Roche Holding AG (ROG) Earnings Call Transcript & Summary

So welcome to our 2024 Pharma Day in London. It's again a great pleasure to have you all with us and have the opportunity to meet you in person. Let me quickly take you through today's agenda. And let me also make an upfront comment first. Last year, around the same time, at the same place, we provided you a thorough review not only of our pipeline, but also some very important topics, which we uncovered in our internal business review topics like, for example, R&D excellence. At that occasion, we also had the new management team on stage for the very first time and since then, I think 12 months have passed and a lot has happened at Roche and some smaller news items, I think, became public, indicating that there is a lot happening at our company. Today, I think we have now the opportunity to wrap up all these bits and pieces and to provide you with some bigger picture insights and also what is going on behind the scenes. So with that, let me quickly take you through the agenda and mention a few housekeeping items. We will have 2 sessions today. So we will start with a 2-hour 10-minute morning session, primarily focusing on strategy. And then we have a 2-hour afternoon session, which we're focusing on our evolving pipeline. Both sessions include a 30-minutes Q&A where we will have -- where you will have the opportunity to ask your questions here in the room, but also then via the web. Let's start with the morning sessions. The first speaker of today will be our CEO, Thomas Schinecker, providing an update on the overall group strategy. The second speaker will be our pharma CEO, Teresa Graham. Teresa will outline the new pharma strategy based on the 5 newly defined therapeutic areas, and she will also highlight some of the capabilities we are focusing on to win in the future. Teresa will also take us through our, compared to the industry, young on-market portfolio, focusing on additional growth opportunities and she will summarize some of our mid- and long-term opportunities. The third speaker in the morning will be Levi Garraway, our Chief Medical Officer and Head of Global Product Development. Levi will share with you some insights on our R&D excellence initiative which we -- was started about a year ago. He will outline our ambitions and also provide an update on what has been achieved so far. Following these three presentations, we'll have a 30-minutes Q&A with the three speakers of the morning session on stage before we go into the lunch break. Lunch will be for 50 minutes, as you can see, from 11:40 to 12:30. At lunch, you will have the opportunity to meet all of our speakers and also the IR officers who will be around. After lunch, then we will continue with our deep dive into the primarily late-stage pipeline. We will have five sessions, one session each for our newly defined 5 therapeutic areas. So the first afternoon presentation will be given by Charlie Fuchs, our Global Head of Oncology and Hematology Product Development, who will take us through the oncology and hematology pipelines. Charlie will also provide us some details on the Regor deal, which was -- which includes the acquisition of a next-generation CDK inhibitor portfolio just announced today, and he will provide also an important update on our next development steps for hemophilia A. The second presentation of the afternoon will be held by Azad Bonni, our Global Head of Neuroscience and Rare Diseases at pRED. Azad will represent Hideki Garren, our new Global Head of Neurology Product Development, which just got announced last week and was not able due to the short notice to make it to the event today. Azad will provide us with updates on some exciting pipeline projects, including our anti-Aß Brainshuttle and gamma secretase modulator, both projects in Alzheimer's disease. The third presentation then will be held by Larry Tsai, our new Global Head of Immunology and Product Development. Larry will share with us an update on the TL1A development program and summarize our efforts in kidney disease where we just had a positive readout for Gazyva in lupus nephritis. And he will also present two novel antibiotics with truly novel MOAs now in development. If successfully developed, these antibiotics would represent two novel classes, the first ones to actually discover since more than 50 years. The next speaker, Chris Brittain, our Global Head of Ophthalmology product -- is Chris Brittain, our Global Head of Ophthalmology Product Development. Chris will take us through our exciting ophthalmology pipeline, summarizing the most recent progress made. He will also cover the AntlerA acquisition, which we have announced today and will provide the background why we are excited about targeting the wind signaling pathway in diseases like DME and AMD. And the final presentation will be with Manu Chakravarthy, our new Global Head of Cardiovascular, Renal and Metabolism Product Development, which just -- we just had on stage two weeks ago when we hosted our IR call related to EASD. Manu will summarize again our ongoing efforts in obesity, diabetes and share some additional preclinical combination data with our PYY analog. And after the closing remarks from Teresa, we will have an additional 30 minutes Q&A with all the speakers from the morning and the afternoon session on stage. And in addition, we will have our group CFO, Alan Hippe, joining on stage as well. The event will close at 2:30 p.m., but you have the opportunity here to stay around for a buffet reception, which will give you additional time here to talk to the management. Let me also please mention one additional housekeeping item. We have again prepared a short 10 question feedback survey. The link to the survey will be shown to the participants in the webinar 15 minutes before the end of the event. Participants in the room will receive an e-mail about 1 hour after the event. And we would very much appreciate if you could give us your feedback as we always strive for improvement. And with that, it's my pleasure to hand over to Thomas Schinecker for a group strategy update. Thomas, please.

Thank you very much, Bruno, and also welcome from my side. We're looking forward to giving you an update of what has happened over the last 12 months. I think the team has been very busy and has made a lot of progress, and I hope that we can demonstrate that during the day today. But let me start with the performance and what we believe is the outlook over the next years in terms of our performance. Here on this slide, you see the progress that we've made over the last 12 months on a high level, but we'll give you a lot more detail during the presentation. On the pharma side, we've launched 2 new NMEs. So we're on track to really delivering 2 NMEs on an annual basis. We've had 11 regulatory approvals in the time period. Also, Diagnostics has been very productive with 5 new instruments being launched and 39 new assays being launched. One number that's really, I mean, amazing is that we've had, over the last 5 years, more than 50% of all FDA approvals, PMA and BLA in the entire industry. And for sure, we don't spend 50% of all the R&D money that's being spent in diagnostics in the industry. So you can see how productive we've been over many years in Diagnostics. On the external innovation front, we've already announced in the past Telavant and Carmot. But two further acquisitions that we're just announcing today is the CDK portfolio, which is the next-generation CDKs and also the Wnt agonist, which is a very conserved pathway, which plays -- there's a lot of data that shows that it plays a role in ophthalmology. LumiraDx really breaks through a technology in point of care, both from a modality perspective because you can do clinical chemistry, immunochemistry, but also PCR on that one system. And the cost position makes it just very unique for the point-of-care setting in an area where -- which is actually the only area where diagnostics is not number one. And with that, we can go for the number one position. We've also worked very hard on operational efficiency. One topic that Levi will talk about in detail is R&D excellence and how we've applied The Bar and how we're prioritizing our portfolio. But we also work very hard in making our R&D engine a lot more efficient, and Levi will talk about that. One way to do that is actually as we looked at all the systems and processes across the different R&D organizations, we worked a lot on harmonizing those systems and processes. And we've also aligned our structure, as you can see with the people here today to the 5 therapeutic areas that pharma has defined as the focus areas. And we've done that throughout the organization. This includes also promoting good talent within, but also bringing talent in from the outside that will help us build a good franchise in these areas in the future. We are still working on optimizing our manufacturing network. I know Teresa will talk about that, too. On the Diagnostics side, we've had in Diagnostics basically two organizations, diabetes care and diagnostics. We have merged these two organizations. That's complete. Went live middle of this year. And with that, we've really simplified further our organization and we could leverage a lot of synergies we have within Diagnostics, with that also improve our cost position. Lastly, we mentioned that before. We shifted FMI into diagnostics because at the end, it's a diagnostics business, and it should be led out of diagnostics. Now to the sales momentum. On the left-hand side, you can see the group sales growth over the last 4.5 years approximately. And you can see that between 2020 and '22, we had a contribution of about CHF 19 billion in COVID sales. Now we always knew that COVID sales will come and they would go. The good thing is this has washed out. So you can see that if you