Good morning, everyone. Good morning. Thank you very much for joining Takeda R&D Day 2024 out of your very busy schedule. My name is O'Reilly. I am IR head. I am your moderator today. Very nice to meet you. First, about the interpretation service. If you are here in the venue, please use the receiver in front of you. Channel 1 is for Japanese. Channel 2 is for English. If you are joining online, please click on the language button at the bottom of the Zoom window and select Japanese or English or original audio. Before starting, I'd like to remind everyone that we will be discussing forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those discussed today. The factors that could cause our actual results to differ materially are discussed in our most recent Form 20-F and in our other SEC filings. Today's presentation also covers elritercept, which is included for reference only. Takeda entered into an exclusive license agreement with Keros for global rights in all territories outside of mainland China, Hong Kong, and Macau to elritercept. The closing of the transaction is subject to receipt of regulatory approvals expected in the first calendar quarter of 2025. Takeda does not currently have rights to elritercept. Please also refer to the important notice on page 2 of the presentation. Now, let me introduce today's agenda and today's presenters. First, a global innovation-driven biopharmaceutical company to be presented by Christophe Weber, President and CEO. Next, R&D strategy and pipeline highlights to be presented by Andy Plump, President, Research and Development. And next, neuroscience deep dive on orexin franchise to be presented by Sarah Sheikh, Head of Neuroscience Therapeutic Area Unit and Head of Global Development, and Ramona Sequeira, President of Global Portfolio Division. And after a break, we will have gastrointestinal and inflammation deep dive on zasocitinib, rusfertide, mezagitamab, and fazirsiran. The presenters are Ramona Sequeira and Chinwe Ukomadu, Head of GI & Inflammation Therapeutic Area Unit. And after lunch, we will have oncology deep dive on elritercept, newly announced ADC. The presenters are P.K. Morrow, Head of Oncology Therapeutic Area Unit, and Teresa Bitetti, President of Global Oncology Business Unit. After all the presentations are made, we will have a Q&A session, and this will be joined by the seven presenters and Milano Furuta, Chief Financial Officer. If you are here in the venue, we have prepared a reception for you to join, so please stay until the end. Let's get started with the presentations. Good morning, everyone. Good evening if you are in the U.S. I think we have about 200 people connected online, so it's really a great pleasure to be with you today for this R&D Day. Last time we did an R&D Day was about five years ago. It was exactly five years ago, so time has passed. I hope you will feel today that the maturity level of our pipeline, of our R&D organization to deliver this pipeline, has improved so much since 2019, which is great because in 2019, not everything played out as we had in mind. You will feel, I'm sure, today that, again, the majority of the pipeline, the data we have on these molecules, the stage they are in, but also the way we developed this pipeline has progressed so much in the last five years. So I'm very excited about sharing that with you. We will focus really on our vision, which is to discover and deliver life-transforming treatments. You will see that all the molecules that we are highlighting today have the potential to transform the life of patients. They are differentiated. They will change the standard of care. We are convinced that they can compete often in quite competitive therapy areas and environments. So this is really core to our vision and what we do. We now at Takeda have the ability to develop these molecules globally. Many of our clinical trials are done in multiple countries, so we have this ability to develop globally these molecules. And we also have the scale and the ability to launch this new product globally by ourselves. And that's also very important. If you want to be a global biopharmaceutical company and a competitive one, you need to have these two capabilities. You need to have the capital investment, the R&D investment potential. We invest about $5 billion per year in R&D. You need to be able to develop globally these products. Many of our trials are done in many countries at the same time with many centers. We have this capability, and you need to be able to launch globally this product. So what we will see today is a late-stage pipeline. Many of these products will be launched before the end of this decade, so before 2030. They will have a significant revenue potential, which will help us to grow in the long term. You will see that we believe that this pipeline will allow us to grow in the decade post-2030 when we will start facing biosimilars against one of our main products, Entyvio. So this pipeline will allow us to grow in the very long term. Between now and 2031, once Vyvanse's impact is behind us, we are facing significant generic exposure on one of our key products, Vyvanse. It's almost behind us. Then we will grow because of our growth in launched products, which represents 50% of our revenue, and this group of products is growing double-digit. So we have between now and 2031, our growth agenda will be driven by growth in launched products. We will start launching some of these pipeline assets pretty soon. You will see that. Then post-2031, when we will start facing biosimilars on Entyvio, this pipeline will help us to continue to grow. So revenue growth is key, both short, mid, and long term. We have a very strong cost management as well, so it will translate into margin improvement, again, once Vyvanse is washed out. That's how we will generate shareholder value in the mid-, short-, and long-term. So here are the six molecules that we will focus on today. You will have a broader perspective on our pipeline, but that are the six that are late stage, in phase III, or about to enter phase III. And that's the potential that we see in these molecules, between $10 billion -$20 billion peak revenue for these six molecules. And we will highlight, we will explain how we ended up with these numbers. So that's, of course, very material, and that's why we believe that it will help us to grow in the long term. And actually, of these six, three will have phase III readout in the next 12 months in 2025, and filing will happen right after. So we are talking about a really late-stage pipeline with potential launch for at least three of these assets in the next three years. So that's also very, very exciting. It's truly a new era for us because we have never launched so many potential assets with that type of revenue potential, and we are obviously very excited about it, especially now that we have, again, that presence, that scale to be able to launch it globally. So very exciting time. And without further ado, I'll ask Andy to join me to kick off this pipeline day. Thank you very much. Thank you. Thank you very much, Christophe, and hello, everybody. I have two takeaways for you to carry with you from today's R&D Day. One, as Christophe just mentioned, we have a very exciting, high-value late-stage pipeline, and we are very confident, very confident that we can deliver on this pipeline. The second is we have an R&D organization that's primed to sustain Takeda for the long term based on our cutting-edge research engine, our early and mid-stage pipeline, and our partnership and business development model. So let me start, though, by grounding you to our strategy. This is a strategy that for almost a decade now has been unwavering. Unwavering, but of course, evolving. Evolving based on changes in the dynamic external landscape, evolving based on our successes and on our failures. We've pivoted this strategy over time, but it's an unwavering strategy. And that strategy is that we discover, develop, and deliver life-transforming medicines for rare and more prevalent diseases across our three core therapeutic areas. Those are oncology, neuroscience, and gastrointestinal and inflammation. We have two smaller R&D organizations in plasma-derived therapeutics and vaccines that support their respective businesses. Our research laboratories are outstanding. They can and do innovate from within, but they're also inverted to nurture our large network of partnerships. And then wrapped around everything we do is data science and operational excellence. We are committed to this strategy, and as you'll see over the course of this morning, this strategy is working. Now, 90% of our R&D budget is in our three core therapeutic areas. That's what we focus on today, and in particular on the six programs that Christophe just articulated. But before moving on, it's important for you to have some foundation of the journey that we've been on over the last eight to 10 years. The complexion of Takeda and Takeda R&D has changed immensely over the last decade. In 2015, we were a smaller organization. We were regionally focused predominantly here in Japan. We had one, essentially one therapeutic modality. That was small molecules, and we worked across many therapeutic areas. Today, as I just mentioned, we're a much larger organization. We are a global R&D organization with three therapeutic areas and now four core therapeutic modalities. Those are small molecules, biologics, antibody-drug conjugates, and allogeneic cell therapies. And most importantly, most importantly in that transition is that we now have a mature, rich, high-value late-stage pipeline. Now, I've been here for this entire journey, and I have to tell you it's not been easy. We've had successes, and we've had setbacks, but we are absolutely 100% a learning organization, and we've taken those setbacks, and we've persevered, we've pivoted, and we've learned, and we've translated those learnings into capabilities that have fueled the pipeline that you will hear about today and that will carry us forward as we deliver on this pipeline into the next few years. Today, we are in a privileged position. It's quite a unique position in the history of Takeda. Let me tell you a little bit why, so this is a slide that you will see 10 times throughout the day. It is our North Star slide for today. We have a very exciting late-stage pipeline, and today, through all the speakers, you will hear about the differentiated science. You will hear about the transformational potential of each of these assets for patients. You'll hear about our development timelines, and in many places, those development timelines are greatly accelerated. And then you'll hear about the market potential of each of these assets. As Christophe just mentioned, 2025, just a month from now, next year is a critical year for us as we have three of these six programs with pivotal phase III readouts. oveporexton, which is TAK-861 for narcolepsy type 1. zasocitinib, which is TAK-279 in psoriasis, and rusfertide in polycythemia vera. Beyond next year, we'll have pivotal readouts in five additional indications across four molecules. zasocitinib in psoriatic arthritis, mezagitamab in IgA nephropathy and immune thrombocytopenia, fazirsiran in alpha-1 antitrypsin-associated liver disease, and elritercept, our newest addition to the pipeline in myelodysplastic syndrome. And we are very confident that we can deliver on this. So let me help you understand why we feel so confident that we can deliver on this. The first reason is that we've had demonstrated success. So if you look at this slide, look at the top row, we've had five new molecular entities approved by the FDA over the last three years. This puts us in the top 50% of our biopharmaceutical peers. We've had important life-cycle management programs that we've brought through the finish line, like the Entyvio Pen, like HyQvia for the CIDP maintenance indication. And importantly, when you look across our major markets, U.S., China, Japan, Europe, we've had a substantial number of approvals. And in fact, our success rate is close to 100%, significantly above the industry average. Now, I don't think that the outside world is familiar with this level of success. Why? Many of these indications are smaller indications. Many of these approvals are regional approvals. In many cases, the revenue potential is not as high as what we perhaps need to sustain our future. But with that said, what this tells us is that we can execute and we can deliver. We look at this as a leading measure of what's to come over the next few years. Now, the second reason that we're confident is the rigorous prioritization that we've undertaken over the last one to two years. And I'll walk you through this in a little bit of detail. Firstly, we've been working hard to advance our pipeline to get to this point. A couple of years ago, a year and a half ago, we started to really look at our pipeline, and we instituted a new set of prioritization criteria, and you can see them here: unmet medical need, scientific validity, an accelerated development path, and commercial opportunity. That led to this transition, as you can see in the pie chart, that's quite dramatic. Just in 2021, we had three phase III programs and four phase III studies. Fast forward just three years, today, six phase III programs and 14 phase III studies. Secondly, if you look to the right-hand side of the slide, our investment thesis. In 2021, the majority of our R&D investment was in our early-stage pipeline. We were signal-seeking. We were looking for those next great assets that we could bring to patients. As you fast forward now to our current time in 2024, you can see that now the majority of our investment is behind these six late-stage assets, and as we project out in our forecast over the next two to three years, that percentage will increase as these phase III programs continue to evolve. And now the third reason that we're confident is that over the last three years, we've fundamentally, fundamentally changed our development model. A lot of work has gone into this over the last three years. It's a model that we've named Future Fit. And we've named it Future Fit because it's supposed to impart a mindset around a very dynamic development model. It's a model that will not be static. It will evolve as the rapidly evolving external landscape changes. Now, there are two core features to Future Fit. The first is that we've rebuilt capabilities within Takeda. These are strategic nodes. These are parts of development that we do better internally than sourcing. And since we had such a highly outsourced model for so many years, we've learned from that. We've learned what capabilities we absolutely need to have, and we've built those capabilities without overbuilding. And the second core element of Future Fit is data digital and technology. Everything that we do in Future Fit is enabled in some way today by data digital and technology. And as we advance towards the future and as the world becomes more and more sophisticated, we're able to continue to integrate those new tools into our operating model. I'll give you one example, and maybe it's not exciting to you, but I'll tell you it's very exciting to me. And that's a tool that we have called Compass. It's a very sophisticated tool, and it's like a control tower. It allows us in real time at the push of a button to track and to monitor every one of our clinical trials, level of information that could be of interest to me, and level of information that could be of interest to someone who's running one of our trials, someone with boots on the ground. The kind of data that we can get from Compass are not just data that tell us where we are, but they're leading measures of whether a trial is actually going well or not going well. That allows us to intervene more quickly. In the past, we waited oftentimes months, sometimes years before we'd see issues with trials. With Compass, we're now way ahead of the game. Now, it's really hard for me to describe Future Fit because it's so large and so substantial. Perhaps the best way to explain Future Fit to you is to give you two examples. The first two programs that we put into this new operating model are, of course, two of our most important programs, zasocitinib and TAK-861. In both cases, we've seen dramatic effects on both quality and speed. For zasocitinib, you can see that our two Phase III trials completed enrollment seven months ahead of schedule, seven months ahead of schedule. And the forecast wasn't a number, the schedule wasn't a number that we put down. It was the actual number that it took deucravacitinib to run its similar studies. And then for TAK-861, we're actually looking at a three-year acceleration relative to from first in human to filing relative to what other sleep medicines have accomplished. So this is where we are today. It's a late-stage pipeline that sets up Takeda for success, six programs, all high value, all with robust phase II data sets and high probabilities of success, and all, as you'll hear over the course of the day, with substantive revenue potential. So let me spend a few minutes now switching gears. The majority of today, almost all of today, will be about these six programs. So let me just spend a few minutes telling you about how we will drive the second key message, sustainability. There are three core drivers to our sustainability strategy. The first is our strong internal research laboratory. The second is our early and mid-stage clinical pipeline. And the third is our partnering and business development capability. So let's start with the first. I won't go into much detail, but our research organization is an outstanding organization that has the ability both to discover medicines on its own, but also because it's so integrated with our network of partners to enable partnership and external innovation. We have two main research centers today. One close to where we are at Shonan. This is at our iPark. At our iPark, we focus predominantly on neuroscience, and it was the labs that brought us orexin. We are the industry leaders in this really exciting biology that came from Shonan. The second laboratory is in Boston, and we're in the process over the next couple of years of consolidating all of our labs to a new facility in Cambridge at 585 Kendall, and we call this the lab of the future. We call it the lab of the future because we're designing it with an eye towards automation and AI. It's not like automation and AI will solve every problem, but we know more and more as these tools become more and more sophisticated, they will become integral to how we work. We're building from the ground up a capability and a way of working that will fully embrace these new tools. In fact, we've already been successful in using AI to enable our drug discovery. TAK-360, which you'll hear a little bit about, our next generation orexin agonist, was developed in part leveraging several AI-enabled tools. Then the second reason, so research, the second reason we believe we have sustainability is our early to mid-stage pipeline. As you'll see here, we have about 20 programs in this pipeline. You won't hear about these today. All of them are creative science, addressing unmet need and significant commercial opportunities. Let me just highlight two that you may not be so familiar with because these are option-based deals. One is a partnership with a company in Switzerland called AC Immune. This is ACI-24.060. It's an active immunization therapy for Alzheimer's disease, has the potential to transform treatment of this disease with a safe and efficacious vaccine. And the second is olverembatinib, which is a partnership that we have with a Chinese company called Ascentage Pharma. olverembatinib is a next-generation BCR-ABL inhibitor for the treatment of CML. And you think CML, we know that there are agents that treat CML, but the reality is that the majority of patients still end up dying from this disease. There's still very significant unmet medical need. And then the third pillar of our sustainability research, the existing pipeline, is our BD and partnering model. Now, you saw earlier that we're organized by therapeutic area. Our strategy is very much therapeutic area aligned. And that's how we align, as you'll see in the presentations today, from research to development to commercial. We have immense alignment across those three tiers. This gives us the ability to come up with really compelling strategies that recognize the science, the development challenges, and the commercial opportunities. It allows us to put these strategies rapidly in place so that we can identify opportunities externally, so that we can quickly diligence those opportunities and rapidly work through deal structures. We are, in most situations, when we're excited about an asset, the partner of choice. Now, I've talked to you about two of the option-based deals that we have with olverembatinib and ACI-24.060, as you can see in the lower right. These option-based deals are really creative. They have two benefits for us. One is they're less expensive because you're opting in, you're starting the process earlier in the process. And the second, which is very important to the comments that Christophe made earlier, is we're very focused on bringing our margins up. And so we're very thoughtful about the level of R&D investment and the increases in R&D investment that we're making. These option deals give us the ability to expand our pipeline without expending our R&D budget. And there are many other examples of successful business development. I'll say that in every case, all of these have positive NPVs, and if successful, all of these can be highly profitable for Takeda. All right, you are in for a really fun and exciting day. So let me just ground you again in the two key messages. The first is we have a very exciting, very robust late-stage pipeline, and I hope after today you understand why we feel that way. We also feel very confident in our ability to execute on that pipeline with all the learnings and capabilities that we've built into our organization. Secondly, what you won't hear so much about today is sustainability. We recognize that Takeda has a goal. We are a 243-year-old company. We want to live for another 243 years. Sustainability is critical, and I've talked to you about the elements of sustainability. So with that said, it's my pleasure to now hand it off to Sarah Sheikh and Ramona Sequeira to talk about neuroscience and our orexin franchise. Great, Sarah. Thank you, Andy. Good morning and good evening, everybody. Now we have a chance to talk about neuroscience and in particular orexin. At Takeda, we're doubling down on neuroscience as a key therapeutic area, really for three main reasons. The first is the significant unmet need in an area that robs us of the essence of what it means to be human, our ability to use language, our ability to lay down memories. Even our ability to sleep can actually be affected, and neurological diseases in aggregate place an enormous burden and cost on aging societies. The second reason is our growing