Thank you for joining us today. We are excited to share with you our impressive TAK-861 phase II data that was presented earlier today at the Sleep Congress. This is Noby from Investor Relations. I'd like to take a moment to remind everyone how to set their interpretation settings. You'll see a globe icon at the bottom of your screen. If you'd like to listen to the call in English, choose English. If you'd like to listen in Japanese, please choose Japanese. If you'd like to listen to the original language in either language, please choose off. 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. Please also refer to the important notice on page 2 of the presentation. With that said, I'd like to hand it over to Andy Plump, President of R&D. Please go ahead. Thank you very much, Noby. I'm Andy Plump, the head of R&D here at Takeda, and I'm joined by Elena Koundourakis, who's the head of our Orexin franchise, by Christian von Hehn, who's the head of development for our Orexin franchise, and by Erika Gill, who's the head of Neuroscience, Global Product and Launch Strategy. We are very excited to be here with you today. As we discussed a few weeks ago at our fourth quarter earnings report, we have very strong pipeline momentum right now, and as we move into fiscal year 2024, we will have six new molecular entities in our late stage portfolio. Several of these already have ongoing phase III programs, and several have multiple indications. One of these six is our oral Orexin receptor two agonist, TAK-861, which we've previously shared with you, will begin phase III this year. We are in Houston right now at the Sleep 2024 conference, and as Noby mentioned, earlier today, our principal investigator, Yves Dauvilliers, presented results from our type one narcolepsy phase IIb trial for TAK-861. We're really looking forward to sharing those trial results, along with some additional context with you today. With that, Elena, I will hand it over to you. Thank you, Andy, and hello to everyone on today's call. It is a great pleasure to welcome you to discuss TAK-861 Phase IIb data presented this morning as an oral session. First, let's remind ourselves how we got here. Takeda has been working in the orexin field for quite some time, looking to address the underlying pathophysiology in narcolepsy, which is caused by the profound loss of orexin neurons in the brain, leading to orexin deficiency. Following the initial results with short-term therapy, TAK-925 IV in 2019, we were able to demonstrate the potential for an oral orexin receptor two agonist, hereafter referred to as an orexin agonist, to meaningfully improve sustained wakefulness and cataplexy with TAK-994, as published in New England Journal of Medicine in 2023. Unfortunately, we had to discontinue development due to some cases of severe liver toxicity. However, our deep understanding from this large dataset and experiences in the orexin field led to the accelerated efforts to develop TAK-861. We believe, based on the data we have today, that TAK-861 has the potential to be the first treatment for patients with Narcolepsy Type one, addressing the entire spectrum of disease symptoms. In addition to our efforts in NT1, we continue to address the needs in patients with sleep-wake disorders with normal orexin levels, such as Narcolepsy Type two, otherwise referred to as NT2, and idiopathic hypersomnia, IH. From TAK-925 data, we know that it likely requires higher exposures of an orexin agonist to provide potent and sustained pharmacodynamic effects. Therefore, we design new molecules like TAK-360 with unique chemistry and undifferentiated profile, initially focusing on the development in indications with normal orexin levels like NT2 and IH, leveraging our deep learnings from prior compounds. We're accelerating the development of TAK-360, now in phase I. Finally, we are continuing our efforts in the orexin field with the discovery and development of additional assets and tailored profiles, aiming to explore additional indications pertinent to orexin biology. Moving to slide five and coming back to NT1, there is a substantial unmet need for patients living with a severe debilitating disease. As you can see in the left panel of the slide, we know from published data and our own real-world insights, that most patients experience residual symptoms with the currently available therapies. The lack of adequate disease control has a substantial impact on school, work, and social life. Moreover, the disease requires polypharmacy for many of these patients as it does not address the underlying pathophysiology of the disease. Finally, the cost of the disease and the societal impact are not adequately addressed today. With all of that in mind, patients with NT1 need more as they report having inadequate wakefulness control, many comorbidities, and they often cannot function normally, which meaningfully affects their quality of life.... With TAK-861, we hope to deliver a treatment that helps patients to restore function, to re-rediscover life. Moving on to slide six. From our data, we know that orexin agonists have the potential to address the unmet needs of NT1, which is mainly characterized by excessive daytime sleepiness, EDS, cataplexy, disrupted nighttime sleep, hallucination, and sleep paralysis. We refer to these symptoms as the pentad of NT1. Today's oral presentations, and posters tomorrow, demonstrate TAK-861 potential to address the entirety of these symptoms in NT1. To date, no treatment has been able to address the full spectrum of the disease symptoms, because existing therapies are not addressing the underlying cause of the disease. Based on the discovery of Yanagisawa and Mignot, who were recently awarded the Breakthrough Prize in Life Sciences, we know that the cause of NT1 is the profound loss of orexin neurons in the brain. We also know that while the neurons are lost, the orexin receptors remain intact, providing a unique opportunity for a pharmacological intervention. By stimulating the receptors