look at the second quarter '24 versus -- on the left-hand side and the right-hand side, the two numbers are the same. When we now look into Q3, you will have the same situation. The two numbers will be the same. So we will not have any COVID effect in Q3, which is very important. But what you also see is that for the last 1.5 years, we've been growing around high single digits. So there's a really, really good momentum in our business. And we believe this will continue for this year but also will carry us into next year. So very optimistic about the momentum that we have. Furthermore, we've been very disciplined. So we've been reallocating money, looking for areas where we can reduce our spending in order to shift into areas that are much more valuable to our business. And we've been very, very stringent in doing that. So even though we don't -- and that's, I think, the company culture, we don't make huge announcements to the outside. I can tell you, there is a lot of movement within the organization because otherwise, you would not be able to get to a P&L that is a shape of this one. So very good cost discipline and operating profit growing double digit. Now I would assume that the second half year from a shape of the P&L will look very similar to what you see here. And it's our ambition as we go into next year, also to have a good -- to carry this momentum into next year and for R&D spending to be broadly flat into next year. Now let's take a quick look back how the performance of Roche has been over the last 10 years. And here, you can see that Roche has been growing 5% on average in constant exchange rates and 7% in core EPS. Diagnostics has always contributed during this time period. And you can also see how we have substituted the AH&R business through the diversification of our portfolio. We went from 8 blockbusters in 2013 to 16 blockbusters in this year. By the end of the year, we may have 17 blockbusters. So you can see that the new portfolio is really performing for us. And that's why we're also confident as we go into the future. And here on this slide, I would like to focus first on Diagnostics. So built from the bottom up. So on the Diagnostics side, we have a very strong growth on our own market portfolio. But this year, we have probably the biggest launch here in the history of our company. We have a number of launches coming up also in next year. So we have a very good performing R&D engine in Diagnostics. That's why we are confident, and we've communicated that also over the last couple of years that diagnostics will continue to grow ahead of the market, and the guidance that we've given is mid- to high single digits for Diagnostics. And I think that's a good number to start out with. At the same time, we've communicated that core growth will be ahead of sales growth. Now on the Pharma side, we know that we have a very good on-market portfolio, and that's in the light blue. And we know that this portfolio would give us growth until '27. What will happen after '27, there is no patent cliff situation for Roche. And that's very different to a number of other pharma companies who have significant cliffs coming up. So what we expect is that if there are new -- no new launches in the next couple of years, all that will happen is we will get in an equilibrium state. We would not be in a downward trend. Then the other thing that we can also commit and that's very important, is that our margins will be at least stable. So that overall, whatever the situation, we'll manage the costs always efficiently. Now what can happen on top of that? On top of that, at first, it's our in-house pipeline. And we have a number of very important short term goal, and you will hear that from Teresa later that can continue to drive growth in the other years. Now this gray line is kind of risk adjusted. So -- but we also know you have binary events. If the event is positive, the curve upwards can be very significant. But we always have to wait for the results of these trials, and then we know how the future will look like. But it's very clear that something will come on top. And the last element is BD, which can also help us to continue to drive growth. And so we're very confident that we can deliver this kind of growth also going into the future. Now looking at what you tell us, and this is basically looking at the consensus. On the consensus, you see on the left-hand side that you expect that between '23 and '28 that there is a biosimilar gap of about CHF 7 billion. That, I would say, is basically also something that we agree with that there is a biosimilar erosion of CHF 1 billion to CHF 1.5 billion on an annual basis, which we can cover with the momentum that we have in our portfolio. On the middle column, again, taking it from the consensus, you see the on-market portfolio and what the on-market portfolio contributes and it contributes approximately CHF 14 billion in growth. So CHF 14 billion is significantly higher than the CHF 7 billion. And then there is sales are in there, about CHF 3.7 billion pipeline. Again, these are risk-adjusted numbers. So I guess if the trials are positive, the potential is even significantly higher. But what's very clear is that we'll continue to grow until '28 because what's very clear is that at least already the on-market portfolio will drive the growth. And everything that comes after that is basically the cherry on the top and will drive more growth going forward. On the right-hand side, you see those molecules that have pretty much no coverage, and some of them, for example, Gazyva in lupus nephritis is coming already next year. So these are models that don't have a lot in their portfolio -- in the model. But there is a lot that's coming, which can then add also to this improved sales outlook. Now let me go into the strategy piece. When I started in March last year, we did a survey with leaders where we asked them about the strategy, we asked them about the goals and how should we achieve them? Is there clarity? And this, we used as a basis, so to drive the change and adapt some things in the organization. And basically, we've now completed the entire house. So what we started with and rolled out at the beginning of the year is our 10-year ambition. So what goals do we want to achieve? We started with the group strategy, which we've now rolled out. Digital health, which used to be called insights on what do we want to do with that, sustainability, people and culture, but also in the Pharma and Diagnostic side and very importantly, operational excellence. Now here are our 10-year ambitions. Let me start with Pharma, which was updated. It is to deliver 20 transformative medicines addressing diseases with the highest societal burden, and I know Teresa will go into that. These must be very differentiated medicines that are really impactful that will be delivered by the end of this decade. The Diagnostic side launching 75 novel differentiated assays. Now we know that last year, we launched more than 30, but here it's about completely novel. As a leader in diagnostics, we want to develop assays that no other company has in their portfolio. And we are tracking really well on that. We're actually ahead of this plan. On the group side, we want to realize more the synergies between Diagnostics and Pharma, one, by providing solutions to health care systems to more effectively deliver care, but also in the value chain, we can be much more effective in delivering the synergies between the two divisions. And in data and digital, we want to transform our business, the way we do our business from R&D throughout the entire value chain. So these are the goals that everyone is following through on. Now let me go through the group strategy. And there are six key trends that really informed our group strategy. One is there's an increasing disease burden over the next 10 years. And interestingly, 50% of this disease burden is in only three different disease areas. So cardiovascular metabolism, oncology and neurology. Those three will contribute to the 50% of the disease burden in the world. So this is where the biggest need is in the health care systems, and that's why this is a major focus for us. Second, the health care systems are massively under pressure. If you look at the last 20 years, health care budgets have always grown faster than GDP. Now this will not be a trend that we'll be able to go on forever. So it's also our responsibility to help the systems address the costs in the system. One of the ways they do that is decentralizing care. So care no longer only delivered in the hospital but really at home or in the outpatient setting. So what does that mean in terms of the diagnostics but also in the pharma products that we deliver, that we actually meet that trend and treat patients where they are and not where do we think they are. The other trend that we see is early detection, monitoring and intervention. And as you go into even more earlier detection, Diagnostics will play a bigger, bigger role, a much bigger role in the future, and also taking the treatments into much earlier settings will be critical. Access to health care is still a topic and will continue to be a topic when not even half of the world's population have access to good health care. And there are transformative technologies like AI that we need to leverage in order to accelerate and become a better organization. Now just one proof point from what I've just mentioned is on this slide. On the left-hand side, you can see all the disease burden across the world. And you can see the highest disease burden is cardiovascular metabolic. So now you also understand why we have to be in cardiovascular metabolic. It's the #1 problem in the world. Second is oncology. Third is Neurology. All of these areas are growing in terms of disease burden between 14% and 24%. The other areas -- so these are the shared areas that are of interest for Diagnostics and Pharma. Now the other areas where pharma is focusing on is immunology and ophthalmology. Again, areas that are growing significantly. If you then look at all the other areas, they are declining by 5%. So we're really focusing on those areas that have the biggest unmet need where health care systems will focus on -- especially when they have less budget available, they will focus on those areas where they can have the biggest impact on better health care. So what does that all mean for us? Well, we have to prioritize those diseases where -- which cause the highest burden in the health care system and where there's the biggest unmet need for patients because this is where in a future environment where health care systems will start to prioritize the money more and more will actually also focus on. Second, we need to find ways in order to reduce cost in the health care system and really understand the patient journey on how we can intersect the patient much earlier so that the patient has a better outcome. And with that, we can also reduce cost of care. On the decentralized delivery, really focusing in point of care the one area that I told you we were not a market leader to make sure that we are set up for the future where care is more decentralized, but also deliver devices so that people can medicate themselves at home. People that have multiple sclerosis or other diseases, they don't want to go to the hospital every time, sit in an infusion chair for hours and then get reminded of their disease constantly. They actually want to live a normal life, especially in chronic diseases. And with that, they want to treat themselves at home. Also, we need to move into earlier detection, prevention but also curing diseases because this is what the health care system will expect from us. And on access to health care, clearly, a big focus and also investing in the breakthrough technologies. So overall, with Diagnostics and Pharma and digital products that link the two, we believe we are very well set up for a future where care will be much more decentralized, where the combination of diagnostics and medicine will play a big role, where treatments will become more chronic and you have to monitor yourself, treat yourself. This is where Diagnostics in combination with Pharma will play a significant role in moments where it's much more important to detect the [Technical Difficulty] hence, once people are being treated, they want to be monitored. And they don't want to go to a hospital every time to be monitored. They also have to do that at home. So we need to be prepared much more for a future in that direction. Hence we have three shared priority areas with cardiovascular metabolic oncology, neurology, which are the key areas that will drive the increase in disease burden over the next 10 years. So clear focus for us that these are the areas where we want to work together and improve outcomes to patients along the patient journey. Now beyond the products that we can build, there are other significant synergies that we have across the organization. Just on the research and development side, developing biomarkers for research is one, but also diagnostics instruments for R&D. So as we launch then our sequencer, our R&D organization can have the sequences at cost because we don't recognize sales within intercompany sales. So we can actually sell between our organizations, systems at cost, our PCR systems, our nucleic acid extraction systems, digital PCR, we can sell everything in cost. So with that, reducing the cost of our own R&D significantly. That's a good example in R&D. On the manufacturing side, we've actually shared antibody production methods. And Teresa will share how the Team Pharma has been able to increase the yields 5x. So with the same amount of manufacturing footprint, you can produce 5x more of the antibody. And we use that in Diagnostics to actually not have to build a number of new manufacturing buildings. And with that, we're saving hundreds of millions already because we don't have to build new manufacturing sites for Diagnostics. And on the commercialization side, we are doing this already. We are the market leader in cardiovascular metabolic. We can leverage our know-how, our market leadership position to position us well in the cardiovascular metabolic space also pharma. So all in all, what we want to achieve is improving outcomes and reducing cost for patients because we know that this is what the health care system expects from us. And we want to do the same for the health care system, improve outcomes and reduce cost of patients. And we can do that by combining pharma and diagnostics, by identifying high-risk patients early and then treat these patients with the right medicine because the earlier you detect -- Alzheimer is definitely one of those. The earlier you detect, the better you have in terms of outcomes. And sometimes, you can prevent disease completely. Also by stopping the progression of diseases by accurately diagnosing and stratifying patients to halt disease progression. But also, we need to go towards cure. We need to understand diseases better and the cause of these diseases. And with that, also using diagnostics and to restore health through curative medicines. And we need to do all of that where patients are. And patients in the future will not be necessarily anymore in the hospital, but they will be also in the home setting. Now let me take you to digital health, something that was called Insights before. This is an area where we've rolled out the strategy already last September because we worked on it for the first couple of months last year. And that's why we now call it Digital Health, no longer Insights. And what we also said is we are not going to have a third pillar. Digital Health is supposed to help us make better products in Pharma and better products in Diagnostics. And in that, we have agreed at the time that we will have four product segments that we'll focus on. At the same time, because in a very centralized way, we had different platforms and technologies all over the organization. We agreed that we will only have one infrastructure platform, we'll only have 1 data and analytics layer platform and that we are going to use reusable pieces throughout all of the digital solutions, meaning, for example, logins. Logins, you don't have to have 50 different logins that you develop, but you can use one, use that as a reuse piece and then basically roll it out through all of the software programs, which, by the way, is a big benefit because then people will actually know that they're working with the same company. And then on top of that, you can build the products. Now on the operating model, we said that the informatics organization will deliver the infrastructure platform. In Diagnostics will provide a lot of the data analytics layer. In terms of selling products, that will then be in Diagnostics or Pharma. Now we implemented all of that and what happens? What happened is that we have consolidated a number of products in Diagnostics and Pharma and took some of them out. We actually generated after implementing that savings for this year of about CHF 170 million. We provided 50 reusable components all going into different softwares. We reduced the data analytics platform. We had three data platforms now into one, which will also help data flow much more effectively. And we also discontinued a duplicative infrastructure platform. So you can see this is an area where we've already rolled it out last year and how consequently we went through the implementation in order to make sure that our organization is very efficient, very focused and set for delivery because implementation is critical. And I think this is a very good proof point on how we have been very diligent in execution. Let me just briefly talk also about sustainability because it's an important part. Here, we focus on three areas where we can have the biggest impact. One is access to innovation. Second is our people. And the third is environment. Now let me just focus on the topic of environment. And you can see that on the right-hand side, we are on track to meet our Net Zero targets. So far, we've reduced Scope 1 and 2 in greenhouse gas emissions by 67%. By 2025, so that's not far around the corner, we expect to be at 100% sustainable electricity. And we are committed to deliver Net Zero for Scope 1, 2 and 3 by 2045 and the absolute 0 of Scope 1 and 2 by 2050. And with that, we're the only company in the world that has given a commitment for absolute Zero. And I think that's a big differentiation to other companies. Now let me talk about our commitment to Global Health Security and you will hear about that a little bit earlier -- later. On the Diagnostics side, with SARS-CoV-2 -- with SARS-CoV-1, with MPOX, I think we've shown that our global surveillance program works well and that we are very fast in then delivering tests to the world. In fact, we're usually the first for a big company, we are faster than small companies. And I think this shows that we are very committed and that we can also deliver here. On the Pharma side, over the last years, we've invested and ring-fenced a certain amount of money in terms of investments into -- in developing new antibiotics. This is part of our commitment to sustainability that we will make a contribution here. And you can see the last antibiotic was discovered in 1960. And so this is 54 -- 64 years ago. And now we have two in the pipeline that look promising, but Larry will talk about that. Then let me also talk about people and culture because at the end, anything you do depends highly on the people that you have and the culture that you have in the organization. One topic I already talked about is talent. Strengthening the talent development