AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

Good morning to those joining from the U.K., Central Europe and the U.S., and good afternoon to those listening in Asia. Welcome, ladies and gentlemen, to AstraZeneca's Investor Day 2024 webinar for investors and analysts. Before I hand over to AstraZeneca, I'd like to read the safe harbor statement. The company intends to utilize the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webinar. There will be an opportunity to ask questions after today's presentations. [Operator Instructions] And with that, we'll now connect you to the auditorium in Cambridge. [Presentation]

Good morning, everybody. I hope you had a good night last night and enjoyed the dinner for those of you who were with us. And those who had a chance to look at the DISC this morning, I hope you enjoyed the visit and understood why we are so excited to be here and why our scientists are so pleased to be here. Today is a very special day for us because it's the starting point of a new journey of growth to 2030 and beyond. And it's really a great pleasure to present to you our strategy over the next few hours, our ambition and how we actually plan to get to this new goal we've given ourselves for 2030. And it's really a great pleasure to do it here from this site, which has been a little bit long coming, but I'm sure you've realized, it's an amazing place for people to do science. It's been an amazing place for us to bring the company together over the years. The MedImmune organization and AstraZeneca, we tend to forget, that's where we started from 10 years ago, has brought everybody together here. It's really galvanized our scientists to develop, build the best lives in the world. That's the mission we gave then 10 years ago when we started on this site. And today, it is really something that will fuel our pipeline and help us deliver the very ambitious goals we've given ourselves. Some of you may have seen this picture outside and the name José Baselga. José is with us every day. He was a giant of cancer care. He was a fantastic scientist, a fantastic clinician, a great doctor, a great leader and a very good man. And he had a huge impact on this company in a very short period of time. And some of the work actually that will be presented today was triggered, was initiated by José when he was Head of R&D Oncology, and we decided to actually recognize him outside of this room. So these are the forward-looking statements. You know them. They are very traditional. I wanted to start here because 10 years ago -- a bit more than 10 years ago, actually, we told you that we would achieve $45 billion by 2023, which at the time was $45 billion, but actually using 2023 exchanges, it would have been more like $40 billion or $42 billion. So it was a very ambitious target, and it really was a fantastic rallying cry at the time for the company to mobilize and work toward this very ambitious goal. And actually, we delivered it. It was certainly very challenging because you can see that we went through a period of time that was a little bit scary, I have to say, we declined. But we managed to turn the company around, and we did this through science. We did this through focusing on great science, great products, rebuilding our pipeline and launching the medicines that today are blockbusters and driving our growth. We did this through a strategy that really hasn't changed overall, but has been very dynamic in the sense of being adjusted as we went along. We decided that we want to focus on science and innovation, growth and therapy area leadership, having our global footprint and being a sustainable organization. But of course, as the world changed around us, new technologies emerged, new products, new ways to treat patients, we adjusted to this and complemented our plans with new technologies, and we'll talk about this in a minute. As it relates to science, we leveraged our global R&D network. We've constantly focused on building therapy area leadership. We believe it's important to be a leader in the areas where you play because you need to be an expert. You need to be an expert in science, but it's not enough. You need to be an expert in how you develop -- clinically develop your product. And you need to be an expert in how you commercialize your product. The world of medicine is becoming extremely complicated. We have to become leaders and experts in the field where we operate. So we're focused on building this area leadership in oncology, in cardiovascular disease, respiratory disease, rare diseases. And now we are making some progress in immunology. We've also always focused on growth. Growth is really what drives people, what energizes people and, of course, the best way to create shareholder value in the long term. We've leveraged our global footprint. We started 10, 12 years ago, I can tell you, we were in the emerging market, not that strong. I remember my first visit to Mexico, I left the country almost depressed because we were really in bad shape at the time. And today, we are the #1 pharma company in the emerging markets. And Leon Wang, who is very competitive, want to be #1 in every single country. And in every single country, he wants to be #1 in every therapy area where we operate. But overall, we are #1 in China, and we are #1 outside of China and the emerging markets. And it's really important because as the world changes around us, these countries actually grow, their economies develop, they become more able to pay for innovative medicines. They also get older like everybody. And of course, their health care needs increase. And having a global footprint, I believe, is a fantastic advantage in terms of globalizing the products we have, including for rare disease. And you'll hear Marc a little later talk about the progress we're making, commercializing products that many would think are too expensive for the emerging markets. Actually, we're making very good progress there. And finally, we believe that we need to be a sustainable organization and play our part in reducing carbon footprint, in particular; but not only carbon footprint, also reducing the use of natural resources, water, reduce the waste production and try, to the best of our ability, try to get as many patients as possible getting access to our medicines around the world. And so based -- we have -- yes, sorry. Yes, sorry. I was looking at Andy and had a hesitation for a second. So we have actually done this, leveraging our R&D network around the world. And we have now 5 strategic R&D centers: 2 in Europe, in Sweden and the U.K., here in Cambridge, as you know; 2 in the United States, in Gaithersburg, but also now in Cambridge in – Kendall Square. We are actually going to move into a new facility by 2025, bringing teams from Waltham and elsewhere around Boston to this Kendall Square site. And finally, in Shanghai, we established this large R&D center in Shanghai not long ago. And China is becoming a very fundamental part of our R&D network in many ways. First of all, of course, developing medicines we bring to patients in China. But that's not the only thing. They are now taking the lead on global programs that are relevant to China and also liaising with local innovation. Innovation in China has exploded, as I'm sure you know. And they're extremely fast and extremely innovative in the new technologies, new medicines they're developing. It's important to actually connect with that new world of innovation and partner with it, so we can actually benefit from it, but also help them globalize their medicines. And in the last 18 months, 2 years, as you know, we've done quite a number of partnerships and acquisitions in China to leverage this. We also intend to actually leverage our Chinese presence for cell therapy. Cell therapy in China has a very specific aspect to it, which is in the early phase of clinical development, you can move much faster than anywhere else in the world. And we have the ability, through the acquisition of Gracell and the presence of a very strong local AZ R&D team, we have the ability to leverage that specificity, which is both regulatory driven, but also the way people operate. And that will help us save time and be much faster developing cell therapies. We have -- because of our progress with our R&D pipeline, we've been able to upgrade our ambition. Initially, we had the ambition to launch 15 new medicines by 2020 -- '30, sorry. we've upgraded this ambition to launching 20 NMEs by 2030. And we already have launched 6 that are listed here, and there is more to come. And certainly, we feel very confident we can deliver 20 new molecular entities by 2030 and, on top of it, very innovative products in many different fields. Today, we announced a new ambition, which is to reach $80 billion by 2030. And our ambition is to grow to this level, but also to continue growing beyond 2030 because we want to be a growth company for the long term until 2030, but also beyond. We want to reconfirm our ambition and our commitment to deliver a mid-30s operating margin by 2026. And we also decided that we wanted to give some indication of our objective post-2026. And as you can understand, and hopefully, you will also see throughout the day, we are in an innovation-driven industry. And innovation means risks. It carries a lot of risks and a lot of uncertainties. It really also brings a lot of rewards if you succeed, of course. And in the last few years, we've tended to be relatively successful, but it carries risk. And therefore, it's very hard to predict precisely what the future will look like. So our commitment, our ambition is actually to maintain our operating margin at the mid-30s post-2026. But it will, of course, be depending, whether it goes above or not, will depend on how much we have in our pipeline, how many products we have to launch and, fundamentally, how much growth we can deliver beyond 2026 and, importantly, beyond 2030. So those are some of the commitments, but also ambition for some of them that we wanted to share with you. How do we achieve this? Last year, we achieved 45 -- a bit more than $45 billion in sales. And of course, we have to recognize we're going to face headwinds. This is the nature of our industry. We lose patent protection after a while. And of course, a number of governments around the world are trying to address the cost of health care and the cost of medicines. So we recognize we'll have to address the IRA impact. I think it's -- and maybe we'll cover this in the discussion. It's important to keep in mind or put the IRA impact in the context of our overall global sales and it is, we believe, completely manageable. But we also have loss of exclusivity with Brilinta, Farxiga, Lynparza and Soliris. And we're working very hard to address those. Soliris, we transfer to Ultomiris. Lynparza, we're working on the PARP1. In Farxiga, we're working on combinations, as we will share with you a little later today. We have an existing portfolio that actually will deliver ongoing growth between now and 2030. And you know those products, they are listed here, and a lot of them still have a lot of growth to deliver. On HER2, in particular, Imfinzi -- Airsupra was just launched. Many of those still have a lot of growth that they can deliver between now and 2030. On top of this, we are going to launch, over the next period of time, quite a number of NMEs. And of course, when we tell you $80 billion, I should have clarified that it's a risk-adjusted number. And if everything works perfectly, which would be great, but I don't think it's reasonable to expect everything is going to work, but if everything works perfectly, we would be able to deliver more than that. So the $80 billion is a risk-adjusted number, taking all these medicines that you see as new molecular entities here, taking those into account and risk-adjusting them. But I can tell you many of them, and hopefully, you all agree with me, many of them have a very good chance to succeed. The question often is, are they successful or very successful, depending on how many indications we actually can bring to the market. And beyond 2030, we've been working on those technologies that will, we believe, shape the future of medicine. Whether it's in cancer care or immunology or elsewhere, antibody-drug conjugates, radioconjugates, cell therapy, T-cell engagers, gene therapy for rare diseases, our next-generation IO bispecifics, products around weight management, obesity, management of risk factors, all of those, we believe, will shape the future of medicine in many fields and will sustain our growth as a company post-2030. Some of these products will launch, of course, before 2030, but they will deliver a lot of growth post-2030 and, we believe, will enable us to continue growing through the patent expiries we are facing post-2030. We've listed here a number of our product -- the products we believe have peak year potential -- peak year sales potential of $5 billion plus. And you can see here, there's quite a number of those that will deliver very strong revenue growth to 2030 and have very substantial peak year revenue potential. We also have not listed here, but we have another bucket of products that you will deliver -- you will discover through the presentations today, another bucket of products that have a $3 billion to $5 billion potential; and then the third bucket that have $1 billion to $3 billion potential. And we've created 3 buckets so you can get a sense for the potential we see in those products. And of course, we can discuss that throughout the day and later as you dig into the presentations more. I've talked about investments in new technologies. And essentially, weight management, we call it weight management as opposed to obesity because we believe fundamentally there are 2 large group of patients. One is the so-called obese group who are people who have a very high BMI or high BMI above 28 or 30 and need to probably be treated through titration regimens and combination regimens. And there's another very large group of patients who would be well served with a 10% rate reduction, but have risk factors, and you need to manage those risk factors. And in this area, we are developing a number of products to treat patients either with oral medicines that can be combined through ADCs or injectables for the segment of patients who need more aggressive weight reduction. We're investing in antibody-drug conjugates and radioconjugates with the ambition to replace traditional chemo and traditional radiotherapy, and you'll hear more about this. We're investing in 2 -- in particular, 2 next-generation IO bispecifics to bring the IO space to the next level beyond PD-1/PD-L1s. We're investing in cell therapy and T-cell engagers with a vision that in cancer, our ambition is to eliminate cancers as cause of deaths. And we believe the best way to do this for metastatic disease is to attack the cancer with the combination of ADCs and IO, take it to a level where you can actually bring in cell therapy or T-cell engagers and potentially cure people. Now the day when we can actually cure people with metastatic disease is not that far away. And if some of those technologies work, it would become actually possible. And finally, gene therapy. We're investing in gene therapy and gene editing, in particular, for our rare disease team and portfolio, and you will hear more from Mark and the team about this. Now you've seen in the last 18 months or so, you've seen a lot of activity around business development and partnerships that we were announcing. And I wanted to bring this slide to you to make sure you understand, there was a strategy behind all these technologies. Now back in 2019, '20, we thought we are halfway through our journey, a bit more than halfway actually through our journey to 2023. Let's work on our 2025 strategy. And we identified a number of technologies we thought we needed to start building: ADCs, at the time, we had not identified radioconjugates, I have to say; cell therapy with this T-cell engagers; gene therapy, no, because we didn't have Alexion at the time, and we complemented gene therapy more recently in the last 3 years or so. So with those technologies, we started building internal efforts, building internal teams and internal programs. And we decided to accelerate this over the last 18 months after really having studied the field and the options open to us. We decided to accelerate the build, and we now have what we believe we need to have in terms of technologies to address those new platforms, those new options, being cell therapy or T-cell engagers And actually bring them not only to oncology, but also immunology, biopharma and rare disease, in many cases, as you can see here on the slide. So now the focus of the teams is execution, integration of all these technologies, and we've made very good progress doing this and delivering products, of course, through those efforts. If you look at this, we forecast that those new technologies will actually take a growing proportion of our pipeline in the future. And it's really important, I believe, if you want to be a long-term successful pharma company, you need to be in those technologies because the world is changing. The industry has been dominated historically by small molecules. 25 years ago or so, large molecules, biologics came to the market with Herceptin and a few others. More recently, in the last 10 years or so, we had IO. But the world is now changing. You had in the past the products for 15, 17 years to yourself and then you would lose it to generics, analogs, biosimilars. These technologies will deliver products that will be very difficult to copy rapidly by generic companies. On the other hand, the rate of replacement of products in those -- coming from this technology is going to accelerate, especially with China coming on board and coming on stream with innovation. And you look at it, if you look at what is presented at the ASCO, the number of ADCs is very, very large, of course. And then you have efforts in cell therapy and many other technologies. So the rate of replacement of products will potentially accelerate. And if we are not experts in those technologies in the long run, I think we'll progressively lose ground. You can see here some of the estimates given to the size of the markets in cell therapy or gene therapy. I personally believe that if cell therapy works to the extent we want to make it work, i.e., if we can actually bring it to solid tumors, if we can actually turn it into an allogeneic cell therapy approach, the potential is much bigger because you can actually totally change the way many diseases are being treated. We also believe we have a unique opportunity with our portfolio, which is quite broad. And it is a strength, we believe. It's a strength because we can combine our products. And if you look at many diseases, the treatment of those diseases is going to be made of combinations. These are combinations to bring patients to a stable state and keep them in that state the long term or potentially to cure them. And cure in oncology will require a combination. So if you look at oncology, but also cardiovascular disease, our focus is identifying patients early, diagnosing the disease early, intercepting the disease early and trying to cure patients with combinations. So a lot of our efforts are in identifying disease early, having biomarker to select populations and then combining. And you'll hear from the team today about our strategy to combine ADCs with IO bispecifics. If we can do this, we can actually completely change the treatment of many cancers, in particular, in lung cancer, our first-line metastatic, we can actually displace chemo-pembro with a combination of ADCs with IO and transform outcomes as a result. Now the same approach is true for cardiovascular disease. People who have excess weight have risk factors. And sometimes people think, well, if they lose weight, they're going to lose the risk factors. The problem is when people have been overweight for too long, and then, of course, age is also playing a role, they get additional dysregulations either in their lipid metabolism or in the endothelial vascular walls. And then they stay with their hypertension or they stay with some level of diabetes because their pancreatic cells in PARP are gone. So you have to have those patients manage their weight, but also manage the risk factors. And in that field, we believe with the combination potential that we will show you today, we can actually play a very important role in helping these millions, hundreds of millions of patients around the world, who have some issue with their weight, but also have risk factors being heart disease, kidney disease, hypertension, diabetes, dyslipidemia, that we can help those people live a longer life. One other aspect of our strategy we wanted to highlight to you is the ability we have to globalize products very rapidly through our global footprint. If you look at the last few years, we have grown a lot in China. Of course, today, China is going through its own transition from older products to reimbursed products, innovative products, but we've also lost medicines like Pulmicort and a few others that have lost patent protection. China, this year, is starting to grow again as it launches new products. But outside of China, you can see the very consistent and strong rate of growth we've experienced since 2021, 20%, 40%, 35%. This is becoming a very large part of our company. And moving forward, it will -- there's no reason to believe it will not become even bigger because we have to remember, most of the population of the world lives outside of the U.S., Europe and Japan and maybe Australia, Canada. Most of the world lives in these so-called emerging markets. That's where the population is. That's where the population growth is. That's, of course, where aging is, but also economic development is happening, and therefore, they would be able to access our medicines. We've done this, and we will continue to do this, driving our growth, but reducing our impact on the planet. If you look at this graph, the red bar shows you our growth since 2015. And the reason why we used 2015, it's the year when the Paris Agreement was signed and a large number of countries committed to a reduction in carbon reductions. And since 2015, our company has almost doubled in size. And even though we doubled in size, our carbon emissions have reduced by 68%. But not only this, our water consumption has reduced by 20%, and we've reduced our waste by 13%. Our goal is to reduce our Scope 1 and 2 emissions by 98% by 2026 and reduce Scope 3, which is, for most companies, the most difficult part of the carbon emissions of the entire supply chain. Scope 3, we will reduce by 50% by 2030, and we're making very good progress in that direction. So we wanted to share this with you because it is important for everybody to remember, it's possible to grow, it's possible to deliver value to patients and shareholders, but at the same time, reduce your impact on the planet. And we are not doing this, increasing our costs. There are cases where indeed some of our projects increased costs, but in most cases, what we do reduced our costs. Most of the time, almost immediately, sometimes in the midterm, but it's always economically attractive to do it. I will close by sharing a few thoughts on the catalyst for 2024 and next year. This year, we've already announced 4 -- 8 of those catalysts, 4 are positive Phase III readouts and 4 are new approvals and launches. Out of those Phase III readouts, actually 3 will be presented at the ASCO very soon, 2 of them are the Plenary. In fact, maybe we could have even had 3 at the Plenary, where DBO6 read at a little too late still made it into the ASCO even though the data came out late, which tells you that the clinical benefit must be substantial, otherwise, it wouldn't have made it into the ASCO. And also, we have to recognize 2 out of 5 at the Plenary is already pretty good. We believe it's probably the first time a company has 2 presentations at the Plenary in one go. So really great data. And the point I wanted to make also in this slide is, on this slide, you have several billion dollars of 2030 sales. So it really is important because we are not even halfway through 2025 -- '24, sorry, and we have already had clinical news, approvals, launches that will generate billions of dollars of additional 2030 sales. And it's not -- it doesn't stop here. These are the readouts for the rest of the year until 2025. Many of those you know, and we've only listed here the most important ones. There are more than those, of course, others are smaller ones. And collectively, these readouts will deliver $20 billion of potential revenue in 2030, non-risk-adjusted. So of course, we have to recognize not everything is going to work. But we think we have a good chance as many of -- seeing many of those working out positively, and that will fuel our growth over the next few years. And I also wanted to show you this graph because sometimes people -- I'm sure some people are saying, well, 2030 is so far away, I mean it doesn't matter. We'll have to wait so long to know whether you deliver your $80 billion. My message to you is by the end of 2025, you will always have -- already have a very good idea of the trajectory we are on, not only a trajectory of ourselves having gone through the impact of IRA in 2025, but also what new clinical data we have to drive our growth beyond 2025 and onto 2030. So within 1.5 years, 2 years, you will have a very good sense for the direction of travel that we are on and whether we have a fair chance to achieve the 2030. So I will stop here and hand over to my good friend, Ruud. Over to you, Ruud. Thank you so much. [Presentation]