scientific understanding of the underlying pathophysiology of disease, our ability to drug previously undruggable targets in the central nervous system, and our ability to de-risk programs much earlier in development, and our narcolepsy type 1 program, NT1 program, is a great example of that. And then the third reason is our ability to have success in bringing meaningful medicines to patients, as evidenced by approvals in diseases like ALS and Alzheimer's disease just recently, so in diseases previously thought too difficult to treat. So then with that, our vision here at Takeda is to be a leader and partner in neuroscience by discovering and delivering life-changing medicines for patients and society. Our focus is in three areas: our leading orexin franchise, which is the topic of today's discussion. We're also focused on advancing treatments in neurodegenerative diseases, and we're building in rare neurology, particularly in neuromuscular disease. What you've all been waiting for is to hear about our leading orexin franchise. What I want to share with you today is just how well our pioneering orexin franchise is progressing, and I want to focus on two areas. Our lead molecule, TAK-861, newly christened oveporexton, which is being developed first and fast in narcolepsy type 1, NT1. And then we'll talk about additional assets and indications led by TAK-360, which is about to enter phase II. As you heard, we are confident that we will soon have the first and best in-class treatment for narcolepsy type 1 with an oral orexin-2 receptor agonist that addresses the underlying pathophysiology of disease. And we're confident in our ability to accelerate the Phase III trials with readouts in 2025 and an expeditious filing soon thereafter. Why this confidence? Three reasons. Number one, our phase II data, which I'll share with you today, shows for the first time the potential for a treatment to address the broad spectrum of disease symptoms with potential for a functional cure. Number two, again, our ability to execute. We've gained deep experience and learnings in the orexin field from our previous molecules, and our focus on execution, of course, in partnership with sites, patients, and investigators, have allowed us to substantially accelerate our programs, and then the third reason is that these outstanding data and the potential for patients are being recognized by regulators, and in recognition of that, we've been granted breakthrough therapy designation. Today, we'll also focus on TAK-360, which has a differentiated profile in development for orexin-normal indications. phase II studies will commence later this fiscal year, so 2024, in idiopathic hypersomnia and narcolepsy type 2, and phase II results are then expected in fiscal year 2025, and we're also pursuing other tailored molecules to address additional indications pertinent to orexin biology, including sleep-wake cycle, respiration, and metabolism, so now let's talk about narcolepsy type 1, NT1. What is it like for patients to live with NT1? Our ability to both stay awake during the day when we need to be awake and experience restorative sleep at night is critical for us to live healthy and productive lives. But when sleep intrudes into wakefulness and wakefulness intrudes into sleep, our ability to function is significantly impaired. This is a relentless disease. Patients experience symptoms both during the day and at night, and I'll take you through the symptoms from left to right, as you see here on the slide. Excessive daytime sleepiness is one of the most commonly recognized symptoms, and it manifests in the most inopportune of situations, like in a meeting like this or in class or while driving, often with serious consequences not just to patients' grades, but to their lives. A second very well-identified symptom is cataplexy, which describes the sudden loss of muscle tone upon experiencing an emotional stimulus, such as hearing a joke or hearing something profoundly moving, and how it manifests can be various, such as a very subtle drop of the face, a facial droop, or it can be quite dramatic, like falling to the ground, and it can be absolutely terrifying because the patient is fully awake, unable to move, but able to hear and see everything, so you can imagine that that isn't just socially stigmatizing if you literally fall over laughing and then lie down paralyzed on the ground, unable to move, but very quickly, patients then avoid social interactions. They limit themselves to feel emotions for fear of bringing on a cataplectic event, and in extreme events, it can cause serious injury. The third symptom is cognitive symptoms, and the domains predominantly affected are things like executive function, learning and memory, and sustained attention, which can have profound effects on our ability to function at work or school, even at home and in social interactions. There's no respite at night either from this disease. At night, sleep is disrupted by an increased number of awakenings and terrifying nightmares. And then at the peripheries of sleep, so while falling asleep or waking up, patients experience sleep paralysis and hallucinations. These are phenomena of a part of sleep, REM sleep, occurring where it shouldn't be occurring and significantly impacting quality of sleep. So with this constellation of symptoms, you can easily see why patients are often misdiagnosed and misjudged, not just by their healthcare providers, but by their families. Being ridiculed, poor job performance, poor school performance are just a few of the devastating socioeconomic consequences of this disease. Now, today, patients have to take multiple medicines, dosed multiple times a day, some multiple times at night, to control these different symptoms. And despite that, patients can't live up to their full potential. They have to limit themselves in everything they do. These patients do deserve better treatments to live better lives. So what causes NT1, and how might we address the broad spectrum of symptoms to help patients in this quest to live normal and fulfilling lives? Up on the top, panel one shows you healthy orexin neurons, which are located at the base of the brain in an area called the lateral hypothalamus. What they do is they produce orexin. The function of orexin is to couple the demands of the external world with the internal state as a master regulator of the sleep-wake cycle, respiration, and metabolism. Panel two here shows you the cause of narcolepsy type 1. Based on the discovery of Professors Yanagisawa and Mignot, who were recently awarded the Breakthrough Prize in Life Sciences, we know that the cause of NT1 is the loss of orexin neurons. We also know that while the neurons are lost, the orexin receptors remain intact, offering us a unique opportunity for a pharmacological intervention to address the underlying pathophysiology. And then panel three just shows you that stimulating the receptor with a selective orexin-2 receptor agonist allows you the ability to modulate downstream neurotransmitters, and as I'll show you in just a minute, allows us the ability to improve symptoms across the range with restoration of patient function and improved quality of life. So with this goal of functional normalization in mind, we've designed our clinical trials to evaluate the full spectrum of NT1 using established and also some more novel endpoints. And what you'll see as I take you through this program is you'll see regulatory endpoints that, for example, assess excessive daytime sleepiness, such as the objective maintenance of wakefulness test, the MWT, or the Patient-Reported Epworth Sleepiness Scale, the ESS. You will see measures to assess cataplexy, for example, the weekly cataplexy rate. You will also see novel endpoints that have never before been measured in an NT1 trial, such as the Psychomotor Vigilance Test, the PVT, which is a measure of cognitive function, or a sleep diary to assess the quality of sleep, as well as other quality-of-life measures. Now let's talk about the longest and most comprehensive data set of any oral orexin agonist to date, which has laid a solid foundation for our phase III program. In this phase II study, 112 patients were randomized equally into one of five arms, placebo or four active doses, three BID doses and one QD dose. 95% of patients after eight weeks entered a long-term extension study. I have to emphasize here something that's important, and that is that longer-term data are critically enabling to treat a chronic disease. We have a data cut here from the long-term extension for an additional six months of dosing that I will show you, but at this point in time, some patients have been on study drug for up to 18 months. The endpoints that we just discussed also feature in this trial. But before we go into the results, I'll just hold you on tenterhooks for a little bit longer. What I want to show you here is the compellingness of the dosing regimen we've chosen, the BID dose. On the left-hand side, what you see is orexin tone in a non-human primate. What you see is it gradually increases during the day, probably to fight against the mounting sleep pressure that we all experience as the day wears on, and then it abruptly falls at night, but it doesn't go to zero. There's a small amount of orexin present even in the night. And then when you go to the right-hand panel, you see an idealized profile here that we're able to reach with oveporexton BID dosing, which is able to mimic the natural orexin tone and makes this molecule uniquely suited to the treatment of narcolepsy type 1. I'm going to take you through a number of different endpoints. And as I take you through the data, there are two themes that will be emerging: normalization of symptoms, so look out for the gray box, which indicates normal on these slides, and maintenance over the longer term. Remember, the parent study was eight weeks. We've now got an additional six months at week 34. On this slide, we see the Maintenance of Wakefulness Test, the primary endpoint, which is an objective measure of excessive daytime sleepiness. It's an important, validated regulatory endpoint, but it's rarely used in the clinical setting. You'll see the reason why in a second. It is a truly boring test. Patients have to lie in a darkened, quiet room and are asked to stay awake for as long as possible. The test lasts 40 minutes and is repeated four times. Now look at the gray box here at the top. Healthy people in this setting, in this soporific setting, are able to stay awake for 20 minutes or longer, with significant interindividual variability. It depends how well you slept the night before, for example, compared to NT1 patients who are only able to stay awake for between three to five minutes. You don't need to be a statistician here to see that the MWT values, particularly for the higher twice-daily doses, fall well into the normal range of healthy individuals. And what that means is that NT1 patients can now stay similarly awake to healthy people. It can't really get much better than that. But what's more, these effects are maintained for an additional six months of dosing. Now let's turn to a different measure of excessive daytime sleepiness, the more subjective endpoint called the Epworth Sleepiness Scale, which recalls the patient experience and again shows normalization of function and is consistent with the MWT. What the ESS is, is a short self-assessment to identify how likely one would be to fall asleep during the daytime in eight different hypothetical situations, like watching TV, being a passenger in a car, being a driver in a car, etc. And each question can receive between zero to three points. The more points you have, the more sleepy you are. Scores from zero to ten reflect normal levels of daytime sleepiness, and scores over ten are considered to reflect excessive daytime sleepiness. The results again speak for themselves in that the vast majority of patients achieved normal levels on the ESS, putting them again firmly in congruence with the maintenance of wakefulness test, and again, results are sustained over six months of treatment. That was excessive daytime sleepiness. Now we'll move to a different symptom, to cataplexy. What we see here again is profound reductions in the weekly cataplexy rate. Patients record their cataplexy episodes using a daily diary, which then is used to calculate the weekly cataplexy rate. What you can see here again is that the twice-daily arms had the strongest reductions in cataplexy, showing statistically significant and again clinically meaningful improvements versus placebo, with cataplexy rates close to zero maintained again for an additional six months. Okay, if that wasn't exciting enough, we're going to get to something really exciting and novel that speaks to the normalization of cognitive function, and I'm only going to share one of the domains with you because I wasn't given more time. To illustrate this, I'm going to share one measure of cognitive function using the Psychomotor Vigilance Test, which measures sustained attention. What the PVT is, is it's actually a widely used reaction performance task where a subject is asked to press a button when a signal appears on a screen. The signal occurs randomly every few seconds, and the main measure of the test is to count the number of mistakes or lapses in attention. This test is routinely used in situations where sustained attention is critical to performance. For example, it's regularly used by astronauts in space, where lapses in attention can actually lead to disaster. In the broader context, this test can be linked to the inability to function at work or even the ability to maintain a conversation. Again, focus on the gray box. The results don't just show a statistically significant improvement in this measure, but normalization of sustained attention in all dose arms, and that's seven hours after the first dose. That's important. Seven hours after the first dose. So that's roughly in the middle of the afternoon. Now, the middle of the afternoon happens to be the time when most patients on standard of care today struggle. They struggle to keep awake. They struggle to function. They struggle to do their job. I can also tell you that we've looked at additional endpoints measuring executive function and memory, which show similarly impressive results. Okay, now we'll turn to symptoms experienced at night. We heard that sleep is non-restorative at night, despite the overwhelming tiredness experienced during the day. It sounds really like torture. In the phase II trial, we included exploratory, both qualitative and quantitative assessments of nighttime sleep, including sleep diaries that record what the patient actually experiences and how they feel. And these data we haven't shared before, but what patients reported were significantly fewer disturbing dreams and hallucinations. And again, the theme here of normalization of function comes through even on sleep. Now, we talked about a number of different established and more novel endpoints, and I want to end the efficacy assessment here on the Narcolepsy Severity Scale for Clinical Trials, which we also included in phase II, which is a self-administered 15-item scale that evaluates the frequency and severity of the key narcolepsy symptoms. And higher scores mean the patient's doing worse. And what you see here again is that oveporexton resulted in clinically meaningful changes, rendering all patients to the lowest scores on the NSS-CT. And these results correlated very nicely with other measures of patient-reported outcomes. These will all be part of our phase III program. Of course, I can't not talk about safety. This is an important thing for these molecules. And so let's talk about safety and tolerability. We now have many patients treated for more than a year and up to 18 months in this study. oveporexton was generally safe and well tolerated. There were no treatment-related serious adverse events, and no discontinuations due to adverse events were seen. The most common treatment-emergent adverse events were insomnia, urinary urgency and frequency, and salivary hypersecretion, which were all mild to moderate and occurred within one to two weeks of treatment and were transient and self-limiting without intervention. Importantly, there were no cases of hepatotoxicity or visual disturbances that were reported in this study or in the ongoing long-term extension study. So based on these phase II data and in consultation with global health authorities, we've initiated two pivotal Phase III studies, which are rapidly enrolling patients. Patients who complete the 12-week duration of the study can then enroll into a long-term extension. We've optimized the study design to allow for inclusion of key endpoints that have the ability to capture the holistic effect of TAK-861 across the spectrum of disease. We're exploring two dose levels to enable flexibility of dosing for patients and physicians. And I can tell you again that our focus on excellence in study execution, along with our own experiences in the orexin field, have allowed us and continue to allow us to turbocharge those Phase III programs. So we aim to complete the studies this coming year, 2025, have readouts, and then have an expeditious filing soon thereafter. These data that I just shared should leave you similarly excited and confident as they do us. You have seen the longest and most comprehensive data set in over 100 patients, where efficacy is seen across the whole spectrum of symptoms affecting patients with NT1, both by established and more novel endpoints. And what's more, these effects are maintained over the longer term. Specifically, the majority of patients reached normalization of the excessive daytime sleepiness symptoms across multiple measures. The cataplexy rate is approaching zero in most dose groups, and this efficacy profile across endpoints is sustained over the longer term. You've also seen for the first time improvements related to cognitive function and to nocturnal sleep, the first time this has ever been shown with an orexin-2 receptor agonist. And we just went over the safety. TAK-861 was generally safe and well tolerated. And again, importantly, no hepatotoxicity or visual disturbances were seen. So in summary, this profile of TAK-861 is optimized to balance efficacy and safety with the potential for a functional cure. There's more. So now let's switch gears and talk about other assets and potential indications. We know from our previous experience of orexin-2 receptor agonists that they lend themselves to the treatment of orexin-deficient conditions like NT1, but they also have potential in the treatment of certain conditions where patients have normal or near-normal levels of orexin. We also know from emerging biology that orexin pathways are involved in far more than just the sleep-wake cycle and play important roles in respiration and metabolism, and with these insights, we're developing a suite of tailored molecules that could address this breadth of indications to really maximize the potential that this biology is guiding us to and our leadership in the field. The first one along on this journey is TAK-360, which is currently in phase I and due to start phase II in idiopathic hypersomnia IH and narcolepsy type 2, NT2, within this fiscal year of 2024. Here's a bit of an overview of these diseases, so like NT1, NT2 and IH are hypersomnolence disorders with significant unmet need, but unlike NT1, where we know the cause, very little is known about the pathophysiology of NT2 and IH that have normal or at least near-normal orexin levels. They're different disorders with overlapping clinical features and especially the excessive daytime sleepiness, and that you can easily see can lead to diagnostic challenges that in turn can then lead to a more heterogeneous patient population. Now, our experience, our clinical experience in this field positions us very nicely to successfully meet this challenge and to develop medicines to help these patient populations. What we also know from our own data with past molecules is that higher exposures are likely required to address the needs of people who have sleep-wake disorders with normal orexin levels, and so what we've done is we've designed tailored orexin agonists like TAK-360 with completely new chemistry and distinct pharmacodynamic and pharmacokinetic profiles. TAK-360 filed its IND in April of this year and is gearing towards phase II study starts in IH and NT2 this fiscal year. We're very encouraged by the initial safety, PK and PD markers that are emerging, and in conjunction with our internal capabilities and deep relationship with sites and investigators, those are going to support us in progressing TAK-360 very quickly. I believe that TAK-360 has the potential for a first- and best-in-class for NT2 and IH and potentially additional indications, so in closing, we are excited about how far we have come with our multi-asset orexin franchise. We have accelerated oveporexton development with a readout expected in 2025 and the filing soon thereafter, and we're making great progress with our next-generation molecule TAK-360 that's currently dosing in healthy volunteers with the goal to start phase II studies, as I just mentioned, later this fiscal year, and then to read out these phase II studies in fiscal year 2025. And of course, we're continuing to work in our labs on the discovery and development of additional tailored orexin profiles that have the potential to address the vast unmet need in areas where orexin plays a role. Now I'd like to pass the mic to my colleague, Ramona Sequeira, to talk about the commercial aspects of NT1. Ramona. Good morning, everyone. It's really nice to be here to follow up from Sarah and talk to you about how we are excited to be commercializing TAK-861 in the future and bringing it to patients, and let me just say first that in our global commercial organization, we work in a very close and integrated way with our R&D organization. We base all of our commercial strategies and our positioning off the data that we see based on the asset and the particular molecule, and then we work very closely with them to develop evidence generation, including our Phase III registration packages, so that the molecules will have the best access to the patients who can most benefit and so that we can truly win in our marketplace, and I think you'll see that as we go through TAK-861. As Sarah mentioned, really the symptoms that we see, the excessive daytime sleepiness, the cataplexy, are just the tip of the iceberg for patients with narcolepsy. It has a huge level of functional impairment on their daily lives. And many of these patients are afraid to engage in the highs and the lows and the joys of daily life because of the risk of a cataplexy attack. And they're functionally impaired in being able to just go about the daily activities of their lives because of all of the plethora of symptoms around narcolepsy type 1. So thinking about the patient journey here, it's a long journey. Patients can take on average 10 to 15 years to get diagnosed with narcolepsy