Hello, everyone, and welcome to IRLAB's Capital Markets Day. Today, you will be treated to a fantastic set of presentations where you will not only get a refresher on the company, its main projects, its scientific platform, but you will also hear directly from the company's development and commercial partner. Dr. Steven Glyman, Head of Neuroscience at Ipsen, will be calling in to talk about the project and answer your questions. We will also hear directly from Professor Karl Kieburtz. He's one of the world's foremost authorities on clinical trials in Parkinson's disease. He will speak to you about motor control in Parkinson's disease, the need for new treatments, and the potential role for mesdopetam in treating this. Fantastically enough, that's not all. We will also hear from Professor Bastiaan Bloem. He's the Medical Director of the Parkinson Center in Nijmegen. He's engaged in both the ParkinsonNet and the Michael J. Fox Foundation, and is one of the world's leading experts in balance and falls in Parkinson's disease, and he will speak to you about the need for better treatment and what Pirepemat can do in this regard. My name is Mats Thorén. I've spent the last 20 years being an equity analyst, a corporate finance banker, an institutional investor. I am an individual investor and a board member of 4 listed Nordic healthcare companies. In terms of disclosures, I'm not affiliated with the company, and I'm not getting paid, but I do know Nicholas and the team for more than 20 years. My first corporate finance assignment was actually with the team. Turned out to be for free. Today, they're not getting away free. I asked the company to make a donation to help with the refugee situation in Ukraine, and they not only accepted, but they also doubled that donation. I would urge you all to look deeply into your pockets and try to help with whatever you can. Thank you. CNS diseases, central nervous system, brain stuff. It sounds very complicated, and for sure, it's not easy. If I just change the words and I say mental health, cognitive decline, addiction, pain, neuromuscular disorders, then it becomes personal, doesn't it? I don't think there's a single one in this room or watching remotely that does not have a loved one, a colleague, an acquaintance that is not deeply affected by a CNS disease. I think we can all agree that the focus from society has never been greater in this area. We read about it every day in the newspapers. We even learn new things we didn't know we needed, like dopamine fasting, and we will be hearing a lot about dopamine in just a little bit. The focus on CNS diseases is as high as it's ever been, and this is translating into money. After oncology, CNS is now the second-largest area for deal-making in the pharmaceutical industry. What's hopefully the smart money is already flowing into this. The need, the market, and the money is there. Some of that has flowed already into IRLAB, and today we will understand better why that is. If you don't understand why, then I am here to take your questions. For you in this room, to ask a question, you will raise your hand, you will get a mic, since this is recorded, and ask your question. For those of you watching remotely, you can ask a question just below, the presentation view, and I will be seeing the questions here and asking them. Now, without further ado, I present to you Dr. Nicholas Waters, IRLAB's CEO and one of the founders. Thank you very much, Mats, for that kind introduction to IRLAB, a company with the vision of becoming one of the world's best deliverers of and developer of innovative new treatments for Parkinson's disease. If you saw our press release yesterday, we're trying to expand that a little bit further into other neurological disorders now with a new compound that we are starting to develop. I'll come back to that. With that strategy, we have been working on it for a while and collecting a number of validating points over the years. If you go back a couple of years, looking at the science, we have published and documented our science and our results in high-ranked publications, which have led to further discussions and recognition with the scientific community. Perhaps the most important aspect here is the translation of our ideas into clinical data, which have been successful through phase II-A for both our two main products, Pirepemat and Mesdopetam. We hope to see more data coming out of our preclinical development and going into clinical development in the near future. The innovation, the level of innovation that we can generate using our platform is, as we see it, unprecedented. We have delivered to date from the platform three different new classes of CNS active compounds. It's not us who say it's they are new classes, it's actually WHO through their INN system who gives us that privilege actually to have three different new classes of CNS drugs developed. Then we have the commercial value, which perhaps to you as an audience is just as important as the other aspects. That is also shown through the commercial deal we did with Ipsen last summer. And also the capital raisings we've done over the years, since the inception of IRLAB. At present, we are well positioned with our pipeline, with the projects that we're running. With the two first-in-class programs in late stage or mid stage, clinical development phase IIb, the last stage before the initiation of phase III studies. These are very important studies for us of course, but also for our partner, Ipsen. We are addressing large global markets with huge unmet needs, as Mats alluded to. These are problems for the patients which are not well treated today, and we think we have a better solution to the problems. The partnership with Ipsen is, of course, an important milestone in our development of IRLAB. This is a leading global neuroscience company. You'll hear more from Steven Glyman in a while. We have a number of programs in preclinical development now towards clinical trials, which we'll talk about today. The perhaps most interesting part from my perspective in our company is the discovery platform. It's a system that we have developed over a number of years, and I'll come back to that in just a second. Looking at the pipeline products, we are well ahead of competition. We don't see any competition with the same mechanisms as we base our hypothesis on in the global pipeline. There are other programs addressing similar problems for patients. However, not via the same mechanisms as we are addressing with our compounds, which means we are quite unique in the global pipeline. One of the most important aspects right now in our portfolio is Mesdopetam, or programs I should say, Mesdopetam. Of course, it should be noted that this is a program which is fully financed through phase III, through marketing, all the way to the end of sales way off in the 2040s, by our partnering deal with Ipsen. This was a big achievement for us, we think, and a very important signal to the market that we're having a very efficient business development organization supporting financing and delivering the compounds to the right partners. At present, we have a strong cash position, which should not be forgotten these days with the turbulence in the markets and the geopolitical issues that are, of course, in the back of our heads every day. This gives us strength. It gives us the opportunity now also to expand our operations. To that, there will be a very strong news flow from our pipeline and from our other operations in the coming years. I'll give you a glimpse of that. First, a few words about the discovery platform, and we call it the integrative screening process. This is what we call an advanced systems biological strategy. It differentiates itself from the traditional target-based methodology, which is commonly used in the industry. We link collection of large amounts of data from animal experiments that we perform in our laboratories with machine learning and, more recently, also AI methodology. This allows us to see things which have not been seen before. Actually, the graph here, which is rotating, is actually data collected over 30 years. This is real data describing the property space, that is the space that all CNS classes and many representatives from each class span in property space. Sounds like fantasy, but it's an extremely important tool for us in determining the structures that we're gonna make and also to test molecules and get predictions of what we can use them for. We have a tool that predicts the use of our novelty synthesized molecules. This also allows for our discovery of first in class molecules. As I said before, we have three novel classes where we have representatives from each discovered by ISP. Another aspect of this is that since we discover things others cannot, we get rather strong IPR. We have not had any problems in getting our IPR approved or granted over the years. We're building strong IPR protection around our assets. As I said, the predictive science around this is very important, where we also see the indications that are proposed. We also see a result of this is also that we see improvement in the probability of success through the development pipeline, development systems. These are real data comparing industry phase transition data with our own internal data. We