with a selective orexin agonist, we have the ability to modulate downstream neurotransmitter activity and restore wakefulness. This unique pharmacological action can lead to restoration of patient function and improved quality of life, as we have shown today with TAK-861 data. In slide seven, we would like to point out the complexity of the development of an orexin agonist to fulfill its great potential. Unlike our previous efforts with TAK-994, with TAK-861, we were able to now optimize the required profile for an oral orexin agonist to deliver on functional normalization and to restore the quality of life for patients with NT1, while minimizing the safety and tolerability events. Using highly sensitive methods developed by Takeda, we have been able to measure the natural fluctuation of orexin levels in cerebrospinal fluid in primates. We believe this primate model translates very well into humans. Orexin levels gradually increase during the day and fall overnight, about a third of the daily levels. However, they are not going to zero, suggesting that some level of orexin tone is essential for normal function. With TAK-861 twice daily, we think we were able to provide optimal coverage to ensure sustained wakefulness in the day, but allow for levels to come back to baseline orexin levels at night to minimize on-target pharmacological side effects, like insomnia. With its improved twice daily regimen, we believe TAK-861 has achieved the optimal balance between potency, pharmacokinetics, and safety, establishing the potential best-in-class profile. I will now turn over to Dr. von Hehn to walk you through today's data presentation. I will come back later to discuss the next steps for the Orexin franchise. Christian, over to you. Thank you very much, Elena, and thank you very much for calling in, and your interest in this exciting program. My name is Christian von Hehn, and I lead the clinical development of our Orexin franchise. I'm looking forward to walking you through our latest Orexin clinical data, starting on slide nine. Based on our extensive experience with other orexin receptor agonists and the TAK-861 phase I program, this phase IIb study was designed to assess the efficacy and safety of multiple doses and dosing regimens. Over an eight week duration, we compared placebo to four active dose arms, where three were dosed twice daily and 1 was dosed once daily. This study included patients with confirmed narcolepsy type one diagnosis, who in addition, were HLA genotyped and had confirmed low orexin levels. Before enrolling, any stimulants and anti-cataplexy medication had to be stopped. After the eight week period, patients had the option to continue TAK-861 treatment in a dose-blinded extension study. It was impressive to see that 95% of the patients who completed the phase IIb study chose to roll over, and the majority of patients remain in the long-term extension study, with our first patients passing 1 year of treatment, and we're looking forward to presenting this data at future congresses. On slide 10, I would like to come back to our phase II study and our key endpoints. To remind you, the unmet need in narcolepsy type one cannot be defined by a single symptom. There are multiple different symptoms during the day and night that narcolepsy type one patients are living with. This study investigated the effect of TAK-861 on multiple symptoms using several different endpoints. We will start here with our primary endpoint, changes on the Maintenance of Wakefulness Test, or MWT, as an assessment of objective wakefulness. And we will also show you our secondary endpoints, looking at, one, the impact of TAK-861 on the Epworth Sleepiness Scale as a subjective measure of sleepiness, and two, changes on the weekly cataplexy rate. Of course, we also continuously collected safety and tolerability data to fully understand the benefit risk profile of TAK-861. In addition to the data we are showing you here, we encourage you to also to look at our very consistent exploratory endpoints here at Sleep, as well as at future congresses. Slide 11 is showing that the study enrolled 112 narcolepsy type one patients evenly across the five arms, and only three patients discontinued the study, where one patient didn't meet the original inclusion criteria, the second tested positive for amphetamines during the study, and the third became pregnant during the study. No patient stopped prematurely due to adverse events or a lack of efficacy. As mentioned previously, this apparent treatment satisfaction was also supported by the very high rollover rate into our long-term extension study. With this start, we had a very good foundation to assess the efficacy and safety profile of TAK-861. Let me start to show you our efficacy data with the MWT on slide 12. The maintenance of wakefulness test lasts up to 40 minutes and is an objective measure of how long the subject can stay awake under quiet, sleep-inducing conditions. It is not frequently used in clinical practice, but it is important objective endpoint, commonly used for regulatory purposes. On the MWT, TAK-861 showed highly significant and clinically meaningful increases on sleep latency on all tested doses. The graph shows the mean sleep onset latency over the course of the study at baseline, at week four, and at week eight. At baseline, participants fell asleep in three to six minutes, which is in line with past reports for our NT1 patients. At week four and eight, all those arms approached or were within the normative range of what has been described by healthy individuals, whereas placebo patients remained in the range typical for untreated Narcolepsy Type one patients, and on average, are falling asleep within 5 minutes or less. We would like to highlight that the treatment effects were maintained consistently with no loss of effect over time. In summary, the MWT is an important endpoint, and we see patients reverting back to normal levels of wakefulness sustained over time. Turning next to slide 13 and to