First of all, thank you so much, Pascal, for the introduction. And equally, together with Sharon and the teams of Biopharma, we are extremely pleased to kick off the first of 3 sessions in order to do an in-depth analysis of why we think biopharma is such an interesting and attractive place to be. You saw it already in the video, but here, you see some of the numbers about what is going on in the world. And it's quite, yes, daunting to see the enormous impact of chronic diseases across the world. More than 2 billion people in the world are suffering from chronic diseases, whether it's cardiovascular disease, renal disease, respiratory disease. And then fourthly, that will continue in the years to come. If you see, in 2030, 1 out of 6 people in the world will have an age over 60. And we know that those, including myself, by the way, that those people are highly vulnerable in order to develop diseases and not only one disease, but in many cases, multiple diseases. Equally, the burden on health care systems is increasing day in, day out. I have the privilege to travel a lot around the world. And in every country where I am, I hear, let's say, the sense of urgency in order to help health systems in order to manage the enormous patient flow we see across the world. So early detection, early diagnosis are pivotal in order to help health systems and governments in order to further manage the burden on their systems. The costs associated with chronic diseases are enormous, and that will continue [ importantly ] if we are not intervening as an industry, but also as health care professionals. So why are we so excited about the journey of biopharma? First of all, and I want to be humble, but equally, I'm very proud to say that we have a long history and a tremendous heritage in the disease areas we are representing. We have been able, in the last few years, to build the #1 cardiorenal product, it's Farxiga. And I know a lot of you have questions about, is there life after Farxiga? And hopefully, at the end of the day, you will say yes, because I have all the confidence that we have a fantastic plan in place in order to help even more patients moving forward. Equally, we're clearly one of the leaders in respiratory disease. And in asthma, we cover everything from inhalers up to the severe asthmatics with biologics. And COPD is one of the, I would say, almost most under-recognized diseases across the world. We see a phenomenal surge of COPD, especially also in the emerging markets, where Pascal was referring to earlier. And clearly, COPD is still the third leading cause of death across the world. And finally, Iskra and Mark Esser will tell you more about what we are doing in order to help the vulnerable patients in the world, vulnerable for infections like RSV. And hopefully, we will launch relatively soon in the next 2 years, a very attractive new vaccine for HMPV and RSV. Now equally, you see we are building on a very strong platform of existing molecules in AstraZeneca. And personally, I'm very proud that only in the last 12 months, we have launched 3 complete new medicines in the world: Airsupra for the rescue of asthma, the first rescue medication in the United States; Wainua for hATTR-PN in the first indication, and ATTR is a very important point for attention also during the day because we truly believe that we have one of the best, perhaps the best portfolio of treating a very debilitating disease. And together with our colleagues of Alexion, I truly believe that we have an opportunity to really change the curve of this disease. And last but not least, of course, Beyfortus, together with our partner, Sanofi, where there's a lot of excitement in order to protect the vulnerable babies. Hopefully, you all agree that in the last few years, we have seen a very strong delivery of our commercial presence. And I also would like to take the opportunity to thank all the commercial teams around the world who are working tirelessly to bring our new medicines to the patients who deserve that. But what does it mean? And why do we think that biopharma is going to contribute to the very clear and bold ambition Pascal was outlining earlier in the discussion, the $80 billion? First of all, yes, we need to acknowledge that we will face some headwinds. And of course, primarily Farxiga is the biggest headwind in biopharma in the next few years. But let me also remind you that this is not a falling-off-a-cliff situation. We have full patent protection until October 2028 in Europe. We will lose it in 2026, but our strength in the emerging markets will also help us to keep the brand alive. And we have a very clear ambition that with the fixed dose combinations that more than 60 million people will benefit from Farxiga and the combinations in the years to come. Equally, I think we have a very attractive existing portfolio. I've already spoken about Wainua, but clearly also the fact that Fasenra, Tezspire and Airsupra are all still having long patent protection. And last but not least, we will focus a lot on the new and exciting new molecular entities in the years to come: baxdrostat both in mono and combination therapy, the fixed-dose combinations, of course, and our very attractive anti-IL-33, tozorakimab. Last but not least, be aware that also biopharma is completely pleased obsessed about what is beyond 2030. And I'm sure that Sharon will tell more about our efforts in weight management, our efforts in cell therapy. Cell therapy is no longer, let's say, the domain for oncology, but it's also moving into autoimmune diseases. And we're very, very excited about that story as well. So over to Sharon in order to give us a little bit of flavor of the exciting science in biopharma.

Thank you so much, Ruud. Can I have the next slide?

Yes.

So as Ruud mentioned, the growing burden of chronic disease, coupled with advances in science and technology, means that we have a tremendous opportunity to create transformative medicines for the tens of millions of people that need them. And we can do this because we have invested in capabilities across a broad range of modalities, from small molecules and monoclonals to additional modalities, including antisense oligonucleotides, bispecifics and cell therapy. And what this means is that we can match the right modality to the target or the disease. We are working to catalyze earlier diagnosis and earlier intervention. And this means that we can stop and even reverse disease progression to offer better health outcomes. Now we know, as Ruud mentioned, in an aging population, that the majority of people are living with multiple comorbidities. So we are developing novel combinations to be able to address the complexities of disease and the full spectrum of disease. And we are moving from treating individual diseases to more holistic health care management to offer better treatment outcomes. And with the tools and capabilities in our arsenal, we are now able to move from effective management of symptoms to disease modification, clinical remission and potentially even cure. And we can do this because at AstraZeneca, we believe in the power of what science and talented scientists can do. So we are working within our core areas of expertise to explore more innovative, less understood areas of biology, connecting with external experts to expand the boundaries and to be able to identify emerging areas of biology in which we can create more transformative medicines. And this is fueling our innovative pipeline, which, in the coming years, has an increasing proportion of exciting new molecular entities. So collectively, we believe that we have the capabilities to deliver on our bold ambition. And if I leave you with one thought from this slide, it is that biopharma is not following these trends. We are driving these trends and driving towards creating transformative medicines for the tens of millions of people that need them. So turning now to focus on 3 exciting new areas in which we are building today for long-term impact, let's first explore new modalities which we are leveraging to be able to address a broader range of disease. Starting with amyloidosis, in our core focus area, AstraZeneca is uniquely well positioned to drive competitive differentiation. Beginning with our silencer, Wainua, which is designed to [ hot ] hepatic expression of the proteins that lead to formation of amyloid fibrils, with utility as a monotherapy or in combination with our depleter, ALXN2220, a monoclonal antibody, it is designed to bind, disrupt and help to remove amyloid plaques. Together with our Alexion colleagues, we are building an industry-leading portfolio in amyloidosis. And we believe that multiple mechanisms of action may be necessary to treat the full spectrum of disease, including severe advanced cardiomyopathy. Turning to another very exciting molecule, the first-ever inhaled biologic designed to treat a subset of respiratory patients who have traditionally been under-treated, AZD8630 targets TSLP. And we have just, in the past day, released exciting new Phase Ib data at ATS in which we demonstrate that 8630 has an excellent safety profile and was able to provide a statistically significant reduction in pheno. And we are excited to see this molecule move forward into Phase II later this year. Now because we know that the majority of our patients are living with interrelated disease, we are designing novel combinations that allow us to address complex conditions such as healthy weight management and cardiometabolic risk. Turning to our weight management portfolio, we are creating a portfolio of molecules that move past short-term weight-loss targets and instead focus on healthy weight management, quality of weight loss and cardiometabolic risk. Our orally bioavailable GLP-1 receptor agonist has utility as a monotherapy as well as in combination with other small molecules in our portfolio, such as Farxiga or our oral PCSK9 inhibitor. And we are excited about our ability to address unmet medical need, and we are moving forward at pace and with a sense of urgency. Also turning to dapagliflozin, building on the strength of dapagliflozin and expanding beyond monotherapy, we are moving forward with 3 different fixed-dose combinations in 3 disease areas across 5 different indications. This represents one of our largest development programs, and we are excited to announce that each of these combinations is now in Phase III. Thinking about the future in immunology, we are working to reimagine a treatment paradigm for people dealing with autoimmune disease. We have expanded our modalities so that we can build on the strength of Saphnelo, considering Saphnelo and our success in lupus, moving into additional disease areas as well as additional modalities that will help us to expand the range of diseases that we are able to treat. So our acquisition of Gracell allows us to accelerate our ambitions in this space and gives us the ability to use the autologous by CAR-T against BCMA and CD19 to address autoimmune disease. And we are very excited to launch a Phase I study in lupus later this year and are planning for additional indications to apply with this autoimmune CAR-T. We are also -- if we could just back up a second, I'm still going at it. So we're also exploring potential new modalities to use in this space, including allogeneic CAR-T as well as bispecific T-cell engagers. And we are looking ahead to also consider resetting the immune system with CAR-Tregs. In our partnership with Quell, we're focused on IBD as well as type 1 diabetes using Quell's proprietary FOXP3 lock technology to create smarter, stronger, more stable CAR-Tregs. Collectively, we are reimagining the paradigm for treatment of chronic prevalent diseases. I'd love to see the next slide now. Okay. So thinking about today, tomorrow and the day after tomorrow, in Pascal's words, Pascal has told you about today and tomorrow, and I'd like to tell you about the day after tomorrow. We have a robust portfolio with catalysts across all of our therapeutic areas in the coming years and key data readouts for each of our major therapeutic areas. Let's focus on the day after tomorrow, where we see that we have a number of exciting readouts to look forward to. Let's take a look at our respiratory and immunology portfolio in which our systemic biologics continue to gain momentum. Fasenra, Tezspire, tozorakimab and Saphnelo all have key readouts moving forward, and we're very excited to see the success for these molecules in new patient populations, including COPD. For vaccines in immune therapies, the pivotal readout for our new RSV, HMPV vaccine is key. And in cardiovascular, renal and metabolic disease, highlights include delivery of the CARDIO-TTRansform trial for eplontersen in ATTR cardiomyopathy as well as 3 dapagliflozin combinations: zibotentan plus dapa, balcinerone plus dapa and baxdrostat plus dapa. In our weight management portfolio, we are moving forward with multiple assets to address healthy weight management combined with cardiometabolic risk and organ protection, and we are moving forward at pace and with a sense of urgency. We can do this because we have a strong R&D platform. We have built capabilities across a range of modalities and technologies as well as deep expertise in our core therapeutic areas where we remain focused on success. And we look forward to delivering on these critical molecules because we have the capability with this innovative pipeline and these exciting molecules to expand treatment for the tens of millions potentially billion people who need them. And we believe that our contribution to AZ 2030's bold ambition and to our continued growth is clear. Now my colleagues will tell you more about each one of these things. But first, we have a short video. [Presentation]

Excellent. Wonderful to be with you today. Martin and I are looking forward to sharing, over the next 25 to 30 minutes or so, our cardiovascular, renal and metabolism strategy. So as you saw in the video, a 40-year history of bringing innovation to CVRM diseases. Today, this therapeutic area is treating over 100 million patients a year throughout the world. The TA is well over $10 billion a year, growing at strong high double-digit growth, as you see on the left. And what's importantly, as you see on the right, is we continue to strengthen our cardiorenal leadership, predominantly through the success of Farxiga, which has established itself as the foundational treatment across 3 disease areas of CKD, heart failure and diabetes. If you look at the middle graph, you see the significant growth year-on-year. But what's important to recognize behind that is that, that revenue, unlike many products within our industry, that revenue is almost equally divided among the 4 regions of the globe between the U.S., Europe, China and the emerging markets. And what that allows is a couple of things. It establishes a strong platform for the future pipeline of many of the orals like oral GLP-1 and PCSK9 and others that have broad global potential, but it also allows for a very different type of LOE curve, where beyond U.S. LOE, this brand will continue to deliver significant revenue for many years to come. The second importance of Farxiga to our future pipeline is what you see in that third graph, which is the 8 million to 10 million patients, new patients that we add every year to this medicine are evenly divided among heart failure, CKD and diabetes. And the importance of that is, as we'll come on in a moment to talk about our dapa combination strategy, many of those indications are in CKD and heart failure. And in fact, we expect by the time we launch the dapa combinations that there will be about 60 million patients globally on dapa that are many of them candidates for one of the combination therapies. So oftentimes, we're asked what are -- who are the patients for which each of your medicines are designed for? And I think it's a very good question because it is not unintentional exactly why we built the pipeline that we've built. We're very much focused in CVRM on the diseases where we think and we hear from our physicians the disease burden is significant. The need for innovation beyond current available treatments is critical, and the populations are large and growing. And so let me walk you through these populations because I think it'll make a lot of sense for each of the molecules that we're going to share. So if you look at cardiovascular, the first column, we're focused on 3 populations. The first is the ATTR-CM, which is one of the largest cardiomyopathies in cardiovascular disease, 300,000 to 500,000 patients, growing significant disease burden. And while there are -- there is one mechanism available today, there is a need for multiple more mechanisms. The second is hypertension. And despite all of the many decades and years of hypertension therapies, the reality is the majority of patients are still not a goal, and hypertension is one of the biggest drivers of morbidity and mortality, and there's need for new mechanisms. And the third is dyslipidemia where despite all of the statins and the statin therapies, and we understand that very well with Crestor, the reality is the majority of patients, despite statin therapy today, are still not at their LDL goal. And ASCVD is still the biggest driver of mortality within cardiovascular disease. And then if we move into renal disease, you see 3 populations that our nephrologists and our cardiologists tell us consistently and have been for years, these are my challenging populations. These are where I need innovation. The first is in the kidney disease patient who also has comorbid heart failure. And in fact, heart failure patients, 50% of them also have chronic kidney disease. And there's 4 medicines that are guideline-directed therapy for those patients. But when you have heart failure and chronic kidney disease, the vast majority of those patients are not able to tolerate a particular class, the MRAs, and as a result, are not on guideline-directed therapy; clear unmet need there. The second population in the middle are chronic kidney disease with hypertension. 75% of kidney disease patients have comorbid hypertension. Along with diabetes, it is the biggest driver of kidney decline. They're more likely to be resistant hypertension. They're more likely to be uncontrolled, and they're more likely to not be as responsive to current treatments. So there is a need to address the hypertensive CKD. And finally, probably the most severe of the populations you see there in the third box are the proteinuric CKD patients, those with significant protein in the urine, which is a sign of significant kidney decline. It contributes to additional kidney decline. And current treatments in these populations, there are very few therapies that are able to reduce the protein in the urine to the degree that we need to be able to address these patients' needs. So these 3 patients are clear priorities for us and for our medicines. And finally, as you heard already the discussion around overweight and obesity, I mentioned hypertension in dyslipidemia as a risk factor. The third as big or bigger risk factor is obesity and overweight, particularly in the populations that are carrying comorbidities. And in there, there is a clear need to address the weight, but also to address the comorbidities that live with them. So if we think then about the portfolio that we've built, we've built a very strong portfolio, we believe, of novel single and dual mechanisms. And as Pascal mentioned earlier, there are populations for which dual mechanisms are the only way to take the next step of treatment. And so if you look at this pipeline, these are the products that we intend to launch before 2030. And they go along with the populations that I just shared with you on the previous page, and we'll walk through each of these populations in detail in a moment. In cardiovascular disease, we're going to focus on Wainua, in ATTR cardiomyopathy as well as a little bit of into the portfolio that we're building in amyloidosis. Baxdrostat as a new mechanism within hypertension, that is the primary mechanism that patients who are still resistant or uncontrolled need addressed, which is aldosterone. Oral PCSK9, which is [ AZD070 ], which we believe is transformative. It's important not to think of oral PCSK9 is in the same space of just injectables in that market. This is going to be like a statin type of breadth of use when you put in the hands of physicians an oral PCSK9. And then in the middle, we're going to cover the dapa dual-mechanism combinations for each of the 3 chronic kidney disease as well as heart failure populations. And then we'll finally end with a discussion around our metabolism and our 3 molecules that will be moving into Phase II later this year and into next, our oral GLP-1, our oral -- or our injectable long-acting amylin as well as our GLP-1 glucagon and the potential for triples there. As we walk through these and as I turn it over to Martin to go through these, you'll see in the top corner, what we believe is the potential, the peak year potential of each of these molecules, and we can certainly discuss that in the Q&A section. So with that, why don't we jump into cardiovascular?

