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

[Interpreted] Good morning. Thank you very much for joining Takeda Pharmaceuticals Wave 1 Pipeline Market Opportunity Call. I am O'Reilly, Global IR Head. I'd like to serve as the moderator today. 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 1 of the presentation today. Now let me introduce you today's agenda and the speakers. First, Christophe Weber, President and CEO, makes you introduction; followed by Andy Plump, R&D President, introduce you R&D strategies; and next, U.S. Business Unit President and Global Portfolio Commercialization President, Ramona Sequeira, will discuss about the case studies of ENTYVIO. And then 2 Wave 1 pipelines deep dive are planned. First is TAK-721. Global Program Lead Mike Nedham will discuss TAK-721. And then Global Vaccine Business Unit President, Rajeev Venkayya, will discuss TAK-003. And last but not least in the panel discussion, we will have 5 presenters and the CFO, Costa Saroukos, and Teresa Bitetti, Oncology Business Unit President, to answer to your questions. Now I'd like to start with the President's presentation.

Thank you, Chris. Good morning, everyone, and good evening. We are very much, very much delighted to share with you all our Wave 1 pipeline opportunity this morning and Takeda's long-term growth outlook. If you go to the Slide #4, titled A Values-based and R&D-driven Biopharmaceutical Leader, you see that our vision is to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. In other words, our commitment to sustainability. And I hope that you will have a sense that our Wave 1 pipeline is very much aligned with this vision to discover and deliver life-transforming treatment. On the next slide, you see that it has been a long journey. We started our transformation, especially our R&D transformation, back in 2014. We also accelerated our globalization at this time. And our goal was to be an R&D-driven company, value-based, R&D-driven company. Today, 6 years later, we have, we believe, a very attractive pipeline with 12 new molecular entities. We have 14 global brands, which are driving our growth. Back in 2014, we were about to launch our first global brand, ENTYVIO, which is today our leading product by revenue. The globalization and the scale that we gain has also allowed us to increase our profit margin, which is important and which is now in the low 30s, very competitive compared to our peers. But of course, today is only a milestone, we are looking forward to the next 10 years, to accelerate our transformation further, to increase further, improve further our pipeline. Today, we'll not talk a lot about Wave 2 pipeline, which we believe that they are even more innovative than the Wave 1 pipeline. So our growth will continue to accelerate. And our goal, and you will see how we come to this goal, our goal is to be a company with a JPY 5 trillion revenue by 2030. So what we have done today is, first, we want to talk about our global brand. Then we will give more detailed information about the value of our Wave 1 pipeline. So on the next slide, I'll start with our global brand because, obviously, today, these are our growth drivers. This global brand represents USD 10 billion revenue growing -- in 2019, growing 20% -- more than 20%, exactly 21.7%. And we believe that this growth will not decelerate. Quite the contrary, we will continue to grow this global brand, adding USD 2 billion of revenue every year. And today, we have updated what our vision of the peak revenue for some key brands. I'll start with ENTYVIO. ENTYVIO is continuing to grow. Ramona will talk more about it. We believe that it will continue to grow in the -- in the coming years. We are giving an update, a peak revenue on Gattex and ALOFISEL for the first time, both very competitive products in the field of GI. We are also providing a peak estimate for TAKHZYRO. TAKHZYRO has been launched a few years ago, has been extremely successful. In fact, TAKHZYRO is redefining the treatment of hereditary angioedema. And we believe that it will be a key growth driver for the future. And then we are confirming the peak revenue estimate of our key oncology products, NINLARO and ALUNBRIG. Another key growth driver that we shouldn't underestimate at all is the immunoglobulin business, which will continue to grow in the high single-digit range in the next decade. We are extremely confident about this growth outlook. We are now strategically managing this plasma-derived therapy business. We are aligning all the pieces of the puzzle from collection, manufacturing, to access to market, and we believe that we will continue to grow in the next decade this business. So this is very significant growth drivers for us, these 14 global brands, especially in the next 5 years. Let's now move to the Wave 1 pipeline assets. And what we are providing today is more granularity about these 12 new molecular entities, 12 products in our Wave 1 pipeline. All of them are extremely innovative. In fact, many of them have a breakthrough therapy status, Andy will talk about that. They are extremely targeted. Their revenue potential differ depending on the size of the population, of the number of patients, how competitive they are as well in the marketplace. So what we wanted to really provide today is a sense about the revenue potential of these 12 new molecular entities because, obviously, they will be key growth drivers, especially in the second part of the decade. And I hope that it will be useful for everyone to understand how we see every single product in its market and what type of revenue potential we have with every single of these products. We didn't include all the product. And of course, this will evolve over time. For example, TAK-999, it's a product that we recently added to our pipeline. We didn't include it yet. And of course, we believe that it has a significant potential for the future. But this is the first time we are providing this level of detail on our pipeline. We feel this is the right time because this is a pipeline which is about to come. We -- in fact, we have already filed TAK-721, Eohilia. So that would be our first launch. We are about to file our dengue vaccine. So that's why today, we are doing a deep dive on both products. We are planning to file 7 NDAs in the next 12 months. So today is a key milestone because this pipeline is not a dream, it's not a vision, but it's a reality and we are very excited about that. On the next slide, we are breaking down our growth outlook. First, between now and 2014 -- 2024, between now and 2024 and then between 2024 and 2030. And you can see that in the first part of the decade, our growth will be mainly driven by our global brands. As I mentioned earlier, these global brands are adding about USD 2 billion of incremental revenue per year. And we believe that, that trajectory will continue in the near future. Then in the second part of the decade, we are assuming for the moment that ENTYVIO biosimilar entry will be in Europe in May 2024 and the U.S. in May 2026. So this is our assumption in this modelization. What I would like to stress out that this biosimilar entry date is the earliest entry date because we have some patents with an expiry date beyond 2026. And then the Wave 1 pipeline assets will really start to have an impact in the second part of the decade. And what you can see here is that if you take a PTS-adjusted approach, our CAGR, our growth for the decade will be low single digit. Non-PTS adjusted is mid-single digit. We believe that our growth outlook will be closer to the non-PTS adjusted than the PTS adjusted. Why? Because many of our Wave 1 pipeline assets are about to be derisked. Take maribavir, for example. We just announced a few days ago the result of the Phase III programs. So you have a product like that where suddenly, the PTS will jump 20 points from the 70s range to the 90s. And that's what we believe will happen in most cases in the coming 12 months. So this is our belief. These assets have been very carefully selected and worked out by Andy and his team and we are very confident about our success rate in the coming years. And this is why we are committed to reach JPY 5 trillion revenue by 2030. This is an ambitious but realistic goal. We'll have other opportunities on top of the Wave 1 pipeline assets that we are showcasing today. We could do some bolt-on acquisitions in case we need, but JPY 5 trillion is our goal for 2030. Thank you very much.