an endpoint more frequently used in clinical practice, the Epworth Sleepiness Scale, or ESS. The ESS is a patient-reported symptom questionnaire asking about the likelihood of falling asleep or nodding off in certain situations. For 8 different settings, like, for example, watching TV or sitting or reading, patients are recording a score from 0 to 3, where higher scores indicate a higher likelihood to fall asleep. The total score for healthy individuals for this scale is between 0 and 10. The baseline values show, again, balance between the treatment arms and are aligned with previously reported scores for narcolepsy Type one patients. Very consistent with our MWT data, the ESS showed highly significant and clinically meaningful decreases in sleepiness at all time points and on all tested doses. Over the course of the study, the average ESS score remained stable below a score of 10, and in the two milligram twice-daily arm, up to 95% of patients reached the normative range. In addition to excessive daytime sleepiness, Narcolepsy Type one patients can experience a sudden involuntary loss of muscle tone called cataplexy. Study participants recorded their cataplexy episodes daily in a diary, which then was used to calculate the weekly cataplexy rate. On slide 14, let me draw your attention first to the right. In today's presentation by Dr. Dauvilliers, you have seen the actual cataplexy values for each arm, where especially twice-daily dosing reduced cataplexy events close to a median weekly rate of zero. In addition, we also wanted to share how our primary analysis was conducted, shown in the table and forest plot on the left, and how the placebo response contributed to the primary analysis. Here, we are showing you the weekly cataplexy rate, incidence rate ratio, or IRR, relative to placebo at week eight. This rate ratio is the cataplexy incidence rate for the treatment arms, divided by the placebo cataplexy incidence rate. So a lower IRR indicates a greater improvement from placebo. As you can see, the twice-daily arms had the strongest reduction in cataplexy, with all three twice-daily dosing regimens showing statistically significant improvement compared to placebo. We have shown you what we think is very impressive efficacy data and would like to turn now to the risk profile of TAK-861 on slide 15. The collective reports of adverse events throughout the study are used to determine the safety and tolerability profile. Our eight week phase IIb study showed that TAK-861 was generally safe and well tolerated. The table provides a more detailed view for each treatment arm, highlighting the adverse event severity as well as the most common adverse events. Overall, more adverse events were reported by the participants treated with TAK-861. However, they were mostly expected on target events, such as reports of insomnia and urinary events. Most adverse events were mild or moderate in severity, and importantly, throughout the trial, no participant discontinued due to adverse events. Furthermore, most AEs occurred in the beginning of the treatment and were transient and self-limiting, resolving within one to two weeks.... No safety concerns were noted across all laboratory parameters, including liver function tests. We would like to highlight here that we have had no signs of liver, drug-induced liver injury or visual disturbances in this eight week APIC study or in our long-term extension study, with the first patients, as mentioned previously, passing one year of TAK-861 treatment. Let us briefly look a little bit closer at the time course of insomnia events on slide 16. We are illustrating here the number of patients over the duration of insomnia events for each patient. For most patients, these events started at the very beginning of the treatment. They were mild to moderate in severity and were self-limiting, lasting five days or less. For patients reporting insomnia for longer than five days, it is important to note here that none of them led to study discontinuation. Before we conclude the data presentation of our TAK-861 Phase IIb study in NT1, we would like to emphasize again that symptoms and disease burden of narcolepsy go beyond excessive daytime sleepiness and cataplexy. Slide 17 shows that we assessed multiple domains to really understand the impact TAK-861 can have on the full spectrum of narcolepsy type one symptoms and patients' lives. We have started today and will continue tomorrow morning and Wednesday morning during the poster sessions, to show additional data that show the improvement of functioning and quality of life, as well as overall treatment satisfaction. In addition to the data presented here in Houston at Sleep, we're looking forward to showing you additional measures and analyses, including data from our extension study at future congresses. Let me conclude the data presentation on slide 18. Looking at the totality of our data, we are very encouraged with the consistent results of TAK-861 addressing different narcolepsy symptoms. TAK-861 demonstrated statistically significant and clinically meaningful improvements across multiple objective and subjective endpoints versus placebo over an eight week treatment period. The majority of patients are within normal ranges for ESS and MWT, and the cataplexy rate is approaching zero in most dose groups. The efficacy profile is consistent across multiple endpoints, and it is sustained over the treatment period of eight weeks and beyond. TAK-861 was generally safe and well tolerated. No treatment-related serious adverse events and no discontinuations due to adverse events were observed. No cases of hepatotoxicity or visual disturbances were reported in the study or in the ongoing long-term extension study. In summary, TAK-861 has an optimized profile that balances efficacy and on-target, off-target adverse events. Based on the results, TAK-861 has the potential to provide transformative efficacy in addressing the overall disease burden in people living with narcolepsy type one. We