Thanks very much, Mina. Great pleasure to be here. So let's talk about Wainua. So this is our antisense oligonucleotide, very specifically targeted to switch off production of the protein that's then deposited in the nerves and neuropathy or the heart if it's cardiomyopathy. And we already have launched in the U.S.A. for peripheral neuropathy, very good data from the NEURO-TTRansform. That's doing very well, and we'll roll that out across different geographies. But as a cardiologist, bridging from there to the huge opportunity of unmet need of cardiomyopathy related to amyloid, a particularly severe form of heart failure, average survival only 3 years from the time of diagnosis, 500,000 people globally, every cardiologist sees these patients very frustrated because there are so few things you can do to change the future in front of them. So we're very excited about that opportunity. And the more you look for this, the more you find, recent epi suggests 500,000 may be a conservative estimate. But why as a cardiologist am I so enthusiastic about this? We've got our study in neuropathy related to this disease, and we took the opportunity to take a little snapshot from the NEURO-TTRansform study. And about 1/3 of those patients also have amyloid in the heart. So we looked at the heart, we imaged it throughout that study. And on the right-hand side, it doesn't really matter what measure of cardiac structure or function or the circulating biomarker, NT-proBNP, which relates to cardiac strain, they all went in the right direction, which gives us reason to believe that our very large study, CARDIO-TTRansform, which is fully enrolled, will be positive, we believe. So let's go on to the design of CARDIO-TTRansform. I'm sure you've noticed this, this is the world's largest study in amyloid cardiomyopathy, more than 1,400 patients. And we're comparing using the silencer on top of standard of care with standard of care. And we designed it specifically to run to 140 weeks to give robust evidence to the cardiologist, the prescribers, the patients and the payers. So the primary endpoint in the bottom left, you'll recognize this from all heart failure trials, cardiovascular mortality and recurrent clinical events. So very robust data answering the question, does our antisense oligonucleotide, Wainua, make a meaningful difference to these patients. Moving on to the next slide, though, as Sharon mentioned, we have a whole portfolio of assets that are looking at different mechanisms of action for this large group of patients. And we believe these will be transformational either on their own or in combination, depending on the severity of the disease, the progression and the time they present. So I've talked about Wainua on the top there, that's the gene silencer, switching off production of the TTR protein. Our Rare Disease unit has a super stabilizer, acoramadis that you'll hear more about this afternoon. And then very exciting from a cardiologist perspective is the depleter, which is a monoclonal antibody goes into the tissue, binds to the fibrils, triggers reaction to actually remove it, so taking the concrete out of the heart rather than just stopping pouring it in. So we believe that we have a portfolio will change guidelines, change practice and most importantly, change the outcome for patients with this dreaded condition. But let's change focus now, move to hypertension. And looking around the room, I know a few of you have hypertension and all your families have people with hypertension. So pay attention to this one. This is really important. There are billions of people with hypertension and the best will in the world with conventional drugs, many people cannot get to the target. So they know, their families know, their physicians know that they have an increased risk of stroke or heart failure, of kidney disease, and are really wanting to get to that target. 50% of U.S. patients, for example, have difficult to treat hypertension. This is a huge number of individuals. So baxdrostat comes into this, one of the first molecules of innovation in this space, which we believe will be best-in-class, first-in-class. This blocks the hormone that drives a lot of difficult to treat hypertension, aldosterone. And we've seen in our Phase II, the BRIGHT ON study that when you add those to conventional therapy, you get very impressive reductions in blood pressure. On the right-hand side, you can see placebo adjusted double digits difference. So something that a physician and the patient can recognize immediately make a meaningful difference. And that's given us the confidence to go into Phase III, which is recruiting well, and we hope to give the results to you at some point in 2025. So a very important asset here. Another one that's very interesting is cholesterol and statins are very well known. But even with high intensity statin, 70% of patients who have cardiovascular disease do not get to the modern targets. So there's a huge unmet need in millions, if not billions of patients across the world. So we have an oral small molecule, PCSK9, underlying oral, is not an injectable. This is a medication you can take once a day and it's particularly effective at reducing LDL. Now the results of this, and you can see what I mean by particularly effective, will be presented on Leon at the European Atherosclerosis Society next week, and I think you'll see why I'm so optimistic about this. We set it up to show at least a 50% reduction on top of statin. We have confidence and we have gone into our Phase IIb, which is recruiting extremely fast, well ahead of schedule for the simple reason that both patients and physicians see the absolute need for new solutions in this space. So we're very excited about that asset. But let's frame the dapa combinations now, Mina.

Excellent. So hopefully, in the cardiovascular section, you got a good sense between Wainua and baxdrostat as well as our oral PCSK9. And let's shift gears a little bit now and talk about the dapa dual mechanism combinations, in particular, in CKD, but also in heart failure and what is the rationale behind them and where are we. This is one of probably the most ambitious programs we've done as a company. If you think about the 3 enemies across 3 different disease areas: Heart, kidney and liver, 5-plus indications, tens of thousands of patients in these programs. And the primary indication, the first indication is already in Phase III and recruiting very well for each of the combinations. Let's take them from the left and move to the right. So balcinaroned, dapagliflozin, and Martin will speak much more into the science of it. But if you think about the populations that we're treating here, the first indication will be in the heart failure, chronic kidney disease overlapping patients. You see there's 12 million of these patients between the U.S. and the EU 5 markets. That program is ongoing in Phase III and it potentially gives patients the ability to finally be on all 4 guideline directed therapies, 2 of them in this single tablet. Then we move into chronic kidney disease, broader chronic kidney disease with MIRO-CKD Phase IIb. Then you see in the middle, baxdrostat dapagliflozin, which is very much targeted at the chronic kidney disease hypertensive population. We believe between the hypertension benefit of baxdrostat, the organ protecting effect of dapagliflozin that we can make a step change in these patients beyond what dapa can do alone. And then you see to the right, zibotentan, dapagliflozin in 2 populations where today, there are no approved treatments. So you think about CKD with high proteinuria. And the ZENITH high proteinuria Phase III program, recruiting months ahead of schedule, very well a sign of just how much physicians need something beyond an SGLT2 alone for these patients. And then liver cirrhosis with the ZEAL Phase IIb program, where this would be the only treatment for an extremely urgent population to be able to address. You see the size of the populations at the bottom. And what I mentioned on the first slide, I think, is important to reinforce is by the time these launch, we anticipate at least 60 million patients across the globe will be on dapa monotherapy. And if you imagine a patient, likely many of them will be one of these. And if you imagine a physician being able to tell a patient, well, let me take your once a day, easy to take, simple dapa and replace it with a once a day, simple, easy to use dual mechanism that now gives you an additional level of risk reduction and addresses an issue, right, beyond what you're able to address today. We think it is that simple. And clearly, we see a significant opportunity across each of these dual mechanisms. So why don't we take a little bit of time and talk about the science of each.

So just to be really clear, these are 3 very clear patient segments where the science makes sense and there's a big unmet clinical need. So physicians tell us, and I can identify with it, this is exactly the problems that you need to solve for us. And I'm very proud that our teams have gone into Phase III at or ahead of schedule on this. We will produce the evidence space. So let's talk about the first one. And this is dapa combined with balcinrenone. Now this is a mineralocorticoid receptor modulator. So it's a very much more modern version of spironolactone or eplerenone that should be given to patients with heart failure. But half of those patients have chronic kidney disease and they can't take those drugs despite all the benefits because their potassium goes up and you're looking at me going, well, what's the problem. If your potassium goes up, your risk of sudden death goes up, which is pretty serious. So you can see why physicians and patients reluctant to take the older fashioned drugs. We very cleverly chemistry modified this drug to go in and to give you all the benefits, anti-inflammation, antifibrosis, antioxidative stress but really downplayed the potassium issue. And the reason that we're confident about this is on the right-hand side, and this was presented at the Heart Failure meeting in Lisbon last week. And if you look at here, and we took heart failure patients with CKD that also had protein in the urine. So their kidneys were complaining. And if you look at dapa, you get the slight reduction in proteinuria, but you are on balcinrenone, you immediately see this dramatic improvement in protein link in the kidneys. So the organ protection effect of dapa plus balcinrenone. Dapa also protects from potassium going up to a slight extent. So you can see the science rationale of putting these together for this subset of patients. It's not a small group though, 50% of all heart failure patients could benefit from this and we'll take it into Phase III to demonstrate the evidence. So that's the first combination, heart failure with chronic kidney disease, a very specific group of patients. Let's move the focus to another totally different but very specific group. And this is baxdrostat. I mentioned it for hypertension. Here, we're using it to block aldosterone. It blocks a synthesis of aldosterone. And in combination with that for patients with chronic kidney disease and hypertension, we believe that there will be an additive or synergistic effect for this. Now the reason we believe this is if you look at our Brighton study, so this is a treatment of resistant hypertension with this agent. If you look at the patients who have kidney problems and leaking protein into the urine, look at the reduction in the blue bars there of the proteinuria even a small dose because this is a highly selective drug. We've deliberately designed and took a lot of work to design this. So it very selectively blocks aldosterone without affecting cortisol. It's also very powerful. So it's once daily, 24-hour control using it in that patient population, very impressive signals in our Phase II of renal protection. And that's why we've gone with confidence into back to dual Arctic, our Phase III study, which is recruiting globally. So I've talked about heart failure with CKD, specific population where the science makes sense. This is patients with CKD in hypertension, which are absolutely in every nephrologist clinic across the world, trying to control the hypertension, slow decline to transplantation or dialysis. Let's look at the third, very carefully selected population here. And this is slightly complicated, so I'll take slightly longer over this slide with your permission. And this is a combination of zibotentan, with dapa. Now zibotentan is an endothelin A antagonist. And we know endothelin is a very powerful vasoconstrictor that narrows the blood vessels and spoils the blood supply and flow within organs. So if you antagonize that, with this thing, you actually improve the blood flow within the kidney, within the liver, other organs. It also anti-inflammatory to that effect. The problem with this drug is that tends to retain fluid, which is what you don't want. So the combination of dapa, which actually stops you retaining fluid with Zibo, carefully designed to be used at low dose and very effective, very selective, makes perfect sense for 2 groups of patients. So the first one I want to talk about is CKD with high proteinuria. So these are patients who live with chronic kidney disease but are leaking a huge amount of protein into the urine all the time. These are the patients in clinic. You know as a physician are going to rapidly deteriorate and are going to need renal transplant or dialysis are going to die. So these are the really high risk group patients, very frustrating that they're still leaking so much protein despite standard of care. We published this in the Lancet last year. If you look at the right-hand side, the ZENITH study. Look at that 50% reduction in that proteinuria with zibo dapa combination. So something you would see massively with a round of applause by the patient or family and the clinician by using this agent in their clinic. So I think this is very exciting. We've gone into Phase III, and it's recruiting well above schedule. And the reason again is because clinicians and patients see the sense of this in this segment. The other group of patients, though, which is often not talked about is patients with cirrhosis, that's the end stage of a lot of liver problems, such as viral hepatitis, which has been in the news in the U.K. this weekend, but also excess alcohol and also the end stage of fatty liver or MASH. So in those patients, there are no modern licensed therapies at all, no therapies. They do extremely badly and as the pressure on the liver goes up, they do even worse. Zibotentan, very powerfully drops the pressure within the circulation of the liver. And we believe this could end up, could, we'll have to see how the data plays out, to be the only modern therapy for this large group of patients. 120 million people with liver cirrhosis around the world and at least 10% of them the high-risk group within that. So that's zibo dapa also for 2 separate populations. So very exciting time. My job to give the evidence to change practice.

Excellent. So hopefully, you saw with the dapa combinations, why we're excited and why we believe the dual mechanism is required to actually address each of these populations. So let's shift gears now to metabolism, our final section. And we'll speak a little bit here to our weight management, our obesity, our comorbidity strategy. And as you all are very well aware, this is a significant issue, half the world's population over time, over the next decade is either going to be obese or overweight, meaning BMI above 30 or in that 27 to 30 range. What's more important or as important as what you see on the right, which is 2/3 of these patients are carrying at least one, if not multiple comorbidities, and you see what those are below. And that's one of the strengths that we have as really a cardiorenal metabolic company with molecules across the breadth is the opportunity we see, and that's why it was so important for us, for example, to find a small molecule. Oral GLP-1 that we can combine with our other cardiorenal medicines because it's all about not just rate reduction, but about managing the cardio -- renal cardiometabolic risk of these patients. And so we have 3 molecules in particular that are moving into Phase II in the coming year. So why don't we go through a little bit of the populations as well as the 3 molecules.