and narcolepsy type 1 in particular. So why is that? Often this will present in late teens, early adulthood. Patients might be misdiagnosed. Think about the symptoms they're presenting with sleepiness and disrupted nighttime sleep. They might be misdiagnosed with a psychiatric disorder, maybe depression, maybe anxiety, maybe an attention disorder. They cycle through different specialists and different medication regimens that are not at all addressing the root cause of treating narcolepsy. Then over time, they're fortunate enough to get referred to a sleep center. Often for a sleep center, whether in the U.S. or many other countries, there's multiple months' wait involved to actually get in to see a sleep specialist. And then surprisingly, even when they get in to see a sleep specialist, particularly for narcolepsy type 1, patients can be misdiagnosed. So there's a high overlap of narcolepsy type 1 with, for instance, obstructive sleep apnea. So they get misdiagnosed with sleep apnea. Or we know that about a quarter of patients diagnosed with narcolepsy type 2 actually progress to having cataplexy and have orexin deficiency. So they might get misdiagnosed even within narcolepsy. Then once they reach the diagnosis of narcolepsy type 1, they have this plethora of treatments to address all the various symptoms. And Sarah talked in great detail about all the types of symptoms these patients are experiencing. You can think about the number of medications that need to be used to manage these symptoms on a day-to-day basis. So many of these patients end up with polypharmacy, multiple medications, and often they will even discontinue therapy. Really, this leads to a huge opportunity for us to think about how we can do a better job of helping these patients get diagnosed for narcolepsy type 1 and then connecting them with the treatment that can actually address holistically the burden of narcolepsy type 1 on their lives. Really today, there is nothing that exists that is able to treat the root cause of narcolepsy type 1 and address the functional burden across all of these symptoms for the patients. We know that the diagnostic journey is long and there are delays in diagnosis. There's a significant amount of misdiagnosis that occurs along that way. We know that about 80% of patients, even when they're on multiple therapies, are experiencing residual symptoms. We know that about 25% of patients actually end up discontinuing their therapy because of the number of different medications that they need to take. So there's low treatment expectations today, I would say, and a huge continued burden of illness, even on the existing standard of care. And we have the opportunity to change that. Thinking about the prevalence of narcolepsy type 1, there's a lot of information that sometimes is conflicting on the prevalence of narcolepsy type 1. Our estimate, as you look at all the published data as well as research and information that we have gathered, is there are about in the U.S., 95,000-120,000 people with narcolepsy type 1. And that prevalence is similar globally. So we have an opportunity now to really think about how these patients can have a very different experience in their treatment journey. TAK-861, as Sarah mentioned, from all of the data we have in patients with narcolepsy through our trials, through our long-term extensions, really has an impact across the holistic treatment spectrum of symptoms that patients experience. We get patients into normative ranges for things like excessive daytime sleepiness, cataplexy. We act on cognition, so patients improve in multiple cognitive domains, including attention, as Sarah mentioned. We see very high treatment satisfaction for patients. Really, we believe that's related to the functional improvements these patients are seeing. They do tell us they feel different and they feel better on TAK-861. Across the board, there are so many improvements in their quality of life, in their functionality, in their symptoms of daytime sleepiness, in their symptoms of cataplexy, and in their symptoms of cognition. We've got amazing data on safe and well-tolerated medicine over a significant period of time so far and more to even come. We have the first potentially transformative treatment to treat the root cause of orexin deficiency in narcolepsy type 1, bring patients into normative ranges, and restore their functionality in their lives. Now, there's a lot of work that we need to do in order to really make sure the patients who need this medicine can get this medicine as quickly as possible once we're able to bring it to the market. On either end here, I've got a summary of some of the work we're doing around evidence generation and patient-reported outcomes. There's still a lack of information on the true burden of illness of narcolepsy, and we need to be able to make that argument to payers, to healthcare systems around the world. We can really use patient-reported outcomes to show what good looks like when being treated for narcolepsy type 1. In the middle is some of the work we're doing that we're very excited about on the diagnosis of narcolepsy type 1. As I mentioned, many of these patients take a long time, cycle through other treatments and other specialists before they even get to a sleep center. There are many misdiagnoses along the way before they finally get diagnosed. We have an opportunity to shorten the time to diagnosis so we can accelerate those patients' ability to get treated properly and to improve the specificity of diagnosis of narcolepsy type 1. Today, there is no medicine specifically geared to narcolepsy type 1 and treating the whole patient. That differential diagnosis doesn't always occur. As I mentioned, up to 25% of patients might get diagnosed with narcolepsy type 2, but are found to be orexin deficient and will progress to cataplexy. And in some of these patients, actually, cataplexy can be very hard to diagnose. So we've got a number of initiatives in place, and we're actually partnering with other companies to be able to do this where we can build on our skills and people that have skills in the data analytics and technology spaces as well. For instance, we're looking at algorithms. So when patients go to a sleep center, they have a multitude of tests done on them, and still there is sometimes misdiagnosis. We're looking at algorithms that can be used to interpret results and actually improve the specificity of diagnosis of narcolepsy type 1 so we can really identify those patients. But even before that, we're looking at ways to improve patient self-diagnosis so they can recognize their symptoms and communicate with their doctors. And we're looking at ways to allow sleep centers to have some at-home diagnostic testing done so that patients don't necessarily need to wait months and months in order to come into a sleep center. So across the board, as I mentioned, we're looking at ways to accelerate diagnosis and improve the specificity of diagnosis for narcolepsy type 1. And this will help us to really tap into that prevalence of narcolepsy type 1 patients globally. So a little bit about the commercial opportunity here. And I'm sure you can imagine from what Sarah's talked about and what I'm talking about that the commercial opportunity is significant for this asset. We've got about 95,000-120,000 patients in the U.S., and the prevalence is similar globally. We believe through our initiatives that we can improve diagnosis by 10%-20%, both by accelerating diagnosis and improving the differential diagnosis of narcolepsy type 1. We expect an increase in patients staying on treatment, and this is what we're seeing in our trials because of the way they feel and because they don't no longer need polypharmacy. They have one treatment addressing the root cause of narcolepsy, and we expect a significant preference share given the way that we bring patients into normative ranges across these symptoms. That gives us a potential revenue of $2 billion -$3 billion globally, and as Sarah mentioned, this is the beginning of our journey into sleep-wake disorders, so we're also looking at TAK-360, very excited about its potential to support patients with narcolepsy type 2 and idiopathic hypersomnia, so patients that are not necessarily orexin deficient, but orexin addition will help them. We're looking at that quickly. We're also looking at other opportunities across sleep-wake disorders, respiratory conditions, and even metabolic disorders where we believe orexin can play a role. However, really the beginning, and as Sarah mentioned, our main focus is TAK-861. We've got a very special asset here, and our goal is to get this to the finish line, show these results in Phase III that we've seen in phase II, and be able to bring this to patients as quickly as possible. To summarize, we've got the first potentially best-in-class transformative treatment specifically geared to the underlying cause of narcolepsy type 1. We've got unprecedented data already from phase II and long-term extension showing that we can normalize symptoms for patients across multiple domains. We've got a franchise that we're looking at building on over time. And we're really uniquely positioned with the work we're doing around diagnosis to transform the treatment landscape and the treatment paradigm for narcolepsy type 1 and other indications in the future. Today, for narcolepsy type 1, we see that translating to a global peak revenue potential of $2 billion-$3 billion. So with that, I'm going to turn it over to Chris to take us through the rest of the day. [Foreign language]. We will take a break. And the next session will start at 10:00. So we'll be taking a break for about 15 minutes. Thank you. [Foreign language] We would like to start the next session. Shortly, so if you could please return to your seats. Thank you. [Foreign language]. Now I'd like to move on to the next presentation. It is a gastrointestinal and inflammation presentation. The first speaker here is Chinwe Ukomadu, Head of the GI & Inflammation Therapeutic Area Unit. Good morning, good evening, everyone. My name is Chinwe Ukomadu. I come to you from the gastrointestinal and inflammation therapeutic area. It's a pleasure to be here. Traditionally, our therapeutic area has developed drugs for patients with a variety of gastrointestinal ailments. But we are moving away from this tissue and organ-specific paradigm of drug development to one where we embrace adjacent indications. Adjacencies that are linked by one common thread: the underlying scientific underpinnings of the diseases themselves. As a result, we have an exciting and diverse pipeline in our therapeutic area. Currently, we have 11 unique assets that are in development across 13 indications, with potentially more to come. We remain entrenched in GI, where we are developing programs in IBD, as we always have. But at the same time, we are developing new therapies for celiac and for liver diseases. With regards to the adjacencies that I mentioned, we have programs in dermatology, in rheumatology, and in hematology. We have multiple Phase III programs ongoing, with a few more to come. Should you ask what the strategic thread is for what we're trying to do, it's really simple. We are moving towards being able to develop therapies for patients with a variety of chronic inflammatory conditions. Andy has already shared with you the excitement that is building in our company over the next year. He told you we will have three pivotal readouts in the next 12 months. Two of those, zasocitinib for psoriasis, rusfertide for polycythemia vera, reside in the G&I therapeutic pipeline. We are going to talk about those two programs today. In addition, we will also talk about two other assets, which are mezagitamab and fazirsiran. So we're going to dive deep into four total programs: zasocitinib, Innisentarity, rusfertide, mezagitamab, and fazirsiran. I will handle the research and development aspects of this presentation, and Ramona Sequeira will talk about the commercial aspects of the programs. First off is zasocitinib, our next generation TYK2 inhibitor. TYK2 is an intracellular enzyme that conveys signals from cytokines to the cell interior, where it elicits pro-inflammatory pathway signaling. These same pathways and these same cytokines have been involved and implicated in a number of autoimmune disorders: psoriasis, psoriatic arthritis, and IBD among them. Therefore, the hypothesis is simple: that if you can antagonize this molecule, you should be able to dampen the signaling through it and reduce the burden of disease. What is the scientific evidence for that, you might ask? Nature, in a sense, has helped us do the very first experiment. What I'm showing you here is genetic data that shows that there are people who have very reduced levels of TYK2 kinase activity. In fact, as much as 80% of the signaling is lost. These people are protected from a variety of autoimmune diseases. As you can see on the graphs on the right-hand side of this slide, those carrying two copies of this alteration are protected more than those who are carrying one copy. As you can see, the circles moving to the left of the slides. Protection from autoimmune diseases if you inhibit or you decrease signaling through this kinase. But even more important is the fact that the alteration itself is very well tolerated. These are healthy people. They have no increased risk of mortality, malignancy, or serious infections. So what it says is if you can make a good drug and you can reproduce this natural experiment, you can probably decrease disease burden. TYK2 is a member of the Janus kinase family of enzymes. People have wanted to drug this target, but the problem is that when they try to do it, they encroach on the related family members that are known as JAKs. The uniqueness of zasocitinib is that it avoids this problem. To do this, zasocitinib binds a regulatory domain, not the active site of the enzyme. It locks the enzyme in an active conformation, as shown by the padlock on this graph, rendering it inhibited and therefore reducing signaling through the pathway. This uniqueness allows it to solve part of the problem that has plagued a number of attempts to make drugs against TYK2. And I share the evidence on the right side of the graph to prove this. The selectivity of zasocitinib for TYK2 is so vastly superior to that of JAK. In essence, there's hardly any JAK activity, with over a 1.7 million-fold difference in selectivity for TYK2 over JAK1/3. If you compare that to similar activity of deucravacitinib, it is a 20,000-fold more selective than deucravacitinib for the TYK2 enzyme. Why keep talking about the selectivity? Because it offers us a unique opportunity. An opportunity to dose higher, especially in conditions where we need more drug to have an effect without having to worry about JAK-like adverse events. And I'm going to tell you some more about this. Shown in this slide, it's probably the biggest message I want you to get today. I'm going to take my time a minute or so to explain what is on this graph, on this slide. There are two graphs. The left-hand side is zasocitinib. The right-hand side is deucravacitinib. Both graphs are the same layout. On the y-axis, it's concentration of drug. I'd like to point to you that it's a logarithmic scale on the y-axis. The x-axis, it's time in hours. I will start with the left graph. There are three sort of horizontal lines on this graph. The lower one, the dashed red lines, is the IC50 of zasocitinib for TYK2. That is the concentration of the drug needed to inhibit 50% of the enzyme. The top line, dashed gray line, is the IC50 for JAK1/3, the concentration needed to inhibit 50% of JAK1 or JAK3. The middle red line is the blood concentration from subjects who received 30 mg daily of zasocitinib. There are three points I'd like to make about that specific curve. The first, the concentration of zasocitinib in the blood of these subjects is way above the IC50 for TYK2. Two, that concentration is maintained for over 24 hours. Three, there is a large safety margin between that concentration and JAK1. I'd like you to compare that to the second graph, which is from deucravacitinib and 6 mg daily, which is the approved dose of this drug. You see similar things, but different magnitude. The concentration in the blood does reach IC50, but it doesn't stay there for 24 hours. That margin to JAK1 is much narrower. This, in total, offers us the opportunity to dose, and we believe safely, especially in situations where more drug might be needed to arrive at the desired efficacy. With this drug, we are now beginning to study a number of indications. Our first two lead indications are psoriasis and psoriatic arthritis. I'll take a minute to tell you about these two diseases. Psoriasis affects more than 60 million people. These are painful, disfiguring, disabling, often scaly and reddish lesions that are on the skin of people. The lesions commonly affect the trunk, the scalp, but they can occur anywhere in your body. The consequences of having this are not just the uncomfortableness, but also the social isolation and all the other issues that it presents to the people who have it. The disease is also associated with a number of comorbid conditions. People are more likely to be more obese or have type 2 diabetes, for example. Psoriatic arthritis, on the other hand, is a chronic progressive inflammatory condition of the joints. Patients have painful, swollen joints, and the goal of therapy here is really to prevent this before the joints themselves are destroyed. Up to 30% of people with psoriasis will have psoriatic arthritis, and up to 80% of people with psoriatic arthritis have psoriasis, so an interaction between the skin and the joint lesions in this case. The data we have for this molecule so far really excites us. I'm going to first share with you the data for psoriasis from phase IIb study. In this study, which was only 12 weeks long, four active doses of zasocitinib were compared to placebo. The primary endpoint is PASI 75. The PASI score is a reflection of how effective the drug is percentage-wise from the time of treatment to the time of measurement. So PASI 75, for example, in simple terms, means a 75% improvement. PASI 90, 90% improvement. And PASI 100 is what we call clear skin. So if you look at this data, what you see is just over 12 weeks that the high doses of this drug, the 15 mg and 30 mg, really are similar with respect to PASI 75. But I want to call your attention to the PASI 100, the black bars, which is clear skin. And what you see there is that a third of the patients in the highest dose, 30 mg, achieve clear skin. This is remarkable for a once-a-day oral molecule and only over a 12-week period of time. The drug was very well tolerated. There were no JAK-like adverse events. It is good because science really does work. I told you earlier that we have people walking around who have inhibition or reduced TYK2 signaling, and they are healthy. Here again, we show that they do not manifest JAK-like activity even in the clinical setting. The drug is safe so far. Secondly, we also have data for psoriatic arthritis. This is also a phase IIb study comparing three active doses of zasocitinib against placebo. On the left is a graph that measures the endpoints that really focuses on the joint improvement. The primary endpoint is ACR20. What you see is that the two highest doses here also were really superior to the lower dose and the placebo with respect to ACR20. If you look to the upper right-hand corner of the slide, you will see what happened in the patients who had skin manifestation. They had joint involvement, and they had psoriasis on the skin, and you again show an improvement with this highest dose offering more improvement on the skin than the other doses. There are other ways to look at the data. The lower right-hand corner is the minimal disease activity, which is a composite that looks at seven different things associated with this disease: the joints, the skin, how patients feel, and five of them go towards accounting for response, and you also see that a third of the patients who got the highest dose of this drug improved in this study, so in the case of psoriasis, well-tolerated drug, no JAK-like safety events noted. With this in our back pocket, we have begun studies, first in psoriasis, where we are running two pivotal studies. Both studies compare zasocitinib to apremilast, a drug that's already being used for the treatment of psoriasis and placebo. We began these studies in November of last year. The last patient enrolled in this study in October of this year, seven months ahead of schedule. This rapid enrollment, we think, is a manifestation of the excitement that patients and investigators feel about the possibility of using this drug in treating psoriasis. At the moment, we are expecting pivotal data readout by the end of the calendar year 2025. Because we believe in this drug, we are going to go a step further. We are going to run a head-to-head study of zasocitinib against deucravacitinib. That study is expected to start in the second half of fiscal year 2025. For psoriatic arthritis, we are a few months away from starting our phase III studies. There are two studies being planned here. The first, two doses of zasocitinib against apremilast and placebo. And the second, two doses of zasocitinib against placebo. As I've mentioned, the study should start before the end of our fiscal year. And we expect filing for this indication in fiscal year 2028 to 2029. But there's more. Among the things that excite us for this drug is the possibility that it could be a treatment in IBD. Patients with IBD continue to need medicines that push the boundaries of what is possible in treating this disease. They need more safe, more efficacious, and more convenient therapies available to them. We think zasocitinib should be able to help in this regard. And why do we say that? I've already mentioned to you the strong genetic link between IBD and TYK2. I have told you that zasocitinib can achieve and maintain near-complete TYK2 inhibition without concerns about antagonizing JAK. And here, I show you data from our own preclinical studies that shows that when you dose high enough in these animal models with zasocitinib, you see improvement that parallels what you will see with a biologic in this disease. That's shown in the third bar in red compared to the fourth bar, which is the biologic. So we believe this is indeed an exciting opportunity. But the way to really do this is to prove it. And we're doing just that. We have ongoing phase IIb study in Crohn's disease, three active doses of zasocitinib compared to placebo, and a study in ulcerative colitis, two active doses compared to placebo. Both studies are in progress. Patients will have the option in this study to move to a long-term extension to be followed for safety and remission. In summary, I'd like to share with you what we've done with zasocitinib over this period of time that we've had this asset in our hands. For psoriasis, we've shared with the world our phase IIb readout. We started phase