So this is Andy Plump and I'll take over from here. If you could please advance to Slide #10. To the next slide, please. And the next slide, Slide #11. So I'm going to -- if you will, I know that each of you are advancing the slides on your own. So I'll orient you, and the rest of the speakers will orient you to the slides. I'd like you to please hold on this slide for just a couple of minutes. I have 3 intents in my 15 minutes. If we go back 1 to Slide 11, we're going to stay on the summary slide. The first -- my first goal is to really spend a few minutes summarizing what we've accomplished since 2014 vis-à-vis our R&D transformation. The second is to give you an overview of our R&D strategy and importantly, our pipeline. And thirdly is to outline our strategy for communication with each of you, our investors. A half decade ago, we launched an R&D transformation, strategic and structural, that was quite profound. We are almost an unrecognizable organization, aside from our history and our values, to the one that we were in 2014. What were the main elements of that transformation? Innovation. We raised an innovation bar, a bar that was focused on strong translational science and on patients. As an example of what we've done, if you compare the pipeline today to the one that we had even in early 2016, 90, 9-0, percent of that pipeline is new. That's quite remarkable. Globalization. We're now an R&D organization that strives to deliver all of our pipeline programs globally, including China, concurrently. That's quite different than the regional organization that preceded our transformation. TA focus. We're an R&D organization that's vertically focused in now 4 core therapeutic areas. Modality diversification. We were an organization that was outstanding and still are in small molecule chemistry. We're now an organization that's diversified against -- across large molecules, cell and gene therapies. 90% of our pipeline pre transformation was small molecule. Today, it's half and half. And if you look at our research organization, something that we don't often share, over 75, 75% of our programs in research are recombinant large molecules, cell or gene therapies. Partnership. We are a partnering organization. Partnerships range from smaller and enabling to larger and quite foundational. Over the past 5 years, we've put in place over 200 partnerships. Our footprint is vastly simplified. We're now an R&D organization that has its hub in Boston with regional centers in Japan, in China and in Europe. And let me give you an example, again, of the vastness of the transformation. When Christophe joined the company, when I joined the company 5 or 6 years ago, 10% to 15% of our R&D organization was in Boston. That number is now at close to 70%, 7-0 percent. And then importantly, we're an R&D organization that really builds a culture, a culture of high performance, of diversity. 60% of our extended R&D leadership team is female. An organization that works hard to attract and retain the talent. And actually, I'll give you another statistic that's quite interesting, which is that while we've gotten more and more lean, through our higher integration, and while we've co-localized to Boston, during the COVID pandemic, we've hired over 600 new R&D scientists and experts. So if we can go to the next slide, please. So who are we today? Today, we are an organization that is highly focused in 4 core therapeutic areas, as you can see in this slide. And we have focused and very dedicated experts within our 2 business units, plasma-derived therapies and vaccines. We're an organization that over the past several years have built internally foundational capabilities in cell therapy, in gene therapy and in data sciences. And as we'll discuss, and as Christophe has already mentioned, we're an organization that now has an innovative pipeline. It's not about quantity. It's about quality. And we're an organization that now has 40 high-quality molecules in our pipeline. And as we've discussed, we're an organization that still has a very robust partnership network. Now if you can go to the next slide, which is Slide 13, let me spend a minute talking to you about our innovation model. Our innovation model has 2 elements to it. First, we are a very strong laboratory internally. We have strong scientists in Boston, in Shonan and in San Diego. These are scientists and laboratories that can innovate on their own. And that's exactly what we've done with our Orexin program, a particularly challenging chemistry program. We were the first. We're first-in-class and we're going to be best-in-class. We're also a culture that inverts our science and faces our science outwardly to enable our partners. And that's a huge part of our operating model, to create innovation from within and innovation through our partnership network. And we pride ourselves on partnerships that are a win for Takeda and perhaps more importantly, because oftentimes, our partners are much smaller than us, wins for our partners. Over the course of our transformation, we've restructured our organization and we've integrated key elements of partnering, key capabilities, and reformatted our budget and our incentive system to really align all of our R&D scientists with 1 key mission and that's to drive innovation to patients, no matter where that innovation comes from. Now if you look at our sweet spot for partnering, it's in the research space, but we've done quite a bit outside of the research space. You're all familiar with our 3 acquisitions over the past several years: TiGenix, ARIAD and more recently Shire. We've done in-licensing. But our model fundamentally is predicated on building strong research and platform-based partnerships. And we've been quite successful in doing that and it's delivering. It's delivering in Wave 1. An example of that is our CAR-NK program, TAK-007. It's delivering even more so in Wave 2. And I think the best example of that is in our oncology portfolio, where you see the emergence of novel, first-in-class, innate immunomodulatory mechanisms and cell therapy. And in research, which you don't see, we have dozens of exciting partnerships. And actually, because we partner, we can scale in a way that's much larger than our size across all our therapeutic areas: Denali, blood-brain barrier-penetrating antibodies for Alzheimer's and other forms of dementia, making great progress; Carmine, as you can see on this slide, a new partnership we put in place this year for our rare genetic and hematology franchise. These are nonviral, red blood cell-based gene therapy vectors. Ambys in GI, liver regeneration; and Turnstone, as shown on this slide, as an example of one of our approaches in our immuno-oncology portfolio. We also have partnerships that are designed to expand our capacity and to share risk. We just did a really large and very significant partnership of our psychiatry portfolio just this past year with Neurocrine and that's a great example of the bi-directionality of our partnerships. Now we're often asked in our meetings with many of you, "Are you going to do bolt-ons? Are you going to do mergers and acquisitions?" Well, right now, as Costa and Christophe and all of us have told you, our capital allocation policy is the following: it's pay down the debt; it's continue to support the dividend; it's support our businesses, predominantly in plasma and growing in China; and it's to support R&D. That's exactly what we're doing. And over the last 2 years, since the Shire integration, we've laid out close to $1 billion in upfront capital to support this partnership network. So if we go to the next slide, Slide #14. I won't spend a lot of time on this slide, but I love it. It's a slide that we rolled out in November of 2019 at our R&D Day. And it's a dynamic visualization of our pipeline that's very consistent with how a modern-day biopharmaceutical company should be looking at their pipeline. It's not listed in a static way by phase, because we don't think by phase. We think of the most rapid way to bring our innovation to patients. We think by time, not by phase. Now of course, not every molecule that we're showing you here will make it; not every molecule will make it in the time line that we're forecasting and hoping for. Some will accelerate and some will add. But we're out there, we're really trying to push the limits and drive time and not phase. If I just go through this very quickly and you'll hear more about it today and over the coming weeks and months, in Wave 1, we're delivering. We have 12 new molecular entities that we target, with reasonable to high probability of success, launches by 2024. All 12 of these tackle high, unmet patient need. And as Christophe mentioned, many of these have regulatory designations very consistent with their high innovative potential, breakthrough designations, fast-track designations, Sakigake designation, for one. And actually, we were the first ever multinational company to receive a breakthrough designation by the CFDA, the first ever. It really speaks to what we're doing. So far in Wave 1, we filed one of these molecules. We'll hear more about that shortly from Mike, TAK-721. And we expect and hope to file 6 more over the next 10 to 12 months. And then if you look at the end of this Wave 1 period, we have 2 franchise potential programs that are making great progress and we'll talk briefly about them, TAK-007 and our Orexin program. In Wave 2, Christophe mentioned TAK-999, a program that has the potential to accelerate in Wave 1, depending on what our regulatory path looks like. TAK-981, a molecule that we've discussed previously, really novel, interesting SUMOylation inhibitor that is driving really intriguing effects on innate immune responses and we've seen early responses. Too early to say very much, but if we continue to see these responses, it's a program that will move up by a year or 2 into Wave 1. All right. What you're not seeing on this slide again is research and I'll just comment, because we don't spend a lot of time talking about research, that in order for us to be a biopharmaceutical company that sustains well into our future, it's not just the Wave 1 and Wave 2 pipelines, but it's our deep foundational investment in research. And our focus in research is in quality, not quantity. We're bringing forward molecules that have high quality and high potential of making it. And our research organization has also grown its capacity over the past few years. We now have 50%, 5-0, 50%, more candidates coming through the pipeline. And then the last comment I'll make is that our focus in R&D today is on predictability [Audio Gap] to really deliver it. We're innovating. We've got great science. We've got great partnerships. Now we have to make sure that we can deliver. And that's a major emphasis and a top priority for myself and for the R&D leadership team. And then secondly, we've all worked through this incredibly challenging period. In fact, we're still in it during this pandemic. We've implemented an activity that we call silver linings, in which we're identifying areas where we can leapfrog ahead in our ability to execute and to implement using new tools, new approaches, new ways of thinking. And the vast majority of what we're doing in our silver linings program will involve new digital technologies. So let's go to the next slide. I have 2 more slides left and then I'm going to hand it over to Ramona. If you go to Slide #15, I get a big smile, I know you can't see me right now, but I have a big smile on my face when I present that slide, because this slide speaks to our Wave 1 -- our 12 Wave 1 new molecular entities. And what I love about it is that it shows that it's happening. We're delivering and executing in real time. All 12 of our Wave 1 programs over the next 18 months or so will have major pivotal milestones: submissions and approvals, readouts and pivotal study starts. In fact, there's a -- this slide is already out of date. As Christophe mentioned, we had an exciting result, that we disclosed top line for maribavir and we intend to file maribavir by the end of this fiscal year. And then programs that haven't studied -- that haven't started their pivotal trials such as TAK-007 and TAK-994, we believe, based on the severe nature of these diseases and the profiles that we've seen so far with these molecules, that we can accelerate them very rapidly towards submission and approval, which is a general theme throughout our pipeline, is really to go after targeted focused patient populations where you can see higher effect sizes. All right. If we just go to the next slide, the last slide before I pass it along to Ramona. This is Slide 16 for those of you who are following. I think one of the questions that we've had to ask ourselves is how can we help our investor base better understand our pipeline and assume the same energy and enthusiasm that we have for this pipeline? We recognize it's a very diverse pipeline. We recognize that many of these areas are new for Takeda. And we also recognize that many of these areas are new for all of us. We're going after diseases that don't have any existing therapies or have very poor therapies. And so we realize that these are less -- in many places, less well-defined markets, and so it's incumbent upon us to provide education and an understanding for what we think of this. You guys will make your own decisions for what you think of it, but why we're so enthusiastic. And that's something that we're starting today. So there's 3 ways that we're going to be helping you to understand our thinking around these programs. The first are iterative R&D Days, where rather than going broad, we will go deep. We'll start today. We're going to go into the development status, the commercial potential, and where appropriate, provide additional data. Today, we're going to start with Eohilia, TAK-721, and our dengue vaccine, TAK-003. We have a date set now in April where we'll come back. And our plan then is to dive into our oral Orexin program, into maribavir. Those data will be presented at a congress between now and then. And then probably 1 or 2 of our oncology programs, depending on the timing of data rollout. Secondly, as you will see in the material that we're providing today, we are enhancing our background material so that it's crisper, clearer and more readily available to you. You will have 1 page summaries of all of our Wave 1 programs with updated market potential, unmet medical need, in some cases, data and time lines. For the global and some select important regional brands, we've also provided a sense for disease prevalence, epidemiology and diagnosis rates. Again, very simple -- very simple visuals. And then thirdly and lastly, clinical trial summaries. So for all of our programs, Wave 1, Wave 2 and the important LCM programs, we've provided overviews of each of those clinical trials, again where appropriate with time lines. And then lastly, we're committed. We're committed to keep going, to meet with you individually and also to provide during these interactions and our quarterly analyst meetings, at conferences, as much update as we can. So with that said, I rushed through a lot. I hope that was helpful for you. And I'll, at this point, hand it over to my colleague, Ramona Sequeira, who runs our global commercial organization and our U.S. business unit. Ramona?

Thank you so much, Andy. So good morning and good evening, everyone. If I could just get you to forward to the next slide. The next one. Yes. Thank you. So no, sorry, the last one. One back. Yes, that's it. Stay right there. Thank you. So before we dive into a few of our pipeline assets, we wanted to spend just a few minutes to remind you of the importance of our global brands to our mid- and long-term revenue story. We continue to invest in R&D and in our commercial organization to drive growth globally across these brands. We've built many of these capabilities on the backs of products like ENTYVIO and Trintellix. We were very fortunate to have them at Takeda. With completion of the acquisition of Shire, we even enhanced these capabilities and now can apply them across our entire portfolio of very diverse products, including rare disease, and we're really looking forward to taking these capabilities that make us successful today and applying them to our future pipeline as well, that Andy's team is bringing to life so nicely. So next slide, please. So this is Slide 19 on your deck. Really, as we talk about the future potential for ENTYVIO, and as Christophe mentioned, we've increased that potential based on the very positive momentum that we see today and have seen over the past few years and see continuing. Clearly, we've built strong momentum even through the first half of a very unique year in fiscal 2020. And we've built this through a number of competitive launches in this space over the past few years, in both ulcerative colitis and Crohn's disease. And the reason is we have a multi-pronged growth strategy to ensure that momentum continues so that we can reach our potential with ENTYVIO. And this growth strategy, combined with the fact that ENTYVIO is more and more occupying a very unique place in the market as the only gut-selective biologic for IBD, gives us confidence that we can actually continue this momentum as this market becomes more competitive in the future as well. Next slide. So this is Slide 20 in your decks. A little bit of a double-click on this growth strategy. So currently, we are launching the subcu formulation in Europe. We have both a subcu and an IV formulation on the market. And this launch provides us with the opportunity to expand our patient population through gaining depth with our current prescribers, while at the same time, adding new providers to increase breadth. The initial demand for the subcu is higher than expected and our early research is showing that for both patients and providers, the ENTYVIO pen is the preferred subcutaneous injection device in this market. So very early days, positive news in those early days. The next thing I'll talk about is geographic expansion. We have recent IV launches in both Japan and China and are expecting reimbursement in other markets as well around the world, including Brazil, allowing us to truly make ENTYVIO more available to patients globally. In China specifically, the IBD market here is very undeveloped and we expect significant market expansion in the coming years with up to 8 biologics entering the market in the next few years. I'm going to speak a little bit more about these next 2 buckets, clinical differentiation and real-world evidence, on a future slide, but suffice to say that we have a robust clinical plan in place, including work on risk stratification in Crohn's disease to better support treatment decisions, since we know that Crohn's disease progresses and presents differently from UC. And we believe ENTYVIO has potential for growth across all of the segments in this space. And finally, I'll just mention the needle-free device. And here, we're really pushing the boundaries further in partnership with our R&D organization with work on a needle-free device. We know that up to 25% of patients are needle phobic or needle fatigued, which can certainly affect compliance and efficacy. Certainly, if this was approved, it would be the first of its kind device, and we're excited to be continuing to try to bring new innovation to patients in this space. Then go to the next slide, please. So this is Slide 21 in your deck. We've built a robust portfolio of evidence showing ENTYVIO's profile as really the best first-line biologic to treat IBD. With VARSITY, we completed the first head-to-head study in IBD. Results were published in the New England Journal of Medicine and showed vedolizumab superior to adalimumab in achieving clinical remission and mucosal healing at week 52 in patients with ulcerative colitis. And on the real-world evidence side, we have more than 5 years of real-world usage and data, including VICTORY. Again, we were able to show, this time partnering with a number of centers across the U.S. in a real-world setting, that ENTYVIO was associated with a significantly higher rate of clinical remission when compared with anti-TNF treatments. So that body of evidence spans across multiple sources of data and multiple years of use of ENTYVIO in the market and that is why you see it being used more and more as the ideal first-line biologic to treat IBD. And if I could just go to the next slide, please. So I'll spend a little bit of time on this. Over time, as I mentioned, we've built a strong set of commercial capabilities that we're able to apply across our portfolio. And these capabilities are going to be critical to our future launches as well as we start to build launch excellence and prepare for the pipeline that's coming towards us and our patients. The key here is understanding, first and foremost, the health care ecosystem, which is going to look different in different markets. And we spend a lot of time really making sure that we're embedded in understanding that. Mapping out the patient journey and focusing on diagnosis rates. Many of the molecules we're bringing to market are in areas that are rare, underserved, there's not a lot of knowledge in this space outside of the patient and small provider communities impacted. And many of these patients spend years trying to get a proper diagnosis. So building our capabilities there is incredibly important and we have been doing that and continue to do that. Data, analytics and insights is another one. So we have and continue to build a very strong data backbone, which has then allowed us to be more sophisticated with advanced analytics, especially important in areas of rare disease and many of our pipeline areas, where data is just less available and less accessible. And so our ability to source different types of data and to triangulate different types of data to get the best analytics to be able to dictate our actions is very important. We have, I would say, a best-in-class patient services organization, fit-for-purpose for each disease area. We really take the time to map out what patients with a particular disease need from us and tailor those patient services to that. But at the same time, we have the benefit of a spine of services and analytics that will allow us scalability and best practice sharing as we look to apply patient services to our pipeline as well. And value-based partnership is an area that we've been doing more and more in. Again, using that data as a very strong backbone, along with great alignment between medical affairs, health outcomes and market access. And we've been able to implement a number of value-based agreements, including across rare disease and ENTYVIO. And really, as we look at our pipeline, we're already starting to think about the data that we're seeing from the trials and the types of value-based partnerships that we could create to make these medicines available to as many patients as possible. So these past few years, we've been able to apply these capabilities to our full portfolio across our business. And this is why you see us driving 15% growth across our global brands. We're really proud of the commercial team and the global team's ability to execute, to transform and to perform. And we're very much looking forward to adding launch excellence to that list as well. And with that, it's my pleasure to turn this over to Mike Nedham, who's going to speak to you about what looks likely to be our very first Wave 1 pipeline launch. Mike?