So I think Pascal mentioned this, you've mentioned it, just to be really super clear. There are 3 clear populations here. There are those that are very obese that need to use substantial weight loss and keep that weight loss off, often have comorbidities. So in that space, we have our oral GLP-1 to be titrated up to high dose. We also have long-acting amylin, I'll mention briefly in a second, but we also have a GLP-1 glucagon, which is a dual active peptide and we might even have combinations of those, which will give very competitive weight loss for that group of patients that need substantial weight loss but also control of the long-term risk factors. We also want high-quality weight loss not losing muscle as well as fat and that's super important for the long term. So that's one group. In the middle, larger group of individuals, as Pascal mentioned, are those that are somewhat overweight need to control that long term, but also have those risk factors such as hypertension or high cholesterol, et cetera. And there we see lower dose of oral GLP-1 being very effective in that space. And the logic of adding combinations, GLP-1 plus dapa for long-term super organ protection, but also oral PCSK9 can be combined, which could control your cholesterol and your weight at the same time. And then there's a third group, which is type 2 diabetes, where obviously oral GLP-1 could play a role in combination with dapa perhaps, but also many of those patients have high cholesterol. So you can see the strategy in these 3 different groups of individuals in the molecules. But the next slide just gives you a little snapshot of what are these molecules. So the first one is our oral GLP-1. It's a true small molecule. We've got evidence of strong target engagement in our Phase I study. Pharmacokinetic suggests it's truly once daily dosing and it could be combined with other molecules. So one of our suite of molecules to use in this space. Two Phase IIb trials will be starting this year, one in type 2 diabetes and one in obesity. So that's oral GLP-1. In the middle, you may not have heard of long-acting amylin, but you'll hear a lot more about this as time goes on. And the reason for this is a very powerful weight loss agent in terms of damping down appetite in terms of delaying gastric emptying, but it's much better tolerated than GLP-1s and actually, it spares muscle. So the weight loss you get with this is very likely to be high quality. So you just lose adipose tissue, fat tissue rather than the muscle. It could be used for patients who don't tolerate an oral GLP-1 because of side effects, but it also could be added to increase in therapy to maximize the effect. So very high potential for this molecule. On the right, we could combine this drug with our GLP-1 glucagon. And this would be for a very competitive weight loss in the extreme end, where you need to lose a lot of weight, but also very good organ protection, cardiometabolic risk reduction and fat specific weight loss. So I hope you're getting the message. We have different molecules that could be used either on their own or in combination to fulfill all of the needs of this wide spectrum of patients.

Excellent. And what I will just say as a final comment here is whether it's oral GLP-1, where we believe we will be 1 of the first 2 small molecules or long-acting amylin, 1 of the first 2 true Amylin specific. We think we're very competitive as we come with this portfolio. So to wrap it all up, final slide, hopefully, you saw the excitement that we have and the energy we have and the belief that we have in the portfolio we're building. Hopefully, you saw at the beginning, the clear patient populations that we have made it our mission to find the right solutions for this molecules that address each of those specific populations. You see on the left, the clear growth drivers between now and 2030, each one of the medicines we shared with you, we intend to launch between 2030 if the data readout. And you see on the right, the data readouts that will guide the decisions as we move through the coming years. So with that, thank you for your time, and we'll turn it over to our respiratory and immunology colleagues. [Presentation]

Well, good morning, everybody, and it's a pleasure joining you today to share with you our growth journey in respiratory and immunology. And we thought that probably a good place to start. In line with what Ruud shared with us today is essentially what is the unmet need that we see in respiratory and immunology diseases. A set of diseases that actually concentrate -- one of the most prevalent diseases once the concentrate more mortality across the world. And those have captured a significant proportion of spend across the world. And I think that Ruud painted a very clear picture looking at some of the stats you see on this slide that actually a number of these conditions, particularly in the respiratory space, still present a large unmet need. He mentioned the fact that COPD still remains the third biggest killer, killing actually more people than lung cancer. And in lung cancer, where we've seen a substantial progress, and Dave and Susan will share more. There's been a little innovation in this space. Now there is substantial next wave of innovation coming into the COPD space that I'm sure we're going to be covering today. You talk about disease like asthma, and we have tens of million patients treated with an inhaler. The bad news is that almost 50% of them won't achieve disease control, which highlights the need to develop new medicines to put these patients in controlling the disease. But even in those that present a more severe part of the disease, for which biologic has been quite effective, only a fraction of them get access to them. So a lot more to be done. And beyond asthma, and COPD you see that more mortality in diseases like IPS and bronchiectasis still are subpar. And this is another area in which we're particularly interested in. So against this significant unmet need, we see that this market is poised to deliver substantial growth and not because of our internal projections, but external projections show that there's substantial growth to deliver in the next 7 years, almost doubling the size of this market. As we see more innovation and increased treatment rates and diagnosis rates more than offsetting the LOEs in this space. Now against these strong market fundamentals, we believe that AstraZeneca is uniquely positioned to lead the way and deliver substantial growth. And you can see on this slide hopefully captures what we call our growth in R&I. If you see the left of this slide, you can see how we've been very busy actually over the last 3 years on driving a substantial transformation in our portfolio in which we have lived behind the main patents we have and the last one, Pascal referred to Pulmicort in China, Symbicort in the U.S., but at the same time, bringing significant innovation. As you can see, 4 launches in the last 3 years alone, allowing us to drive single-digit growth and are poised to further accelerate into 2030. So the 3 key pillars of our thesis for growth in R&I you can see on the right of this slide. The first one is the fact that we have this now refreshed portfolio that on one hand, doesn't have any major LOE towards the end of the decade. And on the other hand, we have these recent launches that are set to accelerate and further being supplemented by more than 20 LCMs that we're going to cover in today. In addition to some NMEs, which is the case like tozorakimab that Pascal mentioned. Second element, and I think Pascal painted this very well, is a significant opportunity we see in China and emerging markets, which is probably the region in the world with the highest growth potential. And if AstraZeneca is a leader is more so in respiratory, where we are the #1 company in this region. And last but not least, looking into the future, the very substantial pipeline, certainly, we consider to be industry-leading in respiratory with twice as many clinical programs as our nearest competitor, and now expanding into immunology, both of which will drive further growth towards the end of the decade and indeed beyond. Now what we summarized in this slide is a little bit the format of the session we're going to be sharing with you today. And what we have done is to paint for you how we see our portfolio mapped up across the disease spectrum. If you go left to right, you will see our inhaled therapies. And as disease continue to progress, you'll see our biologics, which are designed to treat severe disease. And we have also indicated our primary indication for these assets, either asthma and COPD and also some of the additional LCMs we project on this slide. And we're going to be using this to guide you through presentation. So you're probably familiar with our leading inhaled asthma portfolio with Symbicort and our recently launched first-in-class antiinflammatory rescue Airsupra in the U.S. And our fixed dose combination triple indicated in COPD Breztri about which we're going to be discussing now more in a second. If I take you to the right of the slides, you'll probably be familiar with our severe asthma biologics, Fasenra and Tezspire, about which we're going to recover in a second as well as our Phase III asset to Tozorakimab, our IL-33 targeting monoclonal antibody. Now I don't want to draw your attention to the middle of the slide. Because as you know as patients start to navigate the earlier phases of their disease, they are traditionally treated with inhalers. As I was saying before, up to 50% of these patients will remain uncontrolled and at risk. Based on our projections, we believe this is about 20 million to 25 million people by the end of the decade, for which there are not many treatments, and only a fraction of this will ever have access to a systemic biology, which we believe is going to be between 2 million and 2.5 million. So a substantial patient opportunity, which we are targeted to address through the emergence of our early portfolio that Maria is working hard in our labs to develop. Today, we're going to be focusing on just one single example of this, and Sharon alluded to that are novel first-in-class in inhaled TSLP AZD8630 that has the ambition to further expand the Tezspire franchise in this space. So let's dive now into the first asset, which is the case of Breztri. And I need to say that we're extremely pleased by the trajectory that Breztri has been showing since its recent launch. Breztri today the fastest-growing triple continuing to surpass expectations and very much on track to become a multibillion dollar asset for AstraZeneca. Of course, the significant proportion of this growth is driven by the increased share that we continue to deliver across all the markets we show. But there are 3 additional growth platforms that we'd like to eliminate for you that will further support Breztri throughout into the future. The first one is the potential that we see in the further growth of the class, right? And as you can see, as of 2023, partially also driven by the launch of Breztri, this class has grown exponentially, right? Now we do believe that through the emergence of new data we're bringing as well as the more favorable position that triple services have shown in global clinical guidelines, this class will continue to grow to potentially double its size and become main stay in COPD. The second opportunity you can see on the right of your slide, and it's related to the point that Pascal was making before about what the huge opportunity we see in China and emerging markets. And China is a particular case for us for triple because in China, leave 1 in 4 of all the COPD population in the world and 1 of 3 people who die of COPD actually live in China at the moment. And that is a country in which Breztri is the absolute leader with 70% market share. Now on the back of better treatment rates, already for last year, we have seen up to 4 million patients nearly being treated with triple therapies. And we believe that this number can triple by the end of the decade and many of these patients will be able to benefit from Breztri. Now on the back of this significant projected growth, we have made a decision last year, many of you have seen the news of investing over $400 million or building a state-of-the-art manufacturing facility in Qingdao, in the Shandong province to supply this Breztri expanded demand for our Sphere portfolio to supply China and some of the region around it. And the third growth platform has to do with the upcoming asthma indication that will expand if you want the potential for Breztri, which we expect to read out in 2025. But we're not stopping there. So Caterina, probably you can tell us what else beyond the midterm, we have plans for Breztri.

Thank you, Pablo. Thank you for changing the slide. So we are definitely driving a transformation in COPD. In particular, with Breztri, we are really focusing on the cardiopulmonary risk. We know that cardiac and pulmonary factors are drivers for mortality in COPD. And we really want to break inertia that existing treatment today. If we focus on the left panel there, we have learned from the ETHOS Phase III trial with Breztri that Breztri was able to demonstrate a significant reduction in the cardiovascular death versus LABA/LAMA. On the central panel, this data demonstrate that the cardiovascular event are significantly higher following a COPD exacerbation. And actually, this risk persists for as long as a year following the exacerbation. These are the recent data that we have been shared with the community from the EXACOS-CV data. Based on this evidence, we decided early this year to start very, very interesting trial as a clinician and pulmonologist, which is called THARROS is a Phase III trial, which will look at the efficacy of Breztri on the cardiopulmonary outcome. And for the first time, we will combine an endpoint, which looks at both cardiac and pulmonary components. If successful, Breztri will give the opportunity. Breztri will be the only triple on the market to demonstrate a significant effect on the cardiopulmonary risk. And this obviously means expanding the use of Breztri to millions of eligible patents but also not only changing the labels, but also changing the clinical guidelines. And you understand the impact that this will have on millions and millions of patients, considering what Ruud just stated that we, unfortunately, have not advanced in COPD as we wished in the past 20 years.

Thank you, Caterina, and definitely very exciting. But I'll suggest we move now to the more severe disease setting and looking at our biologics opportunity. And we are really encouraged actually to see what is the growth potential that we see in this space, particularly around severe asthma when you look at the progression of the category as a whole, right? And as you can see on the right of your slide, we have seen biologic penetration in severe asthma continue to grow and almost triple in the last 7 years on the back of new entrants joining in the market, new mechanisms of actions, which are unlocking new patient populations and also gaps in the health care system being plugged and clinicians more familiar with these therapies. Now when you look at the biologic penetration we have at the moment, and we compare that in severe asthma with that achieved in other more mature autoimmune conditions like IBD or rheumatoid arthritis, you see that there is a substantial potential to almost double if you want this biologic penetration. And now we believe that this will not only benefit a lot more patients, but also will benefit all the biologics space, in particular, our portfolio, considering the fact that AstraZeneca holds the leading portfolio in severe asthma with Tezspire and Fasenra. And probably we can double-click now and picking each one of these one by one. So let me move to Fasenra first. And I need to say that we are extremely, extremely encouraged to see the double-digit growth in a sustained fashion we have delivered with Fasenra over the last couple of years, in spite of the launch of Tezspire. Now clearly, part of this growth is driven by the category growth that I just presented, but the other point comes from the fact that Fasenra has built a stronghold in severe eosinophilic asthma being the most prescribed IL-5 in markets like the U.S. Now looking into the future, we believe there are strong reasons to believe to actually support Fasenra's further growth, and you can see them on this slide. Now on the left, one of those growth opportunities are ability to expand our geographical footprint for Fasenra entered into China. And you can see on the slide, are the results of our Phase III MIRACLE study in Chinese patients where Fasenra demonstrated a super strong 74% reduction in severe exacerbations and indeed, across the different secondary end points and forms the basis of our application for regulatory approval in China, which we expect by the end of this year. Now if approved, this will give us a significant opportunity to further expand the number of patients we can serve with Fasenra and certainly consolidate our leadership position in China. And then on the right of the slide, even going beyond severe asthma, you see that we have coming fairly soon, a set of additional indications, what we call life cycle management opportunities worth more than $1 billion, right, of which we are expecting approvals and readouts already this year and probably for what is the most attractive opportunity our COPD indication with our RESOLUTE trial reads out into next year. Now moving on to our next asset, our recently launched TSLP targeting monoclonal antibody Tezspire, launched about 2 years ago and continue to launch across the world. And I think it's fair to say that we're extremely, extremely encouraged to see the strong trajectory and uptake, launch uptake working with Tezspire that is achieving pretty much everywhere we launch, a second or first place in terms of dynamic share only a few months after launch. Now we believe that this gives us confidence that Tezspire will become not only the broadest biologic in severe asthma, but also the leading biologic in severe asthma. And even if we believe that asthma is going to be the main opportunity for Tezspire, we're clearly not stopping there. And we have built a set of new indications that will further support our ambition of making Tezspire a multibillion-dollar franchise. So probably Caterina you can tell us a little bit more about those.

Yes. So later this year, we are expecting results from the Phase III DIRECTION study, which is our program in severe asthma in China, and also the Phase III WAYPOINT trial, which studies patients with chronic rhinosinusitis and nasal polyps. Our Phase III trial crossing in eosinophilic esophagitis is running as per plan, and we are expecting readout after 2025. Last not least, we have COURSE on the list. COURSE is our Phase IIa trial. We have just read out and announced results yesterday in the context of the American Thoracic Society in San Diego. Let's zoom on this. As I just mentioned, COURSE is a Phase IIa study in moderate to severe COPD patients where Tezspire looked at the effect was investigated to examine the effect on exacerbation rate. We know that Fasenra, dupilumab and Mepolizumab studied in high-EOS patients meaning EOS equal or above 300 microliters per cell, which represents around 30% of the market. Tezspire showed nominally significant 37% reduction in COPD exacerbation in patients with EOS equal or above 150-microliter per cells which actually represents more than 60% of the market. In addition, Tezspire also showed numerically significant 47% reduction in moderate to severe in patients with eosinophilic level equal or above 300. So the study was run in a population irrespective of smoking status as well. And we are now looking at exploring opportunity for this indication by imagine the new Phase III trial and the next phase of development in conjunction with our partner, Amgen. On the strong trajectory of Tezspire, Pablo, please next slide. We are now moving into our inhaled anti-TSLP that Sharon just mentioned in her presentation. This drug has really the potential to deliver an efficacy like Tezspire via an inhaled route, meaning that we could actually unlock a number of patients by expanding the population to moderate asthmatic patients in addition to the severe ones. If you look at the right panel, these are the data from our Phase Ib trial, where inhaled TSLP, AZD8630 was able to demonstrate a reduction in fractional exhaled nitric oxide, FeNO about 23%, which is actually equivalent to the reduction that Tezspire showed at the time in the PATHWAY trial. Our Phase II trial is planned to start in 2024. Now let's move to another very interesting asset, which is Tozorakimab. Let me just simplify for you in a few seconds how Tozorakimab works. Tozorakimab, if you look at the left panel, is released is in a reduced form which signals the ST2 pathway with coarse inflammation. The IL-33 oxidase form also actually signals the RAGE/EGFR complex, which was discovered in our lab. What Tozorakimab does block the 2 pathway. So this is really the differentiator element we have with this compound by reducing inflammation, yes, but also completing inhibiting this pathway, which is related to the epithelial dysfunction. Not only what is very interesting that IL-33 is actually a driver of inflammation, but also the epithelia remodeling and is related to the mucus hyper production. The mucus hyper production is a critical future in COPD patients. So we believe with this differentiated mechanism, we will be able to act on the mucus clearance and the epithelial repair reinforcing the potential for disease modification that we have with this drug. Based on our proof-of-concept trial, we have been able to show potential across all EOS level and also the internal data support efficacy in both former and current smokers. We are currently running a very, very vast Phase III trials, the OBERON, TITANIA, and MIRANDA part of the LUNA program, which we expect to read out after 2025. We have also a great opportunity with this drug in viral lower respiratory tract disease, and our TILIA study is a Phase III study, which we read out again after 2025. In addition, you would imagine that with this very elegant drug, we are investigating additional opportunity in other respiratory disease.

