Takeda Pharmaceutical Company Limited (4502) Earnings Call Transcript & Summary

[Foreign Language] Good morning. At this time, we would like to begin the event. I'll be moderating this session today from Takeda IR. My name is Iwamuro. Thank you for joining us. [Operator Instructions] Yes, we'd like to begin the session. Before we start, I'd like to remind everyone that we'll 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 today's presentation. Now I'd like to begin the event. First, maribavir, soticlestat, and Orexin presentation will be done by our Takeda's development team. We'll be using the presentation material that we provided the other day. I hope you will have it on hand. We will begin with the presentation on maribavir. [ Sano-san ], please.

Thank you very much for the introduction from Takeda. I'm in charge of Japan development of maribavir. My name is [ Sano ]. I'm going to talk about posttransplant CMV infection. And this transformative compound, maribavir, TAK-620 will be discussed. Please refer to the slide. As you can see, this is focusing on posttransplant CMV infection. As you can see, after the infection -- I mean the transplantation is a very important procedure to be given to the patients to save their lives. 190,000 people are saved every year with transplantation. So transplant failure is going to be fatal for the patient as it is going to lead to social loss. So failure of the transplantation may be caused by CMV, cytomegalovirus. About 1/4 of the transplant recipients will be impacted by CMV. And with the infection, it may lead to graft loss, morbidity and mortality. Therefore, clearing CMV helps preserve life-saving benefit of transplantation. And under such an environment, we are working on developing maribavir. Maribavir has a novel MOA and has improved safety profile. This is a new oral antiviral drug, which is under development. And we have strong clinical data, including outstanding Phase III trial results, which I will talk about later. And this has potential to transform management of posttransplant CMV infection. So it can become a game changer. And with that high expectation, we are continuing to develop maribavir. Takeda plans global filings in 2021 and onwards with the goal of bringing maribavir to patients. Please refer to Page 14. With the transplantation, immunosuppression is both necessary and challenging. As you know, with transplantation, there may be some rejection. And it is very important to ensure transplant success. So this -- with immunosuppression, infection risk will increase, and it can lead too deadly infections. As I have said earlier, CMV is one of the risk post transplantation and infection is dormant like chickenpox virus until immune system is compromised. Many people do infect this virus by adulthood. But under immunosuppression environment, the dormant CMV may be reactivated and make infection, and that is the challenge we are facing post transplant. Next slide, please. Now I'd like to talk about the CMV infection using this slide. On the left-hand side, with the CMV infection, if it goes untreated, it can close pneumonia, and it may impact hepatic and also nephrology areas. And with CMV inflection, when -- if it get progress, it has a negative impact on the immune system. And for posttransplant patients, it may lead to graft rejection or GvHD, graft-versus-host disease, and fungal/bacterial co-infection risks are elevated as well. And as you can see here, posttransplant CMV infection more than double the risk of transplant loss, mortality and total cost of transplantation that has been reported. Please move on to the next page. I may be repeating myself, but with this slide, I am going to talk about the unmet needs against the anti-CMV agents. As I have mentioned earlier, with transplantation, immunosuppression is a very important factor. But if there is a weakening of suppression, there will be rejection of the graft and also other infection may be caused, for example, and GvHD can result. But if immunosuppression is still strong, there will be other challenges that we'll be facing. So with the CMV infection, looking at the treatments available today globally, we can say that there is no approved treatment options. There are no approved options for the treatment. And antivirus drugs are used as treatment. But when it comes to anti-CMV agents, of course, there is no approved options. And therefore, other treatments, it may cause other diseases. And of course, if the antivirus treatment is insufficient, it can lead to death or loss of the graft. So in the medical environment, they are faced with very difficult trade-off. With that background, as I mentioned earlier, the anti-CMV agent, there is a clear unmet need for such an agent. And that is the reason why we are continuing to develop maribavir. So this is a very busy slide. But with maribavir, this is MOA and you can see the life cycle of the infection regarding CMV. On the left-hand side, you can see the life cycle of the infection that is related to CMV. In the blue boxes, these are the existing treatments that is provided. But the existing treatments works on the DNA replication. But maribavir, as you can see, with the red arrows, it works on multiple sites. The 3 sites are shown here, so with the DNA replication, DNA maturation and also the egress of viral capsids. I think these are the areas in which it works. So with this novel MOA, virus clearance can be expected. And because it has a novel MOA, which is different from the existing treatments, it has efficacy against drug-resistant CMV. That is the expectation we have towards maribavir. Please move on to the next slide. So now let's take a look at this. This is looking at the major milestone of the development of maribavir. In 2011, and after 2011, in the U.S. as well as in Europe, we have had orphan drug designations granted. And also in the U.S., in December 2017, we obtained breakthrough therapy designation. As you can see from here, we have conducted many studies. Some of them completed and others ongoing. More than 1,500 patients have been administered with maribavir. So this is really an enormous amount of data providing a very good safety profile of maribavir. Next, please. So let's take a look at the Phase III trial design of the study as well as the results with the next several slides. First, let's begin treatment-resistant and refractory CMV infection. Phase III trial was conducted, and let's take a look at the results. In this study, maribavir, a primary endpoint and secondary endpoints were achieved. And we are looking at the overview of the design of that study. First, the comparator -- excuse me -- the population, second line resistant or refractory CMV infection, and solid organ and stem cell transplant patients both were enrolled. And the treatment duration was 8 weeks. And it was an open-label trial. And maribavir 400-milligram BID was dosed, and it compared with the existing drugs at the investigator's discretion with the randomization rate of 2:1, and we tested both efficacy and safety. On the left-hand side, at the bottom, we see the primary endpoint of this study. This is a confirmed clearance of plasma CMV DNA clearance or CMV viremia clearance at the end of study week 8. So CMV viremia clearance was the endpoint. And on top of the primary endpoint, we have the secondary endpoint and this is about achievement of symptom resolution or improvement in patients with symptomatic CMV at baseline or maintain asymptomatic state through week 16. Next slide, Page 20, please. So what we are looking at here is this resistant/refractory CMV patients study was conducted, and we're looking at the overview of the data obtained so far. My emphasis here is that this trial was a large global trial. That's my message. More than 100 sites were there and more than 352 transplant recipients were tested in this study. As you can see from the second point, we were able to collect data from the broad transplant population. Both solid organ as well as hematopoietic stem cell transplant recipients were enrolled. And this was a study for resistant. But not only that nonresistant CMV patients were registered. So both types of the population were enrolled. And as for other parameters, we were able to have the study in the very well balanced treatment arms. And as you can see from the last point, which is a little bit about the results. So compared to conventional antivirals, maribavir had twice or more patients completed 8 weeks treatment without any problem. So this means the high probability of maribavir being demonstrated or suggested, rather. Next, please. And so from now on, I'd like to talk about efficacy of maribavir. So first, this is about the primary endpoint results. So compared to conventional therapies, maribavir has showed a significant result in terms of viremia clearance. And this is clinically meaningful. At 8 weeks after the administration, CMV clearance, in the conventional treatment, which is shown to be IAT, it was 23.9% only. However, in maribavir, it was 55.7%. That was the clearance rate. If you compare to IAT, this is twice as much or more better results. And as for these results, in broader subgroups, we were able to see the same trend, very high efficacy, both in SOT as well as in hematopoietic stem cell, twice or more efficacy was shown. And also in resistant patients as well as in symptomatic CMV patients, we were able to confirm a quite high efficacy. So across different subgroups, we were able to demonstrate quite high efficacy of maribavir. Next slide, Page 22, please. So this is looking at secondary endpoint. After 8 weeks, this is at week 16, which is 8 weeks after the treatment was over. So even 8 weeks after the treatment completion, in terms of the viremia clearance as well as the symptomatic control, we were able to show a superior superiority of maribavir. So in this slide, let's take a look at the safety data of maribavir. So among the conventional trials such as foscarnet and cidofovir and ganciclovir and et cetera, they have toxicities. We have 2 points. On the right-hand side, ganciclovir causes neutropenia post transplant. And this is considered to be an independent risk factor for mortality. As for foscarnet, one of the important side effects is known to be acute kidney injury. And this is a problem that is often seen after bone marrow transplantation, and this is highly related to mortality. On the left, among the ganciclovir and valganciclovir and foscarnet were used for some of the patients, and as known, we have served neutropenia and acute kidney injury among those conventional treatment with quite high ratios. As you can see in the red box in maribavir, those quite severe toxicities were not seen in the maribavir arm. On the other hand, often seen adverse events in maribavir is at the bottom, which is taste disturbance. But this taste disturbance was just transient in many of the patients, and it was just mild and it wasn't close of discontinuation of treatment in most of the cases, meaning that maribavir has been confirmed to be very safe as well as a very tolerable drug. Next, please. So so far, we've been looking at the latest data for resistant and refractory transplant recipients. So as for maribavir, apart from the secondary treatment, refractory and resistant patients, we have been accumulating evidence on maribavir in other patients. This is a New England Journal of Medicine. This has been published already. SOT and after stem cell transplant, this is about the primary treatment of maribavir and a very favorable clinical data has been obtained according to this, meaning that not just for resistant/refractory cases, but also for other types of patients, maribavir has been accumulating a lot of evidence. Next, please. As has been said, we -- based on the Phase II trial data, and -- we have the design for the clinical trial that is ongoing right now. In hematopoietic stem cell patient post transplant, this is the first-line maribavir trial. Aurora trial, which is a Phase III trial that is ongoing right now. So this is a first-line CMV infection patients. And this is a treatment duration for 8 weeks. And this is a trial double-blind and 400-milligram maribavir BID is given compared to VGV as a comparator, valganciclovir. And this is quite a large trial with more than 550 patients to accumulate further evidence with this drug. And with these results, we would like to have a potential approval in fiscal year 2022. Page 26, please. So this is a summary slide for maribavir. There are 4 focuses when it comes to development of maribavir. First, transplantations are extremely precious life-saving treatments. This is what we'd like to emphasize here. And this is a very important treatment. However, there is a threat that is CMV infections. And, it may have devastating consequences for the patient. So CMV infections, there are no currently available antivirals for treatment of CMVs. With the antivirals variable at the moment, they may be toxic or develop resistance, leading to treatment failure and trade-off, which is difficult and risky, may be forced upon the physicians managing CMV. Takeda is developing maribavir and it is an exciting new oral anti-CMV agent with a novel multimodal MOA and improved safety profile and strong clinical data across a broad spectrum of patients with posttransplant CMV infection. So it may have a very strong impact. It may become a game changer in the management of posttransplant CMV going forward. With that, I'd like to end my presentation on maribavir. Thank you very much for your attention.