Great. Thank you, Ramona. So I am Mike Nedham, I'm the global program lead for the TAK-721 program and I'm really pleased to take you through this 30-minute deep dive on what's a lot of exciting progress in recent months. So if we can start on Slide 25. And I actually want to start by highlighting the 3 key takeaways that I'm going to cover in the presentation and come back to at the end. So the first is that the unmet need in this area is really high. It is a growing health care problem and more leadership is needed. We're talking about a chronic inflammatory disease which impacts quality of life, can lead to long-term fibrosis. And the incidence and prevalence are growing, with currently no FDA-approved treatments. Secondly, the 721 product is designed specifically for this disease and for this patient group. The program has breakthrough therapy designation. It's already completed its registration studies and recently filed the NDA with an expectation to be the first approved product in the U.S. And thirdly, to highlight that this fits well within the existing GI portfolio and capabilities for Takeda, as Ramona has just been highlighting, building on the success with our existing GI brands and our future portfolio and we believe we're well prepared to launch next year. So next slide, what is EoE? Well, it's eosinophilic esophagitis. Well, as the name suggests, it is a disease characterized by raised eosinophils in the esophagus. And in a healthy individual, there should not be any eosinophils present here. This is a rare disease and it is increasingly understood to be a chronic disease involving a long-term inflammatory response with the primary symptom being dysphagia, which is the clinical term for pain and difficulty swallowing that you'll hear repeated throughout the presentation. And as with most inflammatory processes, if left untreated, it can progress to fibrosis. And that can result in structural changes, including strictures and narrowing of the esophagus. And ultimately, that means that food cannot pass through the esophagus and can even become stuck, resulting in a food impaction. And a confirmatory diagnosis for EoE currently requires a biopsy of the esophagus using an endoscope and a pathology count of more than 15 eosinophils per high-powered field. And you'll see that term later on, eosinophils per high-powered field, which is an internationally recognized approach used for this disease. So on the next slide, that's technically how the disease is characterized, but what does that mean if you're a patient actually living with EoE? And there's 3 key areas to highlight here. The first is the physical pain of having difficulty swallowing. It's a high level of discomfort as food tries to pass through an inflamed esophagus. And ultimately having a food impaction is often described by patients as feeling like you were choking, which can be frightening and often means you need to go to the ER for endoscopy to remove the food and the associated physical discomfort, both of the procedure -- during the procedure and afterwards. The second is staying nourished and many moderate to severe patients describe the daily battle of trying to consume enough calories to maintain a healthy weight, particularly for adolescents and young adults, where peers can sometimes assume they're making a choice to be very thin when they're not. And this can be a huge issue as well for parents of children who are falling behind in their physical development. We've actually heard at Takeda, directly from parents running the EoE patient associations, of the distress of watching their children fail to thrive and often ending up with other associated health issues due to a lack of nutrition. And for all those patients, including those with the milder symptoms, the main thing we hear again and again is the association of food with socializing. In all cultures around the world, the two are intertwined. Not being able to enjoy food, having anxiety about getting food stuck, having to hide adaptive behaviors like avoiding specific trigger foods or drinking continuous water, having to chop everything very small and chew continuously, being at the table much longer than everyone else. These are very impactful and end up with patients often avoiding any situation involving food and therefore, significantly limiting their social interaction overall. So on the next slide, we're going to have a look at the patient journey and what these patients have to do in terms of getting diagnosed for EoE and some of the challenges around that. This is Slide 28. So working from left to right, you can see that a high number of patients may have already been diagnosed with other atopic disorders and also many have been diagnosed with suspected GERD, which presents with some of the similar symptoms to EoE. A high number may also be on some form of medication for either disease, including inhaled steroids or proton pump inhibitors or PPIs, and this may actually increase the difficulty in getting a confirmed diagnosis for EoE. To get that diagnosis, the majority of patients will be sent for an endoscopy, though not always with a recommended biopsy, and this will be performed by a gastroenterologist. As you can see, there are a small number also diagnosed by allergists without endoscopy, based on symptoms. And allergists can actually play a significant role in terms of managing EoE, especially where there are atopic comorbidities. However, the majority of product initiations are also currently done by the gastroenterologist, though this can take anywhere up to 18 months. And the average persistence of current therapies is somewhere around 3 to 6 out of the first 12 months following initiation. And so 2 key areas for improvement in the management of this disease are that interface between these specialties, especially early in the patient journey to help identify the patients correctly; and then also the educations of the patients themselves, to be able to recognize what these early symptoms are and seek the professional help. And we believe both of these are needed to support the effective management before the chronic consequences of the disease progresses too far. Okay. So on the next slide, we're now going to look at how big a problem this is. While EoE is still relatively new globally, it's thought to affect around 1 in 2,000 people in the U.S. where prevalence is relatively high. And a key feature is the speed at which the prevalence is growing, especially in the last decade. The reasons for the recent rise in EoE cases are still being fully understood, but is likely a combination of both the increased awareness and diagnosis rates among the specialists, but also increases in the underlying causes. There's belief to be both a genetic and an environmental component and the microbiome and early life exposures to antigens also potentially playing a role. The typical patient for EoE will be a young adult male who may have been living with the dysphagia symptoms for quite a while, not fully aware of what is causing his difficulty swallowing and already doing some adaptive behaviors as the symptoms worsen. But this is also a disease that is rising in children, sometimes severely affecting young infants, but often affecting adolescents as they transition through school and college. So that's a little bit on the epidemiology. The next slide, which is Slide 30, is to illustrate how the academic and research interests have grown in parallel to this rising prevalence. So you can see on the left the first case report starting in the 1970s, then experimentation with off-label treatments through the 80s and 90s, but only really around the turn of the century that the first consensus guidelines and official disease codes emerged. But then leading up to the last 12 months, where we've really seen a lot of activity, updated guidelines in the U.S., both from the FDA on drug development, and also the combined medical societies of gastroenterology and allergy immunology on how to approach the diagnosis and treatment. A clear example of this, actually, in terms of the activity is the last DDW, where we saw more than 80 posters and sessions on EoE, covering all aspects of understanding the disease and how to improve standards of care. And that's for the EoE specialist, but it's increasingly for the general gastroenterologists, who aren't that aware but are starting to encounter EoE patients more and more. We're also showing here a quote from one of the global experts in EoE, Dr. Hirano from Northwestern. And this really highlights, again, the challenge of adaptive behaviors by patients and why there is such a need for more education on EoE. So what about the current treatment options available? On Slide 31, we're going to cover what's currently available in the U.S. So firstly, there is food avoidance. That can be by the patient themselves if they believe they know certain trigger foods. Though actually, this can be misleading as they'll often avoid the food which gets stuck in the esophagus rather than the antigen-triggering foods that may be causing the inflammation. For physicians, there are some well-researched and understood approaches to active diet management, like the 6-food elimination diet, which has been shown to be very effective. However, the effort required to identify the triggers, including multiple trials and endoscopies, and also the social impact of food avoidance, often means that patients struggle to comply effectively. And we have seen in market research that esophageal dilation to physically widen the esophagus, is also used, often following a food impaction. And this is temporarily effective, but is not really treating the underlying cause of the issue. And then there is extensive use of off-label treatments necessitated by the lack of any approved therapy. So proton pump inhibitors have been used extensively, but the evidence base is considered low in the recent guidelines. And as we saw, steroids are believed to have been effective for a while, but there is a major challenge in getting a topical mode of action to the relevant site of inflammation without producing systemic effects. So the creative solutions currently include asking patients to spray an asthma inhaler orally, but then try and swallow it instead of breath it, asking compounding pharmacies to create bespoke products at different doses. And actually, the most common approach is using the respules from inside an asthma inhaler and asking patients at home to combine it with thickening agents like sugar or honey to try and stick to the esophagus. And obviously, none of these solutions right now are ideal for the prescribers or for the patients. So on Slide 32, I'm just going to summarize what we see as being the opportunity in EoE. We see increasing prevalence and incidents and increasing health care burden and a high impact on the patient quality of life. There's limited access to high-quality treatment options, limited large-scale studies on the treatment effects for regulators, payers and prescribers to make their treatment decisions and currently no approved products in the U.S. And there's a challenge in the consistency of managing the disease with few centers of excellence but high interest among prescribers and patients for better treatment options and low overall patient awareness and education with sometimes long diagnosis times. So overall, we really see an opportunity for leadership in establishing the development pathway for EoE, in bringing new approved treatment options and in supporting the medical and patient communities to improve the standard of care. So in the second half of the presentation, I'll talk more about Takeda's program and why we think this is a good solution to meet that opportunity in EoE. On the next slide, we're going to show that TAK-721 was developed by a team of pediatric and adult gastroenterologists at UCSD in California in response to this challenge of limited treatment options, and it was bought through Phase III in Shire's pipeline and now preparing for launch as Takeda. It is a topically active, oral viscous formulation of budesonide, which has been specifically formulated to maximize residency time on the esophagus and target the inflammatory process on the epithelial layers whilst being minimally absorbed. It's a second-generation corticosteroid with potent anti-inflammatory and glucocorticoid activity and, specific to information seen in the pathogenesis of EoE, has a wide range of inhibitory activities against multiple cell types. As you can see on the right here, including eosinophils, mast cells, neutrophils, macrophages as well as mediators like histamine and cytokines, all of which are involved in allergic mediated inflammation. And it's this wide spectrum of anti-inflammatory actions which are believed to contribute to its efficacy in reducing inflammation in EoE. So on the next slide, aside from the product itself, we want to talk about what we believe is one of the most important factors in this Wave 1 program, which is the pioneering clinical development program of firsts in EoE, which have been focused on partnering with the FDA in the U.S. This program is the first to have received orphan designation in EoE, the first to receive breakthrough designation and recently reached the critical milestone of being the first to submit an NDA for EoE. In addition, the 721 program took the lead in completing Phase II study specific to EoE and the first and largest Phase III studies to be completed so far. The key leadership aspect within this was actually developing a patient-reported outcome tool to be specific to the symptoms seen in EoE. And this was validated with the FDA through our Phase II and Phase III studies. It's called the DSQ, which stands for the Dysphagia Symptom Questionnaire. And we're pleased, as a company having established this as a gold standard research tool in EoE, to be sharing it widely with other manufacturers now as they advance their own U.S. programs for patients with EoE. And finally, we started the first registration studies, which covered all aspects of EoE including histology, symptoms, endoscopy endpoints and also including adults and adolescents, aged 11 and up, in one comprehensive development program. So on the next slide, we're now going to come on and talk about some of the results of the ORBIT1 study, which was the first Phase III study to read out and was presented during the presidential plenary session at ACG last year. So this was a Phase III randomized, multicenter, double-blind, placebo-controlled trial. Patients were randomized to receive 721, 2 milligrams BID or placebo for a period of 12 weeks and a total of 318 patients were enrolled. Aligned with the FDA, the co-primary efficacy endpoints were histologic response, which was a peak eosinophil count of equal to or less than 6 per high power field across all the available esophageal levels and also the dysphagia symptom response, which was an equal to or greater than 30% reduction in the DSQ score. So as you can see from the chart on the left, the histological response was very strong, with greater than 50% of patients achieving the required eosinophil reduction versus just 1% on placebo. Also bear in mind here that the average eosinophil count at baseline was 75. And in the chart on the right, you can see the symptom response for 721 was also above 50%, with the majority of patients seeing a 30% or more reduction in DSQ. We did also see a significant response on the symptom endpoint from placebo, which is commonly seen when using symptom questionnaires in GI diseases. But the delta for this primary endpoint was still statistically significant, well below the required threshold p-value of 0.05. Moving on now to some of the secondary endpoints. So a key secondary endpoint in ORBIT1 on the left here was required by the FDA to show an alternative way of showing DSQ, which was the mean change from baseline. And you can see this was also significant and actually reached an even stronger p-value than the previous end point. And on the right-hand side is another secondary endpoint looking at the change from baseline in the histology. And again, this was seen as being highly significant. So this really reinforces the effect of 721 on both histology and symptoms from multiple endpoints. And finally, on efficacy on the next slide, which is Slide 37. I wanted to highlight another important endpoint, which was the change in endoscopic appearance. So this was measured using a validated EREFS score, which stands for EoE Endoscopic Reference Score. And basically, this categorizes the common esophageal features in EoE, which are edema, rings, exudates, furrows and strictures. So as you can see from the chart on the left, the 721 arm in the study showed significant improvement in the appearance of the esophageal lining over the 12 weeks and was highly significant versus placebo. But to help visualize the response, we're also showing here on the right a single patient example from this study of endoscopic appearance before and after treatment with 721, which hopefully helps visualize the types of changes that were observed. So that's some of the key efficacy data on Slide 38. We're going to also cover safety. So overall, this study showed that TAK-721 was well tolerated. Treatment-emergent adverse events were similar for 721 in the placebo groups after 12 weeks. Actually, you can see the percentage was actually the same between the groups here. And most of the TEAEs reported were mild or moderate in severity. And this is consistent with what we have previously seen as a safety profile for budesonide. Okay. So having seen some of the pivotal data, I'd now like to cover our expected time line. So as you've seen, the ORBIT1 study was completed last year. We've also recently completed the ORBIT2 study, which is the 12-month long-term extension study, featuring a randomized withdrawal design rolled over from ORBIT1. This is the first long-term maintenance registration study completed in the U.S. for EoE and also formed part of the NDA, which was submitted last quarter. We do expect to release the data from the 302 study as a publication in the coming months and prior to the potential approval of the NDA. The approval itself will depend on whether we receive priority review from the FDA, and we hope that will be confirmed shortly. If granted, we would expect the potential approval in late fiscal year '20 or early fiscal year '21, with a commercial launch to follow quickly afterwards. Okay. So in the next and final section, I'm going to cover a few slides on the commercialization plan for this program. On Slide 40, I'll start by talking about the positioning. So if the NDA is accepted and approved, we would be the first FDA-approved product for EoE. And as such, we believe we will become the gold standard therapy for patients with EoE and be used as a first-line treatment. With the existing knowledge of corticosteroid efficacy, support already in the guidelines and a high level of excitement about access to a product developed and approved for this specific indication for the first time, we're confident in strong uptake in this position. It is exciting to see many other companies also now looking at EoE and particularly with multiple biologics entering clinical trials, and we expect that if successful in their development, they would provide important options of second-line therapy. A key component of the strong uptake that we want will be our patient access. So on the next slide, it highlights that our overall is to ensure that we achieve broad access for the maximum number of both new and existing patients with an EoE diagnosis. As you've seen throughout the presentation, we do believe we have a very strong value proposition for payers to support this. Another important context for existing patients is that many of them have to pay full out-of-pocket expenses due to the off-label status of the current products being utilized. And of course, as Ramona talked about, we will leverage Takeda's existing network of services and solutions to maximize our support for patients to gain access to this product. On the next slide, I'll talk a little more around our commercialization activities. One of the key steps, as Christophe and Andy have already mentioned, is to finalize a brand name. And we're pleased to confirm that we do now have conditional approval from FDA for our proposed brand name as you see here. And this is pronounced Eohilia. In terms of launch preparation, we're already planning for success by completing the hiring and training of our field medical and sales teams, if we can go to the next slide. And we've also already launched a new Disease State Education initiative called SeeEOE.com for health care professionals. And we're working extensively with thought leaders in both GI and allergy immunology to build the excitement around the data and the product launch. On the patient side in the U.S., we're launching new digital initiatives to build awareness around the signs and symptoms of EoE and ensuring that the appropriate patient services and early access plans are put in place. We're also excited to announce now that during the Phase III clinical program, we have worked hard on evolving the product itself to increase stability, remove the need for refrigeration, and also package into a single dose Unistik for maximum patient convenience. And we're pleased that we now plan to have this commercial presentation ready for the patients at launch. And importantly, we continue to work closely with the patient advocacy groups to partner on ways we can continue to drive education about the disease within the EoE community. And lastly, on the next slide, as Ramona talked about, we have fantastic leadership in GI already established through the continued success of ENTYVIO in IBD, but also in the U.S. business unit through the continued growth of Gattex in Short Bowel Syndrome, which is also our rare disease brand, allowing us to really leverage both our GI and our rare disease launch capabilities for Eohilia. We believe launch can build on this leadership and expand into a new area of unmet need and support gastroenterologists to further elevate the current standards of care. And this also continues to set the strongest foundation for launching the exciting Wave 2 pipeline of GI therapies that Andy showed earlier on. And so I'd like to finish again on Slide 45 by reinforcing the 3 key takeaways for this program. First, the unmet need in EoE is high. This is a growing health care problem and leadership is needed. It's a chronic inflammatory disease, which impacts quality of life and can lead to long-term fibrosis. The incidence and prevalence are growing and there are currently no FDA-approved treatments. Secondly, Eohilia is designed specifically for this disease and for this patient group. The program has breakthrough therapy designation, has completed its registration studies and already filed the NDA. And if successful, we expect it to be the first approved product in the U.S. And third, we believe this fits well within the existing GI portfolio and launch capabilities for Takeda, building on the success with our existing GI brands and further building for our future portfolio, and we're well prepared to launch Eohilia in 2021. So with that, I'd now like to hand over to Rajeev, President of our Global Vaccines Business Unit for our next product deep dive.