Thank you very much, Caterina. And indeed, very, very exciting. So hopefully, you get a bit of a sense of some of the key opportunities we went through the inhaled space the systemic biologic space and gave you an example in the pre systemic biologic space, and I suggest we pivot now into immunology. I think if we look back over the last 50 years, we have developed within AstraZeneca deep expertise in modulating this function and immune responses and generally applied into the lung in respiratory, but we're now taking this expertise beyond into other organs and other autoimmune conditions. But we've been very intentional and strategic when deciding where to compete in autoimmune disease. And we have made the decision to build a presence within rheumatology with particular focus in lupus and some adjacent diseases. And there are a number of reasons why we took that decision. First of all, is lupus is an area with relatively limited competition and a relatively low innovation. The launch of Saphnelo has become only the second launch in more than 60 years in this space an area that still remains severely underserved with remission rates that can be severely optimized and access to biologic and advanced therapy is relatively low. And finally, that share with a set of other diseases, relatively common disease drivers, like diseases like myositis, Sjogren's disease, scleroderma that put together represent as an attractive opportunity as lupus alone, right? And with this in mind, we have now started to build what we believe is one of the strongest portfolios in the industry with focusing Lupus first in SLE. And our ambition for this portfolio when we tackle lupus is, first of all, to establish Saphnelo as the frontline treatment as a first-line biologic treating moderate to severe patients. Now for those patients that we believe that we won't be able to achieve disease control, we have now moved into the clinic with our next-generation bispecific targeting pathogenic cells with which we are moving into Phase Ib by the end of the year. And later on in the course of the disease for those that may remain refractory on the disease, and Sharon alluded to this, we're very excited about the portfolio that our cell therapy portfolio can deliver for these patients, and Caterina will tell us a little bit more now in a second. So if I may dive into Saphnelo first. As you probably know, we have launched Saphnelo only north of 2 years ago with an IV formulation only. And I need to say we're very encouraged by the fact that very rapidly in all markets we have launched, we have captured dynamic leading market share in almost every market in the IV segment. But we do know that if we want to expand the potential that Saphnelo and this mechanism can build to patients, we need to develop also a subcu indication, and the reason for that is in the post-pandemic world, this formulation has become very critical and actually explain the majority of the opportunity, right, between 50% and 80% of the opportunity in the market. So Caterina, why don't you tell us our plans about Saphnelo moving forward?

Yes. Early this year, we presented the long-term data analysis from our TULIP trial. You can see on the left panel, where we were able to demonstrate that Saphnelo is the only drug to achieve a clinical remission around 30%, actually at 4 years. And this is really the only drug on the market. Obviously, as Pablo said, we are eager able to read out our next trials in subcu to really expand in a large population and not limiting only to the IV market. And then, of course, Phase III SLE in China is our big program, again, next readout in 2025. But we are not stopping here actually because we have a significant expansion that you can see on the right panel by the number of the indication we have actually already started, for example, Phase III IRIS in lupus nephritis or the Phase III DAISY in systemic sclerosis with the data readout after 2025. And we are planning to start actually this year with a Phase III in cutaneous lupus erythematosus and also in Phase III in myositis. We are also very, very excited by the opportunity we have in cell therapy. Unfortunately, SLE represents a high unmet medical need. 1/3 of these patients actually develop lupus nephritis, which leads to very severe condition and also death and 30% of these patients are completely refractory to current therapy. George Schett data demonstrated that is it possible, and this was data in each subject with SLE to achieve remission after 3 months sustained at 2 years. This is, for us extremely, extremely interesting because there is an opportunity outside oncology to really embark in this indication. But also, we are also accelerating our growing ambition in immunology with the next gen of cell therapy through, for example, the acquisition of Gracell and also collaboration with Quell. For example, with Gracell, we really have an opportunity with AZD021 is an autologous CAR-T dual targeted CD19/BCMA. And thus, of course, at the moment, we have an investigator initiated trial. We open IND in U.S., in China with intent really to start our phase trial soon later this year. With Quell also, we have the potential to be the first-in-class targeted Treg cell therapy to restore immune tolerance across inflammatory disease included inflammatory bowel disease and type 1 diabetes.

Good. So I think we come to the end, and I'll wrap us up now with this one. Let me deal with 3 main final messages. We started a decision today talking about our thesis for growth in R&I and I hope you feel a little bit more reassured about that growth trajectory and our contribution to Pascal ambition for the company. What are the 6 opportunities, the 6 franchises that need to watch out for that we were responsible for the majority of this growth in the years to come. And last but not least, to feel reassured that actually many of the catalyzers driving this growth are not just happening late into the future, but actually are coming pretty soon with 8 Phase III readouts in the next 18 months alone. So with that, I'll thank you for your attention. I'll hand over to our colleagues of V&I. [Presentation]

I hope this was deliberate. I hope you still have energy for one more presentation. Mark and I will definitely try to do our best to excite you with the science behind the vaccine and immunotherapies and also share with you our progress. So in vaccine and immune therapies, what we are trying to do is to develop the portfolio of complementary, innovative vaccine and monoclonal antibodies, primarily to protect the vulnerable patients, to protect the patients who are at the highest risk of developing respiratory -- complications from respiratory infections, but also to the patients that we in AstraZeneca take care of across our portfolio. And therefore, we see vaccine and immune therapy unit as a strategic adjacency to our business. And today, presentation will focus on our recent acquisition of Icosavax. But before that, I'm pleased to share the progress with our 2 long-acting monoclonal antibodies. Last week, we announced the SUPERNOVA Phase III efficacy trial, high-level positive results, showing that sipavibart, long-acting monoclonal against COVID-19, demonstrated statistically significant reduction in the number of the infections against COVID. And this is important because the SUPERNOVA efficacy trial is the only trial that is run in the immunocompromised population. And we know that those patients are under disproportionate risk of the infection that can also impact the underlying disease. Immunocompromised patients are the patients that we know very well in AstraZeneca. Those are the patients with hematological malignancies. Those are the patients with solid tumors and the advanced line of treatment, dialysis or transplant patients and we look forward to announcing the full data set at the upcoming medical conference. Sipavibart or 3152 is building on our know-how experience and heritage in developing long-acting monoclonal antibodies, including a recent launch of Beyfortus for the protection of RSV in infants. Beyfortus is the fastest uptake of any pediatric immunization ever with 2 million infants protected only in the first season. And we are very excited to see our data of the impact Beyfortus has on the infants in Spain and U.S., showing 90% of the reduction in the hospitalization in the first season. Now with the leadership of RSV, we are very excited with our recent acquisition of Icosavax. This acquisition gives us an access to the innovative virus-like particle or VLP platform as well as an access to the IVX A12 Phase III-ready combination of RSV and hMPV. This vaccine is the most advanced in the development of most advanced RSV combination vaccine with the FDA fast designation status. And when approved, it has the potential to bring a few novelties into the fast-moving and growing RSV market. It has the potential to be first vaccine for hMPV and there are no preventative or treatment option for hMPV today. It has the potential to be first combination vaccine with RSV and it has potential to be first VLP vaccine for respiratory viruses. We do believe that the RSV and hMPV ideal target for the combination vaccine. I will tell you more about that. So I'm sure you all know by now why there is a need to protect from RSV. I'm not sure that you necessarily all know as the same for hMPV. And hMPV is actually a less known cousin of RSV, if you want, but equally very important when it comes to the course of the serious respiratory infection and hospitalization, and because of the overlapping seasonality, hMPV and RSV together represent 25% of 1.3 million hospitalization in U.S. and they present a similar level of the hospitalization as flu. Now you heard today that the population is aging everywhere. So with the aging population, if you look at the middle of the slide, this problem will become bigger because those people of 65-plus age actually has significantly higher risk of the hospitalization is 4x higher than influenza. RSV and hMPV are also associated with a more serious disease, longer-staying hospital ICU admissions and hospital readmissions. Another important underlying risk factor is the underlying diseases either in the cardiology or respiratory area. And as mentioned, we know that patients very well, and I'm sure you heard that clear and loud today and treating those patients and protecting them from respiratory infection will really provide the overall holistic improvement of health and outcomes for those patients. We are bringing this differentiated combination vaccine in the already existing clinical pathway. You all know the NITAGs or National Immunization Advisory Technical Committees like ACIP in U.S. have already recommended RSV protection for older adults. We also believe that looking at the current vaccination rates in U.S. pneumococcal and flu vaccines that are above 60% that you can expect the same for RSV and the combination RSV. As mentioned, it is a great combination for the target vaccine because hMPV and RSV have the overlapping seasonality because they are, as mentioned, cousins with the structural -- similar structural biology and because unlikely flu and COVID, they don't show any seasonal variance changes. We also saw that the external forecast of this market is quite bullish. It goes above $10 billion, and we believe that with this differentiated vaccine with our global reach, including China, we can reach significant market share. Therefore, we see the potential of this asset being between $1 billion and $3 billion. Next step is the start of Phase III that is ready to start later this year. And with that, we plan to launch in 2027. And now it's time to look at the exciting science behind this platform. So let's watch the video and then over to Mark. [Presentation]

Great. So I think that video did a really outstanding job explaining why virus-like particles are such powerful immunogens. But for those of you that are interested and would like to see one up close, actually brought a model of an Icosavax virus like particle that you're welcome to check out after the session. So as we look forward to starting the Phase III, we're really building upon a strong foundation of data from the Phase II. And let me just highlight a couple of key points. Of course, this is the first study to show robust immune responses, not just against RSV, but of course, against RSV and hMPV. In particular, it showed very strong immune responses in all adults, specifically those over age 70, and I'll come back to that in a minute. These responses were quite durable in that when we looked at neutralizing antibodies in the serum 6 months after vaccination, those levels were still quite, quite high. And then lastly, as an immunologist, it was really exciting to see that the vaccine did not require an adjuvant or a compound to boost the immune response suggests that the virus-like particles are self adjuvanting all by themselves. So because of these strong data and really the strong platform that these VLPs provide, we really believe that this vaccine is going to have a strong and very competitive target product profile. Let me highlight some of those key features here. Of course, this will be the first vaccine to cover not just RSV, but RSV and hMPV. And importantly, it will have a strong protection in those all adults and specifically those over age 70, where we know both the incidence of disease and importantly, the severity of disease is the greatest. Because of the durability, we anticipate protection for at least 24 months. And as I mentioned, the vaccine does not require an adjuvant, which means it will have a strong, very good tolerability profile. And then lastly, from really a practical perspective, these virus-like particles are incredibly stable. In fact, they're kind of rock solid, which means we're able to formulate the vaccine in an easy and convenient to use prefilled syringe. And this is in sharp contrast to some of the other vaccines that need to be formulated at point of care in sight of use by mixing multiple vials together into a syringe. So because of that, easy-to-use and convenient formulation, we believe, will really broaden the impact and uptake of the vaccine.

Thanks, Mark. So I hope you now understand our excitement with this platform and excitement to explore, and our ability to bring this vaccine to the patient. It strengthened our late-stage pipeline significantly. It also gives us an opportunity to have $1 billion to $3 billion asset that can be in the market in the patient hands by 2027. Now in summary, I hope you heard today that respiratory infections are dangerous. They're especially dangerous for people who are suffering from the underlying cardiometabolic respiratory disease, but also for the patients suffering oncology or immunology diseases because their immune system have been weakened by their underlying medication. Again, therefore, we believe that vaccine and immunotherapy is a great strategic adjacency to our business, and it is another important enabler of our growth until 2030 and day after tomorrow, as Pascal says. Thank you very much for your attention. With that, I give floor back to Ruud.

So that concludes the session of BioPharmaceuticals. And hopefully you felt all of you in the room, the excitement of the presenters and the underlying science and the possibilities we have in our hands. I truly believe we have a proud history in biopharma. We have seen a fantastic growth in the last few years. But I think someone was mentioning it is also the start of a new beginning, and it also felt that same way for biopharmaceuticals. You saw a lot of excitement of the CVRM team, whether it is Wainua, very exciting combination products. But equally, of course, also the possibility in order to move forward in order to help many more patients across the world. Equally in R&I, you saw the excitement of the current portfolio, which is a very young portfolio, a very important asset as well as the possibility of Tozorakimab in order to really make a change in the treatment of COPD. And last but not least, of course, yes, Icosavax acquisition provides us a unique opportunity in order to move into the very attractive RSV, hMPV world. Last but not least, a lot of attention and a lot of question about what is happening after 2030. We're already working on new modalities like cell therapy, T cell engagers. And hopefully, in the next few years, you will see more of that. We are very passionate in order to help patients across the world. If we are helping patients, it's good for societies. And equally, of course, it's also hopefully good for all the people who are supporting us, including our shareholders. So with that, I will conclude the session, and I will hand over now to Pascal for the question and answer. If I can ask Sharon and Iskra to join me on stage as well.

Thank you, Ruud. And so hopefully, you see that we execute well and we try to over deliver on our goals. We are 15 minutes early. And because we are very generous, we decided to pay you a special dividend and extend the time of the lunch by 15 minutes or so. We'll still extend the time of question and answers by 5 minutes. So that's okay. So who wants to start? Sachin, go ahead. By the way, just maybe a role of engagement, if you don't mind. Any questions to do with finance or whatever if we can keep for later in the day, I'm sure many of those questions will be covered. And if not, we have another Q&A at the end of the day. So if we can focus the questions on biopharma. I'm sure you saw there's lots of exciting stuff there, yes.

Sachin Jain, Bank of America. Two questions on CVRM. So firstly, you gave the target profile and timing of data for the PCSK9. Any sense of timing of the Phase I data and target profiles for the oral GLP-1 and Amylin? On the GLP-1 any difference in Mono versus combo? And on the Amylin, you've been very vocal on the quality of weight loss or is that something we should focus on. And then on Eplontersen and the CARDIO-TTRansform study, just wanted to dig in a little bit more to your confidence in being better than a stabilizer to replace it as mono and then confidence in it being better as an add-on to background to tafamidis.

All right, Sachin thank you for those 14 questions, all in one, very nicely done, and I really do appreciate your interest in these molecules. So let me start at the beginning. You asked about oral PCSK9 and about our oral GLP-1 receptor agonist. So beginning with oral PCSK9, what we told you today is that we'll be releasing data shortly later this year on our Phase I data, and we have already moved this molecule into Phase II. And I think that gives you a sense of our excitement about this molecule. What Martin showed you today is that we set ourselves a very aggressive target product profile. And we said this molecule has to be able to demonstrate at least 50% additional LDL-C lowering on top of statins, and we would not move it forward if we hadn't seen that. We have moved it into Phase II. So I think that gives you a sense of what you can expect with our upcoming presentation in the very near future. And when I'm finished, I'll pause and give my colleague, Regina, a chance to offer a little bit more color. With regards to the oral GLP-1 receptor agonist, you asked about timing of data. And I will repeat, as I have said consistently that we look forward to sharing those data at an upcoming medical conference later this year. That said, we have told you today that this molecule recently completed a Phase I that was a highly controlled inpatient Phase I in type 1 diabetic -- or excuse me, type 2 diabetic patients. And that, again, we set ourselves an aggressive threshold to move that forward. And we have told you today that we have planned for 2 Phase IIb studies starting later this year. So that gives you a sense at our encouragement from the Phase I data and our ability to make additional investments in clinical development for this molecule. Amylin and amyloidosis. Thank you for the reminder. So I will hand it over to Regina to tell you a little bit more about our Amylin, which is currently in Phase I, and we are looking forward to moving that forward towards the end of this year or early next year. And you asked about amyloidosis and our excitement about our silencer relative to standard of care. And I think Martin gave you a really nice view of why we are so excited about the opportunity for this molecule, not just where it is approved in polyneuropathy, but where it has the potential for approval in cardiomyopathy. And one of the encouraging pieces of data is that Martin showed you, which was in our polyneuropathy studies, we recognize that not everybody has just neuropathy that a subset of patients also have cardiomyopathy. And in a planned subset analysis within that study, what Martin showed you is we saw a significant benefit to cardiac structure and function. So in that study within a study, we saw very encouraging data, which gives us optimism for our very large cardio transform study, which is the largest ever cardiomyopathy study run today and which is fully powered to help us analyze the subsets there and really understand the utility of this molecule. We have included patients who are currently on standard of care, which is a stabilizer. I note that patients who are on stabilizer are interested in participating in a clinical study, which gives you a sense that they don't believe that their disease is well controlled on stabilizer alone, and there is additional opportunity to offer them further clinical benefit. So let me now refer to my expert colleagues in the room, Regina, if you would like to comment on oral PCSK9 and long-acting amylin and offer further color. And Martin, if there's anything that you would like to add to the amyloidosis study, let's start with Regina?