in-house, but also bringing in key talent from the outside, which we are committed to. It's about creating an environment where everyone can feel inclusive. So diversity and inclusion and equity inclusion is a very important part. But also leadership is an important part, drive urgency, effective decision-making as well as empowerment and accountability. Effective decision-making is very important that people drive to decisions and drive to implementation. And with that, beginning of the year, we introduced a new performance and rewards system, which much more significantly differentiates between high performance and low performance and sets clear expectations on what we want people in our organization to deliver. And this -- some of these measures like also around R&D excellence is actually also included in our corporate goals which everyone in the organization has in order to drive through the changes that we need in the organization going forward. Now let me give you another proof point, one that's a couple of years back that also shows how effective we've been in driving changes. Now I took over the Diagnostics division in 2019. Prior to that, I was Head of R&D for the biggest unit in Diagnostics for 2 years. And then I led the Diagnostics organization for 4 years. So for 6 years directly involved in managing and shaping the pipeline and also the organization. We made the new strategy in 2019, and then we implemented that strategy. And what happened in Diagnostics? We made the organization much more efficient, much faster. We took out a lot of administrative burden in the organization, cutting in areas that didn't contribute to making a product or serving a customer. So we said at that time, everything that's more than two steps away from either the product or the customer, we have to really challenge our investments. We did that at the time. And with that, we could increase R&D investments at the time of CHF 500 million but we took it out of other parts of the organization. And we channeled that money into point of care, things that are developing now and coming to the market, into mass spec, into the new systems in Serum Work Area, into CGM, into next-generation sequencing. So all programs that are now delivering, if we hadn't done that at the time, we would not have been able to make this progress over those number of years. And you can see how effective we were in reducing complexity in the organization. For example, we went from 48 quality management systems to one during that period of time. And you will see we've now done the same in Pharma. We've reduced the organizational complexity. We have reduced the hierarchy levels from 9 to 5. So we were very effective in managing those changes. And with that, we could also fund all of these programs and accelerate all of those programs. And I think that's another proof point that we are committed. And when we say we're going to deliver, we will deliver. Now final points on around operational excellence. And I just want to say maybe that's also maybe one of the benefits coming from a Diagnostics organization where money is not as much around as in the Pharma world. You learn how to run organizations effectively. That's because you have to, right? Now I also believe the same can be happening with pharma because it's actually our job and it's actually our ethical responsibility that every dollar or swiss franc or whatever currency we invest has the biggest return, a, for shareholders but also for patients. We shouldn't waste money. We should make sure that money is effectively used to produce new products. And with that, we also looked at, okay, we were an organization that was very decentralized. But there are areas where we need to be much more centralized. It doesn't make any sense that you have different organizations that are using the same IT systems but from different companies. Also the data doesn't flow effectively if you do that. So really radical simplification, simplifying the systems and processes landscape is something that we've been working on for the last year in a very high degree, and we've made a lot of progress here. But we also want to make sure that decisions are made where there's the best expertise, but you create a framework that people have to make a decision that we don't carry on projects forever, but there is a framework, if these projects don't meet The Bar that we need that these programs are then attritted out of our pipeline. But that gives us the possibility to again invest into areas that can have an impact. And this is an ongoing cycle that you have to manage. And again, the people that are responsible for these programs and the people surrounding them, they need to make the decision that you need to create the framework. And so certain decentralization of decisions are important also in terms of local go-to-market approaches, but there must be some areas where we have a much more centralized approach, like, for example, on systems and processes and governance. And we do the same on the group. We look at where we can share resources, where we can create synergies and the rest we keep it in a decentralized way. Good. Now I'm done from my part, and you'll hear more about Pharma strategy that Teresa will talk about in R&D excellence, where you can then see what's the progress we made in implementing some of these things over the last year. Thank you very much, and over to you, Teresa.

Thank you, Thomas. So normally, when I'm here with you in London, I'm here to give you a whistle-stop tour through our portfolio and to talk to you about all of the things that are going on, whether in market products. But today, I have a special opportunity to share with you for the first time our first end-to-end Pharma strategy, which very neatly lays out how we will work together all the way back from research and early development through commercialization to provide as much impact as possible for patients. Over the next 30 minutes, I'm going to walk you through a high-level overview of the pharma strategy, our target therapeutic areas and disease areas, the core capabilities that will be necessary in combination with our science to ensure that we are reaching as many patients as possible. And then we will end by spotlighting our significant growth opportunities. 2025 is a big year for us in terms of data, and there's a lot of exciting things that we'll be reading out. So let's jump right in. So I think, first and foremost, it's important to know that when we started the exercise around the pharma strategy, we actually started from a place of pretty good strength. We're number one in a number of key therapeutic areas. We're #1 in neurology, OCREVUS, Evrysdi, leading in their disease areas. Vabysmo is certainly coming on strong in ophthalmology, and we continue to hold leadership positions in oncology and hematology. Over the last 10 years, we have more than doubled the number of blockbusters in our pipeline. At the same time, we have significantly diversified our portfolio. This has also allowed us to weather one of the largest patent cliffs in the industry and still grow, something that we committed to you quite some time ago. And that commitment to innovation is clearly evident in the fact that in that same 10-year period, we launched 26 NMEs. We had more than 40 FDA breakthrough designations. And importantly, that history of innovation continues as we now have more than 70 new molecular entities in development. So where do we go from here? Thomas mentioned at the beginning of the year, we set ourselves a very ambitious goal of delivering 20 transformational medicines addressing diseases with the highest societal burden. This is an ambition that will not just happen. It will require every part of Pharma to operate a little bit differently and together in a way that is unique. We want to increase the value of our portfolio by 40% with the average peak pipeline sales. We want 80% of our pipeline to have best-in-disease potential. We are not satisfied with just delivering medicines. We want to deliver transformational medicines. And most importantly, we need to make sure that those transformational medicines actually reach patients. And so we've set ourselves a goal that we will increase by 3x the patients treated with our products. So how are we going to do this? Roche is a company that I think you all first and foremost, would identify with following the science. It's what we've been known for over generations. And it's something that we never want to lose because it is central to who we are as a company. But what we also recognize is it's important to have a purposeful balance between following the science and an intentional focus of making sure that we can turn that fantastic science into medicines that actually reach patients, where we can use the depth of our technical expertise and our operational scale to reach as many people as possible. The Pharma strategy was designed to help us strike that balance between following the science and having that intentional focus so that we can leverage everything that Roche has to bring to ensure that more medicines reach patients faster. At the core of this is something called The Bar. So now I hate to see a Levi's thunder because Levi describes The Bar better than anybody else you'll ever meet. I have to talk about it a little bit. So fundamentally, The Bar is the criteria by which something enters or advances in our portfolio. There are five key criteria that we are now asking ourselves about every asset end-to-end in Roche, all the way back from research through to line extensions, does this pass The Bar? The Bar does not ask the question, can this asset be a medicine. The Bar asks the question, can this asset be a transformational medicine. And if it can be a transformational medicine, it enters the portfolio or it advances. So now going back