Thank you, Mike. And thanks, everyone, for joining today. I'm delighted to speak with you about a very important vaccine that Takeda has been working on since 2013 but has been in development for long before that, and that is TAK-003, our dengue vaccine candidate. As I think many of you know, Takeda has been working in vaccines for over 70 years. And in fact, since 2012, have been advancing a global pipeline of vaccine candidates to tackle unmet needs in infectious diseases, the most advanced of which is this dengue vaccine. Now this has been a long journey for us. And we have weathered significant challenges, the most significant of which was following the launch of the first licensed dengue vaccine after there were safety considerations identified that subsequently led to the restriction of the use of that vaccine to individuals above the age of 9, with a documented prior exposure to dengue. This is a very important consideration for anyone that is working to tackle dengue. And I'm going to speak later in the presentation about the safety considerations in developing vaccine candidates for dengue. Of course, now we are in a new world where another infectious disease has captured the attention of everyone and has also demonstrated to the world the value of vaccines in a way that as we have not seen in a generation. It's an extraordinary time, and we believe the attention to COVID will translate to a lot of attention to dengue, which has been around much longer than COVID, of course. Next slide. Let's begin with the burden of dengue disease on Slide 48. About half the world's population, actually more than that, lives in countries where dengue is endemic. And in fact, this mosquito-borne viral disease causes almost 400 million infections every year. Now this disease has not been static. Before 1970, dengue was only in around 7 countries around the world -- sorry, 9 countries around the world. And today, it's in approximately 125 countries around the world, and that's due to a combination of climate change and urbanization and travel. This has captured the attention of health leaders around the world. And in fact, in 2019, just last year, the World Health Organization listed dengue as one of its top 10 threats to human health. Now you may say, well, we see lots of top 10 lists, and this is just another one. But the WHO is a very credible health organization. And in fact, the other items on the list were things like noncommunicable diseases, which was 1 of the 10. HIV was another, antimicrobial resistance was another, as was vaccine hesitancy. And to that list, dengue alone was 1 of the 10. So it highlights the threat today and that is perceived in the future from this disease. Next slide, 49. Dengue is particularly complicated because we're not just dealing with one virus. In fact, we're dealing with 4 different strains of the virus and exposure to any one of those strains does not necessarily mean protection against other strains. And in fact, what we often see in dengue is something called disease enhancement, such that if you have been exposed to one strain in the past, you may have had a mild illness. But then when you're exposed to a different strain, you're likely to have a more severe form of illness. And again, this is called antibody-mediated disease enhancement or ADE. It's hard to know what strain of dengue you might be exposed to if you're living in an endemic area or traveling to an endemic area because we do see that, in any given country, over the course of years, we'll see cycling through different strains of dengue. You might see 1 or 2 strains co-circulating at a time in a country, but certainly during large outbreak years, 1 strain will dominate that will be followed usually by a period of time where that strain isn't very prevalent, usually because of population immunity, but then another strain will take its place. Interestingly and very importantly for dengue, there is not a specific targeted treatment. This is different from, say Malaria, where there are a number of treatments that are available, including some relatively recent treatments to deal with drug resistance. That is not the case with dengue. Next slide. As I mentioned, the burden around the world is growing. And in fact, there was a paper in the journal, Nature that projected that by 2080, over 6 billion people could be at risk of dengue. Now that, in fairness, is primarily due to population growth in dengue-endemic areas, but it almost certainly would also be driven by further climate change and urbanization and travel. I'll also mention that when we talk about dengue-endemic areas, we typically think about warm climates. But the mosquitoes that transmit dengue are actually widely present. And in fact, just to use the example of the U.S. and Japan, we see mosquitoes, the aedes aegypti and albopictus mosquitoes across much of the country, although there isn't much dengue in the U.S. or Japan currently. However, we have seen local transmission of dengue in the Southern U.S. states of Texas and Florida, and we've seen it even a few years ago in downtown Tokyo. So the mosquito is already there. We believe that as climate change proceeds, we'll see more of the virus accompanying the mosquito. And in the future, places like the U.S., Southern Europe and Japan could be dengue-endemic countries. In terms of where dengue is today though, most of the disease that is documented is present in middle-income countries. That's not to say that we don't find it in low-income countries, but our epidemiologic understanding is fairly limited when it comes to dengue in those countries. So we can't actually quantify that. Next slide. When you have dengue in a country, it puts tremendous strain on health systems. We're hearing a lot about what COVID is doing in countries around the world right now. Dengue does something very similar. You can see hospital beds that are full of individuals with dengue during an outbreak. You can have temporary or makeshift hospitals, tents that are set up in order to care for large numbers of dengue cases. And just as with COVID, when you have hospitals that are overwhelmed with dengue cases, the care for all other conditions suffers. And we see poorer outcomes of maternal child health and noncommunicable diseases that are treated in those hospitals. As you can imagine, the cost of dengue is quite substantial at a family level. If a person who is generating income for the household is the person to take ill, then that can obviously have a significant impact. But also out-of-pocket health care expenditures are quite a significant burden on families and often lead to impoverishment in many countries. Next slide. The economic impact and macroeconomic impact extends beyond households. We see that at the government level, substantial resources are invested and control methods that aren't always effective, including some vector control methods like spraying that is often undertaken, both to try to control the mosquito that transmits dengue, but also often to show that something is being done even though what is being done may not be very effective. Of course, the actual outbreaks themselves cause a significant financial burden on governments. And then, of course, there are the long-term macroeconomic impacts in terms of the impact on the economy, the social impact and overall productivity. Next slide. One of the unique features of dengue that is important to distinguish it from other diseases is that dengue affects a broad range of the population, in fact, almost all age groups are potentially at risk for dengue. And so when we think about bringing a vaccine to the market to address dengue, we are talking about a much larger immunization program than we see with most vaccines. If you look at the examples on the left of human papillomavirus or pneumococcal pneumonia in children or rotavirus diarrhea or varicella, which is also called chicken pox, it's a relatively small portion of the population, the pediatric population or adolescent population that is eligible for the vaccine according to recommendations of local authorities. Dengue is very different. Now we don't know how the dengue vaccine will be recommended in countries. But based upon where we see the disease afflicting people, we could envision a very broad recommendation for use in the population. Now this creates a special challenge because typically, when governments are supporting immunization programs, they only have to deal with that small red triangle that you see on the left, that small portion of the population. If a government has to consider immunization programs for the large red portion on the right, the 85% of the population, that, of course, is going to be a significant challenge. I'll also mention that there are no socioeconomic boundaries to dengue, even though there may be some perceptions that it affects a certain segment of the population. Rich or poor and those across borders and even walled neighborhoods are at risk for dengue as we see time and time again. Let's talk a little bit more about that impact, if we can go to the next slide. I want to compare how a government will have to think about dengue to how it normally thinks about immunization programs. And to do that, I'm going to walk through this slide and ask you to flip through your slides as we build this, we're beginning with Slide 54. So you see a triangle here that represents the overall population, in this case, in Mexico. As you move across the bottom of the triangle, you can see the range of ages in the population. And we have put gray color at the 2 ends of the spectrum because this is -- these are places where we do not expect to have an initial license for use of the vaccine. Along the vertical axis, you can see different levels of income and the portion of the population that falls into each of those [ MINs ]. And those percentages mirror the width of the triangle that you see on the right. If you take a next -- if you advance to the next slide, if you take a routine immunization program, as I mentioned earlier, that will typically target a very narrow age band in the population, usually small children. And because the numbers are small relative to the overall population, the government can afford to subsidize an immunization program for those children. You could envision, in the early days of the launch of the new vaccine, having a larger proportion of children immunized, we often call that a catch-up cohort, meaning that when a new vaccine is entering the population and no one in the population has had the vaccine, we want to get a head start to develop some population immunity. And so if you go to the next slide, you could envision the government front-loading some investment -- go back one, please -- to cover more of the population. But that still is a very small proportion of the overall population. And as I already mentioned, there's likely to be substantial demand across all age groups. And so here we need to think creatively about how we can provide access to those populations. Next slide. And one way to do that, which would be explored on a country-by-country basis in partnership with the government and potential financing entities is to see if there is a way to enable those who are not able to afford the full cost of the vaccine out-of-pocket with some financing options that are essentially invisible to them but allow them to pay for the vaccine over time. This has been tried or used, I should say, with many other services and commodities in countries, often through mobile payments, invisible again, where it's not even apparent to the individual through direct debits, and we think this could help to capture a significant portion of the out-of-pocket population. Next slide. Then, of course, there is going to be a very large remaining population, where we will have to develop customized programs to support access. And when I say we, I don't mean necessarily Takeda alone. What I mean is the -- primarily the government, whose responsibility it is to ensure that individuals have access to essential vaccines and medicines, but there may be ways that we can support those efforts. Zooming out to a macro level, we are also exploring ways to support governments to provide more of this -- to provide more immunization support to the population through macroeconomic support instruments that would be -- could be subsidized by regional development banks or the World Bank itself, and we are in early discussions with partners about ways we can do that. Next slide. I do want to mention that when we talk about dengue, we're not only talking about endemic markets where dengue is circulating on an ongoing basis. There are many travelers to the countries where dengue is circulating. And as those of you who have traveled to such places know, we often recommend certain vaccines or treatments to be taken to prevent or treat illness. In this case, there could be a traveler vaccine, a dengue vaccine for people traveling to any of the areas in red. And beyond that, the areas that are not in red in parts -- many parts of Africa and the Middle East likely have dengue that is not yet recognized, and those could be places where travelers are also recommended to receive vaccines. Travel vaccines would be covered either out-of-pocket or by an employer or by an insurance company. And generally speaking, the travel market for vaccines commands a -- the vaccines are at a higher price point certainly than you would find in the public sector in endemic markets. Next slide. So In this context, we have worked to develop a dengue vaccine to tackle the key gaps in dengue prevention. And I've already mentioned that there is an existing level of attention to safety