Okay. Thank you so much for the question. So we are very excited about ACD0780, which is our low molecular weight through small molecule. And this molecule binds to a completely different binding site versus the other PCSK9 inhibitors. So the other PCSK9 inhibitors, they inhibit interaction between the PCSK9 enzyme and the LDL receptor. This is a huge binding site, protein-protein interaction. Therefore, it's been impossible to develop a true low molecular weight, small molecule to inhibit that interaction. So we have discovered a completely novel binding site on PCSK9. In another part of the molecule called the C-terminal domain, a small binding pocket, which has enabled us to discover and develop these small molecules, low molecular weight 400 Dalton molecules. And with these being really true small molecules means that we can formulate these molecules in a very simple formulation with no interaction on food intake. And we can also co-formulate with other molecules to provide these fixed-dose combinations that expand outside of just targeting dyslipidemia and also target other comorbidities that you heard about today in the CVRM presentation. So that's a little bit more color on the PCSK9. And as Sharon said, we will be presenting the Phase I data next week at the European Arthrosclerosis Society meeting. And we have progressed rapidly through, I would say, Phase IIb, when it comes to long-acting amylase, I would just say that the cracks with Amylin is to have a selective amylin peptide because the amylin receptor is a heterodimer of calcitonin receptor. So other amylin agonist are hitting both calcitonin and the amylin receptor and that leads to tolerability issues. And also with having a selective amylin peptide, we believe that we can achieve the fat mass specific weight loss and better tolerability. So that is really the key when it comes to the Amylin space. And of course, to deliver significant weight loss. But again, improved tolerability, lean mass bearing fat specific weight loss. Thank you. And I'll hand over to Martin for Wainua.

Thanks for the question, Sachin. So just to remind you, transthyretin the protein that's behind amyloid, there's a huge amount circulating. We all produce a lot all the time to stabilize and make some sense of stabilizing it. But actually, what you want to do is reduce the amount of protein that's circulating and that's what our asset does more than 80% knockdown of that. So we believe scientifically that this is a step beyond stabilizing. And just to remind you, in our trial, CARDIO-TTRansform as Sharon mentioned, we have 60% of patients on background tafamidis, 40% not. So we'll report out those separate groups.

Thanks, Martin. Maybe I could ask something -- add something to this, Sachin, is that -- if you look at this TTR protein, of course, you can stabilize it, it makes more sense to stop the production, as Martin explained, but also makes sense to remove the protein that's already there. And it's important to remember that this is a disease, at least today, that is relatively hard to diagnose and patients are diagnosed a little bit late. And so if they are late, it means they have already accumulation of the protein in their heart muscle. So really, looking forward, it makes sense to remove what's in the heart tissue, and you'll see a video later today from the Alexion team and then stop the production and so combine the 2. And so if we do a combination study and we can show the benefit of combining those 2 interventions, we'll be the only company with a combination data. And that will benefit, of course, both products. In particular, it will help further differentiate eplontersen being the only product with this kind of combination treatment. I forgot to say that for those of you who are online, if you have a question, please raise your hand button if you want to ask a question. Jo, go ahead. Sorry. I don't know where to go. Jo, go ahead.

Thank you, Jo Walton, UBS. Three quick ones. Just in terms of the vaccines, you talk about your combination vaccine available for launch in 2027. Is that the start of quite a rapid introduction into a broader vaccine franchise? I feel it's not necessarily particularly commercial or easy to enter with just one vaccine. So I'm just intrigued about the breadth of your ambition there? Secondly, on the oral GLP. There's a huge amount of debate about whether people can make this sort of stuff in the quantities that's required. Is there something about your one that requires a small dose or something that makes it relatively easy to make? So the question is whether you could really do something at scale? And my third question is just a broad one about early diagnosis. You talked a lot at the beginning about it's very important if you're going to really tackle disease to treat people early. Is there anything you're doing that's sort of clever or new in biomarkers or something to improve the early diagnosis so that your treatments actually work better?

So many, many good questions. Let me just make a quick comment on vaccines. So we are absolutely clear. Our intent has never been to build a vaccines portfolio like a vaccine company. Our intent has always been to pursue a strategic adjacency kind of approach, if you want. And looking at patients we already take care of, and I think Iskra said it, patients who have respiratory disease and may experiencing exacerbations of asthma, COPD linked to a viral infection. Patients who have blood cancer and maybe subject to infection, COVID infection or other viral infections is very, very striking in our hematology studies, but also other hematology studies from other companies to see the death rate from COVID, still very high, even though those people are vaccinated. So whether it's antibodies or vaccine, we really want to focus on the adjacencies and helping patients who actually we already take care of. So we're not planning to expand our portfolio beyond this kind of very targeted approach. For instance, we're not going to have a rabies vaccine or diphtheria or whatever. It really is going to be focused on where we are. Now in terms of the commercial aspect of the vaccine, maybe Iskra, you can comment. And Ruud, maybe you could speak about early diagnostics. The efforts we already have in place. Sharon, you could talk about further science around diagnosis, but also the nature of the GLP-1 molecule and the manufacturing costs.

Thanks, Pascal, for taking the majority of the question. It's a great question, and it's really important for us to understand that our strategy that we are building is really different and very specific in the areas where we operate. And therefore, we believe that breadth of the vaccine portfolio may not be the key success factor for your commercial success. We believe the differentiated innovative vaccines also built on our experience, both with Beyfortus and the monoclonal antibodies in COVID as well as understanding and the closeness to the business in the respiratory or other segments in the company. They'll give us a competitive advantage and the different edge, if you want, for the commercial model. And we do believe that the differentiated vaccine we have, if it's the question about IVX812, we have an opportunity and advantage to do that.

And remember that, for instance, Merck does very well with an HPV vaccine without having a whole range of vaccines like Sanofi or GSK would have. So it is possible to do well if you have differentiated vaccines and of course, put together a good commercial plan.

Yes, quickly responding to your question about early detection and diagnosis. One of the success stories of Farxiga clearly is that we have very substantial programs in place for early detection of CKD. It's a relative -- at the moment you are losing protein if it is in the urine, it's relatively easy to detect. So one of the success stories clearly in China is that we have, I believe, now screened more than 15 million people in China. And of course, then you pick up a lot of those CKD patients, and we will continue to do that. In the asthma space, it's equally -- it roughly takes 7 years before a severe asthmatic is diagnosed. So we have programs, patient support programs in place in order to detect much earlier those patients. So they will move from primary care into specialty care, and that's a big part of our, let's say, commercial efforts as well as medical affairs efforts, I need to say, in order to really change the way health care is delivered equally, of course, in amyloidosis, Sharon and the team and the research team are looking for, is it possible to detect, for example, those misfolded proteins in the blood, so a blood test. So those activities are also ongoing from a research perspective.

Great setup, Ruud. So I'll add to that. As Ruud told you, we are working on the very exploratory approach to be able to identify a soluble biomarker for amyloidosis. That's technically very difficult. In the near term, what we think is more achievable is building an AI algorithm that is shareware that allows the echo diagnostician to get a red flag for cardiac wall thickening, which signals that this patient may have amyloidosis. We know that patients who are diagnosed late in their disease have an especially poor prognosis. And that's at a point where stabilizers are unlikely to help them, so if we can bring that diagnosis back earlier, we can offer patients a better health outcome. And so that's been a focus, which is a collaborative effort between the biopharma team as well as our colleagues in Alexion. Your other question was about GLP-1, can we make it at scale and what are we doing to be able to address that? And I'll get started, and then I'll hand it over to my colleague. So I think a number of people have recognized that these molecules in the class tend to be on the larger side and therefore, have complex synthetic routes. We identified opportunities almost immediately to simplify the synthetic route for AZD5004. And we have been working in collaboration between our outstanding team in AstraZeneca, together with our colleagues at EcoGene. We think we've already made substantial inroads. And Elisabeth, who is leading this project across the range of development efforts is put into place a very aggressive plan to ensure that we have the supply that we need. Would you like to add more color?

Yes, I can definitely do that. So when I took this on in the beginning of the year, I had the same fear that maybe CMC will be sort of the limiting factor here. I can tell you, it's not going to be that. We have a fantastic CMC team. And we will be able to deliver both the clinical supply to whatever aggressive clinical plans that we are doing and commercial supply in the end. Also, please remember, this is a small molecule, which is really good for many perspectives. Not only does it make it easier to produce, but it also sets the foundation for fixed-dose combinations. We will be able to combine with this molecule with other great molecules that we have in the area of cardio protection in our portfolio.

That is the beauty of a novel agent and a small molecule, you can manufacture it at scale much more easily than an injectable into a small molecule. You can bring it to millions -- hundreds of millions of patients around the world at lower cost, of course, at the level -- price level, we can still be profitable for sure, but at a lower cost, make it more affordable, and avoid hundreds of millions of plastic pens being put in the rubbish bin every day. So there are lots of benefits to an oral agent. And of course, the combinability is a critical part. There's one here and one behind, and then we'll go there and there's James. And then we'll move to the left side.

Emily Field from Barclays. I just wanted to follow up on the point on weight loss quality as this is obviously being discussed more as a point of potential product differentiation. Do you see this as being an approvable clinical endpoint? Or just how are you going to be able to perhaps add this claim to the label? Will this be intended for development in specific populations such as the elderly? And then maybe a question on COPD. Ahead of potentially the first biologic launch later this year, Tezspire would still need to run a Phase III study and then tozorakimab Phase III data could potentially come after 2 competitors in the class. So just how are you thinking about commercial differentiation here? Is it the potential to be addressing broader population set as the course data from yesterday would suggest? Just any further color there?

Could we ask maybe, Elisabeth, do you want to take the first one? And Ruud or maybe Pablo or -- yes. Yes, let's start with maybe Elisabeth.

Yes. You asked about sort of quality of weight loss and how we are going to measure that and what it will mean for the label and so forth. I think the registrational endpoints in this area is going to remain being sort of the amount of weight loss that you are having, but that's not going to be enough. We will need to show clinical outcomes data, be it in the cardiac space, in the renal space or in other space. And I think as part of these trials, be it the registrational trials or the longer clinical outcomes trials, we will need to show sort of the quality of weight loss in addition to just the weight loss numbers. So I can see us move away from just looking at numbers, but instead looking at both quality and what kind of other cardio, renal endpoints do we effect. And we are very likely to get into a place where it's not just the magnitude that matters, but also how you decrease it and what impact you have on other parts. And I think that's what we will be doing with our development programs in this space.

And then to the question you had around differentiation in COPD biologics, I think that first of all, an important premise is that sometimes, we think there is some of these diseases. And clearly, that is not necessarily very helpful in COPD. We think that we can put medicines in boxes. COPD, as you probably know, is a highly heterogeneous disease, right? And we call COPD a raft of probably sub-patient populations and biology drivers that we probably don't understand yet, right? So it's quite likely, and we believe that some of the way that some of these diseases are not immune disease has evolved is a good market to how we see this market approaching, which will need more than one mechanism to potentially achieve disease control. Remember this, we're talking about the third biggest killer in the world, right? So the mandate is there, and you probably need more than one mechanism to do that. Now at the moment, the only relatively simple marker that we have found to drive activity is eosinophil levels, for instance, although that may be a blunt tool in the future. And certainly, as the science develops, we learn more. Now when it comes to that point, we do have a primary market of activity with Tezspire, and we presented this data now. So we do know that the drug seems to be active in eosinophils 150 and above. Remember, this is 2/3 of the patients, right, which is a very big, if you want, differentiating factor and probably confirming the broader mechanism of action that we can achieve with the SLP related to other eosinophilic agents. When it comes to tozorakimab, I think that Caterina did a great job on explaining why we believe that the dual mechanism of action on targeted -- it's only inflammation, but the oxidative form can probably provide differentiation, particularly working around the mucociliary clearance element that is so prominent in the COPD phenotype. Now beyond that, I mean, the data will be the data, right? So we need to wait for Phase III. But the fact that we believe that tozorakimab can act across the broad eosinophilic spectrum and at the moment, can target current smokers and former smokers, if confirmed in the Phase III, could be additional elements of differentiation.

Sorry, let's keep going there, and then we'll go to James.

Christopher Uhde from SEB. My first would be on the Icosavax. And I guess there, I'm wondering -- I mean, you have a vaccine that looks like it's probably very competitive on the RSV specifically, but then you also add in the NPV. And so I guess I'm wondering if you're saying $1 billion to $3 billion in potential value for something that's roughly twice as much value, I should say, and what's out there and the market is obviously quite a bit bigger, the $1 billion to $3 billion, how much do you leave on the table by having the commercial strategy that you have of not having primary care access instead of at the same time as you get the first pass in specialty care?

It's a great question for Iskra because the ambition is actually more than that, but go ahead.

Thanks for the questions. Let me first reassure you that we are not going to leave anything on the table. But equally, this market is relatively new. We know that there will be a number of players in the next 5-plus years. And we believe that, as I mentioned, we'll reach the reasonable market share. Now how big will be the market will probably drive the final peak year of sales. But you can say that we are a bit on a conservative side with the estimation that we currently have. We will definitely utilize everything that is needed to, a, get access. We know NITAG and ACIP, they have a huge experience with Beyfortus. So we definitely know how -- what needs to happen to get the access in U.S. as well as in other markets across the globe. And we will definitely leverage the huge footprint, not only in U.S. and Europe, but also in China. And I can assure you that we are already discussing and preparing for the access that will be brought that have to go across China and emerging market. So nothing will be left on the table.

Yes. Merci. James, sorry, and then we'll take -- we'll move across the left after James, if I may.

James Gordon, JPMorgan. Two questions on biopharma. The first one was oral GLP-1. So I saw you're starting a Phase IIb this year. But I read in the slides correctly that it looks like that does have $5 billion-plus peak sales potential, but that's not in the 2030 target. So that's something that would happen further out. And is the reason for that, that the real potential is its combos, it might have quite a lengthy development program. So it looks like you're targeting that as a post-2030 contributor really. And the second question was on Tezspire or COPD. So I think I heard a comment that Tezspire, COPD is more modest potential and tozo is the big product. But for tozo, is the excitement on the first 2 Phase IIIs you're running? Or is it -- do we need to be a bit cautious there? And it's really the third Phase III that you started more recently that you think that's the one that's going to make you have the big product in COPD?

So maybe I can cover the first one very quickly, actually. The GLP-1 actually contributes to the 2030 target. But what we wanted to signal is that it's smaller and most of the growth will come post 2030. As you can see, there are lots of assets, and we try to give you pointers as to what would have a substantial impact on 2030 and what had a substantial impact on the peak year revenue as it relates to the GLP-1, the big peak year revenue is post 2030. But it will definitely launch before 2030 and contribute to 2030 growth. Who wants to go to the second one?

I'll start the second one and then Caterina can finish up. So your second question was about Tezspire and tozorakimab and the LUNA in tozorakimab. And I sense that you were sort of reading between the lines and trying to understand if we favored one molecule over the other. So let me just reframe that narrative a little bit in the way that I wish that I could bring it across. So as Pablo mentioned, we don't think of COPD as a single disease. We think of it as a heterogeneous complex condition. It is the third leading cause of death, 400 million people worldwide are suffering from COPD. And we know that we need multiple mechanisms to be able to treat that complexity. So the data that we released yesterday for Tezspire in collaboration with our colleagues at Amgen demonstrates activity for Tezspire across a range of eosinophils. And we saw significant or numerical reduction in moderate to severe exacerbations for patients with over 150 and over 300 eosinophils per microliter. So I think that's really encouraging data. And based on that, we're actively planning for the next phase of development. At the same time, we're progressing tozorakimab which, as Caterina and Pablo explained, has a really beautifully differentiated mechanism of action that we think is addressing aspects of disease that aren't covered by a T-slip blocker. And so we are excited to see those data readout, and we have 3 studies ongoing at the same time. And you asked for a little more detail there. And so I think we've been very open about the fact that we began with TITANIA and OBERON and then added MIRANDA to further expand the dosing regimens, that we could fully explore the activity of this molecule and really optimize the utility for that for future prescribers, one would hope, and the data will tell us what we need to know. But we remain very excited about the potential read is because we think it addresses aspects of the disease, and Pablo hinted at that. Not just reduction of inflammation, but also mucociliary clearance and epithelial remodeling. And with that, I'll hand it to Caterina to add any additional color.

No. I think I have nothing to add to that, except to really highlight the fact that we remain confident. OBERON and TITANIA, we show efficacy with the molecule. We are just complementing with MIRANDA to really expand the full potential of the molecule.