We would now like to move on to Neuroscience strategy. [ Nonomura ] is going to present the soticlestat presentation. Thank you.

Now we'd like to move into the neuroscience territory. We would like to introduce you to 2 transformative medicine for Neuroscience Japan. My name is [ Nonomura ]. Nice to see you all today. Today, I'd like to talk about soticlestat and Orexin. These assets were discovered in Shonan. And they are very important compounds in the Wave 1 pipeline of Takeda. Now I'd like to talk about soticlestat. Please turn to Page 39. Soticlestat works on Dravet syndrome and Lennox-Gastaut syndrome. And soticlestat was discovered at Shonan and Phase II study was done under the partnership with Ovid. And global development and commercialization rights were gained from Ovid by Takeda last month. When it comes to soticlestat, there are 3 focuses: first, potential first-in-class therapy. And second, it is a promising option for patients and caregivers. I would like to talk about the POC study, ELEKTRA later on this point. And number three, Takeda has leveraged capabilities to develop and commercialize globally. So I'd like to step back and first talk about the disease itself. Please turn to Page 40. First, about Dravet syndrome. Dravet syndrome is a rare genetic epilepsy associated with developmental delay. There are about 10,000 patients in the U.S. and 3,000 here in Japan. And they use SCN1A mutation found in the patients. And they have repeated seizures, predominant seizure type is convulsive. So it is very difficult to treat with monotherapy and many patients are on polypharmacy. Of course, they cannot walk straight when walking, and of course, they may have development impairment. 1 in 5 die before adulthood, with 73% due to sudden unexpected death in epilepsy before 11 years of age. So patients' family have to face very large burdens when it comes to Dravet syndrome. Please turn to Page 41. Now I'd like to talk about Lennox-Gastaut syndrome, LGS. LGS, there are 30,000 to 50,000 patients in U.S. and 4,000 here in Japan. When it comes to LGS, it is very serious, and it is heterogenous epilepsy associated with intellectual disability. And it is associated with multiple seizure types, including drop seizures, and very unique brain waves. It takes a few years for that diagnosis to be given. With LGS in order to suppress seizures, they need to take multiple anti-epilepsy drugs because they have multiple seizure types and because the frequency is very high for seizures. And they have development disabilities, and they are unable to perform daily activities of daily living independently. So it has a large impact on the patient as well as the family and the caregivers. Next slide, please. These 2 diseases, of course, there are anti-epilepsy drugs available. However, the seizures do not disappear with these drugs. In order to control them, polypharmacy is often seen and additive drug side effects are also seen. And in order to see the management, safety concerns and monitoring is necessary. In other words, unmet needs exist in these 2 diseases. And against such unmet means, what are the approaches that Takeda takes will be explained you in the next slide. First of all, soticlestat. This is the MOA. As you can see on the right, soticlestat has a cholesterol 24-hydroxylase, as you can see in the red box, and metabolism is seen, and it is suppressed here. And by inhibiting this enzyme, as you can see on the right, 24HC, it is dose dependent, and it causes reduction. And glutamine signaling is reduced, and inflammation is reduced, and it has the potential to reduce seizure susceptibility and improve seizure control. So let me show you some of the clinical data that we have achieved. Please turn to Page 44. The POC study I mentioned earlier, ELEKTRA study is shown here. For DS and LGS, they were included in the study, soticlestat efficacy, safety and tolerability was measured against placebo. It was 8 weeks dose ranging. And in total, 20 weeks of treatment period. So they had an option to go into the optional OLE study. So we had patients with DS and LGS, and primary endpoint was to see the seizure frequency for combined DS and LGS patients. The design of this study for DS and LGS, for each of the diseases, efficacy, safety are not shown for DS and LGS. They were combined. And the data was evaluated in a combined manner. That is the design of the study. This will be explained in depth later. So please turn to the next slide, which is Page 45. So this is our primary endpoint in the ELEKTRA study. We were able to achieve the primary endpoint. As you can see on the left-hand side, this is a primary endpoint for this study. For Dravet and Lennox-Gastaut, these were combined, and this is looking at the frequency of seizure. In 12 weeks, after placebo-adjusted, it was 30.5%. And as you can see on the right-hand side, they are 20-week full treatment period, it was minus 25.1% placebo-adjusted. So the DS and LGS were not separated, but I can show you the breakdown data that were achieved for DS and LGS. First of all, I'd like to talk about the DS cohort. It is not a design that was shown as superiority with just DS, but we were able to show statistical significance. After placebo-adjusted for DS, there was a reduction of 46%. And this data supports moving into Phase III of the study. Next, Page 47, please. So this is about the cohort of Lennox-Gastaut. So this breakdown was not able to show statistical significance, but actually, this study was not powered for this cohort to demonstrate significance. That's not the objective of this study. The objective was to combine DS and Lennox-Gastaut together. This was the design of the study. But Lennox-Gastaut subcohort, we were able to see more or less the same or similar level of numerical improvement compared to the existing drugs addressing the same problem. And this is an encouraging efficacy result that can support moving into Phase III. As I explained to you as the background of this, Lennox-Gastaut is a very heterogeneous disease and related to a primary endpoint, which is the seizures leading to fall. At the baseline, there was quite a heterogeneous not well balanced from 4,000 to 5,000 drop seizures observed at baseline. So 5,000 divided by 28 days. This means every 7 to 8 minutes, there is a drop seizure for such a patient. So caregivers as well as the physicians that need to count those drop seizures, there may be quite a large variability in this study. So moving on to a pivotal trial in the future, we need to have more strict definition of seizures. And also, we need to provide training for counting such seizures in order to obtain much better quality data in Phase III trial. So with this data, we believe that moving into Phase III trial is supported. This is the safety data of the trial in -- on Page 48. In ELEKTRA study, this showed a consistent safety profile seen in the past for soticlestat. No new safety signals were observed. So during the treatment, there were some events and exacerbation of those events and also serious adverse events. In those 3 measures, there was not much difference against placebo. And 5% or more difference was seen in somnolence and constipation. Next, please -- excuse me, lethargy and constipation rather. Next. As for pivotal Phase III trials in the middle of this year, we would like to plan to start these studies. Different from the POC study, Dravet syndrome and Lennox-Gastaut syndromes will have separate studies. So it's not going to be a combined trial like in the POC. So sample sizes are determined separately. And both studies are powered to show significance and to improve the success rate. And in Lennox-Gastaut, as I said already, this is a heterogeneous population. So how to better approach this subgroup in order to improve success rate? So from the design perspective as well as the operational perspective, we are taking care of that point. And FDA, PMDA and EMA, those authorities have already agreed with this study design. So we will move ahead with this design to test this soticlestat on these 2 separate populations. So as for soticlestat, from the fiscal 2023, we will start having regulatory filings. So that's all about soticlestat. Next, Orexin. [ Tanaka ] will give you a presentation on Orexin. [ Tanaka-san ], please.