have now used the system for roughly 20 years in different settings. We can see that going from CD to phase I, around half of the molecules we have nominated as CDs have gone into phase I. That's 50%, as compared to industry average of 35%. Already there, we have an advantage, and that has to do with the way we discover our molecules. In the next phase, going from phase I to phase II, we have an 80% hit rate using ISP, and industry average is about 63%. If you calculate this at the end of the day to phase III, we see around double, twice or three times higher likelihood of reaching phase III with our molecules based on our discovery platform. This is quite important when you calculate the risks for instance, investments in IRLAB and others compared to others. With the technology we have, with a very small organization, hard to calculate, but I would say roughly fout chemists and four people in the biology labs, we have generated the pipeline of this breadth since we started IRLAB. With Mesdopetam at the top and of course Pirepemat, but also the new class of compounds represented by IRL942 and IRL757, going for neurological indications relating to cognitive impairment and apathy. At the bottom, we have an exploratory program where we're now looking for the right CD to select, and we hope to be able to select yet another CD during this year. This is a program we will discuss later on. This can be translated into quite wordy slide like this. But in principle, what we've done over the past few years is building the foundation for the transformative treatments that we believe we have in our pipeline, and also building the foundation for the company to go into growth phase where we build for the future. We think, in our minds at least, it's when the phase III study starts. We believe that is the really important step for the company. In our business plan, we have the idea that we need partners to go into phase III. That's a constant work that we're adding to the pipeline. At the end, 2025-2027 here, we believe we'll be able to deliver the first approvals for drugs in this space. That busy slide can be translated into a news flow over the coming three years. If one looks at the current year, you saw yesterday perhaps, we have a new CD announced yesterday, IRL757. We also believe that we will have the data from the ongoing phase IIb study with mesdopetam this year. Actually, they have started the phase IIb study with pirepemat. It will continue during the year. This is an 18-month study. We will bring IRL942 and IRL757 through preclinical development. That is the regulatory requirements that have to be fulfilled, and then we'll start phase I during next year with those programs, and the first IND in the P003 program. In 2023, we will have the top-line data from the pirepemat study. We will start up phase I studies with IRL942 and IRL757. Hopefully, we'll have a candidate from the P003 program moving towards or into phase I. On top of that, we have the collaboration with Ipsen, where we expect the transition from phase II to phase III will take place in 2023. Also, additional indications are possible to initiate during next year. These are decisions from Ipsen according to the agreement we have with them. In 2024, we expect to see phase III starting with Pirepemat. We expect to see phase II data rolling in on the current preclinical programs, IRL942 and IRL757. Also, we'll see phase I starting or top-line results reading out from the P003 program, the first candidate there. I have to mention in the P003 program, we believe we can include patients in the phase I of the development as well. At that time, there will also be market preparations for mesdopetam, and that will be done by our partner, Ipsen. We expect to see some data on additional indications on mesdopetam. I will now switch over to Joakim and give you the word here to talk a little bit about Parkinson's disease before we invite Steven Glyman. Thank you. Hello, I'm Joakim Tedroff. I am CMO of IRLAB. I'm a neurologist. Been working a lot with neurological disorders such as Parkinson's disease. I take you through some, you know, basics around Parkinson's disease, so you all get a grip on what it's all about. Parkinson's disease is a neurodegenerative disorder. It's a disorder characterized by nerve cell loss. It's progressive. It gets worse every year. It is the second most common neurodegenerative disease after Alzheimer's disease. This slide illustrates the different phases of having Parkinson's disease based on its motor features and disability. It usually starts very insidious with a one-sided bradykinesia, arm doesn't swing, tremor, shaking, and then it subsequently spreads throughout the body to involve bilateral disease, loss of balance, and in the end stage, a patient that is confined to wheelchair. This staging was constructed before the introduction of L-DOPA, which is the most effective treatment we still have to treat the symptoms of Parkinson's disease. With the inclusion of L-DOPA in the therapy, patients lived longer. It was truly disease modifying, but it doesn't slow down the underlying progression of disease. It is estimated that around 1 million people have Parkinson's in Europe and an equal amount in the US. Among these people with Parkinson's, about half of them are in stage 3 or higher. That means that they have balance problems and they have a real type of disability that makes them sometimes unable to take care of themselves. IRLAB is developing compounds that are intended to improve disability, improve quality of life for these patients. When patients progress, different types of symptoms appear. In the early stage, the bradykinesia, tremor, and in later stage, complications of therapy, other features relating to cognitive impairment, and that other cell groups die, including apathy, cognitive impairment, balance, fall problem, psychosis may develop when the patient receives treatment. We have Mesdopetam to counteract dyskinesias and psychosis, which are side effects of the current treatment that the patients really need. We are developing Pirepemat for the more later stage problems, including balance problems and falls, which are more frequent when the patient develop cognitive impairment. We are developing new molecules to treat apathy, which is a syndrome characterized by loss of motivation and initiative and cognitive impairment. We also have the P003 program, which is a program intended to develop compounds that could potentially replace levodopa as the mainstay therapy. These are compounds that may give symptomatic relief for a long time. L-DOPA, which is currently used, only works for a few hours in more advanced stages, whereas the compounds in the P003 program can be much more longer lasting and be equally effective as L-DOPA. This palette of compounds covers a wide widespread area of problems seen in the various stages of Parkinson's disease. Hopefully, this will end off in many compounds reaching the market and improving quality of life for patients with Parkinson's disease. Okay. We have a couple of minutes before we invite Dr. Steven Glyman from Ipsen to hold his presentation. I think we have a question over here. Can we get a mic? Thanks. I was wondering about the disease modification, and you said that you target the specific symptoms, but what would make you confident enough to focus on the disease itself? Well, I mean, disease modification is or could be defined in different ways. If you have a drug that has symptomatic effect, but that delays the advent of the patient coming into a wheelchair, that is a typical modification of the way the functional disability evolves in the patient. There's also disease modification which sort of hinders the nerve cells to break down. Our projects are mainly not focused on that second part. Our projects are possibly disease-modifying in terms of providing longer time with less functional disability. We've also received a question from the web on one of the new programs. Regarding the P003 program, to include patients in phase I, what's the main benefit of doing so? It has to do with, to some extent, with the tolerability of any molecule of this type. Of course, we need to have healthy volunteers in the phase I study. Also, at that stage, it's possible to include patients in phase I, or call it phase I-B. In the phase I program, patients will be part of the evaluation of such a product, definitely. That brings me into a question of my own because that means that your data points from that program will actually include patients with the disease, of course. That has a certain amount of value to a potential partner. You mentioned before, Nicholas, that the only thing you said about partnering was that you wanted to partner for phase III, but there's a lot of phases prior to phase III, so There is. Could you speak a little bit about how you see Yeah your partnering strategy being up until phase III? Absolutely. You've all seen that we did a deal with mesdopetam in the middle of phase II, actually, while the phase II-B study was ongoing with mesdopetam. We have the same strategy for Pirepemat. If we look at the early stage programs, we are, of course, open to discussing deal-making in the early stages. As long as we can find the right partner with the right incentives, that would be a