are committed to initiate our phase III program rapidly in the first half of fiscal year 2024. With that, I'm turning back to Elena for closing remarks. Thank you, Christian. To close today's presentation, I would like to talk about the next steps for our exciting journey in the development of the orexin franchise. Following the very accelerated phase IIb development of TAK-861, and in consultation with health authorities, we will start phase III shortly. We believe the phase III trials will enroll quickly and hope to file in fiscal year 2026, 2027. As part of our regulatory package, we will include the safety data from our long-term extension study, which will be ongoing until approval. We're making great progress for our next generation, differentiated orexin agonist, TAK-360, that is already dosing healthy volunteers, with a goal to transition to start phase II later this fiscal year. We are initially targeting sleep-wake disorders with normal orexin levels, such as NT2, IH, that require much higher exposures than orexin-deficient population, like narcolepsy type one. Finally, we're continuing the discovery and development of tailored orexin profiles that have the potential to address diseases of high unmet need, where orexin plays a key role. As we follow the science, we are leveraging evolved digital technologies to help improving treatment diagnosis, and look to sustain Takeda's leadership in the orexin field for the years to come. With that, I would like to turn over to Noby to open the Q&A. Thank you. Thank you. We'll now open the call up to questions. If you'd like to ask a question, please raise your hand in the Zoom app. When you are called on, please unmute yourself and ask your question. If you have multiple questions, please ask all of them. Please ask your question in the language that your interpretation setting is set to. For instance, if your interpretation is set to English, then please ask your question in English. We will now go to the first caller. Yamaguchi-san, please unmute your line and ask your question. Yamaguchi-san from Citi, please go ahead. Hello, can you hear me? Yes, we can. Thank you. So thank you very much for taking my question, and congratulations for the great data. But, quickly, three questions. Our first question is that, how do you think about the dosage for the phase III? It looks like 0.5 mg twice daily and two mg twice a day. Both looks good, but, how do you think about your phase III dosage among those phase II data? The second question is that it looks like there are, insomnia cases you mentioned too. In the future, are you going to, just wait for the people to go out, insomnia to go away, or do you think about using, medications to treat the insomnia if it's happening, that's the in a practical way in the future? Then thirdly, on a competitive landscape, there are other kind of companies, orexin agonist companies, which kind of showing better in the MWT. But how do you think about competitive landscape? I think the totality might be important, but the MWT itself, sometimes there are higher MWT data has been reported to date. Thank you. Thank you very much, Yamaguchi-san. So maybe, Christian, we'll start with you. And just to again describe the nature of the insomnia events that we're seeing in the phase IIb study, so there's a clear understanding of the severity of the finding. And then, Elena, if you could talk a bit about the phase III program, the competitive landscape as well. Thank you. Thank you, Andy, and thank you very much for the question. So for the insomnia, I would like to highlight again that the insomnia events that we observed here, the vast majority happened within the first five days, so very early in the treatment. They were mild to moderate, and none of them required any medical intervention. I think it's also important to point out here that the vast majority of patients enrolled and chose to enroll in the long-term treatment extension. It was an option that patient could decline. It was not mandatory, obviously, but 95% chose really to do, to do it because of the efficacy and safety profile. So we feel really that, with this optimized efficacy and safety profile, we really have a very good balance for a long-term treatment that will keep patients on treatment. So, to take your question, Yamaguchi-san, on the dosing for phase III, first of all, as I mentioned, we are in a discussion with regulators at the moment on the phase III design, so it's a little bit premature to comment the exact dosing regimen for phase III. I would like, though, to highlight a few points about what you reviewed today and maybe emphasize these data results, to put them into the context with our own experiences with orexin and future compounds. First of all, when we try to balance the optimal profile, we look for several aspects in efficacy, objectives, subjective measurements, wakefulness, cataplexy, safety, tolerability, and as we reviewed today, a number of subjective measurements, exploratory endpoints that tailored the quality of life for patients, including the five symptoms of narcolepsy, the totality of the symptoms. So we learned a lot from 994, and we know that this is difficult to provide the optimal profile. So we are very encouraged by the data that we reviewed today, and we will continue reviewing in sleep as well as future conferences, that we have really many ways to optimize the profile and many doses at our disposal. So I'm very confident that we're going to pick the right dose. While it will be premature to comment on what will be the final dose in phase III, I will say that based on the profile we were looking, we think that the BID dosing that provides, if you like, the coverage throughout the day and the night, has done the best in our phase III trial. So we are very confident that we have a very good profile to bring forward to phase III, and look forward to share the details. With regard to the competition, you know, we are obviously very encouraged to see the class advancing