Thank you very much. I am in charge of Orexin program. My name is [ Tanaka ]. So since this program went into a clinical stage, I started to take care of this program. So I would like to give you explanation following what's been explained since April 6 by Elena. So this is Page 56. Since 2019 R&D Day, this is the Orexin program, what has been pursuing several assets in this franchise. So narcolepsy type 1, NT1. The world first oral Orexin, TAK-994, we have ongoing Phase II trial. This is TAK-994-1501. And with the predefined criteria, it's been agreed to move on to Part B of this trial, which I will explain in depth later on. And in 2024, we would like to deliver this world first oral Orexin agonist to narcolepsy type 1 patients. And towards that goal, we are making very steady steps forward. So we are very encouraged by this. And point number two, 994-1503 trial, this is for healthy volunteer who are sleep deprived, and we were able to achieve the objective here. And this is suggestive of using Orexin for narcolepsy type 2 as well as idiopathic hypersomnia. Such possibility has been supported by the result of this trial. And point number three, Orexin franchise, we have 994, and we have 925, that is IV. And then longer oral agonist that is TAK-861. We also have that asset. So this is a multi-asset approach, trying to address several indications. So we can explore that with this very well-positioned franchise. As for 2 -- 925, this is IV, and in narcolepsy type 1, the transformative efficacy has been suggested already. And Orexin concentration in rather normal patients, in such a population, the POC -- EPOC has been achieved. And OSA, obstructive sleep apnea, that patient population was included in that POC. And this data is planned to be announced in the United States. And as for 861, we will move on to the clinical stage in 2021. So overall, the sleep, wake, respiration, metabolism, this is a master regulator, which can address a multiple number of indications. And with our power of research and development, we would like to continue to pursue this Orexin program going forward. So Page 57 and Page 58 is about the unmet medical needs and also hypersomnia. Narcolepsy type 1 is said to be NT1. Narcolepsy type 2 is NT2 and idiopathic hypersomnia is IH, and it's very difficult to diagnose these sleep disorders. They have all very high unmet medical needs. As you can see, those patients experience excessive daytime sleepiness. This is a clinical manifestation of these conditions. It's very important for them to keep awake and as for NT1, they may suffer cataplexy. And cataplexy, it may be triggered by laughter or a fear, anger, such strong emotions can trigger cataplexy. This is about loss of muscle tone. And IH has a sleep inertia as a characteristic symptom. And this is a kind of a drowsiness. And they do not have clear awakening from sleep. Oftentimes, those sleep disorders are difficult to differentially diagnose and oftentimes, it takes up to 15 years for some patients to be diagnosed appropriately. And this can lead to loss of receiving appropriate treatment. As for NT2 and IH, pathophysiology is not very clear just yet. But for NT1, we have a clear biological correlation. That is the reduction in orexin. So this is about orexin deficiency. And this can be addressed by orexin agonist. That is why we are focusing on NT1 to begin with. Next, Page 58. So this is about NT1 patients, narcolepsy type 1. And they have to live with this condition and what kind of difficulties they face. And this is from the feedback from the patient as well. So in order to maintain wakefulness, it is very important for daily living. However, the patients, it is not known socially. However, they are not able to maintain wakefulness. And because of that burden, they are exhausted, so their daily living is impacted greatly. And of course, they can have sudden cataplexy, so private. And when it comes to work or school life, they are impacted greatly. And during the day and during the night, they are impacted. However, they are not really understood by the society and by the HFCs (sic) [ HCPs ] . So one of the impact is that they are not able to pursue academic wise in schools, and they are not able to achieve what they want through work. And these are the experiences that they have seen. So for the patients, you can see the quote on the bottom of the page, we take current medications to survive. We want new medications to help us live the lives that we want. So Takeda would like to introduce new medications for such patients so they can have a better treatment so they can live normal lives. Please move on to Page 59. So this is looking at the pathophysiology of NT1. So this is caused by severe loss of orexin-producing neurons. And on the left, you can see, this is for the healthy individual. The blue circles are shown with orexin peptide, they are seen. And in the middle, you can see individual with NT1. So orexin-producing neurons are lost and concentration of the orexin is reduced. And downstream neurotransmitter activity is reduced as well. And there are receptors in the middle, and they are left. And on the right, you can see, these are the highly specific OX2R agonists. Using this agonist, you'll be able to activate the neurotransmitter activities, and you are able to recover such activities. Please move on to Page 60. So with orexin agonist development, the agonist, of course -- well, we do see very active development of antagonist. But agonist development is quite low compared to antagonists. So why is this? As you can see on the right-hand side, this is a conceptual diagram of Takeda. On the right-hand side, you can see orexin peptide. And of course, because it is large, it will not penetrate through the blood-brain barrier, but you need that orexin peptide for activation. Antagonist does go through the blood-brain barrier. And you can just block it. And that's why development of antagonist is very active. But as you can see on the bottom, the agonist that we are developing will be able to penetrate through the blood brain barrier and you will be able to achieve wakefulness. And actual agonist switch is required. And that's why we are developing this agonist. And GPCR development history that we have at Takeda is utilized so that we can come up with an orexin agonist that will be able to work in this manner. And please turn to Page 61, please. So with orexin science that we just approached, we were able to come up with a transformative approach and as a result, what we have done in clinic is shown in this slide. There are a number of data actually that we would like to introduce you to. In 2020, this was presented at ESRS. And on the left-hand side, you can see for TAK-925, this is 7-day administration, 11 milligrams and 44 milligrams and it was given IV, and we were able to see 0 cataplexy. And on the right-hand side, this is for MWT. MWT is an objective indicator. We will look at the brain waves to evaluate sleepiness. And as you can see on the red bar, for low and high dose, we were able to see 23 minutes and 40 minutes, respectively. And in this study, with safety, we did not see SAEs leading to discontinuation. And 925, 44 milligrams patients, there was TEAE, urinary and also salivary hypersecretion and hyperhidrosis were reported. It's very soon to know how this AE profile will translate into clinical settings of a prolonged duration, but we'll continue with our clinical program so that we'll be able to optimize the dose going forward to provide optimal efficacy and safety ratio. This is transformative data, innovative data. And we will be able to put the wakefulness at a normal level for such patients. And I think this has a potential for orexin agonist to make patients with NT1 to feel normal again. So other than the early POCs I mentioned earlier, with other indicators, we were able to achieve innovative evidence. As you can see here, for NT2 and for acute sleep phase delay paradigm in HVs, residual EDS and idiopathic hypersomnia, we were able to gain this data. IH POC was also achieved very recently. And this is NWT data that we were able to achieve as well. This is very innovative as well. There are several diseases involved. So day 1 data is shown here. And MWT level is very high. So when it comes to safety, SAEs continuing to discontinuation, we did not see. There was some pulse or high blood pressure resulting with these. However, they were within the safety range. The number of patients is very, very limited. So we would like to draw definitive conclusions going forward. Please turn to Page 63. This is for TAK-994 and 925 IV, orexin agonist. They achieved excellent translatability between preclinical and clinical studies. On the left, TAK-925, you can see wakefulness time and also on the right, cataplexy-like episodes in NT1 mouse model, and we were able to see superior recovery improvement. And on the right, TAK-994 results are shown. So this is wakefulness time in NT1 mouse for 1 hour. And on the right, cataplexy-like episodes in NT1 mouse model for 3 hours. Of course, we need to evaluate further. However, these pharmacological results in 925 and 994 will show similar observations, which is comparable, and efficacy of 994 and 925 maybe similar. So moving on to Page 64. This is a Phase II study that is ongoing, TAK-994 for NT1 and NT2 patients. So this is a design of that study. This is quite complex, but on the left, this is a Part A design, NT1. So 4 weeks treatment is provided for 18 patients, randomized 2:1, TAK-994 against placebo. As I mentioned earlier, so this is open label. So there is an independent part as well. And data review will be conducted and the result of the data review will lead to conduct a Part B. And we have moved on to Part B, as you can see on the right-hand side. For NT1, this is 8 weeks treatment and 994, 3 so -- against placebo. So it is at 3 levels of doses against placebo. And as for Part B, this is going to be a translational or confirmatory study. And of course, we will look at subjective and objective endpoints, sleep latency, MWT, ESS, WCR as well as safety. And we will have a Part D for NT2 patients and Part C for China cohorts. And as for Part A and Part B data, after the completion of the study, we will be disclosing the data at society meetings. As for the Part B, we believe that this is a design that is going to support approval. So that is how we are going to disclose the data. So the data of this study is to show wakefulness of the NT1 patients. Given this profile, we believe that the data out of this study is going to become very promising going forward. So the shift from Part A to Part B, and this is slide number 65, please take a look at the chart on the right. The black bar is what is obtained by currently approved therapies of NT1. This is the time for MWT. There are different studies, placebo-adjusted, what shows the true potency of the drug that is being shown here. And with MWT evaluation, with currently approved therapies, it does not exceed 8 minutes. On the other hand, TAK-994-1501 study had a criteria for Part A that is MWT 30 minutes or longer. So this is to bring narcolepsy patients almost to normal wakefulness level. And this is something that's been demonstrated here. So from -- in terms of the shift from Part A to Part B, we need to clear those criteria overall. And after clearing those criteria, we were able to move to Part B. That is what we think. So with this transformative therapy, we are moving ahead to be able to treat those narcolepsy type 1 patients. We are waiting for safety evaluation -- excuse me, we have evaluated the safety as well. And that included there was a judgment made that we could move to Part B. This is another trial, 1503 trial for also 994. This is for sleep-deprived healthy volunteers with the normal orexin level. On the left, I'm sure that you have seen this MWT data, and we have low dose and high dose. And MWT was 32 minutes and 37 minutes, respectively, against the placebo being 12 minutes. And this is an objective measure. And to the right, we have KSS. That is all subjective sleepiness, how subjects feel. And we have both objective and subjective measures of sleepiness, and we see very good correlation between the 2 parameters. As for safety in this study, TAK-994 tolerability was favorable and serious adverse events were not observed. And no discontinuation due to AEs were observed as well. No clinically significant laboratory values were also observed as well. And OAEs by TAK-994 were mild. And so sleep-deprived healthy volunteer trial was conducted for 925 as well. And between 925 and 994, the safety as well as the efficacy data were both very much consistent between the 2. So with this data, orexin -- the oral orexin agonist, not just the 994, but wide variety of assets in the orexin franchise have been tested. And it can address beyond NT1. So 1501 Part 1 data, and as we have not really disclosed it, but 1503 data. Given those data, we believe that we have had a quite good advancement in this program. And this can support our further development activities to be conducted between the fiscal year 2021 to 2023. And so we will be looking at future clinical data as well as the requirements imposed by the regulatory authorities. And in order to meet high unmet medical needs of the NT1 patients, we would like to continue to develop this compound, aiming for the launch of the compound in 2024. So 925, that is the MV -- IV formulation. Given the data, we would like to also address TAK-861, that is considered longer acting. And as for 861, we would like to continue to have development as well to address these diseases with high unmet medical needs. This is my last slide, Page 68. As you can see at the top, we would like to be the world first oral orexin agonist 994 for narcolepsy type 1. And we'd like to maximize the potential of narcolepsy as a disease condition. So we would like to continue to have development activities for further indications. Narcolepsy type 2 and IH, they are difficult to diagnose. And once we obtain supportive data for these indications, would like to explore the potential indications going forward. As you can see at the bottom, orexin is a master regulator for sleep, wake, respiration and metabolism, and therefore, we would like to explore further potential in other indications going forward as well. Thank you very much for your kind attention. Thank you.