possible way forward for us, which we have talked about a little in previous weeks here. Basically, you would be partnering at the earliest possible stage where you could still get a decent value out of the program, and that ties into the previous question. Because the earlier you introduce patients into the programs, the more it is perceived that data is valued, right? Absolutely. In CNS, I mean, clinical data is the optimal outcome. If you have human data. Mm-hmm From a population of patients suffering from a certain disease, that's optimal from the CNS perspective. On the other hand, good ideas can also be sold at an earlier stage. I also want to because I know you mentioned that and we all know that the financing climate has gotten rougher, to say the least. I mean, you have both secured phase III for Mesdopetam, and there will likely be milestones on the way as well. You mentioned that you had a strong financial position. Usually, what people ask for, in terms of runway, what are we seeing? I mean, for what purposes and at what stage do you feel that you would need additional funding? For those if ever? For those who dig into our numbers, you will see that we have a burn rate around SEK 25 million-SEK 30 million per quarter. That's two and a half to three million dollars a quarter, or euros for that matter. And you can do your own math on that. What is necessary to say here is that the activities that we have initiated now with IRL942, IRL757, the early stage, including the P003 program, they are financed already. We're not. We don't need any more money to run those programs through phase I and into phase II. That's our plan at least at present. Okay. Yeah. I think, is it possible to patch in Steven Glyman at this point? Looking at the control room. I think it is. Yeah. There we go. Thank- Welcome. Welcome. Thank you, everyone. I'm really happy to be here. Thank you for allowing me to join your meeting from Boston. I'm here to tell you a little bit about the collaboration and about Ipsen and then why we like this project. As you know, Ipsen is, we believe, a mid-sized company. We're focused on oncology, rare diseases, and neuroscience. In that mission, we've been successful to date. Our sales in 2021 was EUR 2.9 billion, up by 12.3%. We invest heavily in R&D. We're global in scope. We have four research hubs, and we're in 30 countries with a direct presence. We're driving our pipeline through external innovation, and we've had a lot of changes in our leadership to where we're very much looking for projects in neuroscience as well as the other two therapeutic areas. Our focus is in small molecules primarily, but we're also looking at other innovative strategies, gene therapy. We're very much interested in life cycle management, which was alluded to earlier in the discussion. We can't go into the life cycle plans of some of our other products, but this is very, very important to the organization and important in our therapeutic area. This is something that should we achieve success, we'll be very interested in moving forward with mesdopetam. We have three pillars, as noted. I'll just focus on neuroscience. We have a lot of activities regarding long-acting recombinant neurotoxins as well as targeted secretion inhibitors, which are also a form of neurotoxins. We're doing a lot of work in rare neurologic disorders. We brought in two projects this last year, one in Huntington's, one in Angelman syndrome, and of course, Mesdopetam, which is dealing with a very specific and hard to treat complication of Parkinson's disease. Why Mesdopetam? First of all, it's a great project. I mean, there's been so much work that's been done on this for many years in the preclinical world to sort of establish the role of the dopamine D3 receptors. The publications are great. The work, the foundational work is great. This gave us a lot of confidence when we were looking at strategies to try to treat levodopa-induced dyskinesias. As you know, this is a difficult area. Ipsen has looked at this previously, I think in 2011. We've looked and followed along, and in terms of our new strategy. You know, we're very, you know, impressed and pleased with all the work that had been done preclinically. The clinical work to date is also quite good. The phase I-B, you know, showed good safety and tolerability. The phase II-A, although it was a small population, showed a marked increase in good ON time, which was directionally very important, and decrease in bad ON time. Looking at the phase II-B, it's just a very well-designed study. The advisors who are engaged in this project, one of which is Professor Kieburtz's and his team. The advice that they've gotten from FDA, the sites that they've selected are really quite good. It's a very solid study and, you know, look, we're realistic. Drug development is drug development. This study has a great chance of success. We like what we saw in terms of the design, in terms of the structure, in terms of, you know, how it was organized. That also impressed us when we were looking at the project. I'm a neurologist by training, and I know this space, and it's just a very difficult to manage area that lots and lots of patients struggle with globally. The current strategies are really suboptimal. There are treatments, but they're not great. These patients, you know, just lead very difficult lives at that phase of the disease. It's an important area that, you know, we hope to improve. There's lots of life cycle. We don't really have everything here called out, but there are just a number of different projects that, you know, could be initiated and things that we are thinking about on our own, you know, that haven't been disclosed that could be part of the life cycle. It's just an interesting project. We have high hopes, and we're, you know, waiting for the top-line data, like all of you. That's all I have. Just sort of a brief introduction. I hope that it was helpful. Thank you. Thank you so much, Dr. Glyman. I'm sure we're gonna have a number of questions for you. I'm looking at the audience in the room. First of all, do we have any questions here? Yes. A mic here, please. Thank you. I was wondering about your history in Parkinson's disease and yeah, what made you attempt at this disease again, and maybe if you can elaborate a bit on your learnings historically. I'll tell you about my history. My history as a clinical neurologist for 25 years. In my day, I've treated lots of Parkinson's patients. It's a foundational disease in terms of neurology, one of the most important diseases. The impairment that patients suffer, this particular symptom and having tried to deal with it through my career, you know, I had a personal interest in it. Ipsen, you know, is interested in conditions which have very focused call points. For the most part, individuals treating levodopa-induced dyskinesias are movement disorder specialists, although general neurologists do treat, but for the most part, fairly sophisticated neurologists. These patients tend to be congregated at specialized centers. You know, for a company like Ipsen, it fits into our external sales force and our commercial strategy. I think it's something that we've always been looking at. We also, in terms of, you know, we have a neuroscience interest, but when I came to Ipsen, I've been there now about two years, and really we're sort of reforming R&D. We're trying to expand from doing lots of things with toxins into more of what would be classical neurology. A lot of our treaters we treat right now, cervical dystonia, which is treated by, you know, a subpopulation of movement disorder specialists. We tried to look out and say, "What makes sense? What are the areas that are important?" Parkinson's is certainly one of them, as well as, you know, the other associated movement disorders. I hope that answers your question. Sure, go ahead. Yeah, you mentioned also commercialization. Maybe if you could expand a bit on how that could work, if Mesdopetam were to be successful. Well, you know, look, we have. You know, right now we're working, and in fact we're just like you're, you know, you're having your investor presentations, we're putting together our presentations for our internal organization and trying to get funding for, you know, for additional years. Right now we're planning the phase III based on success. We're looking clearly at, you know, where to commercialize, and I think the biggest opportunity is in the United States, but we know that there are global opportunities, so we're looking at those as well, trying to figure out how to crack different markets, and we're developing our strategies around those. You know, we're Kieburtz interested in China. We're interested in Japan. We're interested in you know all the usual places that a global company would go, the EU, South America. You know depending on what makes sense. We intend to commercialize globally. We also intend to look you know at some of the stated lifecycle opportunities that you saw on the slide. We're looking very hard at Parkinson's disease psychosis. We're looking at some of the other movement disorders you know that have been stated, tardive dyskinesia. We're looking at other areas as well that seem to make sense you know for this that we haven't yet discussed. We have the hope to really do a very