to this idea of purposeful balance between follow the science and intentional focus, The Bar helps us decide what assets come into the portfolio. But ultimately, we need a higher-level look at how we then think about the construction of our portfolio overall. And that's where the Pharma strategy comes in. So this is, in essence, a high-level summary of where we're headed. Where we play? We have five priority therapeutic areas: oncology and hematology, immunology, neurology, ophthalmology and our newest therapeutic area, cardiovascular, renal and metabolism. In addition to those five therapeutic areas, we know that great science is necessary but we also need to make sure that we have the capabilities to deliver that science to patients. And so there are six core capabilities that we are also focused on ensuring that we are continuing to invest in, and we are continuing to make sure that we have the ability to be best-in-class in those areas as we move our portfolio forward. And it is the combination of these two things that will ultimately allow us to deliver on that ambition of 20 transformative medicines. So now let's take a little bit of a deeper dive into our therapeutic areas and our focused diseases. So as we were coming up with our therapeutic areas, we didn't just say, okay, well, what are the five things that Bruno has had on his slide all year and how are we going to retrofit into that. We actually took a very big step back and we said externally and internally, what are the therapeutic areas that make the most sense for us. We looked at the burden of disease and societal costs. Thomas talked quite a bit about this, where are health care systems spending the majority of their resources because they have most of their patients who are unable to be controlled today. These are the areas that have significant unmet need and are needing new standards of care, not only to improve patient outcomes, but to drive down costs in global health care systems. But these also have to be areas where there's tractable science. You have to be able to look at where is our understanding of the science, where is our understanding of the biology going so that we can actually take that transformative science and turn it into medicines that will ultimately help those patients. It's also important that we focused on therapeutic areas where Roche actually had the ability to pull that science through to patients. We're -- in some cases, we already had a pipeline that had best in disease potential, but importantly, where we had therapeutic expertise and knowledge that would allow us to make smart and good decisions as we advanced into these therapeutic areas. What makes us feel good about the choices that we've made is that our therapeutic areas, as Thomas mentioned, comprise 60% of total global disease burden, but they also represent 80% of potential growth over the coming decade. So to put this a little bit in more detail. So you can see here with the global burden of disease in dailies that we are in the areas that are growing the fastest in terms of unmet patient need. And you can see that we also are in areas that have a significant number of patients. So we know that the science that we're developing has the ability to actually help a lot of people, which is quite important. We also know that we're focused in the areas that have significant opportunity for growth. So you can see on the y-axis here, the CAGR from 2024 to 2028 and on the x-axis market size and bubble size also indicates how large this is. You can see that we are in the markets where you have the highest growth and the highest potential to generate revenue. The one question you might ask is ophthalmology, the ophthalmology bubble might seem a little small. That is because largely it's a little bit about time scale, but ophthalmology becomes much, much more important as populations age and more and more patients will ultimately need drugs to help them maintain their sight because we know when you lose sight, you lose a tremendous amount of what makes you able to actually live on your own and live your life the way that you want to. But those five therapeutic areas are quite large. And so we wanted to take a next step and say, within those five therapeutic areas, where are the diseases where we believe we have the opportunity be most transformational. So we took those five therapeutic areas. We put them through another funnel, and we came up with our end-to-end disease areas. There are 11 end-to-end disease areas that we focus on today. What is an end-to-end disease area? These are diseases in which we will have dedicated research teams internally, who are focused on delivering novel science. We will ensure that we have significant early and late-stage development investments, both in our own portfolio and as we look outside. And we will ensure that we have full-scale commercial investments to realize that science as it becomes a medicine. But don't be fooled. We will never lose what makes us Roche. We will never lose the commitment to following the science. And where we see breakthrough potential in different disease areas, we will absolutely continue to follow it. And The Bar will always be our first question as we enter those new diseases and see new assets. So what are those 11 diseases? So here they are. So some of these are places where we already actually have large in-market assets already. Hemophilia, market leader with Hemlibra. Multiple sclerosis, market leader with Ocrevus. Retinal and vascular disorders, fastly coming on with Vabysmo. But some are places where we have pipeline assets that we believe will be truly transformational such as in obesity or in Alzheimer's disease. Importantly, when we look at these five therapeutic areas and our focused disease areas, we are not just looking at disease. There are also a number of mechanisms or pathways that we know are going to be particularly important in these different therapeutic areas that would have the opportunity not only to be important in a particular disease, but potentially across diseases. And so there are also a number of priority pathways that we are focused on as well. It's also important to note that categorization is dynamic. We can and will make changes to our categorization as there are changes either in the science or in the opportunity available for patients. So let's take a little bit of a look about how this actually translates into our portfolio today. So if you actually look at our portfolio today, you can see that the five therapeutic areas are clearly represented and our end-to-end disease areas are also very well represented. If you look at our on-market portfolio, which as Thomas mentioned earlier, is going to continue to drive growth in the coming years, you can see that it's very well aligned with the focused disease areas. As we head into products that we'll launch within the 2025 and 2028 time frame, again, you can see we're very well aligned with our focused disease areas, fenebrutinib, tronti, vamikibart. These are all things that very nicely fit [Technical Difficulty]. This is a great example of what we would call a breakthrough asset. Hypertension wasn't on the end-to-end list, but we believe that zilebesiran has the opportunity to be truly transformational in the treatment of hypertension. We are actively working with our partner to develop that medicine. And if it comes to patients, we believe that it will provide a tremendous sign of benefit, and we will be supporting it with aggressive commercialization. We have our obesity assets here. And we have our GSM asset for Alzheimer's, which Azad will talk to you about later today. But as Thomas alluded to, we are not just looking at our pipeline today, we're also looking at our pipeline tomorrow, and that includes what are the things that we can bring in from the outside. So over the course of the last number of months, we've done a number of very exciting deals. And you can see many of them listed on this slide. But the last few that we've done very nicely aligned with our core therapeutic areas and priority disease areas. AntlerA, the Wnt agonist in and ophthalmology. I won't say much about this because Chris is going to talk about it extensively this afternoon but a great fit for what we're doing in ophthalmology. And you heard this morning about Regor Therapeutics deals, the CDK4/2, CDK4, a perfect fit with our breast cancer franchise. So as we're looking at our partner opportunities, we continue to look for things that fit nicely within our end-to-end disease areas as well as continuing to explore those opportunities for breakthrough science. So now let's actually see what this looks like in practice. And let's start with probably one of our most advanced end-to-end disease areas, and that's breast cancer. So you can see here that across all phases of development, we have quite a good pipeline of breast cancer medicines. But we also have a very impressive presence already in breast cancer, our HER2 portfolio -- our HER2 franchise is expected to continue to grow over the next several years. We expect that it will retain about 40% of its total peak value well into the future. We are moving aggressively into hormone receptor positive breast cancer with the giredestrant trials reading out next year. And in addition, we've just had the Regor deal that is now -- that has now been signed. So we are very, very much committed to not only be in breast cancer but in curing breast cancer. So one of the assets that's actually coming up on its FDA approval is inavolisib. And inavolisib is actually a wonderful example of one of those priority pathways. PI3 kinase mutated tumors appear not only in breast, but they also appear in many other tumor types. So inavolisib, INAVO120 clearly showed phenomenal results for patients who have this mutation. It's been filed. We expect our