Thank you, everyone, for your kind attention. Now we'd like to begin the Q&A session. [Operator Instructions] The second point is [ Sano ], [ Nonomura ] and [ Tanaka ], these are the presenters of today, and we will also have soticlestat, orexin program drug discovery leaders from Shonan Research Center, Kimura and Nishi. So those 5 will be able to take your questions. And as I said at the onset, today, we do not have the people from commercial functions. On April 6 presentation, we had peak sales numbers and others. But we do not have commercial people at hand today for answering your questions. So please refrain from asking commercial-related questions because those can be addressed on other IR occasions. [Operator Instructions] And first, from Shonan, we have Kimura and Nishi, and 2 of them will introduce themselves briefly. First, for orexin drug discovery, Kimura, please take the floor and introduce yourself, Kimura-san.

Neuroscience DDU of Shonan, I am in charge of orexin program. My name is Kimura. Very nice to meet you all.

I am Nishi from Takeda Pharmaceutical Company. I'm also from Neuroscience DDU. I have been in charge of drug discovery of soticlestat as well as Head of Oncology. Thank you very much. Very nice to meet you.

Now let's begin the Q&A session. First of all, from [indiscernible] [ Mr. Sato ], please. Thank you very much for raising your hand. Please ask your question. Please unmute yourself.

This is [ Sato ] speaking. My question is on maribavir, all 3 questions on maribavir. The first question. How is infection caused? When we think about it, there are multiple organs that may be infected and/or the recipient may have infection history. And under immunosuppression, the infection may be caused because of the reaction to that antiviral drug. Is that correct?

Is that the only question?

So I will ask all 3 questions. The second question. When it comes to transplantation, 1 in every 4 cases, there's CMV infection, I think it was mentioned. So simply thinking about this, if you can have various clearance before transplant, maybe this problem will not be caused. So as a treatment approach, is that viable? And the third question. First line, second line Phase III studies are ongoing. At the timing of Phase III -- going into Phase III, I think it was similar in timing for both studies. But the second line is ongoing. Is this because of the study design?