extensive lifecycle plan and to commercialize globally. Other questions? Yeah, I'll go for some of my own here. Firstly, Dr. Glyman, if you could perhaps tell us a little bit, because you mentioned that one thing that attracted you was, well, the quality of the preclinical package, both in terms of, you know, mechanistic knockout models and so on, and the rest of the preclinical package. For early-stage companies, that is, you know, once you're actually in the clinic, it sort of sometimes gets forgotten a little bit. I know that from the industry's perspective, it is actually incredibly important. Could you expand just a little bit on what you're looking for and how specifically what you thought about what you saw in the Mesdopetam program? Yeah, I mean, I think. Look, we're looking at all kinds of companies. We've looked at, you know, there are several other programs that are out there for levodopa-induced dyskinesia. There's a couple other programs for falls. They haven't really developed the data as well as IRLAB has. They also really don't have the preclinical, you know, platform to do some of the preclinical comparative testing that I think that we saw that we found very interesting, where, you know, you can do an animal model and actually look and benchmark, you know, at least to some extent. We'll hope it'll be predictive in terms of dosing, and we'll hope it'll be predictive in terms of of maybe what we're gonna see in the clinic. Looking at comparative data between the same animal model run with pimavanserin and in an animal model of psychosis and looking at some of the amantadine comparisons. You know, that was very interesting to us to look at. I think the other aspects are, you know, you've worked out a lot of the manufacturing issues. I mean, really, I have to say it's a very turnkey project for us. You know, obviously we run the clinical risk of phase II, but there really weren't the issues that, you know, when we go and do a diligence and look at companies, you know, that there's incomplete data, that things weren't thought of. You know, really a very thorough team. It couldn't have been easier really. I don't know. I'm not sure that's exactly the answer, but it's the truth. I mean, we really were very impressed with just the thoroughness of the work, the quality of the work, the organization of the data room. I know that that's maybe something for people who are very, who've done this before, you know, to go into companies and see how they organize their data. The collaboration between the two companies has been fantastic. I mean, I don't know that that's been addressed, you know, previously, but just a very collaborative group, highly productive. Couldn't be better, as far as, from start to finish, from the data, to organizing the data, to working with, you know, a potential partner, even today, the ongoing relationships that we have. You know, we have questions, back and forth that we need to resolve. Our leadership might have a question. Being able to just have a continuing ongoing relationship has just been wonderful. That's really good to hear. I almost had to stop you because Nicholas and Joakim were blushing so much here in the room. Thanks a lot for that. As you probably know, we're gonna have Professor Kieburtz on in just a little while. You also mentioned him and the team of advisors who had participated in designing the phase II-B program, and you decided to take a risk on that. Looking ahead now, are you able to use the same set of experts when you are looking into the phase III protocol and the phase III program? Yes, we're working with them as well. Very happy to work with the team. It was nice to have that foundation set up, as well, so that we were able to sort of join it, to continue some of the ideas, the concepts, and just to have that expertise available was great. I see. I thought it was extremely interesting. You mentioned the potential for life cycle management or indication expansion, looking at PD psychosis or tardive dyskinesia or other types of dyskinesias potentially. I think, for a fairly smallish company as IRLAB is, you know, this also makes a big difference to hear you say it because. I'd be interested in hearing your perspective from Ipsen's side. Are you looking at this in terms of risk mitigation perhaps? Is this an increase of the market potential, or is it an extra shot on goal, so to say, if there would be something that you don't like in the current phase II-B program? I think it's an increase in the potential. I mean, look, the mechanism is sort of foundational. We need to really explore all the possibilities. There are a lot of other conditions, you know, that could be potentially addressed by this mechanism, and I'm all for doing that. I mean, you know, I think we need to. Our leadership is interested as well. You know, hopefully, you know, should we get success, we plan to go through all the logical possibilities in terms of life cycle for this particular agent. It could be great. Okay. I understand. I don't wanna go into too much detail in programs that aren't perhaps even designed yet. It'd be interesting to know, you mentioned it's foundational, so does that mean that you believe that it would have, you know, the same dosing and, you know, the same treatment regimens basically so you could go for a label expansion? Or would you rather try to find some other novelties to get new IPR when looking at different indications? I think we need to obviously do the studies to get the label expansion. I think the dosing, we hope the dosing will be the same. We don't know that for sure. I think in some of the studies, we may need to use an adaptive design to be able to quickly move through the program so that we don't have to necessarily initiate a phase II for some of the indications. For others, we may. It just depends. It's really a question of what looks the most promising and where do we choose to make investment. Some projects could be longer, you know, depending on what it is, I guess, in terms of what we're looking at. Mm. There's many activities. Okay that we're [audio distortion] I understand. I wanted to also give Nicholas the opportunity. Is there anything you would like to add from the company side in terms of your relationship with Ipsen, how it's going, that we might have missed? Not really. I think Steven pointed to some of the most important points, and that is actually in the collaboration that's ongoing. Sorry, I shouldn't look at you, Steven, there. You should be there. No, it's been a really. We had a quite long discussion last spring before we entered into the agreement. After that, on day one, we set out to work together. That was when we signed the deal, I think on July 16th, Jonas, was it? On July 17th, we started the collaboration last year. It's been ongoing since. It's for us also a very important education in this. Ipsen has a lot of experience in the management of clinical development, the late-stage development, which we of course don't have built up in-house, and that is why we have this relationship with Ipsen, from our point of view at least. And also, Steven talked about the manufacturing aspects of the compound as such. Of course- Mm We have done as far as we can, we've done what we could. That was well-received at the other end with Ipsen, which was really good for the program. And that's the CMC parts are sometimes forgotten. ... when you discuss programs like ours. The CMC, the chemistry manufacturing controls, is extremely important also from an investor point of view, to know that those aspects are covered by the program that you're investing in. Getting, let's say, the sign-off from Ipsen on those aspects of the program were really important to us and a point of communication which is difficult but also very important to have. I mean, we're also doing other studies now at risk. I didn't talk about it, but we're doing a Japanese PK study. We're doing some additional preclinical ADME studies. We're doing other things, you know, because we're planning for success. There's a lot of work that we're doing that's not clinical. You know, as I say, the collaboration has just been great. Couldn't be better. Okay. I think those are some great words to end this segment in, and we'd just like to thank you so much, Dr. Glyman, for taking your valuable time and presenting to the owners of, and potential owners of IRLAB. Thank you so much. My pleasure. Thank you. Okay. We're doing fairly well time-wise, but I think we will take the opportunity to just start on the next segment because we have a pretty hard cutoff in terms of our invited presenters. We will now start the deep dive into Mesdopetam and Pirepemat. I leave the word to Dr. Tedroff, please. Hi. Hi, Karl. I see you online. Hey, Joakim. Before we dive into the science around Mesdopetam and the treatment of dyskinesia, psychosis, et cetera, I just want to include that Mesdopetam was developed by our ISP process. It's acting through a new mechanism of action that hasn't been tested in dyskinesias and psychosis in Parkinson's disease. Before, a D3 antagonist, it's a small molecule that fits into the same pocket as dopamine fits into the receptor. The science around D3 as a mechanistic background to dyskinesias has evolved during recent years. Lots of animal studies have been published