as well as the specific need for a vaccine in persons who have not previously been exposed to dengue as well as younger populations because that often correlates with a lower proportion of exposure to dengue. And so when we set forth to develop this vaccine, our goal was to have a vaccine that is effective against all 4 serotypes of the virus and, most importantly, to be effective irrespective of whether a person has previously been exposed to dengue. We have a dengue vaccine candidate that is actually based on the dengue virus itself, which is an important difference relative to the first licensed dengue vaccine, which is based on a yellow fever backbone. Because this -- our vaccine is based on the dengue virus itself, we believe that it elicits a broader immune response of both an antibody response as well as a cell-mediated immune response, as well as specificity to the strain in that response that we think is very important for breadth and duration of protection. Next slide. We started the Phase III clinical trial in 2016, and this was at a time when we had already known that there were questions about the safety of the first licensed dengue vaccine. And for that reason, we did a few things to maximize the safety of the vaccine and certainly maximize the safety assessment of the vaccine. The first thing we did is that we collected baseline blood samples on all individuals in our clinical trial. That was going to be very important for us to be able to assess how the vaccine would perform in both seropositive or previously exposed individuals and seronegative individuals. We also chose to conduct the trial in a broad range of countries across a broad age range so that we would have a large proportion of individuals that were seronegative so that we could robustly assess efficacy in that population. And finally, we chose to take a 2-dose schedule for the vaccine into the Phase III clinical trial. Previous data had suggested that 1 dose might be sufficient, but in the spirit of being conservative and ensuring that we had the safest vaccine possible, we chose the 2-dose schedule. So this is the design of the large Phase III clinical trial. I say large, it's 20,000 individuals, but I think these days, people are becoming quite numb to the size of Phase III clinical trials. In light of COVID, we are often hearing about trials that are 30,000, 40,000 persons or more in size. But let me assure you that a 20,000 subject trial is very, very large. Indeed, this was conducted in 8 countries across Latin America and Asia. And individuals between the age of 4 and 16 were randomized in a 2:1 ratio to receive either the vaccine or placebo respectively. So the active arm, the vaccine arm was twice as large as the placebo arm. As I said, the schedule is 2 doses over 3 months and then beginning 1 month after the second dose of the vaccine when we are confident that the immune response has been elicited, we began assessing for dengue illness. And the way we assess for dengue illness is to simply look for fevers. And whenever a person in the trial has a fever, then they come in and they are assessed by a blood test in a PCR that determines whether their fever is associated with circulating dengue virus, in which case we call that a dengue case. The primary endpoint for the trial, and I'm going to just explain this because you'll be hearing a lot of numbers here, the primary endpoint of the trial was prevention of dengue irrespective of the strain causing it at 1 year after the second dose. So that's -- when I talk about primary endpoint in 1 year, that's what that means. We wanted to assess a number of secondary endpoints robustly. And so we extended the collection of data for 6 more months. This is what we call the 18-month data that would allow us to determine how efficacious the vaccine is according to individual serotype as well as the baseline serostatus or whether or not an individual had been previously exposed to the dengue virus and then efficacy according to severity, either hospitalization or categories of more severe disease. We have published the data on 12 and 18 months and we recently reported out 24 months of data at the ASTMH meeting a few weeks ago. So I'll be talking -- I'll be sharing with you data not to be -- I don't want to confuse things, but I do need to share with you some 12-month data, some 18-month and some 24-month data, and I'll explain why. Next slide. So the top line -- I'm on Slide 62. The top line finding for us was very, very exciting, and it was reported in the New England Journal of Medicine that we had a high degree of efficacy against dengue caused by any of the 4 strains at 12 months after immunization. That efficacy was at 80%. So it's an 80% aggregate efficacy. At 18 months, as I mentioned, we measured our secondary endpoints. Again, we wanted to accrue more cases to give us a more robust assessment. And here, we saw very good news about the efficacy of the vaccine against disease that was severe enough to require hospitalization, so a 90% efficacy against hospitalization. The efficacy continued to be robust against sero -- the virus -- sorry, the efficacy can be robust in seronegative individuals, those who had not been exposed to virus previously. So 76% efficacy in people who had been exposed to dengue before and 66% in those who had not. And this is a marked difference from the efficacy seen in seronegatives in the first licensed dengue vaccine. Now importantly, we did see differences in the efficacy against the individual serotypes. I said before that the vaccine is based on a dengue type 2 virus. We had the best performance there with 95% efficacy. That type 2 virus, by the way, was also the most prevalent virus in the trial, about 38% of the cases were dengue type 2. Behind that, about 33% of the cases were dengue type 1. And there, the efficacy was around 70%. That was followed by dengue type 3, which was about 28% of cases in the trial. And there, the efficacy was lower, it was around 49%. We did not have enough cases to determine efficacy against type 4 in the 18-month analysis. And generally speaking, the vaccine was very well tolerated. And as I'll speak to further, it has a strong safety profile to date. I'm going to walk you through what we call Kaplan-Meier curves to give you a visual representation of what this efficacy means. Can you go to the next slide? I'll start with hospitalizations, where I've already told you that these were reduced by about 90%. Now I'm showing you slightly different data now because we're looking at 24 months now. So this goes beyond the data that I just showed you in numerical form. The graph that you see here has the time on the horizontal axis measured in months. Remember, the first dose is given at time 0 and the second dose is given 3 months afterward. The vertical axis shows the percent of individuals in the trial were hospitalized. And so you can imagine in a trial, you start to accumulate cases of dengue that are hospitalized, and that is what you see in the lines that rise over time. Now the top 2 solid lines represent individuals who received placebo, the red line solid are individuals who were seropositive at baseline, meaning they had previously been exposed to dengue, the blue line are those who had never been exposed to dengue, those are seronegative. Compare that to the individuals who received the vaccine and those are the 2 lines that you see at the bottom, the dotted lines. Again, blue represents seronegative and red represents seropositive or previously exposed. And you can see a very high degree of efficacy at preventing hospitalization due to dengue. If we look at the point estimates after 24 months, the overall efficacy was 89% against hospitalization. In seropositives, it was about 90% and seronegatives, 87%. So essentially no meaningful difference in efficacy according to whether somebody had previously been exposed to dengue. Now let's look at dengue fever alone. So these are individuals who had a fever. They may have had flu-like symptoms, not been feeling well, if we can go to Slide 64. And here, we find that overall dengue illness was reduced by about 73%. I'm not going to walk through with the lines -- the labels and the lines again. In seropositives, that efficacy was about 75% and in seronegatives, 67%. Again, very similar efficacy between seropositives and seronegatives. And this is absolutely a clear differentiator of our dengue vaccine candidate. Let's go to the next slide and talk a little bit more about the strain-specific efficacy on Slide 65. Here, you can see in a simple bar chart, the point estimates and the confidence intervals for types 1, 2, 3 and 4 at 24 months. And once again, you can see that the best performance is against type 2 followed by type 1, followed by type 3. And then type 4, we had more cases, and so we were able to hone in on what directionally on how efficacy is going, but this is not -- the confidence intervals cross 0, so we can't conclude on the efficacy against type 4. There was one important finding that I want to mention in type 3. Well, we see that the overall efficacy in dengue type 3 is robust. It's 51%. If we compare the performance or the efficacy in seropositive individuals that have previously been exposed to dengue versus those who have never been exposed to dengue, we saw lower efficacy, in fact, what appears to be no efficacy of the vaccine in individuals who are seronegative against 1 of the 4 strains, type 3. And in fact, we have seen an imbalance of dengue fevers in type 3 dengue fevers in seronegative individuals, a slight imbalance. Now I can tell you that the imbalance that we saw at 12 and 18 months has improved at 24 months. And so, this numerical difference that we have seen appears to be stabilizing. We have also looked at the clinical profile of illness in individuals who have received the vaccine and then were infected with the type 3 virus, and we do not see that the disease in those individuals is any different from the disease in placebo recipients who were infected with type 3. I mentioned that because everybody is very sensitive, as you can imagine, to how the vaccine is performing in seronegative individuals. And while we see very good performance overall in seronegative individuals, this is something that we are going to continue to watch. Next slide. So let me summarize then on the safety and tolerability. We believe we have a strong safety profile through 2 years after the second dose of the vaccine, with no evidence of disease enhancement. And as I said, we have seen a stabilization of this issue and seronegatives against -- with type 3. Next slide. And so overall, when we think about our vaccine profile, as we prepared to receive the 36-month data and then file early next year, very strong reduction in hospitalized dengue performance against hospitalization, continued high degree of efficacy against dengue. However, we are seeing and I didn't really -- I didn't point this out, but if you compare the numbers over time, we are seeing some waning of the efficacy numbers over time. This appears to be real. We're going to see how things look at 36 months. But there is an indication that we may need a booster dose that is given a few years, potentially 3 years, maybe a little sooner, maybe a little later to maintain the immune response. That's something we'll be watching very closely when we review the 36-month data. The efficacy is fairly similar between seropositive and seronegatives. And we do continue to see this difference in efficacy according to strain. And finally, we continue to feel that we have a strong efficacy profile. Next slide, 68. So just to give you a sense as to what will be -- what's coming up for us. At the end of this fiscal year in March, we are planning to file for licensure initially in the European Union under what's called Article 58, which is a special procedure to assess medicines and vaccines that are not intended to be marketed in Europe. The benefit of that procedure is that a number of endemic countries will be accompanying or joining that process, so they will be reviewing the dossier in parallel with the European authorities. We will also be filing for marketing in Europe that will happen next year as well. And later in the year, we'll be filing in the U.S. Now prior to that, we'll be reviewing the 36-month data. As I mentioned, that's going to be coming to us later this month and that will be shared with the regulatory authorities during the review -- during the review process. The first wave of countries that will receive -- where we will intend to launch the vaccine are listed in the bottom right. And then you can see that we sequence launches -- filings and launches after that. We will be bringing another manufacturing facility on board in Germany for what we call dengue drug product. That will come later, and that will significantly expand our supply capacity. Next slide, 69. So in summary, we are working hard to get ready for the filing and hopefully approval and then a successful launch. We're building capacity now that will eventually get us to over 50 million doses, 5-0 million doses per year. That could be significantly higher depending upon the proportion of multi-dose miles that we use for the supply, and that will be driven by the overall demand that materializes over time. I've mentioned the filings that we're anticipating for next year, and we do believe that the dengue vaccine market and this vaccine could generate USD 1.5 billion to USD 2 billion annually by the end of the decade. So with that, I will close. And I believe this wraps up the formal part of our discussion today, and I'll be joined by my colleagues for questions and answers. Thank you.