Thank you very much for the questions. My name is [ Sano ]. I'm in charge of maribavir. The first question, as you say, the recipient and the donor CMV, they may be positive. It will depend on where the organ is. There may be difference in the risks. However, if donor or the recipient is positive, depending on the organ site, the CMV risk may differ. And the second question. If you could please turn to Page 13. 1/4 of the patients may be infected, and you were talking about prophylaxis available. And as you mentioned, with maribavir, we are going to manage the infected area. And also, we are looking at other ways of control. With maribavir, we are looking at treatment of the infection. And the other is prevention or prophylaxis. And when it comes to prophylaxis, for HSCT patients, there is letermovir that is available. There is such a treatment option. However, CMV infection risk is remaining as a threat. And from that perspective, maribavir is focusing on the treatment side. We believe it is a very, very important focus that has great needs. And when it comes to development milestone, I think that is your third question. In the presentation, I mentioned that for refractory and resistant study, we had 350 patients involved. The first line study, it was a larger data that we want to achieve. That is a plan. Therefore, 550 subjects are involved. So there is a difference in the design that is causing the difference in the time line. We like to gain faster data so that we'll be able to evaluate maribavir so that we can aim for approval and launch of this drug. And when it comes to development milestone, I think that is your third question. In the presentation, I mentioned that, for reflecting a resistant study, we had 350 patients involved. The first line study, it was a larger data that we want to achieve. That is the plan. Therefore, 550 subjects are involved. So there is a difference in the design that is causing the difference in the time line. We'd like to gain vast data so that we'll be able to evaluate maribavir so that we can aim for approval and launch of this drug.

So about maribavir. From Boston, Obi would like to give you some additional comments. Now over to you, Obi.

Thank you very much. I just wanted to add that the -- even though we have prophylaxis as an option, despite prophylaxis, there is still a 25% infection rate. So the unmet need for infection persists despite prevention. So prevention is ineffective at taking care of all the patients who would need this. So prophylaxis is unable to take care of all patients. Despite prophylaxis, 25% of patients still go on to develop CMV infection. And that's why we are developing maribavir. So I just wanted to add that additional clarification. Thank you

Next questions are from Morgan Stanley Securities, Muraoka-san.

I am Muraoka from Morgan Stanley. Do you hear me?

Yes.

My first question is about orexin, and this is about the future. The next update can be in the academic society clinical data. The other day, you said 2022, do we need to wait until that time? Could it be the first half or the second half of 2022? So when will be the next update? So your launch timing is planned to be 2024. But Part B of 1503, apart from that, what kind of studies are needed? That's my first question. The second question is also about orexin 994. The other day, you said that no schedule can be expected because of a very good safety data because it acts on the parts of the brain. So can you give us more details of the reasons why you believe that it's going to be non-scheduled drug? The third question is, I think this is for probably Nishi-san or Kimura-san. This question is about the Shonan Research Center. These 2 drugs are born out of the Shonan Research Center. And you have had downsizing of Shonan Research Center, and I believe that it's because of the low productivity of the research center. Well, that's what's been said by the investors, and you may deny it. Because obviously, this is a result of much creativity in Shonan. So if you can just refute such theory of the low productivity.

As for orexin regulation, Tanaka will address that. And the third one, Nishi, Kimura will answer that question, which is about Shonan Research Center. First, orexin. Tanaka-san, please.

Muraoka-san, thank you very much for your question. The first is about -- I think you are talking about 3 things. Future update of the data. So as of now, I am sorry to say that, as Elena said the other day already, and I would have to repeat this, it's going to be next year, Part A and Part B. As I said in my presentation, in order to maintain the integrity of the data of this study, we would like to have an update of the data next year in appropriate academic societies because this study is still ongoing. Therefore, it's going to be next year. I hope you understand. And as for the launch or approval of 2024 as our target, what other studies may be required? That is the second question. And once again, as for Part A, as we can't disclose the data, but then it's very encouraging. And it's quite satisfactory, I would say. But it is still early times. Therefore, we have to first complete Part B, and we will see more and more data coming out. So looking at the future data, and based on the future data, at an appropriate timing, we will determine what is to be done. So basically, as for confirmation, what is required for an approval, we need to have confirmatory trial. But as for detailed development plan, well, we need to have continuous dialogue with external stakeholders, including regulatory authorities, to finally determine the future clinical program based on the data which will come out in the future. And then as soon as possible, deliver this drug to narcolepsy type 1 patients, which is our goal, to deliver transformative drug to those patients.

And the third question is about the no schedule, why it's not going to be regulated. It's based on the mechanism of action. orexin 1 receptor is for reward system. orexin, there are 2 receptors, 1 and 2. And orexin 1 receptor is much implicated in rewards system. And our agonist works on orexin 2 receptor selectively. Therefore, it will not act on reward system, almost none. That's what we believe. So that is the scientific -- the inference. But of course, we have to see the future clinical data. And towards the sizing of this, we have to check whether our scientific theory can actually be proven by the clinical data. We will be in a continuous dialogue with regulatory authorities. And if some other evaluation is necessary clinically, we will conduct that as appropriate to continue to study this compound.

Kimura from Shonan, why it's not going to be regulated, why is it going to be nonscheduled. Any additional comments?

Well, yes, this has selectivity on orexin 2 receptor. And I think the risk of acting on orexin 1 or reward system is quite low. So about the research center and productivity, please take a look at the Page 9. So soticlestat and orexin. As you have pointed out, that they were born out of the Shonan Research Center. And what I would like you to understand is both are considered to be first-in-class, meaning with novel mode of action. And for CNS, it's not easy to come up with new mode of action compounds. So this is an achievement we have. So we are highly motivated. We are keeping high productivity. We are taking on new challenges. That is something I'd like you to understand. TAK-701 and 653. So these are the 2 compounds, and I'm probably biased because I am also working for these 2 compounds, they were both born out of the Shonan Research Center. And we have very complex control system for mechanism of the target. So we have quite high confidence for these 2, 653 and 701. Of course, we have to still go over quite high hurdle of clinic, but then, we'd like to pursue development of these 2 compounds as well. After the transformation of the research team of Takeda, we have changed a lot as Shonan Research Center is a part of the global drug discovery system. We have the translational science, and we have a close collaboration with the clinical development team. We work closely with the key opinion leaders outside. And we use new technologies and new modalities to have drug discovery. And so in the past, some of the things were considered not druggable. But still, we took on such challenges. So we have new technologies and new environment to work in, in order to produce novel drugs in the future going forward as well. Nishi-san, do you have any additional comments?

Yes, I would like to be very brief from a different angle. So from a local perspective, I would like to give you my comment. So I think I'm very well positioned. So I worked overseas for 4 years, and I came back to Shonan Research Center. And I saw a quite dramatic transformation in Shonan Research Center. With the iPark, it's evolving very quickly. So 100% research center, Takeda Research Center in the past. But right now, we have a lot of tenants. And we have natural interactions with those researchers who are not working for Takeda. We have a lot of events being organized. And this is an environment that is -- environment that can produce a synergistic effect among researchers. This is a source of creativity that is a great advantage for basic research. So this is a source of creativity that is being seen in iPark, and that is something I would like you to highly regard. Thank you very much.

Moving on to the next question, please. From Goldman Sachs Securities, Mr. Ueda.

Goldman Sachs Securities, my name is Ueda. I have 3 questions on orexin. First of all, about development. orexin, you have not going into the clinical stage, but are you conducting Phase II already. And you have a predecessor when it comes to orexin 2 agonist. So why did you focus on orexin 2 as an agonist? So please talk about the background. Second, you talked about the unmet needs. But can you talk about the unmet needs of the existing treatment? And it is a serious disease. And the number of patients going through treatment is very, very small, limited. What are the problems? And of course, efficacy and safety and maybe dependence is another problem with existing treatment. But how are you going to differentiate this compound from other existing treatments? And the third question from the safety perspective, for narcolepsy patients, of course, they may have neuro diseases, [ DM ] and [ CB ]. And with 994, would you be able to reduce such risks when it comes to [ CV ] or [ DM ]? And you talked about higher blood pressure and also heart rate to be increased with the side effect. So can you talk about the side effects in general, please?

Thank you very much, Ueda-san. As for orexin, the reason why we focus on orexin, Kimura will explain. And the second and third question will be answered by Tanaka.