Maybe one last general comment before I go to the next question that you make me think of actually, James, is, again, our $80 billion is risk adjusted. And so all the projects are risk adjusted. So we take all the projects, and we all risk adjust them and then we look at how they contribute to 2030. Of course, if a product or a project works, then they are -- they become much bigger. So the oral GLP-1 and what we've told you, you have got to think about in our forecast, it's risk adjusted, but it will grow immediately as soon as we know it works and it succeeds. Do we have a microphone there?

Mattias Häggblom, Handelsbanken. Two questions, please. So one of the opening slides you showed, Pascal, the bridge to the $80 billion target by 2030, seemed to show the magnitude of growth from existing portfolio, which appeared larger than the magnitude of benefit from risk-adjusted sales from your new medicines. Is that the right way to think of the contributions? And then secondly, thanks for the transparency on the peak sales potential per asset, but we don't know your risk adjustment per asset. So is there any particular asset that we've covered so far, where you think probability of success and perhaps not only the potential is in particular underappreciated?

So can you help me with the first question so I'm sure I'll answer the correct?

I think the question was that the arrows on the chart that you showed, the existing product arrow looked bigger than the contribution, the NMEs. And is that reflective of where the revenue is likely to come from?

Yes. Don't read too much in this cosmetics, the cosmetics of the arrows. We went back and forth on the arrows, but they're not meant to represent that one bucket is growing more than the other. They are really direction of bucket. In terms of the risk adjustment by project, we can't, of course, tell you every single aspect of our forecast. So this one, it's hard to answer, and you'll have to figure out yourself really what the risk adjustment is for the various different products.

Maybe if I can add. On the first bucket, which was the existing product, it's actually almost 2 categories within those existing products. There's existing products with existing indications, the Breztris and et cetera, which are still very early in their launch and still have a long trajectory to go. And then there's the existing products with new indications, and you'll hear in oncology and all the indication expansions and so on and so forth. And those life cycle management are probably lower risk from a risk standpoint, if you were to risk adjust it. And then the third category, which is the NME are probably slightly higher risk. But again, the risk adjustment there, industry standards for what is the risk adjustment for Phase I or Phase II or Phase III. And then we, based on our knowledge and experience with the molecule and data, we know we may up- or down-modulate, but that hopefully gives you a good context.

The only thing I would say that historically, our pipeline has delivered, on average, a better than our probability of success was in our plan. So we -- because essentially, as Aradhana said, we are just a little bit the industry sort of average, but not that much. We are close to the industry average. And in fact, reality has been above industry average. So the reality of our delivery has been better than what we planned for.

It's Luisa Hector, Berenberg. On obesity, based on your time line, how confident are you that you will be running placebo-controlled Phase III trials across the portfolio? And then maybe just a broader question on pricing because you've talked a lot about combination therapies. I know you've got different examples of Farxiga, which will be generic and then more novel combinations and the vaccine. So how have you thought about pricing in terms of 1 plus 1 is 2 or maybe not?

Ruud?

Yes. So that last one, the 1 plus 1 is 2 is certainly not what we are aiming for. We are clearly aiming for a level of differentiation. And of course, the clinical studies, they need to show that. But if you move into relatively highly specialized areas like kidney disease, we're aiming for a relatively high price per day. And of course, if the data will come out, we will make sure that we will create so-called value packs, value stories for our payers. But the whole assumption is that those combination products will be well priced and above, of course, far above the generic Farxiga.

The price, we always set the price based on the clinical benefit we deliver and the cost effectiveness of the intervention. So when you look at patients that Martin described that have high level of proteinuria, they are very likely to progress very quickly towards transplantation or dialysis. Of course, the clinical benefit, if you deliver a good benefit, the clinical benefit justifies a higher price. On the other hand, if you deal with a very large population of patients where essentially, it's going to be harder to justify the value, then you adjust your price differently. But that's the beauty of the fixed-dose combinations is that you can bring a product with a broader clinical benefit because you have 2 medicines in 1 and then price it at the right level rather than have 2 medicines at different prices.

Great. I think there was also a question in there about 5004, and I think you were reflecting on the competitive landscape and asking if by the time we get to Phase III, we would be running placebo-controlled trials. Excellent question, and I'll hand that to the clinical development expert, Elisabeth.

Thank you. It is a very good question. Our assumption is that at that time when we are starting Phase III with the oral GLP-1 that we have, AZD5004, we will be able to run those studies placebo controlled. Of course, over time, this will evolve. And if we go into patient population with a really high unmet need and very high obesity, high BMI and you might need combination treatments in the end, that's a different setting. But for sort of the approval for AZD5004, we -- our anticipation is that we will be able to do that placebo.

The number of patients, as we all know, in this space is still extremely high. So...

Okay. I'll go. Emmanuel Papadakis, DB. I'll save the dividend question for later. So maybe a couple of product-specific biopharma questions. Just a follow-up on your answer before, I didn't really understand. I mean you can't really make a strong compliance argument in many of those larger indication, CKD, et cetera. Why would anyone pay more than the generic price for the dapagliflozin component of a combination molecule? If you could just elaborate on that, that would be helpful. And then 2 of the combination programs, balcinrenone earlier endeavors to replace for second-generation MRAs haven't succeeded spectacularly well. It doesn't look like you're running a head-to-head study. So perhaps you could just give us your target profile for the rate of hyperkalemia you're hoping to show in Phase III and where do you think you will need to do head-to-head study? And then on zibotentan, the Phase II was impressive, but we did see edema. We saw a double -- I think it was actually triple of discontinuations versus placebo. So labeling, do you expect to see anything typical for endothelin receptor antagonist on the label with respect to the addressable population?

Great question. Maybe, Martin, you want to take those? That's another beauty of the combinations with dapa.

Yes. So for balcinrenone, so I don't [ confuse ] who was asking the question. Balcinrenone, these are patients who don't tolerate first- or second-generation agent, so it wouldn't make sense to randomize patients back on to a drug. We know they're failed on. So we're not planning on doing a head-to-head comparison. We think it's a very clearly identifiable group, and we think we can then find them and put them into a trial and show the benefit. In terms of the potassium profile, we're hoping to be very competitive on that front, and the data has been published from a MIRACLE study that you can read.

And zibotentan?

Zibotentan, yes. So that also, there isn't really a competitor in that space. These are patients who have heavy proteinuria despite standard of care such as ACE inhibitors. So we think that's a group where zibotentan and dapa will go together, and that's what we tend to do in the study. Not sure if I completely answered that question.

Yes. I mean I guess what I wanted just to add is the hope here or the belief is dapa will also help reduce the risk of hyperkalemia and reduce the, in the case of zibotentan, reduce the edema, and that's what we've seen before. And that's the beauty of combining the 2 again is that the potential edema, you see zibotentan will be managed down by the combination with dapa. Do you want to cover the points...

Yes. So perhaps Mina can give a little bit more flavor because we have done extensive market research. But just for the audience, that those combinations are unique, not so much because of the dapagliflozin component, which will be generic over time, but it's a unique patent-protected molecule in that combination. And that combination in itself will be priced according to the clinical effectiveness.

Yes. Exactly. Is my microphone on? Okay. If you think about Farxiga alone, even though now it's in CKD and heart failure, it actually initiated in diabetes, and it's priced as a diabetes medicine. As you know, the pricing of diabetes therapies is very low compared to CKD and heart failure. And the new indications that are coming in the case of balcinrenone/dapa or baxdrostat/dapa, et cetera, zibo/dapa are in CKD and are in heart failure and in some cases, more difficult-to-treat CKD population. So it's a very different price equation. And dapa's price is not really a factor within that combination. It's really what you're bringing as the innovation to that dual mechanism, whether it's balcinrenone, whether it's baxdrostat, whether it's zibotentan, that is really bringing a very different price to that dual mechanism than the addition of dapa plus, if that makes sense.

Compare it -- to make it very simple, compare it a little bit with Entresto. The price of Entresto is not driven by a [indiscernible]. So it's the combination of this new molecular entity.

And then in terms of hyperkalemia, our expectation is that balcinrenone/dapa has no greater hyperkalemia than dapa alone. And that's the promise of that combination and why we think if it delivers against that become so compelling in the heart failure/CKD population.

Thanks, Mina. I'm starting to be given a hard time by Andy and Aradhana, so we're going to have to close here, so if we may. And so we'll break for lunch. And you're most than welcome to wander around to cafeteria. If you want to go out there rather than have lunch closer to this room, just go around. And then what time do we meet again?

25 minutes past...

25 past 1. Okay. See you soon. [Break]

[Presentation] Good afternoon, and welcome back from lunch. We are delighted, Gianluca and me to be making Rare Disease presentation. The first slide will show you a flashback to the announcement that we made at the time of announcement of the Alexion acquisition. And we said on that day that the Rare Disease would help or contribute to the growth of AstraZeneca through 2025. And I think the numbers that we will show you in a second are going to demonstrate that we, indeed, did not dilute the growth of AstraZeneca. So Alexion is very pleased to have contributed to the growth of AstraZeneca. On the right, we have just summarized and simplified our strategy. Our strategy is to continue to be the leader in the complement. Complement, we have leadership in hematology, nephrology as well as neurology. Now the second avenue for us is to go beyond the complement because obviously, there are many other rare disease which are not accessible to the complement. And there, we focused on first-in-class or best-in-class medicine. The areas that we are going through are bone disease, endocrine rare disease as well as amyloidosis. We have this morning some reference to our depleter in the transthyretin amyloidosis, but we have also another depleter in light-chain amyloidosis that Gianluca will describe for you in a second. And longer term, we have at the bottom, the technologies that we want to invest in. And obviously, we're going to try to find transformative and potentially curative medicine and in particular, in gene therapy. So on the left of this slide, you have the performance for 2022 as well as 2023. The loss of exclusivity of Soliris, but we are counteracting this with a very rapid conversion to Ultomiris. And in most indications where we have double indications, we have already a conversion above 80%. Ultomiris is going to grow, and I will explain this in a minute through large -- more indications, but also a very strong regional expansion. And then you have several key NMEs, which are listed on this, and we will go through them later on. So this is basically the first thing. I wanted to talk also to the topic that we discussed at the time of the announcement, which was the sustainability of the robustness of the growth of Alexion. And I think you can see on the left, first, the revenues; and on the right, the patient growth for Alexion in the last 2 years and some. And you can see that the growth, both on revenues, but also more importantly, maybe on the patient is very robust. You can see this acceleration of the patient reach. And it's important to put in perspective these 2 metrics, the revenues on the left and the patient growth on the right because we have several effects within our portfolio. We have, obviously, a product mix. We are enlarging 2 different population, and we also have a geographic mix. We are expanding in many other countries, which have lower price than maybe the key countries where we are present in 2020 or '21. So it's important to keep in mind both this product mix effect as well as this geographic mix. I get now to this slide, which talks, first of all, about the regional expansion, and it's a very important growth factor for us. So Pascal in his first slide this morning introduced the compounded growth rate of a rare disease since 2019 to 2023, and you may remember that this growth rate was 22%. But if you look post acquisition of Alexion. You see this growth rate is much stronger, in particular, in 2023 and first quarter of 2024. At the bottom, you have the progression of our reach in terms of countries. At the time of Alexion -- before the Alexion acquisition, Alexion was present in 20 countries, 20 most important countries, probably, but only 20 countries. We are now currently present in 70 countries, and our ambition is to reach 100 countries by the year 2030. On the right, we have a small vignette on China where the products of Alexion were not present until the acquisition. And then Alexion has been able to leverage the very strong presence of AstraZeneca in China. AstraZeneca has a strong presence for the last 30 years, and we could leverage that strength to rapidly get our product registered, but also -- and you see at the bottom, it's extremely important, the listing on the National Reimbursement Drug List. So now we have 2 products indicated, Soliris in several indications, and Koselugo in NF1. These two products were launched in 2022 and '23. And then we received the National Reimbursement Drug List in January of 2024. So we are now in this NRDL listing and both products are doing very well, and we are gaining patients every day. So now I'm going to turn to the complement, which obviously is the main franchise of Alexion. So if you look at, in a similar fashion, the sales revenue growth for C5. This is this constant growth, 7%, 8% and 10%. And then more importantly, at the bottom, we have tried to analyze the cause of the growth of the patients. And you can see that at the bottom, the ultra-orphan indication or the legacy indications of Alexion continue to grow over this period. But it's also very important to see the dramatic growth of the neurology indication, which we first obtained with Soliris in 2017, and more recently in 2022 with Ultomiris. And basically, the reason of this continued growth in the number of patients is, one, the superior efficacy of the C5 inhibitors. They provide very rapid and sustained inhibition. And also, very importantly for the neurology indication, they enable physicians and patients to reduce the steroids and, in some cases, eliminate the steroids, and that's extremely important for the neurology indications. I described earlier on the geographic reach. It's a very important growth factor for us. And longer term, the expansion of indications for Ultomiris will be important. We will cover that topic in a second, but these are the reasons. At the top, you have the rapid conversion, as I mentioned earlier on, from Soliris to Ultomiris. You will all remember that the price of Ultomiris is about 30% lower than that of Soliris. But longer term, obviously, this provides greater robustness in our portfolio as we expect the entry of bio-similars. So I'm turning now to neurology. So on neurology, you can see the growth rate, both in revenue as well as in patient growth, is about twice as fast. As what we have seen for the overall C5. And this is due to the extreme performance of strength in neurology, in particular. Ultomiris had, after 3 years results, showed that we have 88% of patients with clinical meaningful improvement. So the objective of the treatment is to sustain the control of symptoms over time, to avoid the patient goes through various cycles and Ultomiris provides you this stability of efficacy. And most guidelines nowadays also talk about the need to spare the steroid or reduce the use of steroid. And in 75% of patients -- after 2 years, 75% of patients can have a low dose of steroid after 2 years. This is now more and more indicated in every guideline of the world. There is a competition with the FcRn. And usually, they gain a lot of naive patients from unbranded. But if we just look at a very interesting metric or dynamic metric, switch from FcRn since late third quarter of 2023, we have been gaining more patients than we lose to FcRn. So continuing on myasthenia gravis. So basically, historically, Soliris was first approved as a pioneer in this indication in 2017. We then launched Ultomiris in 2022. And gefurulimab is our third-generation C5 inhibitor currently under development. And it's a subcu formulation. It will be a weekly subcu formulation. So this will be an easier treatment in comparison to the IV. If you look on the panel on the right, you look at historically, Soliris started with gaining very refractory patients for the more severe population. And then with the introduction of Ultomiris, we have now the patient population that's less severe than what Soliris was. And with gefurulimab, we will further increase the patient population. These 3 class of products will certainly continue to expand the usage of branded medicine in myasthenia gravis. And to provide you some perspective on that, we have prepared this slide where you have today current usage of branded medicine, ours and that of competitors, which is probably in the 25% or 30% currently. We expect the branded medicine to occupy about 80% in 10 years from now. So there will be a very rapid increase in most developed countries of the use of branded medicine in myasthenia gravis at the expense of steroids and immunosuppressants. Today, our products are launched in 31 countries. So a good job has been done, but there are still 25 more countries where we expect to launch by 2025. And again, as I said earlier on, indeed, it's extremely important that the guidelines of most countries now do talk about the control of symptoms, but talk also about the necessity to reduce the steroid usage and this is where Ultomiris and the other C5 inhibitors have a benefit. I will now talk to the extension of indications for Ultomiris. We start on the left. This dark red panel where we describe here the legacy indication, atypical HUS as well as PNH. And then I was just talking about the pioneering work in the neurology indication, myasthenia gravis and neuromyelitis optica. And on the right of that, you have a series of other indications, which are mostly renal indication or transplantology. Gianluca will, in a second, talk to you about hematopoietic stem cells as well as ICAN. But we have also other trials, as you can see, in lupus nephritis, AKI, and delayed graft function for renal transplant. We will talk about those indications in a moment. The clinical trials that we have on the right are ongoing and their data readout is planned for 2025 for HSCT-TMA, and for ARTEMIS and ICAN, the data will come post 2025. So we have seen and we are going to see, for several more years, the growth which is fueled by the neurology indications, and further the next wave of growth will come mostly from the renal indication as well as the transplantology indications. Gianluca?