PDUFA at the end of November. Charlie will talk to you in much more detail about all of this data, but what we see here is something that has the potential between the initial trials in breast cancer to be a $1 billion to $2 billion opportunity but also has the opportunity to move into many other tumor types. So this is a great example of a priority disease area and a priority pathway. Now looking at our malignant heme portfolio. Again, there are tremendous -- a tremendous amount of activity, not only with our bispecifics, but you'll notice down here at the bottom, we have also moved our allogenic CAR T programs with Poseida into the clinic in Phase I in both B-cell malignancies and in multiple myeloma. So lots of activity going on in the hematology portfolio. And that very nicely complements our on-market presence. Polivy continuing to entrench itself in first-line DLBCL. We now have more than 33,000 patients who've been treated. It is beginning to show up as the standard of care. We have just recently submitted the 5-year POLARIX data to a conference. So now we'll begin to see the long-term data associated with Polivy. Columvi and Lunsumio are continuing to gain traction in the market. We have filed, as you know, the positive STARGLO data in second-line DLBCL for Columvi. And we just recently announced positive data in third-line follicular lymphoma in a subcut for Lunsumio, which is also being filed with regulators. So hematology is an area where we have historically been very strong. We continue to make deep investments from a clinical perspective as well as having a very strong on-market presence. So now let's move over to hemophilia A. So again, this is an example of something that about a decade ago would have been a breakthrough technology. This would have been a breakthrough area for us, but we saw great science. We followed it, and it is now an end-to-end disease category. So obviously, Hemlibra continues to be the market leader, but you see NXT-007 has now moved into Phase II, and we're very excited that this could actually be possibly one of the drugs that provides a bleed-free experience for hemophilia patients. And Charlie will talk a little bit more about this, this afternoon. I also just did want to highlight for you that dirloc, which is our SPARK program in gene therapy has been placed on pause while we reevaluate that program and see what will be necessary for any gene therapy to effectively compete against standards of care like Hemlibra that are already dominant in the market. So that program is currently paused as it is being reevaluated. Hemlibra remains the global standard of care, 41% market share in the U.S. and the EU5. 80% of patients remain bleed-free and we are continuing to do more and more to enhance the patient experience of people who are on Hemlibra, whether that's new vial options, the updated admin kit, or the auto-injector, which is currently in development. Hemlibra is a great example of a drug that provided transformational benefit to patients that changed the standard of care in an entire disease and one where we continue to think about how we raise The Bar on ourselves to ensure that we continue to bring better and better treatments to patients. Multiple sclerosis is another relatively new end-to-end disease area for us. Again, you can see that we have quite some investment in the pipeline, whether it's the line extensions for Ocrevus, subcut, which has just recently been launched or Ocrevus high dose, which reads out next year. We have fenebrutinib, which is our oral BTK, which is reading out next year in both RMS and in PPMS. And then we have our Brainshuttle CD20, which is an earlier stage for MS. Ocrevus, again, continues to be market dominant in the MS sector. The approval of Ocrevus subcut, Zunovo, as it's known in the U.S., has recently happened, and it now takes patient treatment down to 10 minutes every 6 months, which is really a tremendous advance for patients. This has the potential to drive and unlock significant expansion for Ocrevus, allowing us to reach patients who, for whatever reason, we're not able to access IV treatment or to -- in the U.S. to reach a whole selection of patients who primarily are in with community neurologists who don't have access to IV capacity. So this is not only a great advance for patients, it also unlocks a significant market opportunity. The other thing I'm really, really proud of for Ocrevus is the amount of time that we have spent doing Phase IV trials that actually look at the impact of Ocrevus on family planning. I think most people know that the primary -- MS primarily hits young women who are in the phase of life where they want to start planning their families. Ocrevus is the only high-efficacy therapy that has this significant body of evidence that talks about its impact on reproductive health for women. And I think we should be really proud that, that data exists. So this is hot news of write-off of last week's announcement that the Gazyva lupus nephritis study has come back positive. Many of you will remember, this is a trial that I was personally really excited about on being a big believer in B-cell therapy for lupus. Again, you can see that there are a number of trials that Gazyva is currently in. The sum of those trials, if positive, lead to about a $1 billion to $2 billion opportunity for Gazyva. You will hear a lot more about this trial later this afternoon. But I think, again, the fact that we had positive Phase III data in lupus nephritis in a very strict endpoint, complete renal response is -- it represents a really positive opportunity for patients to get control of a very debilitating type of lupus. Moving on to ophthalmology. So I will not spend a lot of time on our portfolio because Chris is going to take you through this in a lot of detail. But what I will say is, as a company, we have one of the most diverse and exciting pipelines in ophthalmology, covering a number of different diseases and modalities. And so I think there's a lot to look at and be really excited about as well as some great readouts that will be happening next year. But Vabysmo is clearly the center stone here. The launch of the prefilled syringe has just happened. It is going exceptionally well. I was just at Uvetna -- was that last week, 2 weeks ago. And what I can tell you is that there was a tremendous amount of excitement about the prefilled syringe. It is getting a lot of positive reception in the U.S. It requires only one hand to use. And the growing body of evidence that we are seeing with Vabysmo, not only with real-world data, but also real-world clinical experience is incredibly exciting. And so again I continue to say that Vabysmo should be the standard of care for these patients. This growth has consistently outpaced annual expectations, and we expect that it will continue to grow in a really meaningful way, providing a lot of value to patients. And last but not least, our obesity profile or portfolio. So we all know that obesity is a major problem in the world. By 2035, 50% of adults in the world will be obese. And that's not just Western adults. Sadly, this is now not a disease Western countries, this is a disease of the world. These patients will not only suffer for being overweight. We know that overweight and obese people tend to have more significant comorbidities. We also know that this is going to be an incredibly large market with estimates upwards of $100 billion and more by 2030 and beyond. We do believe that our pipeline has the potential to be best-in-class and extremely competitive in a market that will be highly segmented. You saw the data that was released at EASD just a couple of weeks ago. There is more data coming by the end of this year and beginning of next year, Manu will cover all of this in a tremendous amount of detail this afternoon. But I think what is especially exciting to us is the fact that we believe that with the assets that we obtained through the purchase of Carmot, we have a great suite of highly differentiated assets that we believe either through the efficacy and safety of the individual molecules themselves, or importantly, in combination with drugs that we have in our own pipeline have the opportunity to be very competitive in a number of different ways. I also want to call out here that we will see data on CT-176, which is our analog as well. So now let's shift to our core capabilities. Again, the science is the first step, but it's not the last step. We also know that we will need core capabilities that allow us to commercialize that science around the world. And we're focused on 6. Modalities and technologies, devices, our manufacturing footprint, customer experience and access, data NII and our people. So let's start with technologies and modalities. So we increasingly know that understanding the biology of a disease is just not enough. You also need to know what are the -- what is the modality that is most likely to be able to access the target. And Roche has a long legacy in a number of leading in a number of different modalities from monoclonal antibodies to bispecifics. And you can see across our pipeline and portfolio, we have a tremendous amount of experience in all of the new modalities that are coming. And small molecule -- all the way from small molecules to our allogeneic CAR Ts. This is a place that we realize we will need to continue to be strong. We will need to continue to focus, and we are constantly on the hunt for new modalities that help us to better target the biology that we know we need to tackle to provide more benefit to patients and new diseases. Thomas already mentioned the growing trend of decentralized health care, core part of being able to help patients in a decentralized way is actually having a device. We estimate that 60% of our current pipeline, either from a new molecular entity standpoint