Thank you very much, Mr. Ueda for your question. The reason why we focused on orexin is because, in the CNS research, translatability is very low. So preclinical is not reflected in the clinical stage very often. But however, with orexin, the narcolepsy, we understand the cause is loss of orexin. Therefore, GPCR drug delivery and direct discovery was a strength at Takeda, so we were looking at the synergy. We believe that the pathophysiology was very clear. And that's why we decided to focus on orexin. And when it comes to the unmet needs, I'd like to talk from the nonclinical perspective. Please turn to Page 59. As you can see, Page 59, when it comes to narcolepsy, this is looking at their proposal. And you can see that there is loss of the orexin neurons. And the orexin 2 receptor in mouse, you can see that it can be -- one, for Type 1, there is no prototype -- or phenotype that is lost. Therefore, there is orexin signal can be recovered. That is what we expect to happen in the mouse. With the observation that we have had with the orexin 2 receptor agonist, we were able to see [ transient ] sleep or [ cataplexy ] to be suppressed. And when it comes to narcolepsy model mouse, we had lots of that neuron. And in such patients, similar to such patients, that mouse showed that abnormal increase in the weight was also observed in such mouse. And excessive weight gain is suppressed using orexin. Tanaka-san. Do you have any additional comments you'd like to give, please?

Yes. Thank you very much, Mr. Ueda for your question. When it comes to the unmet need. If you could turn to Page 57 or 58 of the slides. As you can see, the symptoms are not really understood by others. And there are existing treatments available. However, listening to the feedback from the patients, they say that existing treatments is allowing them to live. However, they would like to live in their own way, and they would like to see new treatments that will make that possible. And I believe that is a very high unmet need. April 6, there was a presentation given, and Erika explained that patients may change treatment or go on polypharmacy. And in many patients, they need to change the treatment within 1 year. So 65%, I think, was the number given, but they are not on monotherapy, but they are on polypharmacy. So even with the existing treatment, they are not able to really control the symptoms, and cataplexy is seen and EDS is also not improved. And these data is available. And with that, at Takeda, as Kimura mentioned earlier, I may be redundant, but we looked at the mechanism. And for NT1, I believe that the mechanism will address directly NT1 symptoms. So for NT1, symptoms in general can be improved. And that is going to lead to differentiation. That is what we have high expectations for. So I believe our compound is different from other drugs available in that area. When it comes to safety, so it is related to what I have just said. But for NT1 patients' pathophysiology, this is going to solve directly the symptoms of NT1 symptoms. So with monotherapy, we will be able to improve the symptoms that NT1 patients experience. Of course, you talked about elevated blood pressure or heart rate. Of course, these were reported, but we are still in early stages. And basically, when it comes to tolerance, we are seeing high tolerability. And this is because SAEs or AEs leading to discontinuation for 925 and 994, they are not seen in 95. Therefore when it comes to tolerability, we believe that high tolerability is as shown currently. And during the presentation, we said that the safety data, not only for elevated heart rate or for the blood pressure, they will continue to be monitored. We're in early stages, still. So when it comes to dose going forward, we will look for optimal dose with efficacy and also safety. Efficacy will be maximized and the safety risk will be minimized. So the balance will be taken in deciding that dosage. The data to be achieved going forward will be utilized so that we'll be able to choose the right balance.

Next, Mitsubishi UFJ Morgan Stanley. Kumagai-san, you have raised your hand. Kumagai from Mitsubishi UFJ Morgan Stanley. Do you hear me?

Orexin, I have 2 questions. 994 and 861 blood half-life. That is my question. If 994 is BID and 861 can be OD. Apart from convenience, what is the benefit of 861? Do we need to have these 2 compounds? Are they different? That is what I would like to double check. And the selectivity on receptors, is there any difference between the 2? Do you have any information regarding the difference in profile of these 2 compounds? That's my first question. The second question is about the timing of administration, 994 and 861. For instance, for migraine patients, which is a different disease, they have some kind of aura. But for narcolepsy, do they also have some kind of aura? And when they experience that, the precursor, can they take these drugs only when they have such precursor? Or do they have to take this every day?

So for this first and second questions, Tanaka and probably Kimura-san can also step in. Tanaka-san, over to you.

Thank you very much, Kumagai-san. So for 994 and 861 half-life and convenience. I think that's the first question. And whether these are the same compounds or not, I think that's another question. So as the compounds, 994 and 861, there are different compounds. 994 and 861, for both basically, I'm sorry that the blood half-life data is not disclosed for either of the two. And as for convenience, BID or OD, optimal dose or dosing regimen, especially for 861 -- well, for 994, it's already in clinic. But as for 861, it's not even in clinic. We are going to move on to the clinical stage for 861 in the future. So we'll be seeing the data in the future. So just like I said, for safety, we'll be seeing more data coming out. Therefore, we will take a look at PK, efficacy, safety data going forward. And we will make overall judgment as to what would be the optimal dosing regimen or the dose for both 994 and 861. And as for the second question, which is about the timing of taking the drug, I think narcolepsy, those patients do they feel some kind of aura or precursor, and can they take this drug at that stage? So I'd like to address that question. For narcolepsy patients and sleep of these patients, their sleepiness. When we are deprived of sleep, and we may feel sleepy. And the level of the sleepiness they feel, that's completely different. It's as if they fall into sleep unnoticed. So it's such an intense sleepiness they feel. It's very different from the sleepiness we feel. So to take a drug when they start to feel sleepiness, that's probably not possible. Or some kind of aura, do they feel that for sleepiness? It seems there's nothing like that according to what patients say or report. So right now, we have a clinical trial ongoing. So we will take a look at the data in the future to come up with the optimal regimen as well as how to optimally take this drug. So we will continue to explore that.

Mr. Arai from [ BofA ] Securities.

Hello?

Yes, we can hear you.

My name is Arai. Thank you very much for the explanation. I would also like to ask questions on orexin, sorry to be persistent. The first question, it may be related to Mr. Ueda's question. The GPCR technology that you have, what is special about it compared to the competitors? Is there something that you can do that others cannot do? And how was TAK-994 born? Can you talk about the competitiveness background, please? And the second question for TAK-994 about the efficacy, how it is maintained, how long it is maintained? I'm looking at actually Page 66. On the right-hand side, you see subjective measures. And from the administration, 7 hours or 8 hours in the active arm, people start to feel sleepiness, and that number increases towards 7 hours, 8 hours. So with TAK-994, the maintenance of the efficacy of 994, do you have data that indicate that? Or is it too early in the development stage to show that? Please share the background with us.

Thank you very much, Mr. Arai, for your question. About GPCR, Kimura will answer, please.

Yes, I'd like to use this slide -- Page 60, please. As you know, orexin antagonist is used as a sleeper drug. And as you can see, major pharmaceutical companies are working on R&D. In other words, many companies are interested in the orexin system. And they are searching for antagonists. So they have the biological platform to look for agonists. So antagonist and agonists are completely different in that sense. Agonist, antagonist, what is different between the 2? Agonist needs to activate the receptor. In other words, they need to cause the changes. And orexin peptide, which is larger in molecule, is advantageous. But we are trying to create a medication, therefore, we need to come up with a compound that is going to penetrate the blood-brain barrier, and agonist needs to be small in molecule. So with both, you need to be a bull in order to show that power to penetrate the blood-brain barrier. So TAK-994 has efficacy, it's oral and it has safety That kind of a compound to be explored is very, very difficult. The details of the technology, I cannot disclose here. But this is something that Takeda has nurtured over a long time. So GPCR and also CNS. We have [ lozerin ] as well. I think these are the basis of the research and development of orexin. As for the second question, Tanaka will answer that question.

Mr. Arai, thank you very much for your question. Please turn to Page 66. Thank you. So this data I think you're referring to. This is 994-1503, 925. For the healthy volunteer study, the efficacy and safety, I think we see consistent results with that study. And as a conclusion, we can say that we had seen very significant data. So this is a very good, favorable. The administration period is very limited. And when it comes to 925, it was 7 days; and for 994, it was 4-week administration. So for Part A -- 1501 Part A, so efficacy was indicated. Therefore, we believe that we can have high expectations and we can be confident with the results achieved. So continuing on, we will have 8 weeks in Part B. So that data will be considered going forward. So with that data, we hope that we'll be able to disclose the data at significant society meetings going forward.