validating this target as important for dyskinesias. Mesdopetam is in same doses in animals, it's equally effective in dyskinesias as it is in psychosis models. That is a sort of foundation for. There is, you know, we can use the same doses for psychosis as for dyskinesias. With that, I would like to present Professor Karl Kieburtz, who is our next speaker. He is currently professor of neurology at the University of Rochester, New York, U.S. He is also the president of Clintrex, which is a consultancy group providing consultancy in regulatory and scientific issues around drug development in neurology, particularly in Parkinson's disease. Dr. Kieburtz has extensive experience in conducting clinical trials and leading clinical trials. He has also served as the chair of the Peripheral and Central Nervous System Drugs Advisory Committee. He has been chair of the Parkinson Study Group Executive Committee and also a member of the Huntington Study Group Executive Committee. He has been editor of multiple journals in the field and has published extensively in this area. Thank you, Karl, for checking in and please go ahead. Thanks. Good afternoon, good morning, depending on your location. Pleased to talk to you today. I'm mostly gonna talk about the background on what the slide says here, about important motor and non-motor outcomes in Parkinson's disease, and in that context, give a sense of where Mesdopetam may fit into this picture. This is a slide going from left to right, describing the course of Parkinson's disease. Sort of the left half of this is so-called prodromal area or premotor prior to diagnosis. Time zero there in the middle of the chart reflects the diagnosis of Parkinson's disease. You can see to the left, there could be premonitory signs and symptoms, largely non-motor, prior to the onset of Parkinson's disease by classic diagnosis. Over time, the various colors are meant to reflect the evolution of both non-motor and motor symptoms and signs and the accumulating disability over time. The sort of dark blue wedge is marked complications. It says fluctuations in dyskinesia and psychosis. It's really that wedge I wanna talk about. That wedge is really part of Parkinson's disease, fair enough, but is also related to and exacerbated by the treatments we provide. That's why it says complications. These are complications of dopaminergic therapy. I just wanna point out as we go along that what we use to treat Parkinson's disease and how we use it actually influences the development of these complications, and that over time, these complications are some of the most disabling features of Parkinson's disease. You can see that there are progression of the motor and non-motor aspects that are not related to complications. These complications, particularly psychosis, can be one of the most disabling features leading, for example, to institutionalization. Very importantly, these complications are not aided, in fact, are usually worsened by our current therapies. I'll get into that a little bit more as we go along. This next slide is from a trial we did quite some time ago called the CALM-PD study. Took individuals with Parkinson's disease just at the point that they are about to start treatment, so now have a sufficient disability to warrant initiation of dopaminergic medications. Many patients at the time of diagnosis have no real disability and are reluctant to begin treatment. As that disability increases, they are interested in starting treatment. These are the types of patients that were enrolled in this study and randomized to start that treatment either with a dopamine agonist, in this case pramipexole, or with a levodopa. There are several such studies like this looking at a range of dopamine agonists. I just chose this one 'cause I was directly involved in running the study, so I'm most familiar with it. What you see across these graphs here are the time from the initiation of that treatment, these are survival curves, until the time of the development of the first complication. Complication was defined as the development of wearing off, dyskinesias or freezing. Wearing off is the development of the phenomena that an individual feels that the benefit they're receiving from their treatment doesn't persist throughout the dosing interval. What does that mean? That means that when people start treatment with Parkinson's, with dopaminergic treatment for Parkinson's disease, the effect is remarkable alleviation of their symptoms and signs virtually 24 hours a day. They take their medicine at a regular interval because that's what the physician or clinician tells them to. They don't really feel that they need it. Their symptoms are virtually gone. I used to tell my patients, "My goal of treatment is that you forget you have Parkinson's disease except when you have to come see me twice a year." The problem is that remarkable benefit, as you can see from here, 'cause the timescale here is only two years, is not that long. Before people start to develop this first phenomena here, wearing off, which is noticing that the benefit wanes before the next dose. I always used to ask my patients, "Why do you take your medicine when you take it?" And as long as they said, "Well, that's when you told me to take it," I knew they had not yet developed wearing off. When they say, "Well, I know I have to take it 'cause I feel like I need it," means that they're actually starting to experience this wearing off. In contrast, dyskinesias are extra involuntary movements, non-rhythmic, that can involve the face, the mouth, the hands. Those of you who have seen Michael J. Fox can see what dyskinesias look like. There's other people in the public sphere who have dyskinesias, but he's probably one of the most famous people to have this problem. Dyskinesias are another one of these complications. The graph on the far left is the sum of the frequency of wearing off dyskinesia and freezing. I didn't show freezing 'cause it's quite uncommon in these first two years. What you can see here is that 50% of people develop these motor complications within two years of starting treatment. The second thing you can see here is that the initiation matters. What you start treatment with matters in that the people who started on a dopamine agonist have less dyskinesias and less wearing off. This was not only found in this study, but in all the studies that looked at the difference between initiation with levodopa and a dopamine agonist. The effect of that, we've done secondary analysis, is really related to the timing of initiation of levodopa because those re-randomized to pramipexole could eventually start levodopa, the timing and the dose. What we know is that motor complications are related to when you start levodopa and how much you start, and any interventions that can reduce the time that you're on levodopa or reduce the amount of dose you take helps reduce the incidence of these complications. As it stands, 50% of people, at least starting on levodopa, will develop motor complications within two years of starting. Now, some of these may be mild and some of these may not be that troublesome, but over time, most of the day becomes bad time. Sorry. What do I mean by bad time? When a person is feeling that their medications are working, we call that on. When their medications are not working, we call that off. You can see over here, this is off time and on. When you're on, you may or may not have these dyskinesias. If you have dyskinesias that interfere with function, that's called troublesome dyskinesias. These are individuals who went to have deep brain stimulation. On average, they spent four hours of the day on with troublesome dyskinesias and about five and a half hours of the day off, meaning that 10 hours of the day they had bad time and only seven hours of the day did they have on time without troublesome dyskinesias. In other words, from the time of initiation of therapy, when basically 24 hours a day you have relief of signs and symptoms, these patients, about eight to 10 years into treatment, spend the majority of their day without a good response to treatment. This study compared best medical therapy to deep brain stimulation, and what you can see here is that continued management with medication has no impact on that. In contrast, deep brain stimulation increases by four hours on time without troublesome dyskinesia and reduces off time by half, essentially flipping the ratio around such that most people who had deep brain stimulation now spend most of the day in a good state and a minority of the day in a bad state. That sounds terrific. In fact, DBS, deep brain stimulation, is really the second miracle in the treatment of Parkinson's disease after levodopa. Like all miracles, it has a darker lining. Number one, there's only certain people who can have deep brain stimulation, because of their age and the fact they have to undergo a major neurosurgical procedure. There are impacts on cognition, balance, and speech, all of which are deleterious in a population with Parkinson's disease. DBS turns out to only be really tractable in a minority of patients. It's also extremely costly, and it is a cumbersome thing to have. All my patients who've had DBS, I told them, "Sometime within the first four weeks of having your procedure, you will wish you never had it because of the complications and difficulties virtually everyone encounters in the initial postoperative period." This is the most dramatic thing we can do for dyskinesias wearing off, so-called motor complications. It's very invasive, expensive, and limited in who it can be used in. Intestinal infusion, now perhaps with the release of some of the AbbVie data about subcutaneous infusion, can also help with fluctuations. This is also still invasive, requiring a surgical procedure for the insertion of the tube, and that tube can migrate, cause problems such as intestinal perforation and other problems. 