Thank you, Rajeev.

[Interpreted] Now, up to 9:15 in Japan time, we'd like to take questions. Operator, please go ahead.

[Operator Instructions] [Interpreted] The first question is from Mr. Yamaguchi, Citigroup.

[Interpreted] This is Yamaguchi speaking. Can you hear me?

[Interpreted] Yes, we can.

[Interpreted] I think it's better to ask you all the questions, right? My first question is as follows. About PTS, probability of success adjustment you made. And for each project, according to the project, did you apply different success rate? If the phase is more advanced, then all the way, PTS goes up, or depending on the asset, you have a different PTS? So how you apply the PTS? That's my first question. The second question is TAK-003. I have 2 questions on 003. First, about the travel vaccine you mentioned. Going forward, in the future, out of the total revenue, how much is in emerging market sales? And how much is travel vaccine sales? If we have any estimate of the ratio of these, please tell me. And the second, Sanofi product had ADE issue, and I think it's difficult to prove. But at the moment, I think that your product don't have such problem. But in how many subjects or people we need to vaccinate so that we'll be able to demonstrate that there is no ADE concern?

[Audio Gap] for the PTS question. And for Rajeev, the question related to the vaccines. Andy?

I'm sorry, Christophe, you were cut off. Sure. So Yamaguchi-san, it's Andy. So we have a governance process for PTS. It's -- there's a baseline PTS that's defined by modality, by phase and by disease area. And we use KMR benchmarks, and then we have a fit-for-purpose adjustment. So the specific answer to your question is it's not 1 size fits all. It's an individualized PTS for each individual asset.

Thank you, Andy. Rajeev?

Thank you for the question, Yamaguchi-san. So on the breakdown between endemic sales and travel sales, this is something that, of course, is subject to many assumptions, and we would not divulge our current thinking on at this early stage. But certainly, the majority -- the significant majority of revenues from the product we would expect from endemic markets. With regard to the disease enhancement that I mentioned earlier, one of the points to make about the first licensed vaccine is that when you look at the data around when the safety issues emerged, it was around 1.5 years after immunization -- actually within the first 1.5 years of immunization. We will have about twice as much follow-up on our vaccine to assess for the presence of ADE. We, at this point -- and again, this will hopefully be confirmed soon at the 36-month data. We are not seeing signs of ADE. Our expectation is that if ADE was to be an issue, we would have seen it well before this moment in time. So I would expect by the time of licensure, we should have a great degree of confidence about the absence of ADE if everything continues as we have seen thus far.

[Interpreted] Yamaguchi-san, did that answer your question?

[Interpreted] Yes. Thank you very much.

[Interpreted] Moving on to the next question. Next question is from Morgan Stanley, Mr. Muraoka.

[Interpreted] This is Muraoka from Morgan Stanley. Can you hear me?

[Interpreted] Yes.

[Interpreted] My first question about ENTYVIO. For 2032, you talked about administration patent. Can you talk about the potency of the administration with VELCADE? It was very potent. So is it similar? Or is there something that we can avoid? Can you talk about potency, please? And the second question, about 003. The sales target, if it is accomplished, what is the operating margin -- core operating margin? Do you think it will exceed 30%? That is my question.

Thank you, Muraoka-san. I'll take the first question, and Costa can comment on the operating margin. We cannot comment on the robustness of our patent. We do have a formulation on dosing patents, and some of them are expiring up to 2032. So we cannot give more details about that. But we wanted to flag today that we take a conservative assumption about biosimilar entry. At the moment, we don't see any development of biosimilars. And we just wanted to flag that the entry will happen between '24, '26 and later, but we took a conservative assumption in the growth outlook that we shared today. Costa?

Thanks, Muraoka-san. At this stage, we're not giving specific product-by-product margin, but I can give you some guidance. It will not be dilutive to our target of mid-30s for TAK-003. Thanks for the question.

[Interpreted] Next question is from Mr. Ueda from Goldman Sachs.

[Interpreted] Ueda from Goldman Sachs. I have 2 questions. First, on Page 8. And this is -- this question is about ENTYVIO. About LOE, biosimilar impact and also JAK inhibitor competition impact, how much of that is being incorporated from 2024 to 2030? Most of the global brands revenue is flattening. So what are the assumptions? So including LOE assumptions of other medicines, could you please comment on that? The second question is regarding Page 81, which is about Orexin program. TAK-994 final data is going to be presented, and this is in the latter half of the fiscal year 2021. But what about the interim analysis? Is it going to take place before that? And in the announcement in the quarter 1, I think disclosure was expected to be around 2020 or 2021. So what would be the most recent future data presentation timing? And another question is about positioning of 861. Is it going to be a subsequent drug? Or is it going to be just a backup as a positioning? Or is it going to be also fully fledged compound?