But I have additional question. On the right graph, this is, after 8 or 9 hours in the active arm, the graph goes up significantly. In other words, the patients with 994, after 7 hours or 8 hours, only the efficacy is maintained for half a day. So it's a very early in the stages to read that from this graph. Is that correct?

In this study, as you mentioned, you can see an increase in that arm. However, I may be repeating myself, but this is with just limited patients or very limited data. This is for sleep-deprived healthy volunteers, so 994 efficacy and safety for NT1. So longer period, narcolepsy, the data is something that we will achieve going forward. And we need to maximize the efficacy, and dosing will be done in accordance with that. And the regimen will be evaluated accordingly with the data that is going to come in the future.

Next, Daiwa Shoken's Hashiguchi-san.

Hashiguchi from Daiwa Shoken Securities. I have, broadly speaking, two questions. One question is about the 861 longer-acting. What is the value of this compound? So sleep disorder symptoms, and different conditions are there with such symptoms. And long-acting drug, what is your expectation in terms of indications, that if 861 may be used, just generally speaking? But if you can mention some specific conditions. The second question is to Kimura-san and Nishi-san. Soticlestat and orexin drug discovery projects. Back in 2016, you had research organization transformation. How this transformation has affected or has not affected those 2 projects, Soticlestat and orexin? Looking at the timing of the patents, I think you started those 2 projects before the large transformation. So when this breakthrough moment came to advance this research very rapidly. And how did that transformation affect those projects? I'm sure that the organization has changed very much since the start of these 2 projects. Can you expect anything like this, being out of the research center going forward after the transformation?

So the benefit and the profile of TAK-861, Tanaka will answer. About the R&D transformation at the research center, Kimura and Nishi will answer The question. Over to you, Tanaka-san.

Thank you very much. For 861, what is the value of that compound? And as for sleep disorders, more specifically, what kind of conditions can be addressed? I think that was the question. So Page 66, that one or this one here. Page 68 is okay. Page 56 and 68, as you can see from both slides. We would like to address high unmet needs. That is the criteria. Based on Orexin science, we'd like to address those indications as appropriate, wherever we have unmet medical needs. We'd like to explore those potential indications going forward. So far, among sleep disorders, unmet -- high unmet medical needs are there identified and also, based on Orexin science, we have identified NT1, NT2 and IH. We believe that these are the conditions that fulfill those requirements. And as for other indications, Orexin is a master regulator of sleep-wake respiration and metabolism. Therefore, given such a function or a role of Orexin, we would like to continue to focus on high unmet medical need areas. As for 861, it's not in the clinical stage yet. It's going to move to the clinical stage. Going forward, we will be seeing more PK and safety data. So given such data, we'd like to continue to explore what is the suitable indications for 861.

Mr. Kimura, I would like to add some comments, Orexin for sleep and wake. Orexin is very important for sleep-wake but also for metabolism and also for respiration. For such physiological functions, Orexin is a master regulator. So not just for sleep and awake. From the research perspective, 925, 994 and 861, they have different profiles as Orexin agonists. And we can address the different indications that can be a good expectation, and we are very much excited about it. Talking about the status of the research center, as I said already, and as on Page 9, Orexin, soticlestat and on top of that, TAK-653 and 701 -- 071, excuse me, were also borne out of the Shonan. And soticlestat, Orexin, they are completely new. Nishi is here and also Kimura, myself in charge of 071, 653, I'm here as well. So with the transformation, did we lose anything? No. I think we have gained new power. For instance, in Boston, the latest technologies, a translational science team is there with the new or latest availability -- ability and technologies. So with this new direction and we are pursuing strategically drug discovery. So we'd like to take on challenges of producing new molecules going forward as well.

I'd like to add one thing. For transformation and how has it affected. And as for CH24 project, I think transformation has only worked positively because the globalization advanced very rapidly, thanks to transformation. Before, we had some silos. But then after the transformation, we were able to work very closely with overseas researchers to advance our projects. This is already a new normal in a research center. As for CH24H inhibitor, this was completely novel as Kimura-san said. And without the collaboration with overseas researchers, probably we were -- had not been able to advance this program thus far. So my own program has been very much benefited by the transformation. So when this breakthrough moment come, that was another question. There were so many breakthrough moments. I don't know which breakthrough moment I should be talking about. But just to mention one, why CH24H inhibitor could become a drug for epilepsy? And this was actually serendipitous. Let me talk about that. Our group was working on soticlestat at Boston, and we were addressing the Alzheimer with the model mouse. We were analyzing the pharmacology in such model mouse. It has a characteristic, which was a sudden death in this model mouse. TAK-935, that's right now soticlestat. But with the administration of soticlestat we, by chance, found that the sudden death rate was reduced in such a mice. But because it was a sudden death, we didn't know what was going on there. And what was stopping such sudden death. But we were observing such animals. And most of those sudden deaths seems to be caused by seizures. That's something -- or conversion, that's what we found. So that was one of the breakthrough moment to use soticlestat TAK-935 for epilepsy. So that was the kind of a serendipity.

From JPMorgan Securities, Mr. Wakao.

From JPMorgan, my name is Wakao. I have 2 questions. One, about 994 and 925 about the efficacy. How similar are they? Will they be of the same degree. Compared to the existing treatment, 994 and 925 superior data has been achieved. Looking at the mouse data, 994 compared to 925, the data, the values are low. But the efficacy to human, depending on the dose setting, do you believe that the data will be achievable comparable to 994 or 925? Now for NT1, for nighttime sleep disorders, you mentioned that cataplexy or very strong sleepiness, you mentioned an NT1 daytime sleepiness problems were clear. However, as you can see, when it comes to NT1, you can see intermittent sleep and then sleep disorders. Sleep disorders for NT1, how problematic is that for such patients? And for 994, the efficacy endpoint is similar without the medication. MWT, ESS and also WCR was mentioned. And I think that's for daytime sleepiness. But what about the quality of sleep? Does it need to be evaluated? Or if it's valuated, will it be differentiation for 994? I'm sorry to be continuing. But the MWT, such data is available. So improvement of quality of sleep, can that be expected? Is there a correlation between MWT and quality of sleep? That is my question.

Thank you very much for the questions. Kanata-san, I think there were 3 questions on 994 and 925. Can you answer those questions, please?

Yes. Thank you very much, Mr. Wakao for your question. For 994 and 925, so dose setting, whether the data has consistency? I think that was your first question. Basically speaking, for 994-1503, we have shown you the data today. And basically, I think it is similar 925. So I think we were able to show persistent efficacy and safety for intermittent sleep-deprived patients. I think that has been proved in the studies, and that is what I explained earlier. For narcolepsy type 1, 925 data has been disclosed. But for 994, the data has not been disclosed yet. So I may be redundant, but basically speaking, for Part A. So I think this is a slide before, 65 please, yes. So Part A, so early POC criteria have been met and possibly shows that all the symptoms have been improved or resolved in the same manner. So I am very happy about achieving such results, but the number of cases is still very, very limited. So 8-week long-term data for Part B is going to be available going forward. So the dose setting will be done looking at the Part B data so that we can look at optimal dosage to receive and see maximum efficacy and safety, low toxicity. When it comes to nonclinical, Kimura-san, do you have any additional comments?

In the mouse model, narcolepsy, so this is a pharmacological efficacy. So PK for mouse and for monkeys is different and human is very, very different between the 3. So a detailed analysis shows that the current conclusion for 925 and 994, there is no difference in the pharmacological effect. And the second question about the intermittent sleep during the night. So sleep disorders during the night, yes. As you can see here, so nighttime sleep deprivation is one of the symptoms of narcolepsy. And Erika used a slide the other day. Such patients during the night has sleepiness, but during the night, he can go to sleep instantly without problems. However, after going to sleep, wakefulness appears during the night, and they're disrupted. In other words, they cannot sleep in a continuous manner. It's very intermittent, disrupted. And we believe that is one of the unmet needs that we need to focus on.

