types of modalities. We have started addressing this now. We are working with enzymes and antibodies. I would say we have started to figure out how we can deal with antisense, small molecules. There are a lot of interesting small molecules. We are now building a complete new system in the field, I would say. We do this quite differently compared, again. I cannot talk about it because we are in the middle of building it, validating it, and we need to file a patent on it before we disclose exactly how we do it. We think we have a very unique way of merging the BrainTransporter technology with small modalities. If we are able to do that, we think we will end up with BT with a lot of different mode of actions. If you think about it, we have worked with toxic proteins. We have data on that. Knockdown with antisense oligos. We are working to replace enzymes or even protein deficiency. We are also thinking about restoring dysfunctional immune cells and neurons. If we can integrate these as strong BT modalities, I think we can actually address by combining the right target and the right modality. We can address many types of pathology. Here we are working really hard now to make sure that we have, hopefully, the first data that potentially we can show in the autumn, I would say. We will come back. Stay tuned, I would say. I don't think I need to repeat this again. We have validated the brain transporter platform. We have a strong internal portfolio, not only on the brain transporter platform, but also for other sort of standard antibodies. It's a very, very high external interest. The big pharma are really looking into this now. Some of the pharma, the big pharma, I get the feeling that they haven't woken up in time. They need something to address this. Finally, also, I think this will be adaptable to other modalities. We can position the brain transporter as a multi-modality platform for brain delivery. Thank you. Yeah, that leads us to the final presentation of today before concluding remarks. That's Gabrielle will talk about Exidavnemab. Thank you. Our alpha-synuclein program with Exidavnemab as the first molecule is intended for a whole group of very severe neurodegenerative diseases. Our intention is to develop a disease modifier, a drug that actually diminishes the disease progression. I'll take us through some key data on Exidavnemab, phase I data, how we think we differentiate from competitors, what we learned from phase I, where we now are in phase II, and our future plans. You may not think it, but this is actually a new category of disease, neuronal synuclein disease. A whole group of diseases. The term was coined just a couple of years ago, and it encompasses quite a lot of diseases. Parkinson's disease, we know. You may think, is there such a large unmet medical need there? Yes, there is. For Parkinson's, we do have levodopa that actually helps a lot for a couple of years, but there is nothing that can halt the progression. After a couple of years, with Parkinson's, a majority of the patients develop what we see in the second circle, Parkinson's disease dementia. That is common. In the next circle, you see dementia with Lewy bodies. These two, PDD and DLB, are actually the second most common cause of dementia. We have something interesting, prodromal alpha-synucleinopathy. That is the stage before you come into Parkinson's disease, the pre-clinical phase, 10-20 years of pre-clinical phase. We do not have anything to treat these patients with. Of course, that is where we would like to come in and be able to treat early. A very, very severe disorder, a little different from the others. I'm going to mention that multiple system atrophy affecting also autonomic functions, such as blood pressure. All of these are characterized by the alpha-synuclein aggregates in different brain cells. That is depicted here. What we think we do with our antibody targeting the toxic aggregated alpha-synuclein aggregates, the oligomers and the protofibrils, is that when they are released either from the neuron or, in the case of multiple system atrophy, from the oligodendroglia, the yellow cell you can see, we capture them with our antibody. It binds them and can eliminate them. That is the way to hinder what we call prion-like. You may remember the prion diseases, the prion-like progression or propagation of this type of disorders. Importantly, we think that we bind very, very hard with high affinity to the protofibrils. As you can see on the graph to the left, Exidavnemab actually requires a lower dose to bind harder to the protofibrils. While we compare to prasinezumab and amlenetug, prasinezumab is the alpha-synuclein antibody from Roche. And amlenetug, quite recently named, is the alpha-synuclein antibody from Lundbeck. They are different. We also avoid the monomers. The selectivity is high. It's over 100,000-fold. This means that we can probably go with a lower dose, get higher efficacy, and less side effects. That is what we are now in the process of trying to demonstrate. Also, what we see on the graph to the right is that our compound actually has a predicted exposure at a higher level for longer time than the Roche and the Lundbeck compound. From here, of course, we have done a lot of alpha-synuclein pre-clinical models, transgenic mice models. You can say that they represent the different disorders we just talked about. What we see here, I just chose one graph, and that is on survival. That actually these animals survived double as long time as the ones that were not treated. I think it was something like 160 days versus 80 days. It also delayed motor symptom development, and they, as I said, prolonged the lifespan. These data allowed the phase I trial, not only one trial. Actually, these were two trials, quite well-designed two