Thank you, Ueda-san. Perhaps Ramona can comment on ENTYVIO and then followed by Andy for the Orexin.

Yes, absolutely. So Ueda-san, it's Ramona here. So as we look at the -- sorry, I hear a little bit of audio echo here. Let's see if I can get rid of it. So as we look at the -- sorry, the long-term trend for ENTYVIO, absolutely, we factored in new competitors entering the market. We already have a JAK in the market in the U.S. ENTYVIO has been able to grow very successfully through a number of competitive launches in the U.S. And because it is being so uniquely positioned now, more and more for safety and efficacy reasons as a first-line agent. We do expect that we can continue that momentum through future launches, which will include JAKs plus other biologics in the market as well, none of which are as selective as ENTYVIO. And I don't know, Costa, there was a question in there about the total revenue for global brands too. I don't know if you wanted to address that 1 as well. Before I turn it over to Andy?

Sure. That's -- yes, if I understood the question, there was a question around the 14 global brands are flattening out from 2024 to 2030. Really, what the key message here, Ueda-san, is to focus on is a few key drivers. We -- on the Slide 6 of our presentation, you can see we've increased, as we highlighted, peak sales for ENTYVIO. We understand that from 2024 in our model, we're showing a decline because of the assumption of ENTYVIO biosimilar. However, we've got an acceleration of revenue for products like ALOFISEL, TAKHZYRO. You're seeing NINLARO going from 700 -- sorry, $700 million as of fiscal year '19 to $1.5 billion to $2 billion by 2030. And then also ALUNBRIG, $66 million 2019 revenue, up to close to $1 billion within that range by 2030. And also accelerating the revenue here is the PDT business, immunoglobulins and also albumin and FLEXBUMIN, where we're expecting high single-digit CAGR for immunoglobulins and mid-single-digit CAGR for albumin and FLEXBUMIN. So that's really the key pluses and minuses within the 14 global brands, which gives us the confidence we can maintain that from 2024 to 2030.

And just to reinforce, in this long-term growth outlook, we did assume biosimilar entry in Europe, in May '24 and in U.S. in May '26. So that's -- this biosimilar entry is included into our -- this long-term outlook. We just want here to flag that these data are the ones we have used for modelization, but they are the earliest date for biosimilar entry. And perhaps, Andy, on the Orexin?

Yes. Thanks, Christophe. Thank you, Ueda-san. So firstly, the disclosure plan for Orexin. We haven't fully formulated the disclosure plan at this point. There are 2 ongoing studies right now. One is the 1501 study, which is our proof-of-concept in dose ranging study. That study, we do see interim -- we do have interim analysis of that study. We also have an active DSMB with very specific criteria around making go no-go decisions to different doses and different dosing regimens. There's a good chance that we'll end up using the second part of that study as -- to support a filing. So we're being very careful to ensure that we don't -- that we maintain the integrity of that study. Whether we have data from that study that we'd want to disclose next -- the first half of next year at our next R&D Day or before is something that we haven't decided. The second study is a healthy volunteer study, where we're actually looking at individuals who are sleep-deprived and then in much the same way that we did with the IV molecule TAK-925. And I'll remind you that we saw profound effects in those individuals with TAK-925. And so at a minimum, early next year, we'll have data from that study. When we brought TAK-861 forward, just behind TAK-994, the first intent was to ensure that we had an oral molecule that would make it all the way to filing for narcolepsy. We feel quite confident that we have that oral molecule in TAK-994. We have high confidence in TAK-994. There are questions around dose and around the overall profile, but I think we feel quite confident that this is going to be the molecule. What we then do with TAK-861 to some extent will depend on the overall profile of 994. And then likewise, the profile of TAK-861, and there are different possibilities. It could be better in type 1 narcolepsy, in which case that might be the molecule that we jump forward. It could be that we decide to use it in other indications. And then lastly, Ueda-san, in terms of our focus, our focus right now is focused like a laser on type 1 narcolepsy, first and foremost; secondly, focused on other rare indications like type 2 narcolepsy and idiopathic hypersomnia; and thirdly, looking at -- for an oral molecule, looking at a broader array of neurologic and psychiatric disorders. And then fourthly, we actually have a path -- we think we have a potential path forward for the IV molecule for certain in-hospital settings.

[Interpreted] So after LOE -- this is about ENTYVIO. Biosimilar uptake compared to generics of small molecules, is your assumption having a slower uptake of biosimilar? If that is the case, what is the background to that?

Ramona?

Yes. Yes. So what we're seeing with biosimilars today is that the uptake really differs around the world. So you see in some European countries, you can get very quick share gain from biosimilars. Even in the U.S., in different therapy areas, we see the uptick differing a little bit. And so it's very difficult to predict exactly what that's going to look like in this market in 5 or 6 years' time. But we do expect differential uptake in different markets. And we do -- when a biosimilar comes, we do project that the uptake will be greater than it is today. So we expect more and more use of biosimilars as that entire market evolves, both in the U.S. and elsewhere. So we've taken, I think, a conservative assumption on the timing of a biosimilar, knowing that we have patents that extend out. But we've taken more aggressive uptake on the assumption on the impact of a biosimilar, knowing that we believe that market will continue to evolve. Hopefully, that answers your question.

[Interpreted] Thank you, we'd like to move on to the next question.

[Interpreted] Next question is Mr. Wakao, JPMorgan.

[Interpreted] This is Wakao, JPMorgan. I have 2 questions. One is about 003. As it's previously asked, the competitors, I think that there is other dengue vaccine. And then coming from the commercial viewpoint, if you compare with Sanofi's. Once it's infected, and I think that's the main target population of Sanofi. However, concerning 003, you also show efficacy in nonexposed, noninfected population. Therefore, I think probably that differentiation is -- the basis of your estimate of commercial success is right. And also concerning 003, you will see 36 months data, and then you will make filing. And in serotype 4 and if the confidence in [ ENTYVIO ], if it is all right, that's good. However, if it is not good in terms of confidence in [ ENTYVIO ], then what would you do? And regardless of serotype 4, do you think that you can file for 003? And also looking at 003, the 36-month data, would that impact to your estimate of the peak sales of 003? And the second is about Orexin program. And Orexin program, the potential, I think, $3 billion to $4 billion. That's the number given, but what's the assumptions? The [ Xylem ] sales is, I think, $1.6 billion, and your estimate is more than double. So why, compared to existing [ Xylem ], you think that you can achieve more than double revenue? What's the superiority compared to [ Xylem ]? And I think there could be some ineligible population for [ Xylem ]. So what's the potential unmet medical needs or untreated patients with [ Xylem ] or any other treatment, please?

[Foreign Language]

Thank you. So thank you for the questions, Wakao-san. So first of all, on the issue of the differentiator of our vaccine candidate based on the data that we have to date, you are correct that a key differentiator is that we have substantial efficacy against dengue illness as well as hospitalization in individuals who are sero-negative or who have never been exposed to the virus before that has important implications for the recommendations and uptake of the vaccine. First of all, we think that the -- we should -- we are hoping to have an indication at a lower age range than what has been seen with the first licensed vaccine. Our clinical trials being conducted beginning at age 4. Secondly, We would not expect to require a test prior to receiving the vaccine, a test to confirm that a person has previously been exposed to dengue because we are going to be filing or expect to file for a vaccine that could be used in all populations. And then finally, the ability to protect individuals who have not been exposed to dengue is a very important consideration for the traveler population from places where dengue is not currently circulating. So yes, this we believe is a would -- could be a key -- would be a key differentiator. With regard to the confidence intervals around type 4, we do not expect that, that will change our ability to file or likelihood of receiving a license. We will be seeking an indication for prevention of dengue illness, irrespective of which strain is causing the dengue illness. And so that -- even though we have small numbers of type 4, we don't expect that to change our approach to filing. I will point out that there were very few type 4 cases in our clinical trial. Generally speaking, if you speak to dengue experts, type 4 is considered to be the less concerning -- or least concerning of the 4 strains of dengue in circulation. And finally, will the 36-month data affect our commercial projections? We believe our current projections are robust to what we might expect to see at 36 months. But of course, we won't know that for certain until we actually see the data, but I'm fairly confident in the projections that we have presented today even before we see that data.

Christophe, did you want me to speak...

Yes.

To the Orexin? So thank you so much for the question. I would say that our assumptions are based on a couple of things. And they're related, actually. So first of all, if you look at the data that we have today on our lead molecules, the efficacy is transformational. It's different from anything that you see in the market today. And so we're working on this whole portfolio on our Orexin platform, and we believe we can make a step change in efficacy for narcolepsy with this portfolio. And so we believe that efficacy is not only going to lead to higher shares but also lead to more diagnosis because right now, there's few options available and the efficacy is not that strong. So those things kind of go together. But with our efforts on diagnosis and our commercial capabilities and with very strong efficacy of the molecule, that will help lead what we believe is a very healthy uptake and could even be conservative by some estimates. The other thing I will add is that we're also doing work to look at this market globally. So the narcolepsy market in the U.S. is probably the most developed. It's a much less developed market in other parts of the world. But because we have presence there, because we have capabilities there, we can start now to prepare those markets even prior to launch of the molecule. So I would say, strong efficacy, good diagnosis rates and a global uptake will absolutely get us to those assumptions.

[Interpreted] Just 1 follow-up. May I? Regarding Orexin, Phase I, TAK-994 [ take 1 ] in healthy volunteer PK/PD study. Regarding this particular study, compared to IV 925, did you get the similar or same PK/PD profile on 994?

Andy?

Yes. Thanks, Christophe. So no. It's a very different profile. The 925, which is the IV molecule, is a continuous infusion and it has a very short half-life. And so it's very -- the peak-to-trough ratio doesn't get too high. It doesn't get too low. It stays very consistent, which is one of the questions that we have in bringing in an oral molecule. What we have found is we found a PK profile is very consistent with a once- or twice-a-day dose oral molecule. We found a PK profile where we sampled CSF levels of TAK-994. And we know based on our extensive translational work, our modeling in humans and in animals that we achieved concentrations essentially that are more than enough to drive efficacy at the same level that we had seen with TAK-925. So we didn't actually look as we had with TAK-925 at efficacy on daytime sleepiness with 994 in our Phase I program. That's what we're looking at right now with the sleep-deprived healthy volunteers and the type 1 narcolepsy patients in our Phase II program. And I'll just add something, if I may, Ramona, to your comments. Not only transformative efficacy but efficacy across all aspects of a patient with narcolepsy. These patients are characterized by excessive daytime sleepiness that's completely debilitating; cataplexy, which also is debilitating; and then poor sleep at night. And we think because of -- firstly, based on what we've seen with 925, what we've seen in our animal models and based on this mechanism, I mean, it's a very physiologically relevant mechanism. We're replacing what we know is deficient in these individuals based on all 3. And the early data that we've seen, we expect to see transformative benefits on all 3.