And the last question about the quality of sleep and the quality of wakefulness during the day, I believe, was your question. MWT, whether there is correlation with that, is that your question? Yes. For 994 quality of sleep, so distracted sleep, whether that is going to be reduced. Does it need to be evaluated? And if evaluated, is this going to be a differentiation point, correlation with MWT, whether that exists or not? That is my question.

As for your question, of course, we are still in early stages. So going forward, we will have different data coming from Part B as well. So these data will be evaluated. And what you have mentioned will be considered going forward. I believe they're using this going forward. Whether it has correlation with MWT? In the long-term clinical studies that we will be conducting going forward, I think that is something that we will also need to consider as well. I may be repeating myself, but when it comes to symptoms of narcolepsy, as you say, there are a number of symptoms we need to focus on. For NT1, the Orexin deficiency is the pathophysiology. And this is an agonist to work on that, therefore, for daytime sleepiness, and also other symptoms of NT1 may be addressed using this Orexin. So that is why we have very high expectations. And with that, we would like to continue with research and development. Thank you very much.

Next Yamaguchi-san from Citi.

I am Yamaguchi from Citigroup. My first question is about 994, and it's a very similar question. Narcolepsy Type 1 and it works for narcolepsy Type 1, and I do understand why that is the case. But what about the NT2 and IH? The mechanism is not directly linked. But still you believe 994 works for NT2 and IH, Why do you believe so? That's my first question. And the second question is, because you are very much advanced, it's not going to be a competitor, but DPC drug discovery is done by Sosei Group, positive Orexin 1, 2 modulator. They started a new startup for developing that. No data is disclosed, but it's there. There is 1, 2 positive modulator. How is it different from your compound, if there is anything different? The third question is about the ROZEREM vaccination that's been mentioned. ROZEREM, that's a first-in-class as a melatonin agonist, first-in-class, but commercially, it's not been successful. So pharmacologically speaking, the mechanism -- pharmacological mechanism was not well linked with the commercial success. Why is it? Looking back, what was the reason? So these are the 3 questions.

Thank you very much. So as for 994, and not having a linkage with NT2 and IH, Tanaka will address that. As for GPCR, Tanaka and Kimura, will address that. And the third one is the [ Orexin } agonist and in the future going forward, Tanaka will also address that question. Over to you, Tanaka-san.

Yamaguchi-san, thank you for your questions. NT1 and NT2 and IH. Well, compared to NT1, NT2 and IH, and especially for NT1, Orexin level may be slightly lower or normal. And the pathophysiology is not very clear for NT2. There are a lot of unknowns. Although there is such difference, but 925 in clinical trial, it was tested for not just NT1, but also for NT2 and also sleep-deprived healthy volunteers. So Orexin normal populations also can benefit from TAK-925. So given that, we believe that this can work not just for NT1, but also for NT2 and IH. We can expect to have such indications as well. That's what we believe. Kimura-san, do you have anything to add?

Yes, sleep and wake in order to understand that, and this is very much simplified theory. But you can think about the balance. So in the brain, you have substance that can cause sleep, another substance that can cause wakefulness and it's in balance. And which is heavier, that can determine whether you're sleepy or you're awake. And as for NT2 and IH, we do not know the exact mechanism, but as explained by Tanaka-san and as you can see from this data for sleep-deprived healthy volunteers where Orexin level is considered to be normal through nonclinical and clinical studies, our compound actually triggered wakefulness. So the [indiscernible}, that is the master regulator of sleep and wake, still there is much capacity. So NT2 and IH, the [indiscernible] is very much promoted. And the awakeness may be suppressed, but still Orexin can address the balance between the two in NT2 and IH. That is our hypothesis. About the Sosei Group, it's a different company, so we do not have the data. We don't know the details. And if it's a positive [indiscernible] modulator what they are doing, -- if there is endogenous ligand that can be promoted. So I think theoretically speaking, it would be quite difficult for such compound to trigger wakefulness in NT1, but I wouldn't say anything more. So as for ROZEREM, Tanaka-san.

Yes, for ROZEREM, and because I'm an R&D person, I can't really make any comment on the commercial aspects of ROZEREM. But I must cover in our presentation. As for sleep and wake, we had ROZEREM. And we were able to acquire and accumulate knowledge and also drug discovery ability. So we were able to obtain very good experiences from ROZEREM. Tapping into those experiences, we were able to come up with the second one from the GPCR drug discovery activities, which is shown on the slide. So given such experiences, we are able to have this Orexin agonist through our drug discovery activities. So going forward, we'd like to use our R&D power in this area. And advance this program.

It is close to the closing time. I'd like to continue with the Q&A session as we have a number of questions waiting. [Operator Instructions] Mr. Mizuno from Tokio Marine.

About soticlestat. So looking at the material from the past, of course, there was ARCADE study that was conducted. And looking at the presentation of materials from the past, CRB's study was conducted in the past by Ovid. And of course, interim analysis was completed. What has happened with the other studies? For -- about 924, is it going to act as a biomarker? LGS has variability, and it's a heterogenous. So the baseline for drop seizures, there are a lot of factors that need to be contemplated. So there is a lot of variability. So if it works as a biomarker in [ SC24 ] diseases, will it work for other diseases, excluding LGS or DS. May I have your comment, please?

Thank you very much for the questions. So for soticlestat, [ Nonomura ] will answer your questions.

Thank you very much for your question. First of all, about expanding indications. I'd like to talk in general. We are looking at DS and also LGS. We have put all our efforts into these 2 syndromes. So currently, in the pivotal study will be a focus starting this fiscal year. And when it comes to the MOA that I explained earlier, it will be suppressing the glutamine signal so that you will have a good balance between the two. So I believe there is a potential to expand the indications to other epilepsy. When it comes to the biomarker, the number of samples in the clinical study is very, very limited so far. Therefore, there's nothing concrete that I can say as of now. But with a pivotal study that will be conducted, we are going to register more samples or gain more samples. So we believe that knowledge can be gained through such studies going forward. That is all for myself.

In other words, for seizures or you call them seizures, I do not know. But for serious epilepsy, other than LGS or DS, it can be used for such symptoms. Is that correct? Can it be expanded to such figures going forward, but you have not been able to confirm them? Well, the possibility will always exist. So potential for other epilepsy is there. Thank you very much for the answer.

So the next one will be the last one. Tanaka-san from Mizuho Securities.

I have 2 questions. In 2017, you filed some patents. And apart from hypersomnia, you included many different conditions. Those names were listed: Alzheimer's disease and not about appetite, but also the osteopenia. Do you have any rationale for addressing those other indications? Yanagisawa and Sakurai discovered Orexin back in 1998 and, around 2000, Chairperson [indiscernible], started a strategy for orphan receptor discovery. GPCR research activities were very much active. But it's taken so long. [indiscernible] receptors have not been discovered. What's been the problem? So these are the 2 questions.

Thank you very much. So Tanaka-san, can you address the question? But it's about patent. And we would like to refrain from mentioning the patent strategy of our company. So please talk about GPCR research. Kimura-san, over to you.

Yes, as you have pointed out, in Takeda mainly orphan GPCR research activities were going on in the past. You mentioned the problem. But then through those activities, we were able to elucidate the structure and also control of GPCR and through medicinal chemistry, how can we overcome such challenges. We were able to accumulate such knowledge. Why has it taken so long? Well, I wouldn't really say that. This is something to do with the overall drug discovery strategy of Takeda. But please understand soticlestat and Orexin, they are both difficult to discover, but we did that, and then we are pursuing those programs. So that's something I would like you to understand. Thank you very much.

So with this, we conclude today's event. So it's been over 2 hours. It's been a long event, but thank you very much for staying until the end of this event. And I would like to ask you for your future support of our IR activities. Once again, thank you very much for your taking part in this event. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]