many options for patients with sleep-wake disorders. That is definitely very promising. However, for many compounds, these are early days. I think day one data where what has been reported by competitors unlike our large data set where we have been able to demonstrate MWT over eight weeks of treatment and we continue monitoring efficacy in long-term study which we will report in future conference. So we're quite encouraged about the fact that our efficacy reaches normal levels both on MWT and ESS and, most importantly, that the effect consists up to eight weeks and beyond. So we believe we have the most robust profile at the moment with the potential not only to be the first treatment for narcolepsy but also the best in class. Thank you for your question. Thank you very much. Thank you. Our next question comes from Michael Nedelcovych of Cowen. Mike, please go ahead and unmute your line and ask your question. Great. Thanks for the questions. I have a couple. My first is, do you have a hypothesis as to why insomnia apparently is transient, whereas efficacy is persistent? One might assume that both are driven by on-target mechanisms, but maybe that's a bad assumption, so I'm curious your hypothesis there. And then, I know that you have solid efficacy on cataplexy. I'm curious, do you have any data suggesting that cataplexy specifically triggered by emotionality is also affected by TAK-861? And then finally, one more question on the phase III design. Do you have an established primary endpoint and buy-in from the FDA, or is that more of an ongoing discussion for a pivotal trial? Thanks, Michael. Christian, why don't you take the first two questions on speculating why some of the tolerability issues seem to be transient, whereas the efficacy is persistent? And then the second one was around cataplexy, and then, Elena, if you could take the question on the phase III discussions with regulators. Thank you very much. Yes. So with insomnia, as I mentioned before, we have seen events in the very beginning of the trial, and the vast majority stopped after five days or so. So why exactly we see this pattern is something that I can speculate, but obviously we don't really have any data. But I would like you to keep in mind that these patients have not seen any orexin receptor two stimulations, often for decades. So with that in mind, it could be a receptor adjustment, and then afterwards, it goes into normalization. What I mean by that is that throughout the trial, we also looked at nighttime symptoms, something that we have not shared yet, but that we're looking at very carefully, and have multiple endpoints in the trial where we are looking forward to publishing it in future days. So for example, at the NSSCT publication today, the presentation today, for the Narcolepsy Severity Scale, there were questions about disturbed nighttime sleep in there, who contributed to the total score. As you heard today from Dr. Barateau, that results are extremely encouraging. So far they have not seen results like this with any other agent. With that, I think we are very encouraged to treat the narcolepsy spectrum as a whole, and I'm looking forward again to sharing these results in the future. Oh, sorry. Go ahead, please. No, I just did. For cataplexy, the question, if I understood correctly, was whether or not the cataplexy events also were triggered by emotional events. So the patients, we actually write that patients with narcolepsy suffer from cataplexy that are often triggered by emotional events. In our study, patients had to wash out from all medications prior. When they started the medication, the TAK-861 treatment, there may have been a short adjustment period. However, what we heard from treatment satisfaction questionnaires, again, data that we will present tomorrow, we have throughout heard that they are highly satisfied with the treatment, how much it changes their life, how much they can participate in society, something they could not before, because the symptom, exactly as you said, like, for example, that they needed to control their emotions, that they were sustaining from societal events. So, again, I encourage you to look at the posters tomorrow and at future congresses, but it's very, very encouraging from my end. So before you jump in, Elena, maybe Christian, because I don't think you actually presented any data on the narcolepsy symptom score. Maybe you can just quickly describe what that is and summarize the data that was presented, because it's quite meaningful. Yes. Thank you. Thank you, Andy. So at today's talk and slides we did not include, but I think are in the end of the slide deck, there was a presentation about the Narcolepsy Severity Scale, which is to date the only scale that assesses the overall narcolepsy symptoms, the whole panel of symptoms, which includes excessive daytime sleepiness and cataplexy, the data that I presented today to you as well. But it also includes questions about nighttime symptoms, such as hallucinations, sleep paralysis, and generally disrupted nighttime sleep. And the total score of all these five symptoms is then presenting as a total, and it was presented today. Even when you parse out something that we have not shown yet and will present at future congresses, the data look encouraging, and each symptom seems to contribute to the massive effect that we have seen on the scale. But it's again very promising. We're very, very encouraged. Yeah, and with regard, Mike, with regard to the question on the endpoints for phase III, with just to go back to what Christian presented, we have been really very, very fortunate that we've shown consistent results across all the endpoints, both objective endpoints like the MWT, as well as subjective endpoints like ESS, the cataplexy weekly cataplexy rates. And we have included a number of exploratory endpoints, like the one that Christian just described, that encompasses all the symptoms of NT1, and we have additional quality of life endpoints. So while the MWT is a regulatory