50% of patients need that tube manipulated or replaced within the first year. It too is invasive. Not as invasive as a brain procedure, but still is a procedure. What you see here is this, again, was compared to continued best medical management versus the infusion. The infusion you see has this significant decrease in off time. In this case, unlike DBS, where you saw no improvement, there is about a two-hour improvement in off time. In this good on time, that is on time without troublesome dyskinesias, you see about a two-hour improvement versus continued medical management. This is about half the benefit of DBS in terms of the on time without troublesome dyskinesia benefit, but it's less invasive. Again, expensive, cumbersome, people have to wear a pump most of the day. The tube has to be maintained. The uptake has not been that great. For people who respond to it is a useful approach. What about all the medical therapies we have? Pramipexole, these are the dopamine agonists, MAO-B inhibitors, COMT inhibitors. We now have A2A antagonists with the recent approval of istradefylline. There's a lot of data here, but what I'm just gonna take you over to is this final column, which indicates that the net effect of oral therapies is, if you go across all the studies and look at the Cochrane medical review of effectiveness, it's about an hour. These treatments are typically deployed in people who have about six hours of off time. What you get is about 1 hour of off time. To put all that in context, about 1 hour of off time improvement with standard oral therapies, leaving a lot of residual problems. About two hours of improvement in good on time with intestinal infusion, with its complications and invasiveness, and about double that with DBS, with stepped-up complications and invasiveness. What we are left with is a lot of Parkinson's patients with motor complications are left with residual both off time and dyskinesias. These treatments don't necessarily get directly at dyskinesias. They're more directed at improving off time. There is a medication directed directly at dyskinesias, which is amantadine. What we see here, this is one of the randomized studies of amantadine, and this is unlike talking about on and off time, which I was before, is a scale of the severity of observed dyskinesias. Doesn't tell us whether they're troublesome, doesn't tell us how long in the day they last. Tells us this is a little bit like wind speed. It doesn't tell you how windy it is all day long, but it tells you what's the maximum wind speed that was observed. The wind speed or the severity of the dyskinesias here can be reduced very substantially by amantadine. Placebo has some improvement too, but you see the net effect. This is nothing new. When I was in training, I don't wanna say how long ago, 30+ years ago, we used amantadine for this purpose. It was only recently that it was pursued for demonstrating this in a randomized study. Why were we not so interested in pursuing this before? Amantadine is a very double-edged sword. Amantadine has this effect of being able to reduce dyskinesias, but it also has very prominent mental side effects as well as some other side effects, such that many people cannot achieve a dosage that yields an anti-dyskinetic effect without encountering mental side effects, which means they have to reduce it, which means they have to endure more dyskinesia. In its maximum, here you can see the anti-dyskinetic effect, and you can see by reducing dyskinesias, this can translate into increasing on time without troublesome dyskinesia. Now, amantadine has the ability to decrease off time also. It has some intrinsic anti-Parkinsonian effect, and you can see this graph is indicating in hours the amount of off time that has been improved. You can see this on time without troublesome dyskinesia has increased a lot more than this, meaning this anti-dyskinetic effect allowed more of the on time the patients were experiencing to be experienced as on time without troublesome dyskinesia. This is an effect that was desirable, but with a drug that limits its utility both by dosage and the type of patient who can take it, because many patients who are at this stage of Parkinson's disease already are experiencing mental side effects. One of those side effects is hallucinations. Hallucinations are a significant dosage-limiting problem in Parkinson's treatment. If we think about psychotic disorders and antipsychotic treatments, the bulwark of them are anti-dopaminergic. They're dopamine blocking agents, Haldol, even right up to the atypical variation on antipsychotics, they have dopamine blocking capability. If you turn that around and talk about giving dopamine enhancement, you can imagine that hallucinations, one of the aspects of psychosis, could be experienced with patients with Parkinson's disease. In general, patients with Parkinson's disease do not have hallucinations unless they are on treatment. This is a treatment-related complication and a dosage-limiting problem. Patients encounter. It's primarily a visual hallucination, but it can also be associated with auditory hallucinations and can be associated with delusions such as persecutory delusions, a very common one being infidelity, the spouse. Hallucinations and associated delusions are a clear dosage-limiting problem in Parkinson's disease, and the only available treatment we have for this is pimavanserin or NUPLAZID. Turns out, again, it's almost like a miracle having used this myself. It was one of the few times a spouse actually cried in the office about the remarkable transformation of her spouse that the treatment effect was such that he could remain home and not have to be hospitalized. It was a massive effect. That happens very rarely, and this data display actually shows that. It's a little bit complicated. Let me walk you through it. This is looking at an improvement in the SAPS scale, which is a scale of positive symptoms in schizophrenia. It's essentially a scale of the degree of hallucinations. We can see, and placebo is the gray and Nuplazid is the black. This is saying no improvement in the scale, one-point improvement in the scale, three-point, five-point, and looking at the distribution, what percentage of patients experience this? This is a very interesting display here because 13% of the treated population had complete resolution of their hallucinations. Gone. You can see that only one subject in placebo had this experience. This was a very complicated approval by the way, but this finding is what really drove the approval of the drug. That is in a small minority of patients, less than one-sixth, you can get a dramatic response. If you take that 13.7% and add it all the way back up here, what you basically see is the treatment effect of Nuplazid is driven by a dramatic response in a small number of patients. The average response is very small. It's a confusing set of data, but my sum total of this is, this is a drug like amantadine that can work in a small population and the effect can be quite brilliant in fact. Unfortunately, it leaves a lot of residual patients without any meaningful treatment for their psychosis. Where do we stand? Despite all our medical treatments and our interventional surgical treatments, Parkinson's patients continue to have persistent motor fluctuations and hallucinations, representing a significant unmet need. Off time persists but despite available treatments. You know, I showed you that 2.5 hours of off time remains even with Duopa. At the end of Rytary, for example, patients still have four hours of off time. Even though these treatments work, there's a lot of residual disability. Dyskinesias, we don't really have a well-tolerated oral treatment, and an intervention that could decrease both troublesome dyskinesias and increase the good on time would be extremely well-received. I just lost my slides. I don't know if you lost my slides also. Actually, sorry. So a broadly effective treatment for hallucinations that doesn't worsen underlying PD features is also urgently needed. In my view, Mesdopetam, given its mechanism of action, has a remarkable characteristic of being able to fit into both of these pieces for the treatment of these motor complications and also for the prevention or treatment of hallucinations, which may also allow us to better treat the underlying Parkinson's disease. I'm gonna stop there, see if you have any questions about this. I was talking more about the disease and its phenomenology than about the treatment per se, but happy to take questions about either. Thank you. Thank you so much, Professor Kieburtz. As before, we're gonna start with some questions from the local audience. Can we