Thank you very much. Thank you, Marc, and good afternoon, everyone. So I'm going to talk about the first of our catalysts, which is our Phase III efforts in Ultomiris in thrombotic microangiopathy following hematopoietic stem cell transplant or HSCT-TMA. It's a very severe condition. It's a rare disease, life-threatening complication of bone marrow transplant with the presence of blood clots, endothelial damage, end organ damage, and death. Mortality is as high as 40% after 1 year of diagnosis. But in most severe segment of the patient population, which often are children, mortality is as high as 80% after 1 year. So very severe condition. Very importantly, there's no medication available for this indication. Now complement inhibition has demonstrated over the years to be potentially very effective in this thrombotic microangiopathy. As a matter of fact, Soliris has been used by physicians. We have case studies and some publications, which give us confidence that complement has an important role in this disease. For this reason, we started 2 Phase III studies, one in adults, which is a placebo-controlled study, and a pediatric study ongoing as well with 40 patients. The endpoints are hard important. We're looking at complete TMA response measured as hematological response and renal response as well as overall survival in these patient populations. The studies are very well advanced in recruitment, and we do expect data readout in 2025. You can imagine, given the high number of this procedure and the fact there's no medicine available, we believe the Ultomiris can be a game changer in this indication, and most importantly, save lives of many children worldwide. The second indication I would like to talk about is actually efforts in IgAN or IgA nephropathy, immunoglobulin A nephropathy. This is a disease that happens when basically your immune system produces abnormal IgA, which deposits in the kidneys, forming immune complexes. These immune complexes activate complement, which causes inflammation. Inflammation causes damage, chronic kidney disease, leading to dialysis, eventually the requirement of a renal transplant. There's 120,000 diagnosed patients in the U.S. with this condition. As you can see, the outcome is quite poor. 60% to 80% of high-risk patients experience kidney failure within 10 years. To provide you a clinical picture, the typical patient is a young man in 20s. He gets a diagnosis of IgA nephropathy. The disease is slowly progressing. And by the age of 40, you need dialysis or renal transplant. So very severe condition. The first line of intervention, as you can see from the slide, is really ACE or ARB and also the use of FARXIGA. You heard this morning very nicely, our FARXIGA is finding multiple indications. FARXIGA has a very important role here. And in fact, it's becoming part of the standard of care as the first line intervention. There also a number on endothelin antagonist receptors as well, which are currently in development. And we believe that could have an important role as a first line intervention as well. However, the disease is an immune-mediated disease. And as a clinical immunologist myself, I do believe that you need to tackle the underlying disease to be able to really slow progression to end-stage renal disease. So complement inhibition can do that. It has the potential to be a disease modifier. And we do expect disease modifiers in general to be positioned, as you can see, as a second line of therapy in the more severe segment, those with high proteinuria measured at 0.75 gram per gram by UPCR. We have opportunity with 2 assets. Vemircopan is our factor D inhibitor, second generation, and Ultomiris, our, of course, second-generation C5. Vemircopan is currently in Phase II development and Ultomiris is in development in Phase III in this indication. Now more importantly, you can see, with the broad spectrum of assets that we have at AstraZeneca, really able to tackle the disease broadly from mild patients all the way to severe patients. And we are uniquely positioned to do that. I mentioned that complement has a very important role in the disease. Well, evidence comes both from preclinical data as well as clinical data. Here I'm showing you the results of our Phase II study with Ultomiris, the SANCTUARY study, which was presented at the American Society of Nephrology last year. And you can see that the study with Ultomiris is a placebo-controlled study over 26 weeks. We saw a rapid, sustained, and complete complement addition very quickly in the study, which led to an improvement in proteinuria with a reduction of over 40%, which is currently best-in-class among complement inhibition. In addition to that, what is striking is the fast onset of action, which occurred as quickly as 4 weeks and then is sustained over time. And we believe that this fast onset of action is really one of the key elements for differentiation in the class of disease modifiers because of the mechanism of action of complement and the immediate stop of the inflammation, which is causing damage. And this will set us apart as compared to the competition in this cluster of therapies. Of course, we also observed stable GFR during the course of the study. It's by a small number, which is very promising for the final data readout. We're currently running a Phase III study, the ICAN study, which was initiated, and we do expect the data readout after 2025. As you can see, the study has 450 patients. And you can see the endpoint here, we're looking at proteinuria at week 34, basically 9 months, and eGFR at 2 years in the study. And with that, I'll pass it over to Marc to continue to discuss our efforts in renal transplant.

So I will take it from the left of this slide, and as you can see on the left of this slide, you have the chronic kidney disease that Gianluca has just presented to you, IgAN. What I will do now is to move what happens if you progress from this stage? And then basically, you have 2 solutions. Either you go into dialysis or you receive renal transplant. And obviously, we all know that renal transplant is a much better clinical solution than dialysis in terms of long-term prognosis. However, as you all know, the availability of organ donated is well inferior to the people needing a transplant. So basically, what we are going to focus with our complement products is to try and help in the transplantology world in 2 ways. At the top, you have the antibody mediated rejection. So we are not going to intervene at the acute stage, but we plan to have a benefit on the chronic antibody-mediated. And we intend to use our Silencer or C3 for that specific indication. The statistic at the top right, 12% of incidence -- 12% of transplants get to this chronic AMR. And more importantly, once you get the AMR, 75% of these patients will lose their graft function within 5 years. So it's a very grim outlook. At the bottom, it's a totally different thing. We are trying to increase the success rate of the renal transplant and avoid the delayed graft function. Basically, we are trying to accelerate the time to freedom from dialysis. When you receive a renal transplant, you need to be on a short-term dialysis. And hopefully, you will get out of this dialysis within days. What Ultomiris should be able to do is to help accelerate the relief from or the freedom from the dialysis. So now if you -- and then you arrive at this -- if you do that, you can also indirectly do something else. You can improve the utilization rate of the renal donated. Today, in the United States, 28% of the kidneys, which are donated, cannot be implanted within the window of opportunity. So by delaying the window of opportunity, you can also improve the organs that are used, and therefore, reduce the kidney waiting line, which is absolutely very large. I mean, we believe that 350,000 or 400,000 patients globally are in a waiting line for a kidney transplant. So if you can ameliorate the success of the transplant, and then these patients do not have to undergo a second transplant, but also lengthen the duration under which the surgeon can transplant, then you are improving it on both sides. So we are doing some work on this. Our Phase III is going to start for delayed graft function within 2024. Let me sum up now the complement section. Okay, so basically, to summarize, we have 3 products already approved in 4 indications, and we are pursuing 4 more assets in 6 separate indications. And you can see several of them from Ultomiris, in the Ultomiris box, but we have also vemircopan or #2 Factor D as well as danicopan #1. And I mentioned the Silencer 2030 in chronic AMR. And with this, I will go to the beyond the complement, which is the second avenue for us. So for us, beyond the complement means bone and endocrine rare disease as well as amyloidosis. So let me first talk about hypophosphatasia. Hypophosphatasia is a disease caused by a deficiency in the enzyme alkaline phosphatase and the cause of that deficiency is extreme impaired bone formation. In neonatal, it can be absolutely fatal. We have x-rays of what's happening in Strensiq patients. Their bones are absolutely not formed. And in some neonatal cases, the rib of the child is nearly nonexistent. So it's a terrific disease. Strensiq has been on the market since 2015. It has reached blockbuster status in 2023. The product is progressing very well. As you can see on the left panel, a growth of 20% or 21%. So it's a very important product for this disease. However, the product has to be administered every day or every other day through a subcu injection. And what the researchers at Alexion have invented is to find another enzyme replacement, but a product that can be administered every 2 weeks. So this is going to make a very large difference for the patients undergoing treatment. We expect that the population will be 6x as large as that of Strensiq today. We have 3 clinical trials, which are conducted globally, and the data are anticipated post 2025. We have 2 pediatric studies, one switch, one naive, as well as one adolescent and adult comparative trial. And with this, Gianluca?

Thank you. I'm going to discuss about the new product in our pipeline I'm very excited about, which is eneboparatide. You heard earlier this year, we announced the plan to acquire Amolyt Pharma, which will give us eneboparatide, which is the best class-in-class therapy for hypoparathyroidism. Hypoparathyroidism is a hormone deficiency. It's a deficiency in the parathyroid hormone, which is basically responsible for the control of calcium level as well as phosphate in our blood. It's one of the less rare diseases. Many of these patients suffer from multiple symptoms, including muscle spasm, cardiac effects, and neurological effects as well. So the clinical priorities for this disease are normalizing the serum calcium level to be able to avoid all the symptoms that I mentioned. The second priority is about decreasing urinary calcium excretion, especially taking into account that about 50% of these patients have hypercalciuria. They develop calcinosis, which leads to chronic kidney disease. And the third priority is to preserve the bone mineral density, preventing osteoporosis. Here again, you can see that the majority of the patients are women, and more than 50% of them are peri- or post-menopausal. Therefore, they are at risk of osteopenia. Here in the middle, you can see the very strong Phase II data for this drug demonstrating the stabilization of calcium level during the entire treatment period despite the decrease or complete elimination of supplemental calcium and vitamin D. In addition, the Phase II clinical study also demonstrated decreasing urinary calcium levels and the preservation of the bone mineral density, both by biomarkers of bone marrow density and dexa scan. Now I'm highlighting these 2 elements. So urinary calcium and bone mineral density, because these are the 2 elements for great differentiation as compared to the current competition. And that's why we believe that eneboparatide is going to be highly differentiated and potentially a blockbuster medication.

One second, just I forgot to mention it earlier on, these little boxes at the top right, these represent the peak year sales on a non-risk-adjusted basis. Maybe some of you may not have noted, we have not only repaid, but whenever possible, we try to provide some indication on the peak sales revenue.

Excellent. So following the Phase II, the company started a Phase III program, CALYPSO. The study enrolled quicker than expected. And in fact, data readout now is expected for next year. And also, a couple of weeks ago, the company had breakthrough designation from the FDA given the strength and the relevance of the Phase II data dimension. This product will strengthen our presence in rare endocrinology, also expanding from Strensiq physician call points. So it's a very nice synergy as well in terms of call points. And now let me give you a few words about the amyloidosis franchise. You heard previously that we are focusing as a company overall on amyloidosis, and really what is at the core of the disease is the deposition of amyloid fibril in the organs systemically, causing organ damage. The heart is largely one of the main organ affected. So you see a lot of cardiovascular hospitalization in these patients as well as high mortalities. Rate of mortality can be very high, as soon as 1 year after diagnosis. The other critical element of amyloidosis is a lack of diagnosis. You heard how there is a great opportunity to increase diagnostics in general. We represent an expansion of this very large franchise. So how are we tackling the disease at Alexion. We are focusing on the production of depleter antibodies. These antibodies that bind to the amyloid fibrils. They recognize them specifically. They activate the immune system directly in the fibrils to be able to eliminate them from the organ, and therefore, rescue organ function. That's the whole idea because behind depleting antibodies. We have developed 2 of them. The first one is the ALXN2220, which is targeting the ATTR amyloidosis, which is the most prevalent form of amyloidosis with 114,000 patients diagnosed in the U.S. and in Europe, and we currently recently initiated a Phase III study. The second antibody that we developed is anselamimab targeting the second form of amyloidosis, which is the light-chain amyloidosis or AL amyloidosis. Here too, you see 28,000 patients diagnosed and we completed enrollment in the Phase III for this product. We discussed earlier the opportunity in the ATTR amyloidosis. But I would say it's pretty clear that by leveraging both the knowledge and expertise in CVRM as well as in the Rare Disease unit, we're uniquely positioned to tackle the disease from multiple angles, and really treat the broader spectrum of the patient population. You heard previously about Silencer, Wainua, which blocks the TTR synthesis directly in the liver. We are also developing a stabilizer in Japan, the acoramidis. It's a super stabilizer. We have had the opportunity to stabilize the tetramers, therefore reduce the accumulation of amyloid in the fibril as well. But most importantly, we are focusing on the depleter approach, which binds to the misfolded TTR protein, removing the toxic fibrils and, therefore, restoring organ function. As you can see, because the depleter has the opportunity to restore the organ function, we are fundamentally focused on a more severe patient population. So on the right-hand side you see, with ALXN2220, we are targeting moderate-to-severe patients taking the NYHA classification. This corresponds to a part of the Class II, Class III and Class IV, while Silencer and Stabilizer focus on NYHA Class I, II and III. But overall, as you can see, we have the opportunity to treat the broader spectrum of the patient population. Now let's hear a little bit more about the mechanism of action of depletion of the ALXN2220. I'm going to show you a video. What I found very exciting about this video is that we use human samples, bio-samples from patients with CM amyloidosis exposed directly with our antibody. So you can actually see the antibody in action. [Presentation]

I have to say, I was very excited to see for the first time this macrophage chewing up the amyloid deposition. So as a scientist, it's quite revealing in a way, so very exciting. And as matter of fact, we do believe that the ATTR product, the ALXN2220, has the potential to reverse the course of the disease. This was demonstrated already in a Phase Ib study, which was a small study, 40 patients, placebo-controlled, published in the New England Journal of Medicine last year and also presented at the European Society of Cardiology. And the study demonstrated a dramatic reduction of the bulk of amyloid in the tissues via imaging, using MRI and scintigraphy. What you see here is an illustration to resemble one patient. And I think the image says it all. You can see how there was a dramatic reduction of amyloid deposition from the heart already in 4 months with almost normalization and this continued over 12 months treatment period. Importantly, we also saw a reduction of cardiac biomarkers, including NT-proBNP and troponin T, demonstrating improvement of cardiac function, and these biomarkers are also actually related to cardiac outcome, which is very important. The Phase Ib was strong enough to be negotiated with regulators globally to go directly to a Phase III program. This was started this year. It's a 1,000-patient program, 2:1 randomization, and again, focusing on hard endpoints, including all causes of mortality and cardiovascular events. I look forward for the results of this program. And then finally, I would like to conclude by just saying a few words on our AL amyloidosis program. I mean this is also quite exciting and quite novel. The AL amyloidosis is caused by defective plasma cells that produce very high level of light chains deposited in tissues, causing amyloid deposition, therefore, and, of course, organ damage. And in this specific case, the 2 organs mostly damaged are the kidneys and the heart, leading eventually to death. In fact, the median overall survival for newly diagnosed Stage IIIb patients is only 9 months, which is equal to quite severe cancers, as you can see. The approach here is pretty much the same in terms of [indiscernible] reduction. So it's a depleter antibody. They recognize specifically the fibrils in the tissue, eliminate them, and therefore, improve organ function. Our Phase II study demonstrated improvement in cardiac function as early as 10 weeks, and in renal function as early as 14 weeks, giving us confidence. We're now running a Phase III program. Actually, there are 2 studies, one focusing on the 3A, Mayo 3A, so the moderate segment of the patient population. [indiscernible] study focusing on the severe segment, which is the Phase IIIb, overall encompassing about 40% of the patient population with AL amyloidosis. Here again, hard endpoints, all-cause mortality and cardiovascular hospitalizations. And we do anticipate a readout next year. With that, I'll hand it over to Marc to discuss briefly our efforts in gene therapy and for the closing remarks.

Thank you. So I would not -- I needed to spend maybe 1 slide on the day after tomorrow. And for us, the day after tomorrow is genomic medicine. As you know, 80% of the rare disease have genetic cause, either inherited or acquired mutation. So what we have done until now is to assemble -- together with our organic capabilities, we have assembled capabilities from other companies in research or acquired some portfolio, in particular, from Pfizer. And we are working on both on viral and nonviral delivery as well as gene therapy and gene editing. We have a portfolio of more than 10 projects, pre-clinical. Some of them are reaching clinical in the year 2024, and we expect to advance 2 INDs per year to 2030. These products will start generating revenues towards the year 2030. And then my last slide of conclusion, like we have said earlier on, we have given you some vignette of the size of every product, but we have now grouped them in some buckets. Above $5 billion. Clearly, Ultomiris is going to be more than $5 billion drug. Then you have seen the enzyme replacement, the new enzyme replacement, efzimfotase, as well as the product that Gianluca just described, ALXN2220 in [indiscernible] sort of in the category $3 billion to $5 billion. And then in the $1 billion to $3 billion category, we have anselamimab, eneboparatide, as well as gefurulimab or third generation. So I think we are well positioned to continue in our franchise, and we look forward to continuing also pioneering new indication for the complement and outside the complement. Thank you. This opens the Q&A and I will invite 2 other of my colleagues on stage. Yes. We need a microphone, I think.