III, and we've enrolled the last patient into the pivotal studies. We plan to start the head-to-head study against deucravacitinib in FY 2025 with a target filing in FY 2026. For psoriatic arthritis, we have phase II data that we've shared with the world. Targeting phase III start in FY 2024 with a filing planned for 2028-29. For the IBD studies, we are in the midst of the phase II studies with target readout for these phase IIb studies in FY 2026. Because of the unique biology and the promise we think this molecule holds, we are looking at potentially other indications where we can use zasocitinib. Now, I turn you over to my colleague, Ramona, to talk you through the commercial. Thank you, Chinwe. Thank you, Chinwe. Thank you, Chinwe. I'm really excited to talk to you about the commercial potential and our commercial strategies for zasocitinib as we move forward. Let me start by reminding you that for these patients with psoriasis, it is so much more than just a rash. Patients with this autoimmune disease have visible plaques. They can feel very stigmatized. They could come into a setting such as this and find that people don't want to sit near them. They can have trouble in social settings where their plaques are visible and sometimes difficulty even touching loved ones. This disease impacts so many aspects of their life and has a very high mental burden on their lives as well. 30% of patients with psoriasis go on to develop psoriatic arthritis. This even has a higher disease burden. This one can be a little harder to diagnose. It can take a bit longer given the types of symptoms that present, chronic pain and fatigue. Once diagnosed, more patients end up being treated on an advanced therapy. Doctors need to make a trade-off between the safety of the product and the efficacy of the product because they're worried about irreversible joint damage leading to potential disability down the line. Again, a difficult one to diagnose and a difficult one to treat as well and a significant burden on patients' quality of life and significant mental and psychological burden as well. We're really excited to be able to bring a product that can transform patients' lives in psoriatic disease. Thinking about the market opportunity here, so this graph shows the number of patients in the U.S. market, okay? So we expect the market in psoriasis, which is significant today, $23 billion, to grow over time with the advent of new therapies. And in particular, we expect the advanced therapy market to grow from about a third of patients today. So the majority of patients today are not on an advanced therapy to about 45% of patients over the next 10 years. And this will be led by the advent of new therapies, including products like zasocitinib, that can really change the treatment paradigm for psoriatic disease. We expect similar growth in psoriatic arthritis. So it's about a $7 billion market. We expect it also to grow over time. Advanced therapies are about 50% of that market now. And we expect that to grow to about 60% of that market in the future. And I think that just shows us that the way the market is today, there is still an unmet need and an opportunity to provide better care for so many patients with these devastating diseases. Now, thinking about that growth that I talked about of advanced therapies, I'm going to talk a little bit about the use of orals within those advanced therapies. Today, orals are used as a stop on the journey to a biologic. In the future, with the product like zasocitinib, orals will be able to be used as the first stop and the destination on that journey with the number of patients achieving clear skin and minimal disease activity. We expect the oral segment, which is small today because of the lower efficacy expectations that are in this space, to more than double over the next 10 years, really led by products like zasocitinib, which we know from our research with physicians and patients has the potential to change the treatment paradigm for psoriasis and psoriatic arthritis. Really, as we talk to clinicians around the world, they feel that this is where the market is going to head, is the use of orals earlier and really to get high efficacy with patients. I think this is where zasocitinib is very exciting. I'm going to talk a little bit more about our profile and why we believe this product can actually redefine what's possible with oral therapy for psoriatic disease. Now, we know when we talk to patients exactly what they are looking for in treatment. We know what their wish list is. They want something that's going to give them clear skin. I mean, that is absolutely their goal because of these visible plaques that they have, whether they've got psoriasis or psoriatic arthritis with comorbid psoriasis. They want something that's going to be safe to take because many of these patients are young and otherwise healthy. They may have a few other comorbidities, but they lead very active and busy lives, and they're going to be taking this medication for a long period of time. They want it to be well tolerated, so without unwanted side effects that impact their daily lives. And they want it to be easy to take and fitting into their active lives and potentially other medication regimens that they may have. We believe zasocitinib, based on the data that Chinwe showed you, has a very unique opportunity to actually meet the exact profile that patients and clinicians are looking for in an oral. And we will have, as we launch the product, data against both apremilast, which is being used as an active comparator in our phase III trials, as well as data against deucravacitinib, which is involved in our head-to-head that we're getting ready to do now. So at launch, we will have data comparing zasocitinib to apremilast and deucravacitinib and be able to show really that that profile offers patients the efficacy, the safety, and the ease of use that is really on their wish list for treating psoriasis. Thinking about the data that Chinwe showed you about the greater and longer inhibition of TYK2, remember he showed you well above IC50 levels for 24 hours and a big safety margin for JAK, so no JAK effects at the doses that we're using. He showed you that it was highly selective. He showed you a slide saying that it was 20,000 times more selective for TYK2 versus JAK than deucra. Because of that, we end up with a very unique profile for this molecule. We get biologic-like efficacy because we're able to use that selectivity to dose to a level that can really provide clear skin to patients. Patients with psoriasis in our phase II trials saw one-third of patients completely clear skin. Patients with psoriatic arthritis, one-third of patients had minimal disease activity. So truly high efficacy in an oral formulation because we're able to dose to a level that really maximizes the impact this product can have on patients. And yet, at the same time, because of the high, high differential selectivity for TYK2, we don't get JAK-related side effects. So we've got a product that has this amazing biologic-like efficacy with a very clean safety profile. And then it's once daily oral, very easy to take and can be taken any time of the day without regard to food. So thinking about these patients who lead very active lives, maybe on other medication regimens, they're going to be able to fit this product very easily into their day. And importantly, how and when they take this product will not impact the efficacy that they're going to get from zasocitinib. Really, this is the profile that gives us the belief in the potential of this asset to change the treatment paradigm in psoriatic disease. So what does this mean from a commercial opportunity perspective? This is U.S. market evolution, these numbers, but of course, this is going to be a global brand for Takeda. That's how we get to our overall forecast. We know that the number of diagnosed patients with psoriasis and psoriatic arthritis will grow over the next 10 years. We know that advanced therapy will grow from roughly for both markets about 39% on average to 50% for both markets. We know that the number of patients treated with an oral therapy, given the advent of a new oral like zasocitinib, which provides clear skin and minimal disease activity to so many patients, the number of oral-treated patients will more than double in this space so that orals can be an initial treatment and a destination for these patients. And we know that zasocitinib has a profile that when we talk to patients and we talk to clinicians, really puts it out front as a first choice advanced therapy. And certainly, we saw this as we saw how quickly our trials enrolled as we went out to do these psoriasis trials. There's a great deal of excitement about the potential for zasocitinib to change the treatment paradigm for psoriasis and psoriatic arthritis. This gives us a global peak revenue potential of between $3 billion -$6 billion. And in addition, as Chinwe mentioned, the unique profile of zasocitinib gives us confidence in investigating it in diseases like IBD because of the ability to dose to a level where you can get efficacy, high coverage of TYK2 without the JAK side effects. So we're doing work now on both Crohn's and ulcerative colitis, really an area of strength for Takeda. And then we're looking at other indications down the line as well. So we really see this product as being something that we can develop in multiple indications over time, but really starting and most importantly, focusing today on psoriasis and psoriatic arthritis and working to bring this to patients and the marketplace as soon as possible. Let me also mention that we recognize this is a busy marketplace and that launch execution is going to be critical to our success. So we're working very closely with all of our markets to make sure that we're preparing for best-in-class launch execution. We're looking at how we ensure we're targeting the right physicians and working closely with all of our key opinion leaders as well as community clinicians. We're looking at making sure the onboarding process is simplified and streamlined. We're looking at making sure there's early access, early in therapy for the right patients so people can really see the benefit and value of zasocitinib immediately as we bring it into the marketplace. The launch execution combined with having head-to-head superiority data against both apremilast from our Phase III trials where it's active competitors as well as deucravacitinib from our head-to-head will allow us to really make an impact in this market and change the way psoriasis is treated today. So to summarize, we have large and growing markets in both psoriasis and psoriatic arthritis. And we know today the majority of patients are actually not on an advanced therapy. So there is an opportunity to actually treat patients so much more effectively with the advent of a product like zasocitinib that provides efficacy and safety and convenience. We know that we are poised to be the first line advanced therapy really changing the treatment paradigm where orals are not a stop to delay onset to a biologic, but actually are a destination for many patients given the one-third of patients with clear skin, the one-third of patients with minimal disease activity that we saw in our phase II trials. And all of this gives us confidence in a global peak revenue forecast of between $3 billion and $6 billion. So with that, let me turn it over to Chinwe to talk a little bit more about what's happening in GI Squared. Thank you. All right. So we're going to move on to our second asset for the day, and that's rusfertide, which is a therapy we're developing for the treatment of polycythemia vera. So in January of this year, we entered into a worldwide license and collaboration agreement with Protagonist Therapeutics for this asset, which is a synthetic hepcidin mimetic. This drug is being developed for patients with a rare blood cancer known as polycythemia vera. So polycythemia vera is characterized by the presence of excessive red blood cell production. The consequences of having that include sort of a sluggishness and thrombosis of the blood. But these patients over time can also go on to develop other complications such as myelofibrosis and acute leukemias. At the heart of this disease is the elevated blood count. And it is due to overproduction. And one of the critical ingredients needed to produce excessive red blood cells is iron. So we are going to talk about how rusfertide works to blunt this effect and reduce blood counts. Currently, there are around 155,000 patients with this disease in the U.S., with the goal of therapy for most of these patients, the reduction of hematocrit to less than 45. There are therapies available already, so why need another one? Well, there is room to do something better for these patients. Real-world evidence suggests that even though there is a goal to reduce the blood count, either by therapeutic phlebotomy, which is removing the blood from them, or with a number of drugs, that 78% of these patients continue to have uncontrolled hematocrit. These patients have risk of thrombotic events, so they can develop acute coronary syndromes. They can have strokes. They can have deep vein thrombus. They can have pulmonary embolism as a result. Their quality of life is really poor. They are tired all the time. A number spend days in bed. So a therapy that could help alleviate all of that is very much needed. rusfertide, as I told you, mimics hepcidin. And hepcidin is a hormone that is the master regulator of iron metabolism in the body. And the way hepcidin works is simply to block a channel known as ferroportin that allows iron to exit the cell, go into the serum, and be available to the bone marrow to make red blood cells. rusfertide mimics that and blocks this channel, ferroportin, therefore decreasing the amount of iron available to the bone marrow for the production of red blood cells. This is the principal mechanism to control the blood count by this drug. So if this works, one would expect a consistent and sustained maintenance of hematocrit, the abrogation of the need to do phlebotomies by removing blood time after time for patients, and a more stable course of the disease, improvement in symptoms, and as such, because you stabilize the mechanism of iron metabolism. Our colleagues at Protagonist have already done this experiment and published the data in New England Journal. I want to take a minute to walk you through what is shown on this graph. This is a study called the Revive Study, and there are essentially three parts to the graph that you're looking at. I'll start with the first part of the graph, which I've called part one. That is the part before the area that says placebo period. So it's the period between week one and week 29 on the graph that you're looking at. During this time, patients got rusfertide. And what you can see is that their hematocrit is maintained at below that 45 level that I mentioned. In the gray part where it says placebo period, which is part two of the study, there was a randomized withdrawal of rusfertide. Half the patients who were previously on rusfertide had it removed, and the other half continued to stay on it. And what you see is that removal of the drug led to a rise in the hematocrit. When it was reinstituted, which is now under part three, which is continuing, you see a return of the hematocrit to the normal level. This study, it's ongoing. What it simply shows is that the drug can maintain hematocrit. When you remove it, the hematocrit goes back. When you give it back, the hematocrit returns to its normal level. Sustained, rapid, and durable. That's what we think patients who have the disease would want. The drug itself was tolerable. The major treatment adverse events were things that you would expect: some injection site reactions, fatigue, COVID-19. Serious adverse events, most were not attributable to the drug in this study. With this in the back pocket, there is now a Phase III study called the Verify Study that is ongoing. This study randomizes rusfertide on top of ongoing therapy against placebo on top of ongoing therapy. The first part of the study is 32 weeks. It's a double-blind in that period, and then the patients can roll over to an open-label extension cohort. The primary endpoint of this study is a response rate between week 20 and 32 versus placebo, the response of the absence of phlebotomy as defined in this slide, and now I'll turn over to Ramona to talk to you about the commercial aspects. Thank you, Chinwe. I'm really excited to talk to you about the planning that we're doing for launching rusfertide. We signed this partnership agreement about a year ago, and as Andy mentioned in his slides, our partner is doing the research and development for this at this stage. And we are doing all the commercial planning and launch planning. And it's been a really unique opportunity to combine our rare disease commercial capabilities with our deep, deep expertise in hematology and apply that to a program like rusfertide for polycythemia vera. And actually, if you look at our hematology portfolio now, our rare hematology portfolio with the Adzynma for cTTP being studied for aTTP, with mezagitamab that you hear about next for immune thrombocytopenia, and now with rusfertide, it allows us to bring our rare hematology portfolio to growth over the coming years. So how are we going to do that? Well, looking at the patient journey in polycythemia vera, I'm going to talk to you a little bit about how these patients are diagnosed and then the roller coaster they go on through their treatment journey. Many of these patients will be diagnosed either by presenting with a thrombotic event, or they might have symptoms, and they might have a routine blood work done with their physician, and then will be diagnosed with polycythemia vera. Remember, they have excessive red blood cell production. They have too many red blood cells in their body. That puts them at risk, as Chinwe mentioned, for many different types of disease problems. For instance, cardiovascular disease and pulmonary embolism, thrombotic events, acute coronary syndrome. There is a high, high cardiovascular and thrombotic risk for these patients. This is a chronic disease. Often they are diagnosed around 50 or 60 years old, but then they are going to live with this disease for 10, 15, 20, 30 years, living with this increased risk of serious cardiovascular and thrombotic events. So the initial treatment is, as Chinwe mentioned, very rudimentary, a phlebotomy, a therapeutic phlebotomy. They take blood out of the patient. And in essence, that actually exacerbates a lot of the symptoms they experience from polycythemia vera. So as they have these blood draws, they end up feeling very anemic, tired, fatigued. We know that about 20% of patients can spend all day in bed, multiple days in a row. They have trouble functioning. They have brain fog and cognitive challenges. And the phlebotomy is actually making it worse and exacerbating the actual symptoms of polycythemia vera. But today, it's the only way to quickly bring their blood cell count down, red blood cell count down. However, it's not permanent. It's temporary. So they have to go through a cycle of regular phlebotomies over time, which exacerbates their anemia and their symptoms. Then, for patients who are higher risk, they often get put on one or two cytoreductive therapies. These therapies can be very difficult to take and have their own side effects and impacts on patients. And in fact, sometimes patients will tell us that their doctors, who are very comfortable with these cytoreductive therapies, will tell them, "Don't worry. You're doing a lot better than my other patients." But yet these patients don't feel better. They feel worse. And then they feel guilty for feeling worse. And so there's a real need here to amplify the patient's voice and think about treatment that really helps to make them feel better. And that's where we have an opportunity with rusfertide. So with rusfertide, we have the opportunity to deliver rapid, as Chinwe mentioned, consistent and sustained hematocrit control for these patients with polycythemia vera. The first thing I want you to notice here is that half of the patients are actually not on any regimented treatment, so many of these patients are sitting out being cared for by their primary care doctor and a community hematologist. They might be on aspirin, and they might occasionally have a phlebotomy when their hematocrit gets really high, but they still have this disease, and they are still at risk for these cardiovascular and thrombotic events, then, when patients progress to even higher risk and they get treated, they're on this cycle of phlebotomy in a repetitive way over time that's exacerbating symptoms and/or adding cytoreductive therapies, which again causes its own side effects and symptoms. So really, if you look at the whole treatment landscape, there's an opportunity for earlier on in the journey to be able to be on a product like rusfertide that, through redistribution of iron stores, actually helps patients achieve hematocrit control without inducing anemia early in their therapy. But even as they get on other therapies, whether it's phlebotomy or cytoreductive therapies, there's the opportunity to use rusfertide to help these patients feel better. And really, that's something we hear as we talk to patients who have been in the trials for rusfertide. They feel better. It is just such a game changer for them in the way they're able to manage and live with their disease for the rest of their lives. So there's a lot of excitement in the patient community about the potential for rusfertide for polycythemia vera. We're really working hard to drive awareness of the unmet need here to really find and identify risk of these patients who are sitting in the community and not under treatment. We're working to look at including this product into broad access guidelines, but really amplifying the patient voice into those guidelines so it can be used earlier in therapy. We're engaging with key stakeholders to do education, which will be key to this market, and also to really amplify the patient's voice, which will also be key in this market, as we see in many of the rare diseases. So what this does is it gives us the opportunity to have a product that could come in, be used with or without phlebotomy and cytoreductive therapies. And we actually have many patients coming into our trials who are only on phlebotomy, potentially remove the need for phlebotomy, which can really change the treatment that they can come to expect and give us a potential commercial opportunity of $1 billion -$2 billion. So to summarize the potential here, we have about 155,000 patients diagnosed with polycythemia vera. About 78,000 only are currently treated. So a huge opportunity to find and support these untreated patients in the community, as well as patients who are currently being treated and remove the need for phlebotomy in these patients. The goal is hematocrit control less than 45%. And we know