trials. Almost 100 healthy volunteers were exposed. Bottom line is that safety, tolerability, and pharmacokinetics were excellent. What you see in the upper graph is that we used doses from 100 mg up to 6,000 mg in both gray Caucasian healthy volunteers and in the yellow Asian population. One may say, why is that important? It is important to demonstrate that across different ethnic groups, you can actually use the same doses. That is what was demonstrated here. On the bottom, you see the very nice dose linearity, the blue graphs being the highest doses and the pink ones the lowest doses. They pile, they stack upon each other in a way we like to see it. We like it when it looks this way. Also, super important here, the half-life was 30 days. Why is that important? That allows us to dose once monthly. You do not need to dose too frequently. Safety was very nice. This was done during COVID. There were some COVID-related adverse events. Of course, since all these subjects were exposed to lumbar punctures, there were adverse events related to doing the lumbar punctures. We had a very low incidence of ADA, antidrug antibodies, also very important because you do not want antidrug antibodies. What they can do is actually take down the efficacy of a compound. We do not want that. So well tolerated, very nice PK, as I said, and we think it is differentiated. I will just also mention something important here on the competitors, why we actually think there is a solid ground to take next steps in different disorders in this group of synuclein diseases because Roche has tested prasinezumab in two well-designed large phase II trials. You may have heard about the PADOVA and PASADENA. They did not turn out with clinical significance on their primary endpoint, but there were signals both on clinical endpoints and on biomarkers. We think there is something there, even though unfortunately, they did not turn out fully positive. For Lundbeck, they tested their amlenetug in a quite small MSA trial and also did not come out fully significant, but with signals and signals strong enough that they have now decided to go into phase three. It started, oh, December or January, and is ongoing. We call our ongoing phase II-A study EXIST. It is conducted in patients with mild to moderate Parkinson's disease. We just have now decided to expand it into multiple system atrophy, MSA as well. This slide may look a little complicated. It is not. I will start with the conclusion, which is actually in the heading. We have now finished cohort one, and we are preparing for the higher dose cohorts. As I said, the cohort one was in Parkinson's patients. What is really special, and we are very proud about for this study, is what you see to the left. It says alpha-synuclein SAA positive. This is a biomarker test, and we are the first one to use it in a clinical trial. This can be used to diagnose patients with synuclein disorder. It cannot differentiate between the different forms, and it cannot yet be used to follow the patients over time. That is something we expect we will get quite soon. This study is ongoing in two countries in Europe. We are now, in the month of June, approaching the safety review. With the safety review done, we expect to go into the higher dose cohort. The cohort two A will be in Parkinson's patients, and the cohort two B will be in MSA patients. As you see, there are not so many patients in this study, 36 in total, 12 in each cohort. The endpoint is safety and tolerability. Of course, we'll follow pharmacokinetics, immunogenicity. Of course, we're going to look at biomarkers, and we do also follow digital endpoints. We think this is really a good entry point for next steps. Here is a segue because I really want to stress what we do with biomarkers and biomarkers both in the ongoing EXIST trial and what we think around for next steps. If we first start with imaging, I'll start with what it says the third from top. It says alpha-synuclein PET. That is what we really, really want. We know that PET ligands for alpha-synuclein, they are in development. They are not yet in full clinical practice. Of course, that is something we want to include in a next step. That would really make a difference. That scan or that PET is something used for Parkinson's. We use it in the EXIST trial. That can be used both for diagnosis and to follow pure Parkinson's patients. FTG PET, which is a glucose metabolism, is of super interest to DLB and the PDD. You can follow them with that kind of imaging. MRI is of importance, perhaps here primarily in the case of MSA. Several opportunities here. On the biomarkers, of course, CSF, but of course, we want to go over to more blood biomarkers. I already mentioned a little on the alpha-synuclein biomarkers. Another biomarker we like a lot and we follow a lot is NfL, neurofilament light, which speaks to neurodegeneration as such. That is something we will include in our trials. For digital, we in the EXIST trial have both active and passive monitoring. That is with actigraphy for passive that can monitor sleep or active where we can use, for example, for testing cognition, balance, mobility, and gait. There is quite a lot ongoing in this area. With this, I wanted to show you that with the toxic oligomers and protofibrils in the alpha-synuclein disorders, we have them in one space for Parkinson's disease primarily, but not only to what is shown here in red, the basal ganglia. For the Lewy body dementia, you see there the cortical areas in blue are more depicted. That is why they get cognition defects. For multiple system atrophy, one important piece is that they can get affection in the cerebellum, the small brain, and with that, severe balance problems. Of course, we have verified this. Now I'm looking on the right side of this panel by