accepted endpoint in certain with certain authorities, all of these endpoints we believe capture the needs of patients with narcolepsy type one. Based on the encouraging results of phase II, we would like to proceed with many of these endpoints in our phase III trials, because our hope is to replicate the profile and provide an optimal treatment that cover all symptoms of NT1. We plan to bring all of this forward, but again, we are in discussion with regulators, so we have to share the design when these discussions are complete. Thank you for your question. Great. Thank you. Thank you. The next question comes from Matsubara San at Nomura Securities. Matsubara San, please unmute and ask your question. Thank you very much. I'm Matsubara from Nomura Securities. Can you hear me okay? Yes, we can. Thank you for this opportunity. I'd like to ask you, how do you compare yours with Alchemist? MWT baseline, 34 minutes, is shown by eight milligram. I understand that this competitor's compound data is limited in N numbers. However, looking at their MWT results, what is, you know... How do you comment on this, please? Elena? Yeah. This is a very important question as we see the class evolving. Remember, however, that we have made a lot of experiences with multiple orexin agonist, starting with TAK-925, where we have also reported an MWT, very similar at day one, like the Alkermes data. And as we progressed over time with TAK-994, and now with TAK-861, we believe we see very similar results. However, I would like to remind you that narcolepsy type one is a chronic disease. In other words, patients need to be treated over a long period of time. So what we learned with TAK-994, with the oral orexin agonist, and now we see with TAK-861, is that it requires really a sustained efficacy over eight weeks, to hopefully replicate what it would be needed, for patients, in real life. So we're very encouraged by the data that we have presented today, eight weeks data with sustained improvements, both in the objective measurements of MWT, which brings patients to normalized ranges, as reported by Professor Dauvilliers at this morning session, as well as consistent results in the subjective ESS, WCR, and additional exploratory endpoints. So the totality of the data suggests that this is a very suitable profile to be used for chronic administration to address the entire spectrum of patients with narcolepsy type one. Thank you for the question. Thank you. Next question is from Yamakita-san. Is that you, or perhaps it's Steve Barker on the line from Jefferies? Please unmute your line and go ahead. Yes. Thanks. This is Steve Barker from Jefferies. I had a question about the dosing regime. Some other candidates being developed, they're working on once per day. Yours, well, it appears that twice per day seems to be a likely candidate for phase III development. You preface the slides on the with some data, animal data, which seem to indicate that twice per day might actually provide more flexibility to optimize the dose. Would you perhaps comment on how twice per day might compare to once per day, and why one or the other might be preferable? Thank you. Elena, take that? Yes, Steve, thank you for the question. You know, we have tested obviously also in our take, TAK-861, phase II study, both the BID and QD regimen. We've done this on the, if you like, back on the experiences we have had with the class from the TAK-994. We tend to believe that mimicking the – the natural fluctuation of orexin is the better way to treat the disease. And what I tried to show, you know, based on the monkey results, which we believe it's applicable to humans, there is this increased sleep pressure throughout the day. And this is where you need a profile like the TAK-861, where basically you optimize the coverage needed throughout the day. But then you don't want this to be too high, at the end of the day, because you want these patients ideally to go back to sleep. So the levels of TAK-861, you know, fall, if you like, in the later in the evening, and that allows patients to go to sleep. So we achieve this profile with the way we dose the trials with twice daily. You know, in the morning, you take the doses in such a way to avoid, if you like, high exposures in the night. We model this actually very carefully based on all our experiences, and I think the profile that you show with the clinical data show that we have really an optimal coverage in efficacy across objective, subjective endpoints, and safety and tolerability. So, we remain obviously interested to continue exploring the PK/PD profiles to optimize the diseases. But for Narcolepsy Type one, I think we have a very clear dosing regimen, which we showed works very well, pending, of course, confirmation of these results in upcoming phase III studies. Thank you. Thank you. Thank you. Our next caller is Miki from Bernstein. Miki-san, please unmute your line and go ahead. Thank you very much for taking my questions. I have two questions. So first of all, you know, the TAK-861 efficacy does not appear to be dose dependent. So, you know, I'd like to understand your hypothesis, you know, of why this is the case. And then secondly, your positioning of the new molecule, TAK-360. So do you... So we understand, you know, this is a very chemically, structurally different end product from, you know, 861. But do you consider it as a superior orexin the receptor agonist in terms of, you know, the balance between the efficacy and the safety? Also, if that's the case, you know, is it really only for narcolepsy Type two and IH, or is it also, you know, that you're considering the potential, the narcolepsy Type one as well? Those are the two questions. Great. Thanks. Thanks, Miki. Maybe, Christian, you can take on the question around dose dependency and the of 861 in the phase IIb trial, and then, Elena, you could talk a bit about how we, how we look at 360 versus 861. Thank you very much. So for the dose dependency, I mean, what we've seen here in the data