today that even cycling through the many treatment options that are used, 78% of patients are not meeting that goal and are at elevated risk for cardiovascular disease and thrombotic events. Because this is a chronic disease, this will last for the rest of their lives. We know that current treatments can actually exacerbate the symptoms patients feel and can actually make it worse for them. We have an opportunity with rusfertide to really change the way polycythemia vera is treated, to diagnose, to treat earlier, and to give these patients a much better quality of life. Thank you very much. I'm going to turn it back over to Chinwe. Thank you. Right. We're going to talk about mezagitamab, another really beautiful asset in our pipeline. mezagitamab is a monoclonal antibody, and it's directed against CD38. We think it has the potential to be a best-in-class agent and the potential to be a pipeline in a product. We have amazing proof-of-concept data in two indications, ITP and IgA nephropathy. I'm going to share that with you today. mezagitamab is a monoclonal that binds CD38, and in so doing, it selectively depletes long-lived and short-lived plasma cells. The reason this is important is because plasma cells are the factories that make the autoantibodies that cause a variety of autoimmune diseases, so by using this drug in treatment of autoimmune diseases, we're essentially saying that we're going after the cause of the disease itself. When you do this, you get a readout that is really remarkable. You have a rapid and robust reduction in antibody levels as a marker that you're depleting the plasma cells. IgG is decreased by 41%, IgA by 70%, and in the case of IgA nephropathy, which we're going to talk about, a specific autoantibody seen in that disease goes down by 62%. On the graph below on the right, there are a few other points that are worth making. In that study, patients got a dosing-free period. The last 14 weeks of this 36-week monitoring period were dose-free, and during that time, the levels of these autoantibodies remained low and stable, suggesting that we have the opportunity to have something durable when we use this drug for treating patients, so I'm going to talk first about IgA nephropathy, so IgA nephropathy is a kidney disease. It's due to autoimmune antibodies directed against the kidney, and it destroys the kidney over time. The way this actually leads to disease is illustrated in the figure in the middle of this slide. We've described this process as a series of hits going from hit one to hit four. In hit one in IgA nephropathy, a plasma cell of the IgA variety makes an abnormal antibody known as galactose-deficient IgA1. That antibody is recognized by a plasma cell of the IgG variety. That's hit two. Makes an antibody against the previous antibody. And then in hit three, antibodies combine to form an immune complex. And that immune complex in hit four is deposited into the kidney, causing kidney damage. The consequences for the patient include hematuria, proteinuria, progression to kidney failure, potential dialysis, or kidney transplant or death. Therefore, mezagitamab goes after the causative etiology of this disease. We call this a disease-modifying agent. It eliminates these plasma cells that make the factories that make the injurious antibodies, preventing their accumulation in the kidney and then preventing disease subsequently. There are therapies available right now for trying to remediate IgA nephropathy. But as shown here on the left-hand side in the black graph and the black curve, the standard of care therapies don't quite do the job that well because patients continue to lose renal function over time compared to their healthy non-injured colleagues, as shown in the green. We believe that mezagitamab can do this, push the curve back towards the natural attrition you see in healthy people. It can do this because we feel that what patients actually need, it's something that's able to stop the injury from happening in the first place, that prevents additional injury on top of what is already there, that is safe and tolerated. And of course, there is a convenience factor, something they can take at home and maybe give themselves a break while they are taking the medicine without fear that their kidneys will worsen again. That's what we think mezagitamab can do. And why are we feeling confident about this? Going to show you just two data pieces that we've generated from a study. The top left-hand is a measure of ongoing kidney damage. It's proteinuria, the loss of protein through the kidney. It's usually measured by something known as the urine protein-to-creatinine ratio. Subjects who received mezagitamab at 600 mg were able to reduce the amount of protein lost through the kidney to a level 55% below their starting point at week 36. I want to point your attention again to this dosing-free period, during which we weren't dosing patients anymore, but the prevention of protein loss from the kidney was maintained. More importantly, though, the reason we treat patients is not just to make the protein decrease. It's to stabilize kidney function over time. What you see is during these 34 weeks that the kidney function, as measured by the eGFR, stayed stable. Once again, it stayed stable during the dosing-free portion of this study. We're continuing to gather data from these patients, and hopefully, we have that data presented in an upcoming conference. This drug was safe. No discontinuations in the study. We are now planning to start our Phase III studies in the fiscal year 2025. Why are we so invested in mezagitamab and IgA nephropathy? One could argue there are quite a few medicines out there, and there is a pipeline of new medicines coming down. What makes us feel so sure that we have something that is really unique here? A number of reasons. We say they're disease-modifying, which I've noted here. There are other agents that are disease-modifying that also target B cells. But we think targeting CD38, the specificity of just going after the cells that cause the injury, offers something unique. For one, we see a very rapid and sustained reduction in the immunoglobulins, as I've told you. We go after the disease-causing factory itself, the plasma cells. We maintain eGFR over a long period of time, showing that we are not losing more kidney function. And we offer patients a treatment holiday. That's what we think this drug will offer to patients. The second indication where we have data is immune thrombocytopenia, or ITP. Similar to IgA nephropathy, the cause here is also plasma cell that makes an antibody, but this time directed against platelets or its precursors. As a result, the platelets are destroyed, and platelet count is low. When platelet counts drop, especially when they drop below 50,000, patients are at risk of bleeding. So these patients can have significant bleeding, sometimes fatal bleeding, as a result of low platelet counts. The idea here is that if you eliminate these disease-causing plasma cells, the antibodies that destroy the platelets would decrease, platelet counts will rise, and patients should be free of bleeding. That's what we hope to find. And our data suggests that we may well be going there. And I'll share that in a minute. So for this particular indication, what you really need is something that is very rapid. You don't want patients to bleed. The platelet counts drop. The risk of bleeding goes up. So rapid onset of action that is durable and stable over time, that offers long-term remission to these patients, prevents bleeding, and of course, as I've said before, safe and also potential for a holiday should you require one. Here's the data that really drives what we're thinking about this. I'm showing just three data slides in this slide. On the upper left-hand side corner, it's a marker of response. Here we've titled this "Platelet Response." This simply says, did a patient who entered this study raise their platelet count to 50,000 or above in at least two visits when compared to what they came in at baseline? It had to be more than 20,000, the platelet count they came in with. The gray bar is the placebo. Then there are increasing doses, 100 mg, 300 mg, and 600 mg. You can see that the active doses are far superior to the placebo. On the upper right-hand side, it's another measure of response, what we call complete response. We are asking here, did the patients have platelet counts that rose to over 100,000 on at least two separate visits, and you can see that while the active doses have some effect, zero was seen in the placebo group, and then below that is the time course of how this happens over those doses that I just mentioned. What you can see is that the response is rapid. You can see the platelets rise from the dotted lines that's around 20, by my read on this graph, and go up and then stay sustained over a long period of time, and that platelet count remains elevated even during that dosing-free period that I told you about. What's more important, in that 600 mg dose, there were no bleeding events noted. There were 14 such events in the placebo arm, and the drug was safe and well tolerated. With this, we are about to start our phase III study in ITP. The study is mezagitamab, 600 mg, given subcutaneously every week on top of background therapy versus placebo on top of background therapy. Patients will get eight weekly doses, blinded fashion, have a dosing-free period, and be potentially retreated should they need it in the second half. The primary endpoint here is durable platelet response, which is defined as a platelet count that's greater than 50,000 on at least four of six weekly platelet visits at the very end of the 24-week study. And with that, I will pass it on to Ramona. Thanks. Interesting way, so a little bit about the market opportunity for mezagitamab, given the number of indications we'll be focused on two to start with, and then obviously, over time, we'll continue to evaluate other indications because this is such a unique molecule, and we believe it's going to have applicability in other types of diseases down the line, so starting with why we believe this is such a unique molecule, it targets plasma cells, as Chinwe mentioned, so the direct source of autoantibody production, so really getting to the root cause of some of these diseases that we're studying it in. It's got the potential, because of that, to be disease-modifying because of the rapid and sustained remission that you see in these patients, and then it's got a dosing holiday. So patients can take the drug for a certain period of time, stop taking the drug for a period of time, and actually have a durable response, and then go back on the drug. So over their lives, they can have multiple periods of treatment holidays. As well, it's in a subcutaneous formulation. So thinking about the IgA nephropathy patient, as Chinwe talked about, these patients will show up first with blood in their urine. They're diagnosed often as teens or young adults. But because of the formation of these immune complexes that are being deposited in their kidney, they have a steady progression of kidney disease and loss of kidney function. So over time, one in two patients will experience loss of kidney function with IgAN, and that is while on standard of care. One in five patients, and remember how young these patients are, one in five patients within a decade will end up with a need for dialysis and a kidney transplant. Because of the nature of this disease, unfortunately, even if a patient were to receive a kidney transplant, the autoantibodies are still causing these immune complexes to be formed and deposited. So the new kidney will start to have the same challenges with loss of kidney function over time. Really, there's nothing here today in the market that allows for disease modification in this area, meaning stopping the progressive decline of kidney function. That's why we're so excited about the potential of mezagitamab. Thinking about the patients in the IgAN market, so IgA nephropathy, we've got about 1.5 million diagnosed IgAN patients largely globally. I will say IgAN, IgA nephropathy, has a very high burden of illness in Asian populations, and so really, our presence and ability to commercialize this asset across multiple markets around the world is going to be really important to be able to make a meaningful impact on patients' lives. We know today, of those patients, about 90% are treated with standard of care, so they might start with a steroid that can't be taken long-term but can be taken for a short period of time. They might have a number of other medications that are used to treat proteinuria. However, none of the medications today being used as standard of care actually stop that steady disease progression and loss of kidney function, so half of the patients, despite being treated on standard of care today, are progressing with loss of kidney function. Really, there's nothing today to help those patients. What we want to do is really establish the CD38 class as a unique and transformative approach because it's targeting the direct source of autoantibody production, the direct source of the autoantibodies that are forming those immune complexes that are being deposited in the kidneys. We believe this class, the anti-CD38 class, has a unique approach to treating IgA nephropathy, is a disease-modifying agent, and as Chinwe showed, can have a sustained and durable effect on patients and can stop the progression of disease. We also want to differentiate mezagitamab as a very unique anti-CD38. As Chinwe mentioned, we get a very rapid and durable response in patients. We have a subcutaneous formulation that allows for more convenience and ability to use it, as well as these regular treatment holidays. And think about these patients being young patients and taking this product over many, many decades. So let's switch gears a little bit now and talk about immune thrombocytopenia, ITP, that Chinwe also showed you data on. This is a disease that is diagnosed following a severe bleed coming into the emergency or seeing their physician. And first-line treatment is a short course of steroids. Sometimes ITP, immune thrombocytopenia, is only acute in nature. So some of these patients might be OK after a short course of steroids, particularly if they're younger. Children tend to get this, and it's only a one-time acute disease. But older patients, as they are in adulthood, actually more often get persistent or chronic ITP, meaning it doesn't go away but persists. So these patients, because of the lack of platelets, have a lot of bleeding throughout their body. They have bleeding in their nose, in their mouth, bleeding under their skin, leading to bruising, and in rare cases, can lead to fatal hemorrhages or fatal brain bleeds. And that risk of rare complications actually increases as patients get older. Now, there are treatments today, in addition to corticosteroids, that are used to manage these patients. And actually, many of these patients are managed on standard of care. TPO-RAs would be some of the agents that are used in these patients. However, we know that about 20% of patients either don't respond to standard of care or might be on standard of care, but their platelet destruction continues to the point where they're no longer well treated or well controlled on standard of care. And so they need something else. And today, there really is nothing else for these patients. Our focus with mezagitamab in immune thrombocytopenia is really to focus on the patients that are not well controlled on standard of care or progress past standard of care, have ITP, and really don't have other options for themselves. Thinking about ITP, it's, again, another very rare hematology asset. There are about 200,000 diagnosed ITP patients globally, and about 50,000 of those are in the U.S. About 20% today have an inadequate or progressed past response to the current standard of care and have a need for an effective treatment. Really, this is where we can come in and help these patients. However, given the profile of mezagitamab, there's certainly an opportunity for this to be used even earlier in treatment as well, given the rapid platelet response, the direct source of autoantibody production, and really getting to that direct source and the safety and efficacy and utilization of the product with the treatment holidays. So we really feel that mezagitamab has a unique opportunity, both in IgAN and in ITP, to meet high, high unmet patient needs. So thinking about the potential, the commercial potential with these two indications for mezagitamab for IgAN, really, we aim to be the first choice anti-CD38, a disease-modifying agent that stops progression of kidney disease, the promise of a treatment holiday and a subcutaneous dosing, and a very, very rapid and sustained response. If you look at ITP, we want to be the first choice for patients who are not responding well to the current standard of care. Today, there is nothing for those patients. There's a high unmet need. And we believe we have a role to play with mezagitamab in really helping those patients because we get sustained platelet restoration with treatment-free remission periods. And we have a very favorable safety and tolerability profile. Both these assets together, today, it's a little more heavily skewed to IgAN versus ITP. But as I mentioned, as we do more work, as we learn more about the profile and see the data coming out of our trials, there is the potential for this to be used even earlier in therapy and ITP as well. So the global peak revenue potential for IgAN and ITP combined is $1 billion -$3 billion. We're really excited about the mechanism for mezagitamab. As Chinwe mentioned, getting to the direct source of autoantibody production, there are a number of other areas where we'd like to study this. We're doing work now to look at potential additional indications where there's a high unmet need, and we can come in with something that is transformative and disease-modifying. To summarize, we're really well positioned, given the unique profile of Meza, to be a best-in-class anti-CD38 agent with disease-modifying potential, treatment holidays, subcutaneous dosing, rapid and durable response, and able to really transform the treatment paradigm for IgA nephropathy and immune thrombocytopenia. We've got our proof-of-concept studies that demonstrate stabilization of kidney function in IgAN and rapid restoration of platelet count in ITP with a durable response off treatment and subcutaneous dosing. We continue to look at the asset, expanding the potential beyond IgAN and ITP to see other indications where there's a high unmet need. This unique asset could be of great service to patients and the health care community. Today, we see a global peak revenue of $1 billion-$3 billion for these first two indications, IgA nephropathy and immune thrombocytopenia. Thank you. Thank you. All right. And now we go to our last asset, which is for fazirsiran. So we've done a small molecule, peptide mimetic immunoclonal antibody, and now an siRNA therapy. All of them exciting in their own unique ways. We're going to talk about a disease known as Alpha-1 antitrypsin deficiency liver disease. So Alpha-1 antitrypsin, it's a protein that is made in the liver and secreted into the blood, where its major job is to go pretty much to the lungs and protect it from destruction by another enzyme known as neutrophil elastase. So for this to work and protect the lung, the protein has to be made normally. It has to be shipped out of the liver and protect the lungs. So when it's unable to do that, patients can have a lung disease. However, today, we are not talking about the lung disease. We're going to talk about the liver disease because patients who have Alpha-1 antitrypsin deficiency can have a mutation that leads to accumulation of an improperly misfolded protein. That protein clumps up the liver cells, causes cellular stress and injury, and patients can get a liver disease as a result. The disease itself is largely asymptomatic, like most chronic liver diseases, but when clinical effects are manifest, there are no treatments that are available except for liver transplantation. So for fazirsiran, it's a treatment that is geared towards reducing the accumulation of this abnormal protein in the liver, and the hypothesis is that removing the injury prevents sequelae of the injurious protein in the liver. So less inflammation, less fibrosis, less liver damage, and that's the goal of this therapy. This is shown pictorially here. Blown up on the left is the process of how injury occurs in the liver. Those little red patches you see on the liver cell are depictions of this accumulated toxin protein that is building up in the liver. Its consequences do cause inflammation and cellular stress, and that usually leads to fibrosis, typical of any chronic liver condition, not just Alpha-1 antitrypsin, but the fibrosis follows after you kill liver cells, cause inflammation, lead to fibrosis. The fibrosis itself can lead to the very end-stage process of fibrosis in the liver. That's called cirrhosis, and cirrhosis is a precursor to clinical decompensation, so all the things you associate with people who have a liver that's not working, the yellowness in the eyes, the fluid in the belly, all of those come in patients who have cirrhosis. Some patients who have Alpha-1 antitrypsin deficiency and fibrosis also develop liver cancer. So there are multiple ways at the end your liver stops working, either because of clinical demise or because you get cancer. And the only treatment, as I've said at this point, is a liver transplantation. So for fazirsiran, it works to thwart the accumulation of this toxic protein. And I'll take a minute to just illustrate how this works. In this figure, one is the molecule for fazirsiran, siRNA, a double-stranded siRNA, which is taken up into the liver cells. There, it finds number two on the graph, a piece of messenger RNA carrying this abnormal mutation of Alpha-1 antitrypsin. It forms a double-stranded RNA molecule, which is then destroyed inside the liver cells. So the protein is not made. That's number three on this graph. And over time, the accumulated proteins are then resolved, and the liver health is improved. That is the goal of this therapy that we have. Our partners at Arrowhead had done two studies. And I'm going to share both of those with you. The first one is shown here. In this study, the goal is to simply ask how much of this toxic accumulated protein in the liver can you reduce. There's a six-month arm and a 12-month arm to the study. In the six-month arm, patients were dosed with either 100 mg of fazirsiran or 200 mg of fazirsiran. They all had biopsies at baseline and biopsies at week 24. There's a third cohort that got 1,200 mg of fazirsiran, a biopsy at baseline, and another biopsy at at least 48 weeks after the first dose. And then these patients had the biopsy was then analyzed for the content of this toxic protein in the liver, which is shown on the left-hand side in this graph. What you see is that between