or a line extension will require a device. And so we need to remain good at this, and we need to continue to expand how we think about devices. We already lead in intravitreal delivery. So again, that prefilled syringe for Vabysmo is a great example, but the very unique PDS platform for intravitreal drug implant, this has just relaunched in the U.S. We expect to see a launch in the EU in the coming year. But this is a platform that will not only work with Susvimo but will also work with our DutaFabs in the next generation. So a lot of really impressive innovation in the intravitreal space. We also have just launched 2 new subcuts with Ocrevus and Tecentriq, and we are continuing to think about what are the kinds of devices that our patients are going to need into the future, how do we manufacture them at scale with the highest quality and with acceptable COGS. Speaking of manufacturing, as Thomas mentioned, we have spent a lot of time over the course of the last number of decades, looking at how to really streamline our manufacturing processes. We have worked very hard to develop a cutting-edge network that brings the production of our molecules in the highest quality way as close to our delivery systems as possible. You can see across all of a number of different mechanisms, ways that we have really been working to make sure that we are developing a network of the future that allows us to meet our portfolio where it's at and get ahead of the needs of the portfolio in the future. One of the places that becomes particularly important is how we plan to manufacture our integrin profile, our integrin pipeline. So we've talked quite a bit about our plans for CT388 and 868, so the injectable peptides. We know that we have clinical supply space already reserved at CDMOs. We don't see any near-term capacity constraints that would propose a challenge here. Our commercial production will be a mix of in-house and external manufacturing. We believe that we have plenty of resources within our current capital budget in order to be able to make the necessary investments as well as working with our CDMO network. We do expect that by the time we -- our drugs come to launch, there will be more capacity in the CDMO network. I think if you talk to the -- if you talk to the contract manufacturers, you will hear them say this as well. We are consistently investing more in in-house device development capabilities and strategic partnerships to make sure that both of these molecules come to market with a strong device. And then obviously, 996, which is a small molecule will be manufactured by Roche as it's a fairly straightforward chemical synthesis process. But why can we do this given the breadth of the portfolio that we already have in-house, that is because for the last 3 decades, we have focused on making our drug substance manufacturing processes incredibly lean. We have invested heavily in doing a lot of work to make sure that we are getting the highest yield products at the highest quality at the lowest cost. Right now, we have a 5-fold productivity increase from 2000 to 2030, and we continue to lean into ways to increase that. In fact, we just launched a new version of Perjeta, which is 4x more efficient to produce than the prior version. So we're consistently looking at our own molecules and thinking about how can we make them higher yield and how can we make them at lower cost. I'm going to switch gears a little bit here and now talk about our track record in reaching leadership in new therapeutic areas. So we often get a lot of questions about how we plan to enter IBD and obesity and what gives us confidence that we can do this. What gives us confidence that we can do this is that we have done it before. We have done it before multiple times and in places where we were getting asked the same questions. Ocrevus, highly entrenched competitor in Biogen when we came in with this molecule. Hemlibra competing against factor VIII, extremely well entrenched. Vabysmo, again, had a very strong entrenched competitor when we launched. But by taking the time to understand the market, understand what patients needed, what was important to physicians and health care systems, we have been able to create an industry-leading footprint for all of these molecules and position them for very strong growth in commercial success. And it is because of our experience in doing this and replicating it over and over and over again in markets around the world that we have exquisite confidence that we will be able to do the same thing as we enter in IBD and CVRM. So let's also talk about data and digital, AI, in particular. We're talking about ChatGPT earlier today. AI will revolutionize drug development. And it's not going to revolutionize drug development tomorrow, it's happening today. It's happening now. And Roche and Genentech have really been a leader in this space. Everything from lab and a loop to thinking about how we can utilize AI and our regulatory document writing to some very interesting things around digital twins and our manufacturing lines to how we can think about using AI to be more efficient in our commercialization. We have made significant investments in AI, and we will continue. But what makes me particularly confident that we can take full advantage of this going forward is that the number one thing you need to make AI work for you is data. And Roche/Genentech together have more data than just about anybody else. You heard Thomas talk about all of the work that's happening to streamline and harmonize our systems. This is one of the reasons that, that becomes so important because when that data is altogether and we can look at it in ways that make sense across the end-to-end portfolio, it allows us to make better decisions and harmonize the power of AI more. We commercialize our products in over 100 countries. Imagine the power of that second and third launch country being able to know on the day of launch, what customer segmentation, what customer messaging, and what kinds of things they need to do, the minute they pull up to the parking lot of one of their physicians. Imagine what we can do to help patients have a better patient experience if we can truly understand how they're interacting with our medicines in the world. This is a place that we are investing in and we're investing in with a lot of focus and a lot of energy because we believe not only is it the right thing to do. We believe that it will provide us a distinct competitive advantage that is really unique to Roche and Genentech. And then finally, our people. So as Thomas mentioned, there isn't anything that happens without having the best people. We are committed to developing -- we are committed to maintaining a high-performing organization, but it is important that we make sure that we're bringing in talents and capabilities that have the experience that we might need where it doesn't currently exist in the organization today. And so at the same time, we're looking to create the kind of culture that retains the people that we want to retain and attract, we're also making sure that we're being very open-minded to bringing in talent from the outside so that we can take full advantage of this amazing pipeline that we have. And so I'm going to bring us into our home stretch by covering our growth opportunities. So these are some of our key pipeline assets, both NMEs and line extensions. And you can see in our new molecular entities, we currently have 7 NMEs with more than 3 billion -- more than $3 billion peak sales potential. That's giredestrant. It's the anti-TL1A for IBD. It's our obesity assets. These are large potential -- these are very large potential new drugs. We also have 4 NMEs that have between 2 billion and 3 billion peak sales potential. So inavolisib, when you see the totality of its indication; fenebrutinib when you see the totality of its indications; for DMD. Again, these are projects and programs that are in the clinic close to reading out or already with already being sold today, where we believe we have the opportunity to add significant growth to our portfolio. And within our line extensions, we have 6 line extensions that could add between CHF 1 billion and CHF 2 billion peak sales per year. So that's clearly the bispecifics that have a lot more room to go in terms of their life cycle. It's Ocrevus, with subcutaneous coming on to and things like Gazyva, which still has quite a number of indications left to read out. So there is a lot of growth that exists in our pipeline today and a lot of innovation for us to bring forward to patients. And finally, this is a sneak peek at the new for 2025. There is a lot happening next year. We're going to keep you very busy next year. We have six significant regulatory filings expected next year, and we have 12 Phase III readouts and we have more Phase I and Phase II data coming for some of our most exciting earlier pipeline assets. When I think about the opportunity that's before us, we not only have a young, best-in-disease portfolio in the market today that's changing the way the treatment is delivered for patients. We have a very dynamic portfolio. R&D excellence is helping us discover ways to actually streamline that portfolio and bring it faster to patients. We've made some exciting acquisitions and deals which very nicely supplement where we want to go with our end-to-end disease areas. We are well positioned to deliver significant growth and more significant value for patients. I firmly believe that if we maintain the rigor in the science and the discipline in the business, that we will be able to meet that ambition of 20 transformative medicines, and we will able to bring -- we will be able to bring a lot of value to patients in the coming years. And so with that, I'm going to turn it over to Levi to talk a little bit more about R&D excellence.