is that the 0.5 twice daily doses did not perform as well as, for example, the two mg twice daily, or 2.5 mg twice daily. So there are, I would say there is a certain dose response. However, particularly for the week four and week eight, where we see the sustained effect, the higher two twice daily doses are approaching levels that are in the normative range. There's not much more we can improve in patients if they're in the normative range. They're going almost as high as they can. So, there is a potential for a certain ceiling effect for the MWT. Similarly, with the ESS, I would make the same argument here, where you can see that patients are far below below 10. They cannot go lower than than 5. There is a certain certain effect, again, a ceiling effect, how well they can do. When 95% of the patients are approaching normalcy, or 81% of patients are approaching normalcy, I think in that regard, we are at a very good place where we have achieved that we are normalizing patients for wakefulness, for sleepiness, and again many other endpoints that we are looking forward to sharing with you. Overall, we're very excited that how well, particularly the two BID doses, so the three BID doses or two higher BID doses, really perform, and are very excited about it. Miki, with regard to your question about the TAK-360 and the positioning. So we know from, as we reviewed earlier, we know from our TAK-925 data that for indications like NT2 and IH with normal orexin levels, we require a different profile really, to provide this optimal PK/PD, which is different than what we described for TAK-861 with relation to NT1. So therefore, we have really designed, if you like, our next generation molecules, TAK-360 being the front runner here, to provide that ideal profile. Particularly, we look to understand as to whether an orexin agonist works in NT2 and IH the same way as it does in NT1. And we're very, very interested in understanding the sustainability of effect over a longer period of time. With that in mind, we designed TAK-360 to have, if you like, this flexibility in terms of chemical structure, PK/PD, to be able to optimize the profile. So these are early days, so we just started healthy volunteers studies. We hope to progress into patient trials quickly based on the learnings from past compounds. It is premature to speculate which indications we're going to bring this forward, but obviously we look to optimize as with every profile in the orexin franchise, to find, if you like, the optimal indication with the tolerability profile. And we are happy to report on these exciting compounds in the R&D meeting, hopefully later in the year. Thank you. If I may, Elena, maybe, Miki, I can add, because I think that there's an undertone to your question of, is TAK-360 a better molecule than TAK-861? It's not. TAK-861 is a fantastic molecule, and it's played out in the data that you're seeing here. We designed TAK-360 based on a number of parameters that we think will be important in treating patients that have sleep-wake disorders that are characterized by normal orexin levels, like NT2 and idiopathic hypersomnia. TAK-861 is an outstanding molecule for type one narcolepsy, and to just, you know, dial up to everything that Christian said, it's not clear that you could have a better molecule for type one narcolepsy. You know, when you look across all of the different symptoms of type one narcolepsy, we're either normalizing or coming close to normalizing essentially every parameter. Today, there were presentations on patient reported outcomes, known as the PGI, or clinician-reported outcomes, known as the CGI. These are indicators for how a clinician thinks a patient's doing or how a patient thinks they're doing. And you'll have to go back and look at these data, but the vast majority of patients are normalized in terms of how they feel or how a clinician feels that they're doing. Now, there is a question of whether a once-a-day dosing can hit the same efficacy and tolerability profile that TAK-861 has. I think that's still the question. You know, based on everything we know of the biology of orexin, we think that that's going to be a tough needle to thread, and we'll of course see. But regardless, we don't think that there is much room for a better profile in type one narcolepsy than we have with 861. Great. Thank you very much. Thank you. Our next question comes from Wenjing Li of SpringHill. Wenjing, please go ahead and unmute and ask your question. I think you're still muted, Wenjing. Okay, the next question will be from Haruta-san at UBS. Haruta-san, please go ahead and unmute and ask your question. [Foreign language] Haruta from UBS. Do you hear me okay? Yes. Yeah. MWT, regarding 861, compared to Q 4, the latency may be shorter, but it works too much, then too much wakefulness. That is also a possibility. So optimal level is also very important in terms of MWT and 861 showed good efficacy within treatment in phase III narcolepsy. treatment, goals, what is it? Endpoint should be within the normal range. Is that going to be the goal for treatment for eight six one? That is the first question. The second is orexin franchise potential in the, wave one, wave two program in the past, NT1 potential about $3 billion or higher, and orexin as a whole, $3 billion-$4 billion. What's your assessment on this point now? Thank you so much, Haruta-san. Maybe, Erika, you can talk a little bit about the target product profile and the expectations that we have in phase III, and then a bit about some of the market. Great. Thank you so much for the question. So we designed the target product profile really based on the significant unmet needs for people with narcolepsy. And as you heard today, we've actually demonstrated that across subjective and objective criteria. So it's very important for us that ultimately, at the end of the day, this is intended for a person, a person who's interested in being able to function at school and in their job and have productive relationships. And