looking at post-mortem brain material. That is, we have looked at brain material from dead patients with Parkinson's, with Parkinson's dementia, with DLB, and with MSA. We have proven that our molecule, Exidavnemab, actually shows extensive binding to alpha-synuclein pathology. That is also, of course, a proof we can make use of when we say that we could go into any of these disorders. We have seen a little on how many patients there are for these different disorders. This is a way to look at it where you look at the seven major markets. I talked about the early Parkinson's disease, the Parkinson's disease dementia, and dementia with Lewy bodies. You could actually lump them together. Interesting with them is that there is no other alpha-synuclein molecule tested in this population. Why this could be of interest. Prodromal Parkinson's disease, where I said, you know, this is the pre-clinical phase. You can capture them early by, for example, the SAA test, but also by the fact that they have sleep disorders that you can are quite characteristic. Very interestingly, Michael J. Fox Foundation are planning to conduct a very ambitious umbrella study in early or prodromal Parkinson's disease. We are actually in discussions with them and have been selected to join if we are able to. MSA, what I've not said, and you may immediately capture that from the low figures you see there, is an orphan designation, which can be of interest. I think I will say something. Yeah, it comes here. We have been granted orphan designation for MSA both by FDA and EMA. What is that? You know, orphan indications, these are the indications that are unusual. There are very few patients. Because of that, the regulatory authorities, they give financial incentives. They give during development, they give regulatory support. You can come to them with your protocol, and they give you advice on what they want to see. You can actually do smaller and more flexible trials, so smarter trials in a way. You get market exclusivity for a couple of years, a little different in the U.S. and in Europe. Of course, there is the recognition that you enter into these very difficult fields. Last, of course, I need to mention our patent. We have the possibility of extension of our patent U.S., Japan, and Europe until 2046. With that, with Exidavnemab, we are aiming for best in class. We have the opportunity in several indications. We think we have, or we have a unique binding profile, high affinity, high selectivity, and excellent PK. The molecule is validated pre-clinical in several models. Our current study in Parkinson and MSA will actually open up for us going into multiple indications next. Thank you. Thank you. That was the last presentation of the day, but that also means that we now have time for our last Q&A of the day. Do we have any questions there in the room? I have a couple of online. We have Frederick there in back as well. I'd quite like to ask a question regarding the difference between a specific and a non-specific anti-synuclein. The Lundbeck and Roche versus the BioArctic, and then also Teva has a small molecule oral that seems to also have a broad specificity. If we start with the last one, and Teva that comes from MODAG. I think that is actually quite a different approach, which it's not an antibody, it's a small molecule, just as you mentioned, it was termed ANLE previously. We know that they are now progressing with it. We do not know so much more actually. Your question around prasinezumab and amlenetug was? The arguments for why you would want a broad versus you would want a specific, because on talking to Lundbeck, they are quite content with their non-specific approach, while you are quite particular about the specific approach. I mean, one thinking there could be that, of course, one can start by saying that there are a lot of unknowns with the physiological function of alpha-synuclein. Nevertheless, we know that the monomers are the physiological functioning. Our thinking is, why should you then target them? It's better to target the neurotoxic species there. Did that answer sort of your question? What does the physiological alpha-synuclein do that you want to up? I said that there is a lot. Unfortunately, very little is known. It's obviously located presynaptically, and it has to do with overall neuronal functioning. There is a lot more to be known. I don't know if you want to fill in or if Johanna wants to fill in there. If I may say, when managing that is you need to use the I use fields. You can have this one. Sorry. You can have. Another thing that I think is extremely important for the selectivity is also that you have a lot of alpha-synuclein in the periphery actually. If you bind, if you give the antibody periphery in the bloodstream and the antibody is bound to the alpha-synuclein monomers in the periphery, there might be sequestration of the antibody periphery, and it might not be able to go up to the brain to do the trick. Therefore, we think it is more important to actually focus on what we believe are the target, and that is the aggregated forms. I think that is one advantage. I think the other advantage with Exidavnemab as compared to Lundbeck and prasinezumab and amlenetug is really the pharmacokinetic profile, whereas prasinezumab has a half-life around 11 days, we have 30 days, and Lundbeck I think has around 21 days. I think that there is a much better possibility to really test the concept of lowering of the alpha-synuclein aggregates with our antibody. That would be my answer. Okay. I think we have a question by Frederik in the back. Thanks. Thank you. About Parkinson's disease, you mentioned these biomarkers, some are quite new. How are they received by regulators and how do you see them as potential pivotal endpoints? Yeah, I