get a mic to the gentleman in the back, please? Right there. Thank you very much for taking my question. My question is related with the treatment with amantadine, as you were mentioning. Where, I mean, for example, in the phase IIa that was run with mesdopetam, it was shown that mesdopetam improved dyskinesias in patients treated with and without amantadine, with a larger effect in patients without amantadine. Now in the phase IIb, only patients that are not under treatment with amantadine are included. I was wondering, where do you see mesdopetam fitting in the therapeutic landscape? Is it, like, in patients that are not treated with amantadine, or it would be like a co-treatment with amantadine and with the possibility of reducing the dose of amantadine in as a treatment, as a co-treatment? Yeah. Let me talk about two aspects there. One aspect is the study design, which I think, in the study design, it's important to, in the case that we have now, is restrict the use of amantadine. This allows us to have the best chance to see an antidyskinetic effect, in, I'll just say, the cleanest kind of environment. I think that's important from a methodological point of view. I do not think it restricts how the drug will be used post-approval. I think that's your other question, where do you see this fitting in, or where do I see this fitting in? First of all, I think there is a significant number of people who have dyskinesias who are not gonna be candidates for amantadine. They already have some cognitive defects, they're on other concomitant medication, they're elderly and at risk of hallucinations. Clinicians won't use amantadine, and they have no other options, really. I think that's one setting. Another setting is people who are on amantadine and have residual dyskinesias. There are a lot of people like that, who have tried amantadine, can only tolerate a certain dose, and have residual dyskinesias. I think Mesdopetam could be added to that. Will that combination have specifically been studied in the approval process? No, not necessarily, but that usually doesn't limit the clinical use. For example, there are not many studies or any studies in the development process that looked at the combination of dopamine agonists with COMT inhibitors or dopamine agonists with MAO-B inhibitors, that those are extremely common combinations in Parkinson's disease. I think, practically speaking, eventually people will use a combination of them. Okay. We have another question here at the front, please. Thank you. I was just wondering if you could expand a bit on your long-term view of levodopa. Will it always be around, and could Mesdopetam change that in any way? Yeah, what could make levodopa non-relevant? Oh, sorry. I missed the last part. Yeah. What could make levodopa, you know, not useful anymore or replaced? Well, I'm not sure levodopa will ever be replaced, frankly. It's, it's you know, pound for pound the most powerful antiparkinsonian treatment we have. There's nothing essentially problematic with it, except in the way we give it. It's really quite amazing that it was around for 30 years before we ever even did a dosage-ranging randomized comparison. I think, as I alluded to, starting levodopa in such a way that you go to either too high doses or you give it too infrequently, it's really the pulsatile way of giving levodopa that leads to motor complications as best we understand. And if we could ameliorate that, for example, one could imagine. Just picking up on some of the questions of the last speaker, expansion of possible indication. Mesdopetam is the kind of medication if it was given at the initiation of levodopa might help prevent the development of motor complications. We're not studying that right now, but that is a possibility. Then why get rid of levodopa if you can get all its benefit without its subsequent problems? Like, if you could block the motor complications, if you could block the psychosis, it's a great, well-tolerated, safe medication aside from these problems that I was discussing. I don't think levodopa is going away. The question is how can we use it better, and how can we combine it with other things to limit its toxicities? Okay. Right. Thank you. I'll slide into some questions of my- Just one more. Okay. Sorry. Yep. We have another question coming up from the local audience here. Thank you. I wonder if you can expand a little bit about the fundamental causes of the dyskinesias, and to what extent they actually are triggered by the wearing off of levodopa or the inherent causes of the Parkinson's disease? The setting of using levodopa in Parkinson's disease is a unique neurochemical scenario. In Parkinson's disease, striatal—sorry if I'm getting very technical, but bear with me for a minute. Dopamine is a tonically released neurotransmitter, and in the brain, the levels are kept extremely constant, almost like body temperature is regulated very constantly. Striatal dopamine is very constant. In Parkinson's disease, it goes way down because of the loss of dopamine-containing cells. When we then give levodopa, which is converted to dopamine in the brain and elsewhere, we get peaks of striatal dopamine, followed by valleys, peaks of striatal dopamine, followed by valleys. The benefit persists because the dopamine is taken up into synaptic vesicles and stored, but you still get this exposure of peaks. Those peaks followed by valleys trigger transcription of certain genes, expression of other neurotransmitters, and a change in neuronal firing pattern. That neuronal firing pattern underpins both wearing off and dyskinesias. The striatal firing pattern is like a rheostat on a light. It regulates a series of firing, and when that becomes aberrant, the result is both wearing off and dyskinesias. If you continue to give more levodopa, which is the typical response to wearing off, you get more peaks and valleys. You worsen the scenario, and it actually becomes a vicious feedback loop of feeding the system to worsen complications. Complications are essentially a phenomenon of aberrant protein transcription and change in striatal firing pallidal output firing pattern. It's actually reversible. The reversibility has been seen in experimental animals and in humans. If you stop giving pulsatile levodopa and allow the system to restore itself, you can actually reverse motor complications. It's not a permanent transition into motor complications. It takes a long time to unwind it, but it is possible to do so. Hopefully, I answered your question. Thank you. One of the questions I had almost at the bottom here because I thought that, you know, this is way too far out, but you mentioned it yourself, so I'm gonna move it to the top of my questions, and that has to do with the concept of delay of onset of motor complications, because I think that is so interesting. Parkinson's is obviously a progressive disease, and Mesdopetam, the program is aimed to treat motor complications. As you mentioned, one could see a place for Mesdopetam in actually moving the time point at which you see these motor complications, which 50% experienced within two years. Could you talk a little bit about how you could see such a program evolve if you ever wanted to get to that point? Because there could be perhaps ethical considerations. If you have perfectly controlled patients, do you want to treat them with something while they are under perfect controls? It could potentially be fairly large and lengthy studies. Is this something if Mesdopetam gets an approval for the control of motor complications, clinicians might perhaps start prescribing off-label in order to delay the onset of action in well-controlled patient? Could you expand a little bit about how this could, you know, come to be if it ever could? Yeah. Thanks for that. In that slide I showed from CALM-PD was an example of a study trying to get at that, which was a randomized comparison of two different ways to start treatment. Prior to that study, I'll just talk about pramipexole 'cause that's the study I talked about. Pramipexole had been demonstrated to both treat motor complications, reduce off time in people with established fluctuations, and to have an intrinsic antiparkinsonian benefit as monotherapy. The question then arose just naturally as you brought it up about mesdopetam, could you use it earlier to prevent the onset of motor complications? That study, in fact, showed that was the case, that the people who started on pramipexole had less both wearing off and dyskinesia and similar antiparkinsonian benefit. Now, there's some debate about how similar the antiparkinsonian benefit was, but I think it gives us a model of how we could construct a study, which is to take people who are at the point of starting treatment and randomize them to Mesdopetam or not and allow them to start dopaminergic treatment with levodopa and follow them over time for the development of motor complications. We know that about 50% on levodopa alone will develop motor complications by two years. The timing of the study, it is a longer study. It is a longitudinal study for the evolution of a complication, but it need not be more than 150-200 patients per arm and approximately two years long. No drug has an indication for the prevention of motor complications in Parkinson's disease. It always... One of my colleagues in Clintrex is Rusty Katz, who used to run the division at the FDA. It always puzzled him that all these products had one study showing this prevention of motor complications, but never a second study which would have enabled an indication for that. No one's really pursued that. I think it's important because it is a major unmet need that patients are concerned about. They delay effective treatment 'cause they're concerned they're gonna develop motor complications later, and it would be a real advance for people to get over their fear of, you know, quality of life-improving treatment if they knew they could delay the time till they might develop motor complication. Wow. It's just, I think the expression is warranted. I mean, because if I hear you correctly, that would be a 200-patient study over two years, and that would be a fairly massive label expansion and sort of first to the market. I think that's extremely interesting. 