baseline and the end of the study, where there was the 24-week or when they had their second biopsy, there was an 83% relative change in the accumulated amount of this toxic protein in the liver. In the serum, you can also see some of these abnormal proteins. What you also notice is a marked reduction in the amount of this abnormal protein in the serum over that period of time. A second study was also run. This time, a randomized study comparing three active doses of fazirsiran against placebo. The primary endpoint here is the amount of this abnormal protein in the serum. The dosing schedule is at the bottom, a biopsy at baseline, and a biopsy at week 48 or later on, depending on the patient. What you see is shown in the next graph, where you see a nice dose response over time and in the serum on the left-hand side and in the liver on the right-hand side. You notice a 94% decrease in the accumulated amount of this protein in the liver. You see a nice dose response of the serum content of this protein at the same time. This drug is well tolerated. We followed patients now for over 1.5 years. There have been no deaths, no discontinuation, and no dose interruptions. We are in the middle of a phase III study known as the Redwood Study. This is a study where patients are randomized one-to-one to fazirsiran 200 mg subcu against placebo. The dosing schedule is shown in the bottom. There's a biopsy at baseline. There's another biopsy at week 106, which is the primary endpoint of this study. There is a third biopsy at week 202. The primary endpoint here is a one-point reduction in fibrosis content on that week 106 of this study, and there are a number of secondary endpoints, and now I will turn it over to Ramona to talk to you about the commercial aspects of this drug. All right. Thank you so much, Chinwe. So this is my last one. And I'll say it's been such an exciting time for those of us at Takeda learning about all these amazing assets in our pipeline and really benefiting from the amazing work happening in our R&D organization, in our global commercial organization, in our business development organization. We feel really fortunate to be able to bring such transformative assets that are uniquely positioned to make a significant impact on patients' lives and build Takeda's sustainable growth story over time. So we're going to talk a little bit about fazirsiran. And this is a story on the slide here about a woman named Linda who's actually given us the OK to share her story with you. She's very typical of a patient with alpha-1 antitrypsin deficiency liver disease. She lived her whole life not knowing that she had a double genetic mutation. She was healthy and happy until suddenly she presented with very, very severe end-stage liver disease. She got on a transplant list and with only hours left was given a transplant that was able to save her life. Now, since she's been diagnosed, her family has now recognized that this is a genetic disease, and her family is able to go and have genetic testing and screening to see if they also have the double mutation. However, even if they were to have that double mutation and be at risk of developing Alpha-1 antitrypsin deficient liver disease, there's nothing today to treat or cure this disease, so this community, similar to many of the others that we have here, are waiting anxiously for Takeda to be able to bring a solution to the health care system. Linda's journey is very typical of patients with this disease. In general, liver disease is a silent disease. It progresses over many years. They don't know they have it. Now, these patients have a very specific type of liver disease due to this buildup of the mutated protein in their liver, but they don't know. Often they don't get diagnosed until they are at end-stage liver disease. They present with liver cancer on a transplant list and are near death. Sometimes these patients will present earlier with a pulmonologist because they've got two mutations of the Alpha-1 gene. They don't have enough healthy circulating Alpha-1 to be able to preserve lung function. Sometimes they'll present to a pulmonologist. Even then today, if they are to be presented and then monitored for liver disease, there's nothing specifically to treat the Alpha-1 antitrypsin deficient patient. So thinking about the situation, we find ourselves in this place, it's almost a cycle. There's nothing to treat Alpha-1 antitrypsin deficiency liver disease today. Because of that, there's low awareness and a low urgency to find and screen these patients today. Because of that, we see constant underdiagnosis and very long timelines with people getting diagnosed very much at a late stage when they are in end-stage liver disease. And there's a very poor disease understanding. So the very poor understanding that there is a genetic mutation exists, that mutation can cause buildup of the mutated protein in your liver and can lead to long-term liver disease. So there's really an opportunity for Takeda. Bringing the product is not going to be enough here. We really need to transform the diagnostic journey to be able to find these patients earlier to ensure that they can be treated. We think there's a great opportunity to take advantage of enhanced liver screening that's happening in health care systems around the world now with the advent for more products in the MASH space. This is unrelated, but it can be done as part of a general liver screening with a simple genetic screening. It's a blood test, a simple blood test. We're going to do a lot of work as we prepare to bring fazirsiran to market to really make sure we can insert this genetic screening into liver testing regimens so we can find these patients earlier and offer them hope. Thinking about the opportunity for this asset in this very unique space, rare space where there's nothing else available to treat these patients, we've got about 250,000 patients prevalent globally with this genetic mutation. Again, these are patients that have both genes that produce alpha-1, are producing the mutated protein. Of that, about 35% of patients will get this buildup of the mutated protein in their liver and develop liver disease. Today, only about 10%-15% of these patients, sadly, are diagnosed. As I mentioned, they're diagnosed very, very late stage when they're presenting with liver cancer or the need for a liver transplant. Today, there's no available treatment. So there's a huge opportunity for us if we can take advantage of the advancement in liver screening that's happening in health care systems around the world, if we can insert genetic testing and genetic screening into that liver screening so we can identify these patients with Alpha-1 antitrypsin deficient liver disease, if we can do education so that patients go in and get screening and family members also can be watched, we can accelerate diagnosis, be able to intervene earlier with these patients, and be able to give them hope for a long and fulfilling life, and really position fazirsiran as the standard of care for early treatment of Alpha-1 antitrypsin deficient liver disease. This gives us a global peak revenue potential of between $1 billion and $3 billion. So just to summarize, we will be the first available treatment indicated for Alpha-1 antitrypsin deficient liver disease. We have strong phase II clinical data, as Chinwe showed you, that demonstrates that fazirsiran reduces the levels of mutated protein in the serum, reduces the levels of the mutated protein in the liver, reverses fibrosis, and restores liver health. That is significant for these patients. Because of this significance, fazirsiran has been granted breakthrough therapy designation by the FDA and orphan designation by the EC, and we are well positioned to be able to really transform the journey for these patients so we can find them earlier, monitor, and intervene at the right time to restore their liver health. This gives us a global peak revenue potential of between $1 billion and $3 billion. Thank you very much, and I'm going to turn it over to Chris now to take us through the rest of the day. Now we are going to take a lunch break. At the back of the room, we have lunch boxes prepared for you. So please help yourself. The next presentation will start from 12:00 P.M. I'm sorry about this very short break, but please enjoy. Thank you. So we'll resume the session from 12 o'clock. [Foreign language] Now, I'd like to move on to the next presentation. It is a presentation about oncology. The first presenter is P.K. Morrow, oncology therapeutic area head. Good afternoon, good evening. It's great to present to you today. And on the heels of the recent late development programs that we've just discussed, I am delighted to present to you a deep dive on elritercept. So, last week, we disclosed our plans to license this potentially best-in-class program in collaboration with Keros Therapeutics. elritercept will be in an exclusive licensing agreement between Takeda and Keros Therapeutics, enabling us to have global rights in all territories for development and commercialization outside of China, Macau, and Hong Kong. Of course, the closing of this is subject to the receipt of regulatory approvals, which are anticipated to occur in the first quarter of calendar year 2025. But what I want to emphasize to you is that this in-licensing continues to solidify and broaden our footprint in hematologic malignancies, building upon our legacy, and it confirms our deep commitment to serving patients with blood cancers. So, as you can see here, elritercept truly fits hand in glove into our oncology strategy. While our vision, which has always been inspired by patients and powered by innovation, remains constant in the desire to aspire to cure cancer, we have refined our areas of focus to specifically three disease areas and four therapeutic modalities. And to accomplish this vision, what we've determined is we need to refresh the oncology pipeline through internal and particularly external innovation in order to create a robust and impactful pipeline that's designed to address critical areas of unmet need for patients with cancer. So, our pipeline is truly a paradigm of prioritization. If I can walk you through from left to right, on the left-hand side, we'll be spending a lot of time discussing hematologic malignancies today. We start with our successes in acute lymphoblastic leukemia, in which we continue to feel passionate about in development. We've achieved successes, for example, the recent approval in frontline based upon a novel endpoint, which was MRD negative complete response for Iclusig. In addition to this, today we'll spend discussing the potential treatment with a best-in-class asset for myelodysplastic syndrome, which exists on a continuous myeloid spectrum towards acute myelogenous leukemia, truly urgent and life-threatening condition. Last, but definitely not least, within our hematologic malignancies focus, we will continue to focus upon the development in chronic myelogenous leukemia, including not just ponatinib, but as Andy alluded to, also the option agreement for olverembatinib, which gives us the potential to treat critical T315I mutations that occur in the treatment evolution of patients who are being treated for chronic myelogenous leukemia. Beyond that, the second step is in GI malignancies. What I'd like to bring your attention to is the fact that building upon our success in developing, commercializing, and launching a potential chemotherapy-free option in the form of Fruzaqla for patients with colorectal cancer, we will continue to investigate therapies to treat malignancies in gastric cancer, pancreatic cancer, as well as hepatocellular carcinoma, which continue to represent areas of critical unmet need. Finally, we will continue to prioritize investigations in thoracic cancers, including non-small cell lung cancer, small cell lung cancer, as well as head and neck cancer. On the right-hand side, you can see that we are continuing to prioritize and build upon our legacy of successful small molecule development. We're expanding that beyond there to include antibody-drug conjugates, including the recent in-licensing and agreements related to Elahere as well as mirvetuximab, as well as complex biologics, including our bispecific platform and, of course, the fusion protein elritercept and gamma delta cell therapies. So, to realize this vision, we've really leveraged the power of external innovation. And if I can briefly walk you through this slide, let me start from the left-hand corner and note that with Fruzaqla, this enabled us to have global development and commercialization rights ex-China, and has really helped us to bring forward, as I noted, a truly chemo-free option for patients suffering from this grievous disease. In addition to this, the regional in-licensing of Elahere, a novel ADC that serves patients with ovarian cancer in Japan, enabled us to truly address a critical unmet need. On the left bottom-hand corner, you can see that with olverembatinib, this option agreement will allow us to address the mutations that develop during the course of treatment in patients who are treated for CML, as well as potentially have the benefit for patients with acute lymphoblastic leukemia, and last but not least, elritercept is what we will spend much of our time today speaking about. This is a potentially best-in-class fusion protein and marks our fourth late development business development deal in the past two years. This really marks and reinforces our commitment to helping patients who are suffering from hematologic malignancies as well as solid tumors, so to succinctly sum up elritercept, this is a potentially best-in-class fusion protein that potently inhibits activin A and B and has the potential to help patients with anemia-associated myelodysplastic syndrome, myelofibrosis, and other anemia-associated diseases. Let's now deep dive on our reason to believe in this program, so you can see on the left-hand side, why do we believe in elritercept with such conviction? Well, first of all, elritercept has a very differentiated mechanism of action. Its potent inhibition of both activin A and activin B allows it to act at the osteohematopoietic niche, enabling it to increase all cell lineages, including red blood cells, white blood cells, and platelets. As a result, we believe this is a potentially pipeline in a molecule enabling us to treat not just MDS and myelofibrosis, but potentially through lifecycle management, additional anemia-associated hematologic indications, and this fits perfectly with our oncology strategy as I presented to you, so as you see on this slide, I want to talk to you a little bit about myelodysplastic syndromes because this is very dear to my heart. In myelodysplastic syndromes, there is an imbalance in transforming growth factor beta superfamily. And as a result of this, there's an inhibition of normal blood cell production. As a result, patients are not able to produce red blood cells, white blood cells, and platelets normally. What does that mean? Well, related to this anemia, patients can develop increasing fatigue, require chronic red blood cell transfusions, and also may develop iron overload characterized by iron deposition in critical organs such as the liver, the pancreas, and the heart. In addition to this, the decrease in white blood cell count and platelets can increase the risk of infection and hemorrhage. And last, but definitely not least, as I mentioned before, MDS is on a continuous spectrum with acute myeloid leukemia, and about 10%-15% of patients with MDS may progress to this life-threatening disease. As a result, I think I've convinced you, I hope I've convinced you, that this disease has critical unmet need. Now, you might say, well, there's therapies on the market right now that can address this. Absolutely, there are therapies on the market that can address some elements of myelodysplastic syndrome. However, they have hurdles, including early cytopenias, more frequent administration, slower onset of administration, and inability to treat across segments as well as treatment burden. Those are all elements, to be frank, that elritercept can address, and I will talk to you about this in the subsequent slides, so by acting at the osteohematopoietic niche, elritercept inhibits activin A and B. It impacts red blood cell development both along the early and late stages of blood cell development, truly taking the brake off of normal production. What does that do? Not only does it enable it to have a very rapid onset of action, strong efficacy, and a tolerable safety profile, but it also allows elritercept to treat across a very broad population of myelodysplastic syndrome patients. So, as I alluded to, our competitors may have issues with certain histologies. Elritercept, as I will present to you, has strong efficacy in both ring sideroblast-negative and ring sideroblast-positive disease, as well as in patients with high and low transfusion burden. Couple that with a generally well-tolerated safety profile. I hope you can sense the importance of this therapy for patients with anemia-associated hematologic diseases. This slide is fresh off the presses. It actually comes from the American Society of Hematology annual meeting. This was actually presented just this past week in San Diego, California, and provides a very, very recent data cut, and let me walk you through the data here. On this table, you'll see that these patients are patients with erythropoietin levels less than 500. Why did we present that? Because that indicates the majority of all patients with myelodysplastic syndromes. You can see here those patients who achieved the primary endpoint, the RS-positive patients. You had more than 50% of patients experiencing or achieving the primary endpoint of transfusion independence of greater than or equal to eight weeks, and around 36% of patients with RS-negative disease. You can also see that these results are fairly comparable across low and high transfusion burden, really emphasizing the ability of elritercept to be an efficacious therapy across a broad population of patients with low-risk myelodysplastic syndromes. This slide is also quite hot off the presses. It was also just presented at the annual meeting in San Diego, California, and it represents truly a very prolonged and durable transfusion independence that can be achievable in myelodysplastic syndrome patients who are treated with elritercept. This is a very impressive Kaplan-Meier curve because you can see that among the responders, the median duration of transfusion independence was 134 weeks, and among those patients who had ongoing responses, 50% of them had high transfusion burden, reflecting the fact that elritercept is able to treat a typically very refractory population of patients with myelodysplastic syndrome, so this curve further reinforces the benefit of elritercept across patient segments in myelodysplastic syndrome. When we look at the safety profile of elritercept, the majority of the adverse events associated with this asset were mild to moderate, grade one to two. There were no investigator or sponsor-assessed fatal events associated with elritercept. Those patients who received or achieved transfusion independence of greater than or equal to six months showed greater improvement in quality of life, which makes sense given the fact that elritercept therefore gives them a life away from the hospital, away from fatigue, and away from risks of infection, hemorrhage, and progression. As a result of these encouraging results, we plan to begin a phase III registrational study evaluating the efficacy of elritercept in patients with low-risk myelodysplastic syndrome. The primary endpoint is well validated. This is an endpoint related to transfusion independence at greater than or equal to eight weeks, and the data will be stratified by patients with or without RS-positive disease, as well as for high and low transfusion burden. We are targeting a study start in fiscal year 2024. One major takeaway that I would like you to take from this presentation is the fact that we are building upon the preclinical understanding of this differentiated mechanism of action, as well as the robust efficacy and safety data across the populations of myelodysplastic syndrome. To note that this drug can truly be a best-in-class therapy for patients with anemia-associated myelodysplastic syndrome, agnostic of histology or transfusion burden. Its activity in both MDS and myelofibrosis really reinforces its status as a pipeline and a product, and we look forward to developing this very valuable asset and harnessing its value with anemia-associated hematologic indications, and with that, I'll transfer to Teresa. Great. Thank you, PK. Good afternoon. So, PK just shared with you what an excellent fit elritercept is in our pipeline of hematologic malignancies. And it builds really well on the historical legacy that we have in hematologic malignancies that started with Velcade. And I think the most important thing is that this is a meaningful therapeutic option for patients. So, let me give you a sense of the commercial opportunity that we have here. So, today, the market for MDS is $2 billion, and that is projected to grow to $6 billion by 2030. And I think that growth is in large part reflective of the fact that there is a high incidence and a high prevalence. So, taking a look here at the market map today, there are 50,000 patients in terms of incidence. And this is just looking at the U.S., Japan, and your top EU four countries. Now, I'll remind you, MDS is a very heterogeneous disease. So, of that 50,000, 37,000 are categorized as low-risk MDS. And of the 37,000, 25,000 of those are transfusion dependent. This is the population that elritercept will serve. So, when we look at the medicines that are available across lines of therapy, there are a few that are out there in the market today. But I will tell you, the unmet need remains significant. RS-negative patients are extremely difficult to treat. They represent 70% of the marketplace. We also look at high transfusion burden patients. They are also very hard to treat. There's a high unmet need there. They're 40%-50% of the marketplace. When you look at patients that are today starting therapy in first line, 40% of them in less than a year's time will already have had to move on to the next set of therapy. To focus on that unmet need, I'll just talk about that a little bit. One, what do patients want? They want freedom from constant transfusions. That transfusion independence is critical, and they want it to work quickly. Two, they want to make sure that there's broader activity, particularly RS negative. There's a very high unmet need today in the market around efficacy in RS negative patients. Of course, always tolerability. This is something that really matters. This disease is exhausting and fatiguing enough. You don't want the medicine to make it even worse, which is the current case with many of the medicines available today. And then convenient dosing and administration, you know, that matters if you're not going in