mean, actually, some of them are not that new. That SPECT, that scan is regulatory validated for both diagnosis and disease progression, or yeah, in motor form of Parkinson's disease. FDG PET has been around for quite a long time. It has not been used for regulatory purposes in any of these diseases yet, but it is very well accepted. MRI is more where you measure, assess atrophy. I would look upon that as a surrogate biomarker. As I said, of course, what we want to have is the alpha-synuclein PET. It remains to see how good it gets, but we, of course, want it both for diagnosis and for disease progression. Thank you. Any other questions right here? I have a couple online, and I'll go to the online questions now. This is for you, Per Luisa from Kempen, she's impressed by the data you presented, but she's asking for more data. When will we have you? Because you talk a bit about the future and the future possibilities of the brain transport technology. Do we have any timeline for when we expect to be able to present new data externally? Can we say anything about that? Yeah, I think the last part I presented, sort of the unlocking or sort of develop the brain transport for other modalities, I think we will read in the autumn too. Depends on the filing of the patent and so on. We have to take care of the IP very carefully. I mentioned the new approach we're using, but I guess somewhere in the autumn, we will be hopefully ready to share those data. Okay. Thank you. Another question right away then. That's here in this room, Alistair Campbell at RBC. On the Beta technology, you say it can carry molecules into cells. Did that apply to all cells, or are there different cells that are limited when it comes to the transferrin receptor that do not express that? Could there be any implications for safety because you have different cells expressing the TfR? Yeah, that's a really good question and something we're really working on the biology around that. I think to get into brain cells, regardless if it's neuron, glia, or astrocytes, or oligodendrocytes. Cargo basically determines where it ends up. You can't have a cargo that binds some extracellular target or a cell-surface target. The target must be inside the cells. There's a lot of biology around that. The transferrin receptor is expressed at low levels on brain cells. What's really happening, and I think we and others have shown, is that when you have the transport over the blood-brain barrier using the transferrin receptor, if it doesn't have anything to bind to when circulating around the brain cells, you have uptake in neurons, you can have uptake in glial cells, and you can have uptake in astrocytes. Of course, you have to steer the function based on the cargo. You have the neuron target; they should only be active in a neuron, for example. There are many different aspects you have to work on to get it right. But it's a very good question. There's a lot of biology in there. Thank you. Any questions here? I have one more here otherwise, and that's for you, Gabrielle. This is from Louisa at Kempen. What's the rationale of including MSA patients in the Exidavnemab trial and not other alpha-synuclein diseases beyond Parkinson's disease? Is there any thought there? I mean, evidently, we are now in, it's a very small trial. We need to start from there, just 12 patients per cohort. Going further, one could say that now we have done mild to moderate Parkinson lower dose, mild to moderate Parkinson higher dose. Ideally, we would have loved to do all the different other indications in one trial. We did select one where we think there is a difference, there is an orphan drug opportunity. It is the one that sort of stands out in the other corner, even though I must say that we do think that there is an opportunity also for the cognition aspects of DLB and PDD. Prodromal Parkinson was not an option. Those patients need a much longer and more thorough workup. That would not have been an opportunity to do in this type of trial. Thank you. I just tried to say that this trial opens up all the possibilities for the next trial. Yeah, indeed. What Gunilla said, if you did not hear, because the mic was off, is that the trial design as such opens up possibilities in basically all the other areas that we have within alpha-synuclein diseases. That was the last question here, apart from a couple of specific ones for Professor Honig that I will sort out with him. If no other questions in the audience, I would like to thank Gabrielle and Per-Ola and then ask Gunilla to sort of summarize the day. Yeah. Time is flying when you're having fun. I think we have had an amazing day. I'm so happy that you could meet Professor Honig, of course, but also the really skilled people that I have the pleasure of working closely with. Just some closing remarks that I think now you have got the possibility to see some in-depth aspects of BioArctic. Also, you can see how we are thinking about our five-year ambition and that we are well on our way towards building one of Sweden's next major biopharma companies. We are working hard on additional successful global partnerships. We are also planning to expand our portfolio to get it balanced and broader with projects in all different stages of development. Leqembi, I think we heard a lot from Professor Honig how it is in the U.S., where they have had it for a couple of years. We heard Anna-Kaija talk about also how we are preparing for getting it into the Nordics. We hope for the launch next year, which we are really looking forward to. We heard Anders also talk about the company expecting to be profitable and hopefully in the future also with recurring dividends. By that, I say thank you so much for your attention. Thank you to all the speakers and have a great rest of the day. Thank you.