so our goal is really to return patients to normal. So that's what we're hoping to do with TAK-861. Maybe I can share a little bit more about the market and what we're thinking about. So, as I talked about and, as the team has shared today, that, we've really learned so much more about the unmet needs for people with narcolepsy type one. Globally, this disease is underdiagnosed, underappreciated, stigmatized, and treated suboptimally. These patients' stories this year, this week, have been really profound. As we think about the market, there's really three numbers I want you to consider. First, diagnosis rates, second, treatment rates, and those patients still experiencing residual symptoms despite standard of care. So let's walk through the prevalence and diagnosis rates. The population prevalence for narcolepsy type one in major global markets is about 680,000, with 120,000 in the U.S. Diagnostic rates vary, but as I mentioned, this is significantly underdiagnosed. In the US, it's about 50% and much lower outside the US, between 30%-50%. From a treatment rate perspective, it's actually the highest in the US and Japan at 75% and as low as 40% in Europe. In the US, 60% of the patients are on polypharmacy, with over 80% of patients still experiencing residual symptoms. We're pretty excited about this opportunity to advance TAK-861, with the potential to impact the disease holistically and also make an improvement in diagnosis. We believe these two together will grow the market. I've shared with you these possibilities from a market perspective, and for the Takeda team, we're incredibly excited about the possibilities for people with narcolepsy. Thanks so much for the question. Thank you. Next question is from Macquarie. Either Franda or Tony, I believe it's you. Please go ahead and unmute your line and ask your question. Hi, this is Franda from Macquarie. I am asking questions on behalf of Tony Ren. Yes, please go ahead. Yeah. We have one question. Could we have a better understanding of the pathological difference between type one and type two narcolepsy? As you mentioned that type one patients lack orexin, whereas type two patients generally have normal orexin levels. Yeah, that's my question. Thanks. Elena, would you like to talk about the pathophysiology of the two diseases? Yes. Thank you for your question. So just to recap, the role of orexin is much better understood in narcolepsy type one, which is characterized by the profound loss of orexin in the brain. And this has been reported by Yanagisawa and Mignot, as we discussed earlier in the presentation. The role of orexin in what we call population with normal orexin levels is not as well understood. The levels of orexin are a little bit more variable in these diseases. Narcolepsy type two and idiopathic hypersomnia are somewhat overlapping. The orexin levels are also somewhat different between the two diseases. These are heterogeneous populations with which share some symptoms, but they are different in other ways. So, the role of orexin agonist in those diseases is not as well characterized as it is for NT1. So for NT1, we have established, the role of an orexin agonist, promoting wakefulness by restoring, if you like, the biological function of a loss of orexin. We showed this in TAK-994, and we now show it again with TAK-861 over a long period of time, eight weeks, and we're continuing looking the sustainability of that response in longer periods of time in long-term, extension study. We have not shown, us or competitors, the effect, of an orexin agonist over a longer period of time for, an orexin agonist in narcolepsy type two or IH. We have had reported previously effects of TAK-925 IV in NT2 IH after single-dose administration. The data were very encouraging, were very comparable to what we have seen with TAK-925 in NT1. However, these are single-dose studies, and we cannot extrapolate the findings from these studies into long-term administration. Therefore, we would like to start with our next generation compounds, those longer-term phase II studies in patients with narcolepsy type two and other normal orexin level indications to understand the profile that is needed to cover, if you like, these indications. I hope this answer your question. Great. Thanks. Thank you. Our next question comes from Stephen Barker at Jefferies. Please unmute and go ahead. Yeah. Hi, yes, Stephen Barker. Thanks for taking my second question. I wanted to talk about safety, and, in particular, I wanted to talk about, visual disturbance. I think I'm correct to say that you haven't, observed, visual disturbance, with 861, but it is something that's shown up with, other compounds. If you could comment on how serious that could be, and, and what- why haven't you seen it with 861, and, do you think it's a, an on-target effect or, or an off-target effect? Thank you. Christian, you want to talk a bit about visual disturbances? Yes. So with TAK-861, we have a very optimized benefit risk profile. We have no reason to believe that there's a mechanistic connection with visual disturbances and the orexin receptor 2. But to be honest, I'm not in a very good position to speculate here because we had no reports or complaints of visual disturbances. So neither in our phase II study, where we had 112 patients, nor in the ongoing long-term extension study, where we have patients now that are passing 1 year. So, in our view, we don't think it's an on-target effect, and we have not seen it. Great. Thank you. Yeah, thank you very much, Steve. Thank you very much. We're coming up to time. I'd like to thank my colleagues, Christian, Erika, and Elena, and I'd like to thank all of you for joining us. We'll look forward to getting our phase III program started as soon as possible, and as we've mentioned before, we're planning an R&D day for the end of the year, where we can do a much deeper dive into the program, the timelines, and unpack some more on the market potential. Thank you very much. Thank you. That concludes our call.