for an infusion every single week. And every single one of these parameters, elritercept has the potential to be best in class. So, this is the reason why we're very excited about this. And to that end, we want to make sure that we deliver this to as broad a patient population as possible, as fast as possible. So, the plan is that we will enter in second and third line, running in parallel very quickly, a first line study, so we can follow right after that. But I would remind you that elritercept has potential for life cycle management and other indications, and we are already planning through myelofibrosis, which PK mentioned. So, I'll sum it up here. This has a very strong strategic fit when you look at our legacy. And the legacy exists by the fact that we have the development expertise, we have the research expertise. We know how to develop drugs in hematologic malignancy. And when you look at our commercial footprint, this is where we are in the market today. These are the physicians that we are talking to, that we have relationships, long-standing relationships. We know that elritercept is a different mechanism of action, which has parlayed into a very differentiated best-in-class profile. And it's exciting when you're able to get a Phase III ready asset, which is largely de-risked, that has potential not only on the initial indication, but in multiple other indications that we can work through. And so, last but not least, obviously, we're excited about the global peak revenue potential of $2 billion-$3 billion. So, this has been a wonderful deal. We're very excited. We believe that it really fortifies what we'll be doing in oncology. So, without further ado, I will turn it back over to Chris. Thank you very much for your kind attention. We would like to move on to Q&A, and we'll prepare the stage. Please bear with us for a moment. [Foreign language]. We are entertaining Q&A. You can ask two questions at most. Please go ahead. Mr. Wakao, please. I should express my two questions. I have two questions. Firstly, about the zasocitinib competitive landscape. I think the zasocitinib would be a better drug than Sotyktu, but it seems to be difficult compared to J&J's oral IL-23, a receptor antagonist, because based on the J&J's phase III data, and IL-23 is standard of care and very familiar with physicians, so I'd like to know your view on zasocitinib compared to oral IL-23. And next, about the second question about mezagitamab, so I'd like to know the potential of IgA nephropathy, so the incidence rate of infections higher with the mezagitamab compared to Darzalex targeting antibodies. Do you believe this is due to the targeting of B cells? And do you see this as a disadvantage for mezagitamab comparing with the Darzalex targeting antibodies? And also, could you comment on the phase III dosing schedule in IgAN for mezagitamab? Will it be similar to that of ITP? What duration of dosing period are you considering? That's it. All right. Great. Can you hear me okay? Yes. Am I on there? Okay. Perfect. So maybe I'll repeat the question and then identify a speaker. So, I think Chinwe, the first question was around zasocitinib's competitive landscape, particularly relative to oral IL-23s. Maybe you can start, and Ramona, you can add some comments. And then there were two questions, actually, there were two questions on mezagitamab. How do we compare to the Otezla and Sotyktu agents? And then secondly, the phase III dosing schedule. So, maybe you could take that question as well. Yeah. All right. Thank you very much for the question. I cannot really comment on somebody else's drug, but I can tell you what our drug has done and why we are excited about the potential for zasocitinib to really offer something unique for patients with psoriasis. Okay. First, the study I showed you today was only 12 weeks long. The data for most other of our competitors in this space is 16 weeks at the same phase. And we already have compelling efficacy over 12 weeks. And I think we will continue to see that increase as we go into phase III, a longer study with a primary endpoint of 16 weeks at the moment. The other things about this drug that make it really appealing, it's a once-a-day oral drug. You can take it with or without food. So, we feel convenience and compliance will play a role. I shared the data with you on the selectivity of a JAKs at this point, so we have not seen anything to make us worry that we would have any adverse events related to that, so with regards to what we have, we think the data will rule the day, and we are going to have phase III readouts 12 months from now that will show whether we're on the right path or not, and we believe that that data will be fantastic. I can add a little bit from the commercial perspective, Chinwe. Thank you. So, you know, first of all, we're assuming that there is more than one oral coming into this market. So, we're assuming the launch of the J&J as well as ours. And honestly, that helps us because what we want to do is change the treatment paradigm where orals are seen as a better first line advanced therapy. And so, more companies really helping to have physicians see the benefit and possibility in oral medication is going to actually be good for us to more than double the use of oral therapies. But then within that oral therapies, I know we're, you know, going to see the results of the phase III trial. We have excellent results in phase II. I will just say that what we know is in the real-world setting, the way people can take our medication will not impact the absorption and the efficacy. So, we believe in real life and clinical practice, the results are going to be as good as they're seeing in a clinical trial because no matter when or how they take it, the absorption isn't impacted and they're going to get that level of efficacy. And so, we're excited to be able to bring that to market and to be able to show that. Maybe the last thing I'll add is as we've, you know, we've spent a lot of time now with key opinion leaders, clinicians, and investigators in this space as we've been mapping out our phase II and our Phase III trials. I would say, you know, the feedback we're getting from them is a high level of excitement. I think that plays out in how quickly we were actually able to recruit these trials. In a space that's relatively new to us, we were able to go in, build these relationships very quickly, and recruit these trials significantly ahead of schedule. On the commercial side, we always see that as a good indicator of the level of excitement for the asset. Thank you. Okay. So, the other question was about mezagitamab, and there were two parts. First was the risk of infection and how it compares to the other B cell agents that are in development. And then the second part was the Phase III dosing schedule for IgA. So, I'll start with the first. As in the first question, no direct competition, but I can tell you what we've seen. We haven't seen any increased risk of infections in the studies we have done. And I think you're right that there is a biologic reason to believe that the selectivity for plasma cells might actually be a bonus with regards to infections. So, in a sense, we are not disrupting B cell maturation across the board. We still have, say, memory B cells that respond to things like vaccination and protect you from infections very much in play. There is a theoretical reason to believe that the selectivity for CD38 in this case might provide a safety advantage. Obviously, we're doing studies and accumulating more and more safety data, and that will be the way to prove that. Then with regards to IgA in phase III, we are in the process of designing those studies. I cannot share the dosing schedule with you yet since it's not ready. Thank you. I have one follow-up. So, could you comment on the efficacy of mezagitamab in IgA? So, UPCR 55% reduction at 36 weeks seems to be lower than other drugs. So, should we view, I think, clear advantage for mezagitamab with uniqueness for dosing schedule, not efficacy? Yeah. So, the question was that the 55% reduction in UPCR might be lower than, say, other agents. Well, okay. So, here's how I'll address the question. The reason for us to treat this disease is actually to preserve renal function. And the best measurement of preservation of renal function is the maintenance of eGFR. So, on that basis, if the goal is to protect the kidney from failing downstream, the way to do that is to maintain renal functional loss. At 36 weeks, we are essentially flat. There is no decline in the slope of the eGFR. So, the advantage is not just the dosing schedule. It's that what we are seeing right now, and we will continue to gather data as patients continue on the study, is that the ultimate goal, which is to protect their kidneys that are failing, we are meeting that at this point. Okay. Mr., thank you so much. My pleasure. Maybe Chinwe, if I may, I just wanted to add to the timelines. Timeline. We recognize the competitive landscape that we're facing. While we haven't started this study yet, this is a top priority for us, and we're moving extremely quickly. The design that we put in place is a very creative design and recognizes the fact that while we're coming in a little bit later than some of the other agents, there's actually, in some ways, an advantage in doing that because there's a much greater regulatory understanding. There's a much greater appreciation for the predictive value of the early biomarkers, like urinary protein-to-creatinine ratio. We're going to be doing everything we can in running this study to accelerate and move this more quickly. Thank you very much. So, this is the slide that I would like you to remember. Next question, please. Sogi-san, please. I have two questions regarding fazirsiran. So, the first one is, so I'd like to understand that the delivery of this short interfering RNA, is it the organ-specific delivery or it's more kind of broader? So, I'd like to understand what is the kind of special feature of that delivery. And also, secondly, I understand that it's really critical to really identify the patients early because, you know, once the disease, you know, AATD progresses, then, you know, it's too late. And I understand that, you know, that the early diagnosis is really not prevalent today. And you have already mentioned it, but I'd like to a little bit better understand how, what needs to change from now on? Is it going to take a little bit for a while after you launch the drug, or it's something, you know, you can accelerate? That's great. Thank you. Maybe Chinwe, if you could take on the zasocitinib targeting mechanism, and Ramona, if you could talk a little bit about the diagnostic challenges and opportunities. Yeah. So, the question is, is it specific to a particular organ? Yes, it is to the liver and not just to the liver, to the hepatocytes in the liver. So, hepatocytes is where alpha-1 antitrypsin is synthesized before it's secreted in the normal setting. In this case, it accumulates because of the mutation. And the siRNA is a GalNAc that targets hepatocytes. So, it's specific to hepatocytes. I can take the next question around the diagnosis. You know what I would say is the diagnosis for alpha-1 antitrypsin deficient liver disease needs to be done through genetic testing. Our goal is to incorporate genetic screening into the liver screening that's happening today. We know in healthcare systems around the world, there is an increase in liver screening with the advent of more products treating MASH and obesity and fibrosis. Really, these patients are a subset within there that need a very specific treatment. We believe we can work with healthcare systems because it's a very simple and inexpensive test. It's a blood test to do the genetic screening. We believe we can work with healthcare systems to incorporate genetic screening into the liver screening so we can find these patients earlier, put them on some monitoring, and then decide when to intervene in their disease. I wouldn't say that would happen right away, but certainly we're working now, you know, even prior to bringing the drug to market to say, how do we prepare to be able to identify these patients? The real urgency to identify them will come when we have a treatment because today, even identifying them, there's nothing to treat them as they progress. So, that is something that we're very focused on at launch. It won't happen at launch, but it will happen as we launch, I would say. Okay. Next question, please. Tony. Great. Yeah. Thank you for taking my question. Tony Ren from Macquarie. I would like to follow up on TYK2, zasocitinib. So, it's great to see that you guys are conducting a head-to-head trial against Sotyktu, deucravacitinib. Certainly shows the level of confidence in this asset. So, as Wakao already asked you about the psoriasis where the current standard of care is IL23, right? So, would you in psoriatic arthritis consider doing a head-to-head trial against the standard of care in that space, which is IL17 and TNF alpha? TNF alpha, I assume, would not be that difficult of an opponent, whereas IL23 in psoriasis is a very competent rival. Also, just to go to slide 69, if I may. So, it looks like in the psoriatic arthritis trial, you guys are heading into the phase III with two different doses, right? 15 mg QD and 30 mg QD. Just want to see what's the thinking there, taking two different doses into the psoriatic arthritis study, whereas it looks like you fixed on a single dose heading to the psoriasis. So, that will be my first question. That's only like two questions. That's okay. Go ahead. Actually, once you answer that one, otherwise it becomes a memory test, right? That's okay. Please, you can finish the questions. I didn't mean to interrupt. Okay. Sure. You know, if I may, the orexin program or TAK-861. Go to slide 30. One of the higher response doses there is 2 mg followed by 5 mg three hours apart. That doesn't appear to be a very easily compliant dosing regimen to me. I just want to see what's your experience in trials or real patient setting. People are complaining about BID doses, right? I mean, this doesn't look like it's a particularly easy regimen to follow. Also, you know, you guys alluded to the fact that the pathophysiology of narcolepsy type 2 and idiopathic hypersomnia is not yet fully elucidated. In this situation, would you say it's a bit of a more riskier proposition taking an orexin agonist approach in these disease areas versus type 1? All right, Tony. Thanks. I'm glad I was taking notes. So, four questions. So, Chinwe, perhaps you can take the first two, which is head-to-head plans in psoriatic arthritis for zasocitinib. The second is why we chose to move forward with two doses in phase III for zasocitinib in the psoriatic arthritis trial. And then maybe Ramona, on oviparexin, you can comment on the potential for a BID dosing regimen. And then Sarah, Sarah, if you could talk a bit about, on oviparexin, the differences between NT1 development and then NT2 and IH. Okay. So, first question was for me. Are we contemplating a head-to-head against IL-17 or TNF-alpha for psoriatic arthritis? We have no plans at this moment to do that. That can always change, but at the moment, we are not planning a head-to-head against those two assets. The second question is an interesting one. You've nicely noted that we took one dose to phase III for psoriasis, and you're asking why we're taking two for psoriatic arthritis. If you look at the psoriasis, dose is pre-declared 30 mg. It's superior. But if you look at the psoriatic arthritis, there's a plateauing off between 15 and 30. Although when you include the skin, which is a part of this disease, the 30 is superior to the 15. But because what we are studying here is joint disease, we are taking two doses into Phase III just to be sure we have the right dose for the patients who have a joint disease. Maybe I'll briefly comment on psoriatic arthritis and then talk about Oviparexin and turn it over to Sarah. Just to let you know, certainly we are working with the rheumatology community looking at overall evidence generation in psoriatic arthritis. We believe the sweet spot for Zaso is going to be in patients that have comorbid psoriasis and psoriatic arthritis, but we also recognize psoriatic arthritis is a more complex disease, and there's a lot of things that we would like to look at and our opinion leaders would like us to look at. Really, we're looking at more phase four evidence generation for psoriatic arthritis and working with the thought leader community to design a plan that will help give them the type of insights they need when selecting treatment. More to come on that. Then thinking about Oviparexin and the BID dosing, which is, you know, a little bit of a misnomer because BID dosing might be, you know, further apart, kind of morning and evening or something. This is really the purpose of the dosing is to mimic the diurnal tone of Orexin in the body. So, as we talk to our thought leaders, the value of the dosing three hours apart or however, you know, apart we have it in our trials, in our Phase III trials, will be that actually it mimics the natural diurnal tone of Orexin. And it actually brings, this is what helps these patients be like healthy and into the normative ranges. So, there might even be a possibility for tailoring the dose depending on the individual's diurnal tone as they start taking it in real life. We actually think this is going to be helpful to people to actually have full return to normalcy with Narcolepsy type 1. It's a different way to think about treating narcolepsy. It's not the way that people have thought about it before. But because we know so much more now about orexin deficiency, about the ebbs and flows of diurnal tones for orexin in the body, and about the kind of efficacy and functionality you can get by dosing appropriately, we think actually the benefits are going to far outweigh the negatives in that dosing. It's actually going to help us have a differential advantage. Maybe Sarah, you can talk a little bit about the trials and the patients in the trial themselves. I'd be happy to do so. And in addition to mimicking the natural orexin tone, the benefit-risk that you see with the BID dosing is very compelling across all symptoms and maintained for the long term. So, that's an important one. Patients have been adhering in the trial. And as you heard, more than 90% are still ongoing in the long-term extension of the phase II study. And patients are lining up to enroll into Phase III. So, I don't think that's an issue there either. There are a few things I also wanted to just emphasize, and that's the flexibility in dosing, right? Patients wane in their ability to function later in the day, so around 2:00 P.M., 3:00 P.M., 4:00 P.M. That flexibility in dosing is huge. And it allows a tailored approach to individual patient satisfaction. And then just a last point to make is that the current standard of care is multi-therapy, dosed multiple times a day or multiple times at night. And so, this is a huge step towards a single therapy that addresses all symptoms holistically. And we're very excited that we'll have that phase III readout in 2025. All right. So, NT2 and IH, orexin normal populations, you're absolutely right. Those populations are more heterogeneous. And the question was, does orexin help? And we believe it does. Actually, in our hands with earlier molecules, we have proof of concept in patients that orexin normal populations like NT2 and IH can benefit from the orexin mechanism. Now, the trials we're going to conduct have to take the more heterogeneous patient population into account and be designed accordingly. And similarly, the molecules we choose have to be tailored to that population. That's exactly what we're doing. We're very confident in our ability to deliver in these populations and look forward to the phase II starts in the very near future. Thank you, Tony. Thank you. You know, if I may just add a very quick one. So, the North Star slide that Andy showed a few times, right? So, on there you have a number of $10 billion-$20 billion. Is that risk unadjusted, right? Without risk adjustment, I see it. Correct. Okay. Great. Okay. So, currently, the standard therapy, hydroxyurea, has a risk for these diseases, and the phase II extension data showed that 11 malignancies, but the Protagonist analysis provided that there's no relationship between rusfertide and these malignancies. We evaluate the phase II extension data of rusfertide, and next quarter, the Phase III data will be available, and the Phase III hurdle looks very low, only showed the response rate. So, this means FDA set a very easy hurdle for it, I think. Why do you think of it? This is rusfertide. And second is that mezagitamab CD38 antibody is a very old drug. Darzalex is a typical first-generation CD38 antibody. But it has a risk for anemia or thrombocytopenia because, generally speaking, CD38 expresses at red blood cells or platelet cells. But so, generally speaking, the CD38 has a risk for them. But your mezagitamab has no risk for that. At this stage, it is very difficult for us to analyze them. But do you have any hypothesis on why that has no impact on these cells? Thank you. So, just if I understand the first question, because you really did a nice job of laying out a lot of details of the program, are you asking our perception of the regulatory bar for approval for rusfertide? Is that the question? Okay. Great. So, if you can take that, Chinwe. And then the second question was why mezagitamab doesn't have a factor of new-onset thrombocytopenia. Yeah. Okay. So, I'm going to just rephrase how I understood the first question. You're saying that in the open-label extension, our partner saw 11 skin cancers. And you are asking, are we worried about a risk of secondary cancers using this drug? Is that correct? I think that's what you're asking. Okay. So, I think we have to go back. So, this is a disease itself, polycythemia vera, that has an association both with hematologic malignancies like leukemia and non-hematologic malignancies, particularly skin cancer. And then on top of that, some of the patients who have this drug take hydroxyurea, which by itself also has a risk. My understanding of the data that our partners presented is that the 11 skin cancers were not felt attributable to the drug. They rather occurred in patients who had risk factors for developing skin cancer. What it does mean to me is that we are treating a disease where the natural tendency and progression is to have other cancers. And there are multiple ways we can go about trying to unravel whether our drug is adding to that or not. One is just data over time, treating a lot of patients to see if that. So far in humans, we haven't seen any evidence to make that point. We also recently finished a two-year carcinogenesis study. We don't have the final report yet, but we will be getting that. And that could also lend us some insight into what is going on in this case. Next question, which is intriguing, is whether or not we should be seeing some effects