[Interpreted] So we'd like to move on to the next question.

[Interpreted] Ms. Stacy Ku from Cowen.

Stacy Ku from Cowen. I have a few. First, for the U.S. launch of 721 and EOE, can you provide some more details around the initial payer discussions? Would you be willing to discuss potential pricing to get broad reimbursement of 721? Or maybe asked another way, what's the range of cost for off-label treatments for EOE right now? Second, how should we be thinking about 788 peak-revenue estimates in terms of the recent competitive updates, specifically J&J's recent filing for non-small cell lung cancer? And can we get more clarity or confirmation into timing for data release for 788 on the EXCLAIM trial? And maybe which medical conferences we might be able to see these disclosures? And then my third question is kind of if you could help with the expectations for 981, the simulation inhibitor that Andy mentioned in the very beginning, when we might next see any results? And then finally, last question is on ENTYVIO. If we could get some more details around the portal needle-free device? And if we can get an update on maybe some of the development or progress that gives you conviction for a 2023 launch and if this is part of the peak estimate range? I'm happy to repeat any of these questions.

Thank you, Stacy. I think Ramona can cover our TAK-721 launch and ENTYVIO questions. And then Teresa Bitetti, who is leading our global oncology business can cover 788, and Andy will talk about 981. Ramona?

Yes. So let me start with 721. We absolutely are having initial payer discussions. We are not ready to disclose the price yet, so I can't give you any indication of that. I will say many of the off-label treatments today are -- they often go to -- patients often go to compounding pharmacies. And because nothing is indicated, it is often fully out of pocket for the patients. So they're not reimbursed. And so the cost can get quite expensive for patients to continue taking these medicines. The other thing I'll say is that often in -- we see this with IBD as well and these GI spaces, providers will prefer to use something like a steroid first before they go to something more systemic in the future. And so we believe there's a great opportunity for 721 or Eohilia to be used as a first-line treatment. And we will certainly be pricing, and our pricing and access strategy will be done accordingly. We believe this is probably the best first-line treatment. Not probably, it is the best first-line treatment for patients with eosinophilic esophagitis. So we will have our pricing and reimbursement accordingly. On the portal needle-free device, and I might ask Andy to help me a little bit on the situation, but this is a new program for us. It's innovative. It's different. It's in a space that hasn't been tried before. We're very excited about it because it could truly transform patients' ability to take their treatment. And at the same time, there's still risk involved in this program. So we are not projecting any specific revenues from this, but we are continuing to progress our development because if we can bring it to market, it could be transformational. Andy, I don't know if there's anything you want to add to that.

No. Nothing to add, Ramona. But while I have the mic, maybe I'll start with 981 and then hand it over to you if you have anything additional data on 981 and then 788. So Stacy, As you know, we're very excited about 981 based on the early immuno phenotyping data and based on some of the early clinical responses that we've already discussed. 4 months ago or so, we decided to initiate a number of different expansion cohorts to our Phase I study. One of the challenges we face is understanding where and how to target this model through the specific tumor types. And so we've chosen an array of different settings that test a number of hypotheses that we think will help to focus our future development, and a very strong translational effort behind this program as well. There are 3 buckets of activity. One is looking at monotherapy across a range of tumor types. The second is a combination with checkpoint inhibitors. And then the third is an interesting hypothesis that was generated preclinically that we've, in early clinical experience, are quite enthusiastic about, and that's the potential to potentiate the activity of antibodies that the target tumors. And so we're in the process expanding all of those cohorts. The question of we don't have a plan for -- a specific plan for disclosure. It's going to really depend on the data that we see. But we're actively enrolling and our hope is that over the next 12 to 24 months, we should have data sets across a wide range of different tumor types and combinations.

And yes, this is Teresa speaking, on the question around 788. We are confident in the profile that we have for [indiscernible] And of course, when we do look at our forecast, we anticipate competition. So we build that into the numbers that we see. And I think as you know, there's a very high unmet need in that population. We're looking to submit the data to an upcoming congress. And as soon as we have acceptance there, obviously, we'll disclose which congress we'll be presenting that at. But we are working diligently on the file, and we do look forward to making that more broadly available.

[Foreign Language]

[Interpreted] Our next question is from Kohtani from Nomura Securities.

Can you hear me okay?

Yes, we hear you.

Okay. So just first of all, I really would like to thank Takeda for the level of detail disclosed in this presentation. On the peak sales, epidemiology, patient numbers at each stage of the disease, I think all of us analysts will push all the other Japanese pharma companies to disclose information at similar levels, making Takeda the standard for pipeline disclosure in this industry. So 2 questions, please. One, I think this is for Michael, TAK-721. While I appreciate the unmet medical need for eosinophilic esophagitis therapeutics and the outstanding data, I think the recently reported dupilumab data at EEG 2020 was very similar to TAK-721. Looking at Slides 35 and 36, 59.5% of patients on once-a-week dupilumab achieved less than or equal to 6 EOS per HBF, which is similar to, I think, the data for TAK-721. And the change in DSQ score for dupilumab was negative 22 points, which on paper, I think, is larger than TAK-721 at negative 13 points shown on Page 36. So on paper, it does look like dupilumab has a bit of a numerical advantage. How do you see the competitive positioning for this drug? The second question is for Rajeev. Just on the dengue vaccine, the 90% efficacy against hospitalization is quite impressive. But could you remind us why exactly mechanistically, the TAK-003 does show antibody-dependent enhancement on seronegative individuals when Dengvaxia showed this problem? Is it because Dengvaxia has -- was based on the yellow fever virus platform? This is a very important point. So if you could elaborate on this, it would be much appreciated.

Kohtani-san, this is Mike. Thanks for the question. So allow me to address this around DUPIXENT. So clearly, there are different modalities in terms of the drugs. And whilst there are also similarities in the clinical development approach, there's also some differences. So we got to be careful obviously, with making too many comparison. And there's not a direct head to head, obviously. That said, example of some of the differences probably between the data is length of primary end point, statistical analysis, some of the subgroups. I'm also aware for that particular study they've only released, I think, data from their high-dose subgroup so far. So I think I'd also look forward to seeing the full data in the future. So as mentioned in the presentation, from a positioning point of view, if approved, we do believe that [ idiohilia's ] data and the time line will support it being established as the new gold standard first-line therapy for patients with an EOE diagnosis in the U.S. And then we do see the biologics coming, if successful, being important second-line options for that reason. But it's great to see more positive data in this area.

So I'll take the dengue question. Thanks for that. The fact that we have a vaccine that is based on the dengue virus itself is very important. And we think it plays a role in 3 areas. Number one, we have a component of the virus called NS1. N as in Nancy, S as in Sierra, and the number one, that elicits an antibody response that is specific to the dengue virus itself. It turns out that with flaviviruses, this NS1 component is specific to the class of virus. And so by having a dengue NS1, we believe that, that supports the robust efficacy that we see. And when I talk about robust efficacy, the same comments apply to the issue of the potential for antibody-mediated disease enhancement in our assessment. The second is that we do see evidence of type-specific antibodies that are elicited by the vaccine, meaning that we have antibodies that we can collect from individuals who have received the vaccine, and then we can do what we call depletion studies where we pull out the antibodies, for example, against the type 2 virus. And we still find a specific antibody binding against types 1, 3 and 4, which suggests that this is -- or demonstrates that this is not a nonspecific effect that we are -- binding effect that we're seeing in the vaccine. And the third is that we do see evidence of cell-mediated immunity or CMI. You and others have probably heard a lot about CMI lately in the context of COVID, where there is evidence that CMI plays an important role -- or may -- sorry, may play an important role in long-term protection against COVID reinfection. We do see evidence that we have CMI that is elicited by our vaccine, and we believe that's due to the fact that we're immunizing with a form of the dengue virus itself. Thanks for the question.

If I could just add 1 follow-up. What's your current thinking, I think, Rajeev, on the norovirus vaccine? I understand this isn't wave 2, but there were a number of Phase II trials that were already performed. Will it jump straight into Phase III? Or would it require additional Phase [ II ] trials?

Yes. So thanks for that question about norovirus. We have demonstrated that the norovirus vaccine works in healthy adults in preventing norovirus infection, and are very encouraged by that data. It is possible to go directly into -- to go into a Phase III trial in adults. However, that would carry a number of challenges in terms of the size and complexity of doing that trial in the community. We are looking at first going into pediatric population, which would entail another Phase IIb trial to demonstrate what we've seen in adults also applies in children, which [ with norovirus ] a very different population. So that's currently what we are planning on doing.

[Interpreted] We'd like to take a final question.

[Interpreted] Next question is from BofA Securities, Mr. Arai.

[Interpreted] This is Arai speaking, of BofA Securities. I'd like to ask a question about the Page 8. That is to explain your positioning towards the revenue target. And in wave 1 pipeline, regarding your views, what kind of milestones needs to be attained so that we'll be able to achieve the PTS adjusted revenue as well as DPD is nonadjusted? So I'd like to please understand the milestones that you have to achieve to attain this ultimate goal. TAK-994 or 007 [indiscernible] success, I think, are very big contributors. But even before knowing the final result, are there any precursors or signs you may see so that you'll be able to increase the PTS beforehand? So what is the timing of milestones? What kind of milestones? Those are the questions that I'd like to know.

Thank you very much for the question. And actually, it allows me also, I think, to conclude the session. On this Slide 8, you see that first, we are very confident that we will grow in the future. If you look at the PTS adjusted number, we are showing a low single-digit growth. But we're also very confident that we will end up with a higher level of growth because many wave 1 programs will see a derisking event, as Andy showed previously, in the coming months. Take again an example like maribavir. We just got the Phase III results. We made the primary endpoint. You see immediately a PTS increase -- a significant PTS increase when you have this type of readout. Now not all the program will succeed. But on all the wave 1 assets, we already have clinical patient data, and we are in the final stage. And from what we have seen, we are very confident that the majority of them will succeed. And on top of that, we don't have 1 -- we have 12 assets. So we are not relying on 1 or 2 assets. We are -- we're not dependent on 1 program. We have 12 assets now. Not all of them have the same revenue potential and weight, but still, it's relatively a diverse pipeline. And then the second element is that by 2030, we'll have potentially wave 2 assets coming on streams, which will add to the momentum and the PTS level of this wave 1 is extremely low right now, also will further increase in the future. And we have -- we'll continue to also be active on the partnership and in-licensing front. Take TAK-999, for example, it's not included at all in our long range. But of course, this is -- we are very excited about this program. Otherwise, we will not have done this partnership, and this is quite a significant revenue potential program that we didn't disclose today. So all-in-all, this is why we are confident about our long-term growth outlook. This is why we are also confident to have this goal of a JPY 5 trillion revenue by 2030. It's not a number which just came out of the blue. It's a number that we believe we can meet based on what we see with our global brand, with our wave 1 pipeline assets and the wave 2 pipeline also, which is coming a bit later. So that's how we are thinking overall about our business moving forward and the growth outlook that we are confident to meet.

[Interpreted] Thank you very much. Thank you. With this, we would like to conclude the call today. Thank you very much for joining in this conference call. We'd like to ask for your continued support and cooperation. Thank you very much. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]