200 patients per arm. Oh, sorry. 200 per arm, so 400 total. Per arm. Okay. 400 patients. Even so, especially if you've proven effect in treating motor complications already, I think Ipsen would probably be interested in looking into that. Professor Kieburtz, I could speak to you all day probably, but your time is very valuable and we're trying to keep our schedule here as well. I just want to extend the sincerest of thanks for spending your time here with us today. Thank you so much. Thank you. All right. I will talk a little bit about the markets. Finally, the fun parts. Well, we looked into. We're not making up the figures ourselves. We looked into the research company GlobalData and their database of epidemiology throughout the world, and we looked at the eight largest markets in the world, which you can see there. Looking at this, we find out that the number of persons living with Parkinson's disease is about 4.7 million people, so that's quite a massive amount of people. Of those, about 1 million has or experience LIDs, levodopa-induced dyskinesia, which is one of the things that mesdopetam is developed for. About 1.4 million people suffers from psychosis in Parkinson's disease. That means that there are about 2.4 million patients in those eight markets alone that would benefit from or maybe will benefit from Mesdopetam. There might be, you know, a little overlap, but there are no studies showing that. Let's say 2.4 million patients. The other part of looking at how big the market for Mesdopetam would be is the price. As Professor Kieburtz said, there are pimavanserin and there are amantadine, which are used today, at least in the U.S., where they are approved for treatment, and they both cost about $30,000 per year. If we take our 2.4 million patients, and $30,000, that is in the US, and global medication pricing, that's an area of it, of itself. We also looked at third-party estimates, which says that in Europe, we would have about $10,000-$14,000, and in Japan about $15,000, and in China there are not really any reliable data there, so we just estimated about 10% of the US prices. That would give a total market for LIDs of about $12.3 billion a year. In Parkinson's psychosis, it would be about $17.2 billion. That is, of course, the total market. That's $29.5 billion. We do not expect to reach about 100% of all the patients. Penetration, there are different views on penetration, so you would just leave that to you. It's a massive market for Mesdopetam in Parkinson's alone. We have the tardive dyskinesia. That is not Parkinson's disease, but we saw that Dr. Glyman said that tardive dyskinesia is one expansion that we could look for in Mesdopetam. There are a few medications in the U.S. The cheapest one costs about $45,000 per year. The number of patients are on the slide as well. I will not go through all the numbers. That indicates that the total market for tardive dyskinesia is about $11 billion in the eight major markets in the world. All in all, about $40 billion as potential for Mesdopetam. Now some words on Pirepemat. Thank you very much. Let's move on to our next compound, Pirepemat, which is heading towards phase II-B. This is a new compound as well, a new small molecule with a new unique way of acting in the brain. It is a drug that regionally selectively affects the cerebral cortex, parts of the cerebral cortex, that is the gray matter of the brain that is involved in all higher order contexts. It's a tricky thing finding drugs that works only in that part and not so much in other parts of the brain or the body. The phase II-A study we conducted indicated that this drug works as it is intended to work, and that it may help to improve balance and postural responsiveness in patients with Parkinson's disease and cognitive impairment. as I alluded to in my previously, about half of the global population of Parkinson's disease are in stage three or more, meaning that they have impaired postural reflexes and have an increased risk of falling. This is also what we see. We already knew early on in the onset of levodopa treatment that motor functions such as bradykinesia, tremor, rigidity could be improved by L-dopa, but postural instability and falls are not particularly amenable by L-dopa treatment. That is a major medical need that is not met today in the treatment of Parkinson's disease. Do we have Professor Bloem with us? So our next- Yes, we do. Yeah. Wonderful. I'm here. Our next speaker here is Professor Bastiaan Bloem. He is a professor at the Radboud University Medical Centre in the Netherlands. He is a very famous person in the area of postural dysfunction and falls in Parkinson's disease, published extensively, doing a lot of pioneering work, and we're very happy to have him on board because he's very sought after, and we really appreciate you taking your time for this session today. Please, Professor Bloem, go ahead. Well, thank you for your kind introduction. That must have been one of the kindest introductions ever. I'm humbled and blushing here at the other end of the line. It's wonderful to be here and to share some of my thoughts on balance and falls, and in particular, the treatment and the prevention of falls in this disorder. I can't tell you how happy I am with the developments taking place currently, and in particular, the Pirepemat as a new intervention. This is the cover of my thesis. It goes back to 1994. I completed my PhD work at a very young age. The conclusion of my thesis is that postural instability is common, debilitating, and typically unresponsive to levodopa or other dopaminergic interventions. In fact, in quite a number of instances, the dopaminergic medication worsens the balance issues. Think of orthostatic hypotension, confusion, hallucinations, severe dyskinesias that may perturb people, onstage freezing. This is literally a message that I received last night. There you see it. I got the email at 10:45 P.M. last night, and it is a Cochrane review on prevention of falls. Lo and behold, the timing is impeccable. Could not have been better. The overall conclusion is that there is very little evidence to date to prevent falls in Parkinson's disease from happening. The timing indeed could not have been any better. Quickly about the impact of falls. This is one of my best cited papers. It's a meta-analysis published in the Movement Disorders journal. What I want you to look at in particular is these percentages of falls in people with Parkinson's disease. Wood is the longest follow-up study until so far, and you see that single fallers or any fallers happens at a rate of up to 70% annually. Recurrent fallers, which is even more frequent, happens at a rate of 50%. It's a very common issue in Parkinson's disease, much more common than in healthy controls, which you see in the blue circle on the right. What I always find really fascinating, this is another paper we did in the Movement Disorders journal, was the risk of falls as a function of disease severity. Here is the Unified Parkinson's Disease Rating Scale on the x-axis. What you see is that falls are typically absent in early stages of Parkinson's, and then they start to emerge and rise to a peak, and afterwards it declines again. This is, of course, not to say that falls are being cured in later phases of Parkinson's disease. It means that towards the end stage of this disease, people become immobilized, wheelchair-bound, maybe clustered to their beds. Obviously people who are wheelchair-bound no longer fall. Fewer falls is not necessarily good news. You have to depict falls as a function of physical activities. Falls is typically a disease of active people, and immobilized people don't fall. One of the contributing factors and one of the reasons why falls is so debilitating is the fear of falling. Fear of falling is common in Parkinson's disease, but particularly in recurrent fallers, paper in Journal of Neurology that we published some time ago. Fear of falling is debilitating in its own right. It makes people move less, which is sort of a treatment for falls. Of course it's not what you want because evidence is now accumulating that regular exercise and moving out and about is a symptomatic and possibly a disease-modifying treatment for Parkinson's. Injuries are common, including major injuries like hip fractures or hemorrhages in the brain, epidural hematoma in this image.