in platelets, some adverse effect on platelets and red blood cells with mezagitamab. Because in Darzalex, which is used in treating a cancer mostly, it appears you're saying that is a side effect. What I can say is that in our studies, we have definitely not seen any risk of thrombocytopenia. Quite the contrary, the data I showed you was that the platelets went up, not down. So, we have not seen that. We have not seen any risk of anemia. I don't know mechanistically why the other monoclonal antibody has that effect and we can't, but one potential possibility could either be those or the underlying condition itself, which is a cancer. And a bone and a blood cancer at that. But in our studies so far, no evidence of thrombocytopenia, no evidence of anemia. And obviously, we'll continue to gather more safety information. Maybe just to add just quickly, Chinwe, which is that it's important to recognize that mezagitamab is a different molecule and binds a different epitope on CD38 than the other anti-CD38s. That alone doesn't explain why we're not seeing these effects on red blood cells or platelets. But it probably speaks to an underlying difference in the pharmacology and the molecule. Next is Fumiyoshi Sakai-san, please. Thank you. I'm Sakai, UBS. Now, Takeda last year spent JPY 5.3 trillion in R&D. If you take the last five years, it still comes up to JPY 2.7 trillion, which is about double the size of the AstraZeneca and Daiichi Sankyo. Now, I'm not going to ask the past productivity, but you gave us this $10 billion -$20 billion potential. So, my question is, are you going to spend the same way for the next 5-10 years with current R&D productivity? I know when you took over Takeda's pipeline 10 years ago, I know things are collapsing or have already collapsed. So, you have managed the situation better, I think. But for the next 5-10 years, resources are limited, I guess. So, what are you thinking going forward? So, that's my first question. The second question is, this is Ramona-san's presentation, page 47, the patient journey for narcolepsy, which is quite interesting. But it said the diagnostic part could be crucial. So, once you launch the product, whatever the narcolepsy you're aiming at, you have to go through probably the same path. So, that means we should kind of slow ramp up in each product, each product launch. Or you have any means to shorten this process? So, that's my second question. Thank you. Okay. Thank you, Chris. So, maybe Christophe, you can talk a bit about planned future R&D spend or intent. And then Ramona on the narcolepsy patient journey. So, on the R&D productivity, Sakai-san, first, I will highlight that the six molecules that we have highlighted today are not the entire pipeline. We have many more programs, more early stage. So, the value is not there yet. But R&D is always early, mid, and late stage. Otherwise, you have a problem later on. It's very clear that we need to increase our productivity. We know that. I mean, we have been working. It's very clear. Not only because you want to generate more molecules for every JPY or USD you invest, but also the environment is getting more and more stringent. More price control, access is more difficult. And it's very clear that we need to increase our productivity overall as a company. We are doing a lot in that regard. Data and technology and AI will help us a lot in R&D, in research, in development, but also in manufacturing. So, we are very much focusing on that for the future. It's very crucial. It's vital if you want to be successful in the next five years or 10 years. I can comment on the narcolepsy diagnosis. So, you know, I would say two things. First of all, today in the marketplace and in the treatment centers, there are many patients that have been diagnosed with Narcolepsy type 1. About 80% of them have some level of residual symptoms. 25% of them tend to stop or discontinue their treatments. And so, there's a huge unmet need today, even with those patients that over the past years have been diagnosed and are treated with symptomatic treatments, polypharmacy, and still having all of those residual symptoms and don't have their functionality restored. And we hear that a lot from patients with Narcolepsy type 1. So, that's kind of our immediate opportunity. Truly, to unlock the top end of the peak sales revenue forecast, we have to make sure we can do a good job at differentially diagnosing narcolepsy type 1 and more quickly diagnosing narcolepsy type 2 patients, so I would say we're going to be doing both things. The diagnosis work, we're starting now to identify some partners in the marketplace that have expertise maybe in data or algorithms or digital or home monitoring so that we can actually have those partnerships in place. And when we're ready to bring the molecule, we can start that diagnostic work. That will take a little bit longer, but add to the potential upside, and then in the very short term at launch, there's actually a large number of patients today that are undertreated and mistreated and looking for a different solution for narcolepsy type 1. Both those things are very important to us. [Foreign language]. Compared to previous forecast, the progress of development has been delayed. On the other hand, the number of competitors' products has been increased. A second question is about long-term portfolio management strategy. In six products, in my understanding, orexin agonist is only in-house product. Almost all products are M&A or licensed in products. In general, in-house product margin of in-house product is higher than licensed in product. So, in-house products contribute heavily to shareholders' return. Of course, in-house products or M&A products contribute to patient value. But considering shareholders' returns, do you think current portfolio status is healthy? How do you think long-term portfolio management strategy? Thank you. Great. Thank you. So, maybe Ramona, you can talk a bit about the orexin sales projections. And then Christophe, if you could talk about the value of our pipeline. Yeah. So, maybe just to comment on the sales forecast, but in general, also our overall understanding and knowledge of this marketplace has really evolved. The earlier sales forecast that we had disclosed a number of years ago was based on our previous asset. And that asset we were planning on developing across narcolepsy type 1 and narcolepsy type 2 and idiopathic hypersomnia. So, that incorporated three indications at a different time in the market. So, today, as we think about oveporexton and really focus on narcolepsy type 1, which are the patients who have orexin deficiency, where we believe we can have a significant impact by getting to the root cause of the disease, the forecast is really focused on narcolepsy type 1. I would say our understanding of the market and the disease state has also evolved in the sense that we have a better understanding of how to identify those narcolepsy type 1 patients, how they might be misdiagnosed over time, and kind of how big that market is. Actually, the opportunity for narcolepsy type 1 in our mind has grown compared to the last forecast. Because the asset has a narrower focus, that's the reason that the peak sales revenue is different. So, on the second question, what we are aiming for is to have a competitive pipeline in the therapy area that we have selected. And you will always have a mix of in-house product and in-licensed product. Of the six, we have presented two are in-house, for example, with the orexin and mezagitamab. And four are in-licensed. But make no mistake, we don't do any business development deal which does not create shareholder value. The return on invested capital is always very significant. We put the bar very high on what we buy or what we in-license. So, and without the research investment that we make on the development expertise that we have in the different therapy area, we will not be able to assess external compounds anyway. So, obviously, internal is great. Let's make no mistake. But what is important is to have a competitive pipeline which can allow to grow the company. And again, don't think that any business development deal or in-license is not profitable. Absolutely, it's absolutely not true. Especially when we do early deals where there is a lot of work still to be done, not only on the development side, but also often on the pharmaceutical science side. This any BD deal we do creates shareholder return. There is no doubt in that. Thank you. So, this is Yamaguchi for Citi. The first question is kind of a similar question which I have, but on the TYK2 side of the products. I think you used to say around $5 billion - $6 billion. So, the range is getting bigger and also a little bit of a lower end. So, can you give me, also, is there any change on the assumption of the TYK2 inhibitor at the moment compared to when you buy it like a few years ago? So, that assumption change. That's the first question. The second question is that those six assets which we continue to look at today, can you give me what is more on the blue ocean side or red ocean side compared to the competitor advantage? Don't say all blue. There might be some competition. Can you tell me which is more upside or competition? It looks like there is only one product there. Also, there are some second-class products. Can you give me the kind of, how to say, product competitive advantage from your side in the general comments on this one thing? Okay. Great. I think I understand the second question. So, but maybe Ramona, the evolution of our market forecast for zasocitinib from the deal till now. And then Christophe, do you want to talk about the relative competition or? I can. Yeah. Okay. Good. Good. So, you know, when we originally did the deal, I believe the way we had assessed the total value was looking at the initial indications that included UC and potentially Crohn's disease as well. So, we were looking at psoriatic disease plus at least one indication in inflammatory bowel disease as well. I would say since we've done that deal to now, our understanding and actually presence in this market has changed significantly in the sense that we've learned a lot more. We actually have a lot of people with deep experience in this area at Takeda, but we've also gone out and hired some people that have been able to join us and really help us understand. And so, now the focus is more on psoriatic disease and $3 billion-$6 billion. You know, the levers in that have to do with obviously the data that we see from our phase III trial. We're expecting that the data in our phase III trial is going to be similar to what we've seen in phase II and what we see in our analytical chemistry. Looking at the pace of growth of advanced therapies, which, as I mentioned, has actually helped if you have more orals on the market. Looking at the pace of growth of orals within that advanced therapy and growth of the overall market. It's really some of those growth levers that affect the overall forecast. And then something that we call preference share. How many patients will be choosing Zaso or physicians will be choosing Zaso first line. And we always use a range for that. So, there's a number of levers we use with the forecast that help us kind of identify things that we want to be doing to focus on to commercialize successfully. And that gives us a range. And as we get closer to launch, we have more understanding and we can be more maybe deliberate at letting you know what those levers are. But that's the main evolution, I would say. And so, today, we haven't given any revenue expectations yet for UC and Crohn's disease. But obviously, we feel very strongly about the potential for the molecule in those diseases. This is a market we know really well. We think there's a big opportunity here for Takeda. So, that's something that we're working very hard on now. So, on the question, I think behind there is a question like, are we too optimistic? Or, you know, that's what I mean we get to know each other after so many years, right? Well, first, I will say we are very conscious about the market condition. And if you look at the six assets, there are some like TAK's oveporexton, for example, or pharmaceutical. I think there is not much competition. The standard of care is very poor. So, it's all about being successful with the development, the approval, and then improving the management of that disease. It's often very underdiagnosed and undertreated. So, that's on one side. I think it will be up to us to really change the standard of care. And if they make it to approval on launch, it will certainly have a very strong market share because it's all about market shaping and, again, improving diagnosis. So, that's on one side. And then on the other side, you have a product like zasocitinib. It's very clear. It's a hyper-competitive market. So, here we need to be differentiated. We need to show that we have an efficacy profile for an oral which can redefine that segment. We will not be the only one. You mentioned J&J earlier. But we can be a couple of new generation of oral product. The key here will be to double the size of the oral segment. And we don't need to have a huge market share. And if you do the math, I think we have been quite conservative in our range overall. So, I think you have different market situation, either market shaping or market share and differentiation in order to gain market share. Every test set will be more on the market share side. There are already treatments. They are not perfect. We think we have a truly differentiated molecule here. And therefore, it can actually really change the standard of care as well. But there are already treatments available. Sorry. You say that narcolepsy and the orexin is a blue ocean, right? So. Did you say? Pharmaceutical. Narcolepsy and pharma are really where there is not a lot of treatment and we can, you know, we could be first and best in class. Zaso is really entering a market where the diagnosis is done, but it's all about coming with an improved treatment, for example. How about Rus? rusfertide? rusfertide? rusfertide? Yeah. Is it on the blue side or red side? I would say, you know, with rusfertide, and we see this in a number of diseases, we're really competing with phlebotomy, therapeutic phlebotomy, and so it's really working to eliminate phlebotomy. You can have the patients feel so much better while they're on this medicine, and so that's not unusual for us. Competing with the standard of care sometimes can be very difficult, actually, because the standard of care has become so entrenched. Physicians are so comfortable with them and so used to them. Sometimes, in a sense, competition helps us because it helps to change the treatment paradigm and it helps to stimulate growth in the class and in the marketplace. The access challenge is very different depending on the market situation, actually. Thank you. My question. I'm Akinori Ueda from Goldman Sachs. I have two questions regarding your narcolepsy franchise. So, the first question is regarding 861. So, in the context of the narcolepsy treatments, you know, the SOL or in the MWT seems problematic if it's too long or too short. So, TAK-994 indicated a stronger efficacy in terms of MWT. But what do you think about, you know, what level do you think like ideal for the clinical perspective? And also, you know, you indicated the cognitive function related data. So, you know, are such data sets important for considering the clinical meaningfulness for the treatment? That is my first question. And the second question is regarding the 360. So, what are the basis behind the first indication for narcolepsy type 2 under IH rather than type 1? So, do you think 360 will have a better profile in the narcolepsy type 2 rather than type 1 based on the preclinical data or something like that? Or is that mainly to separate it from the development of 861 in your portfolio? Thank you. That's great. Thanks. Maybe Sarah, the first question is about oveporexton on the effects that we're seeing on daytime sleepiness as measured by MWT. Perhaps you can comment on that, the importance of the cognition data that you shared. And then secondly, why are we pursuing type 2 narcolepsy in IH with 360 and not type 1 narcolepsy? Yeah. Thank you, Ueda, for the questions. So, you know, the MWT is a really artificial construct. And it's just one symptom of many. What we see with TAK-861 is normalization of function, okay? And that's maintained over the long term. And it's consistent and correlates across multiple different endpoints. Now, you can't really normalize a patient more than normalizing a patient, right? So, if you've reached normal, you can't get more normal in a way. And so, that to me is the most compelling argument that we have that we have an efficacious dose that also shows a very promising safety and tolerability profile, right? So, that's one. Now, how does cognitive function fit into this? You know, when we think about a treatment for a condition, you think about where's the unmet need in this condition. And we went through all the symptoms. Cognitive symptoms come out loud and clear as distinct from excessive daytime sleepiness. So, if you can normalize cognitive function, imagine what that'll do for patients. It allows them to work, to be productive at school, and to essentially get rid of some of the limitations they've had to set themselves in their daily lives at work and at home. I think this is really a key novel thing that we've been able to show with TAK-861. And it's going to help set the bar really high for this new standard of care. Did you want to add anything to this? No, I just wrote down your line, you can't get more normal than normal, because I think I'm going to use it in my marketing slide. That's great. So, your second question was about why didn't we go into NT1 with our follow-on compound, which is a next-generation chemically distinct, highly potent orexin-2 receptor agonist? And, you know, with TAK-861, we have over-indexed and we have such a compelling leading program in narcolepsy type 1. Let that horse run to the finish. Let those results come in 2025. And then, you know, let's file that very quickly and get that drug to patients expeditiously. The follow-on molecule lends itself to exploration in other populations. And we chose to go into orexin-normal populations led by sleep-wake cycle disorders, including NT2 and IH. And so, that's the reason. Focus with 861 and follow on with additional indications with TAK-360. Thank you so much. [Foreign language]. No, I'd like to take the final question. Just one question, please. Yes, Stephen Barker from Jefferies. I had a question about zasocitinib and your development program in IBD. I don't think you can disclose the doses that are being tested. But maybe you could just help us understand what problem you're trying to solve for. You've got the mouse data. I mean, it looks like at the high dose, it wasn't quite as good as biologic. Is that what you're aiming for? Something that's good but doesn't need to be biologics? Or are you more ambitious? Anything you could, any comments about your thought process that went into deciding those doses would be really helpful. Thank you. Yeah. I think it would be great to hear from both you, Chinwe, and you, Ramona, on how we've designed the rationale for the design of the phase IIb study and some sense of what the doses are. And then, Ramona, you can talk a little bit about the product profile that we're looking to achieve. Who's that? Please, Chinwe. Yeah. Okay. I think the way I'm going to answer your question is, why do we have faith that this will work in IBD, right? A number of reasons. You know, I'll start with what I described earlier, scientifically very strongly. The problem, as I've seen it, is that there have been others ahead of us who've had TYK2 assets that haven't worked in IBD. And that has created this feeling that TYK2 is not useful in this area. But my feeling is it's not the science that's the problem here. It seems to be the molecules that is the problem. And we happen to have a molecule that allows us to do something unique. We can give more. But you might say, why do you need to give more? You've shown me that you have excellent coverage by using 30 mg a day. Why do you need to dose more than that? And my response to that would be that we are not treating a disease in the blood. We are treating a disease in a tissue that is inflamed, grossly underperfused, and where there is likely a scientific reason to believe that you will be losing drug just because of the nature of tissue. So, you actually would need more drug in order to achieve that efficacy. So, if one can do that and take a step back, then what you've got, if it's successful, it's an oral once-a-day drug that can be used to treat IBD. And if the data is compelling, we won't know until we get the data. We can begin to imagine just how hard can you treat this disease with a rather simple, easy-to-administer medicine that can make a change for patients. That's what we're hoping for. I would say from a commercial perspective, Steve, you know, I mean, we obviously know this market really well because of Entyvio. The main goal here is going to be efficacy for this product. I mean, we want to come into the UC and CD market with a product that works and that shows efficacy. As Chinwe mentioned, is also safe and easy to use. At the same time, we know that with all the new medicines, even in the IBD market today, that efficacy ceiling has really still not been broken. We see more and more physicians starting to turn to various types of combination therapy in different types of patients for different reasons. We need to see the efficacy in phase II first. We need a molecule that is going to be efficacious on its own. But because of the safety and efficacy of the molecule, you know, based on the natural mutation that occurs in a healthy population, there is also the potential for combination therapy with this asset. And as we look at that data, that's something we're keeping our eye on to evaluate down the line as well. Thank you. Okay. Thank you very much. So, that brings the Q&A session to a close. Andy, anything you'd like to say at the end to close out the event? You know, thank you for the opportunity. I just thank you all for spending five hours here. We're very much looking forward to having a chance to interact with you informally. I'd just like to give a huge thanks to the team for the outstanding work that they did. I think that really came across today. Thank you all very much. With this, we conclude this event. Once again, thank you very much for joining us despite your busy schedule. For those of you who are in this venue, on this same floor outside of the doors, we have a reception. Please join us. Today's presenters will be there as well. Thank you. Another one. This venue will have another event from 2:00 P.M. Please make sure you bring your own belongings. Outside of these doors, there are some cloaks being set up. So, you can check in your belongings there. Thank you for your understanding.