Hi, everyone. It's great to have a chance to come back to London and talk to everyone, particularly about R&D excellence, which is an initiative that you heard about last year, but we've been working on a great deal over the past year. So for us, R&D excellence has really two overarching objectives. The first is to deliver many of the world's most impactful medicines and to do that consistently over time. And in fact, during the present decade, we hope to deliver 20 such medicines. But the second is to sustain top quartile productivity across the industry. And over the past year, we've taken multiple steps to attain both of those objectives across our divisions. And actually, this has involved significant change. This has changed to our pipeline, change to our decision-making and governance, change to our approach to business development, our incentives and various aspects of our R&D engine. So I'll touch on all of those. But we have six solutions that together, we believe, will help us attain our overarching objectives. And three of them, which are shown across the top of the slide are really focused on assembling and governing pipeline that consists solely of programs that have transformative potential. And this should ultimately enable us to deliver many of the world's most impactful medicines. Now two additional solutions can propel us really towards top-tier productivity, whether that's by making our R&D engine more efficient or by embracing specific objectives that really are tightly coupled to overall financial ambitions. And then finally, we have one solution that ensures that our incentives of our people are really aligned with efforts that will really elevate R&D performance. So we're going to start with the adoption of unified portfolio framework. And really, this is about if we're going to bring more high-impact medicines forward, we first have to be able to recognize programs that have transformative potential wherever they might reside, whether that's in our internal pipeline or in the external world. And just to provide a bit more context on this specific point. In the past, there has sometimes been a sentiment in parts of the sector that perhaps the prevalence of so-called mega blockbuster therapeutics might start to diminish. And this perspective was buttressed by analysis, such as the graph that's shown on the left. And so at first blush, you could say, well, maybe the percentage of launched NMEs that achieve blockbuster status or greater could be going down over time. And you can see there are 2 5-year segments. And in the earlier 5-year interval, about 45% of launched NMEs achieved blockbuster status that's the blue portions of the graph. But in the subsequent 5-year period, that percentage drifted down a bit because you also start to see this growing proportion of NMEs that maybe don't play get there. And actually, there was a plausible basis for this narrative. You have the expansion of precision medicine, and you have increasingly frenzied competition in the sector. So conceivably, that could push the industry towards greater fragmentation and reduced revenues per NMEs and perhaps even a changing business model over time. So that has been a narrative that's been out there. But in reality, the evidence suggests otherwise. So first of all, the actual numbers of launched NMEs that reach blockbuster status, they're actually not going down over time. There were 32 of those medicines in the first 5-year segment, and then there were 38 in the next. But then, of course, we all know that if anything, we're seeing increasingly dramatic examples of transformative medicines in recent years. And that phenomenon is illustrated in the table on the right. And so in this illustration, we're using financial value as sort of a rough proxy for transformative patient impact. I mean it's an imperfect correlation, but not completely unreasonable. But if you simply been the world's most valuable medicines according to annual revenues, you can readily appreciate that there are 48 or 50 or so medicines that stand apart even in the overall upper tier. And we can all name multiple examples of these types of transformative medicines, and they're evident in all five of the therapeutic areas that Teresa introduced earlier. So the bottom line is, we must be able to recognize R&D programs with that kind of potential, whether they're in our pipeline or whether there's somewhere else. And then conversely, we have to be honest, if an R&D program doesn't have that kind of potential. We have to be willing to call it as quickly as possible and divert resources elsewhere as quickly as possible. So about a year ago, many of our senior R&D leaders work together to consider how do we do that? How do we recognize transformative programs? And so one of the exercises was to study some of the world's most valuable medicines. And the concept was maybe we can identify some unifying characteristics. And we did, we observed 5 criteria, which are shown here, and each of them have to be met. All five of them have to be met if a program or a medicine is going to be transformative. So we call this The Bar. And I will be the first to concede that none of these criteria are particularly surprising or controversial. And of course, many companies, including ours, have utilized frameworks to guide R&D efforts in the past and decision-making in the past. But the primary difference here, and Teresa articulated it very well, the primary difference is the question that we're asking. We're not simply asking if an asset can make it across the finish line to become a medicine. We're asking if it can become a transformative medicine. And in doing so, we are finding that systematic application of The Bar across our pipeline end-to-end has devoted different kinds of conversations and provocative questions as we consider how and where to invest. And so I'll just briefly go over these criteria. So the first one is that the candidate has to answer a clear and addressable unmet need. So in other words, the science has to have advanced to the point where there is a compelling opportunity, a compelling therapeutic opportunity that exists to bring new clinical benefit. The second is that we must engage with the medicine a foundational target. So a foundational target is a protein or some other factor for which there's a causal link between either the disease itself or the debilitating clinical manifestations of that disease. So third, the asset must possess worthy pharmacologic characteristics compared to the other contenders out there. And that obviously includes efficacy and safety parameters, but also combinability with other key medicines and developability and manufacturability and patient convenience. So a spectrum of considerations there. Fourth, each asset must be capable of meaningful therapeutic differentiation. And in other words, it has to anchor a treatment that is in some way superior to what's already out there. And finally, there has to exist a path to value. Value, of course, first and foremost, to the health of patients, but equally meaningful economic benefit to Roche. So we've applied The Bar end to end across our R&D pipeline, and we've embedded this approach into our governance and our portfolio review. And we've also incorporated these same characteristics when considering business development opportunities. And there have been three specific outcomes that we've already experienced as a result of The Bar application, and that's shown at the bottom of the slide. So the first is that by catalyzing the right conversations across the board, we see programs with high promise really starting to leap out. And that recognition allows nimble reallocation of resources to either accelerate or maximize their chances for success. And the second outcome is a logical extension to the first, which is that there are some programs with exceptional promise, and they merit additional interventions to fast track their path to launch. And so I'll come back to that in a moment. And of course, the third outcome is that The Bar catalyzes removal of programs that do not have a feasible path to a robust impact, and that allows resources to be pivoted elsewhere without delay. Okay. So let me say a little bit more about the assets that we're going to fast track, including some examples. So as I mentioned, the concept is not only can these assets clear The Bar, but they may also have undergone appreciable clinical derisking and they have outsized potential to bring value to patients in Roche. So we will deploy additional resources across our divisions to bring these assets forward more quickly. And there are three programs for which we've already initiated fast-tracking efforts. And these are our anti-TL1A antibody for ulcerative colitis in Crohn's disease. Trontinemab, our Brainshuttle antibody for beta amyloid plaque removal and CT-388, which is our injectable integrin for obesity and other indications. So you're going to hear about each of these assets after lunch. But the specific fast track opportunities I mean, they differ depending on the asset, but they can include levers to accelerate pivotal trial enrollment or alternatively more rapid expansion into additional studies or indications based on data that's emerging. And of course, we fully expect that other programs will soon progress to the point where fast tracking options make sense. Okay. So over the past year, application of The Bar has had a material impact on the composition of our end-to-end R&D pipeline. And so this graph summarizes pipeline additions and removals that have occurred since around the time we last convened with you here in London. So on the one hand, we have 17 NME additions of which were acquired through business development and 9 others were added through internal progression. And then there are 26 NMEs that were removed from the pipeline. 9 of those removals were specifically linked to application of The Bar. Most of the others are part of kind of natural internal attrition. But of course, those are indirectly related to bar criteria. And then, of course, there was a product launch, which is the ultimate outcome. So leveraging The Bar, the goal is to architect a pipeline that consists solely of programs with transformative potential. And we certainly still have work to do to get all the way there, but hopefully, you see that we've made progress over the past year. So the next R&D excellence solution is really about reconfiguring our portfolio management and governance. And really, there are two critical elements here. The first is about applying The Bar consistently and regularly across the board wherever we are in the pipeline. But the second is about achieving a sustained increase in clinical trial success rates over time, especially pivotal clinical trials. So we've made several changes to how our molecule teams and portfolio governance works. First of all, for each molecule, we have a single team that operates across the chemical development continuum. And this allows kind of a cohesive longitudinal flow, it complements our decentralized structure and it reduces white space particularly as transitions occur from early to late, for example. Now we've also strengthened oversight and technical review during the pivotal enabling and pivotal design stages. And here, it's not just about maximizing The Bar, but it's also maximizing the likelihood of success of our clinical programs that do clear The Bar. And in addition, our R&D group of the Corporate Executive Committee, is reviewing regularly sort of the overall end-to-end pipeline profile to ensure the right balance between risk and value potential. And again, the key concept behind these changes is really to recognize and to resource our pipeline assets that meet The Bar and to maximize the probability of success, in particular, for the pivotal clinical trials. And I'm going to come back to our progress on pivotal trial success rates a bit later. All right. So the next R&D excellence solution really emphasizes the need to recognize opportunities for transformative potential wherever they may be found externally as well as internally. And at a high level, our progress in this area seems pretty clear. You are by now well aware of the business development deals that we did last year, bringing in our Phase III-ready anti-TL1A antibody. Of course, the Carmot assets for obesity metabolism, the partnership with Alnylam involving the RNAi therapeutic zilebesiran for uncontrolled retention. You're going to hear more about all of those this afternoon. And in 2024, we've continued to evaluate external opportunities using The Bar framework, and they have resulted in additional deals. And one of the additional deals, which we've mentioned is the Regor Therapeutics' CDK4/2 inhibitor. And if you think about this through the lens of The Bar, which is again shown on the slide in small font for you. There is clearly still considerable unmet need in ER-positive breast cancer despite advances from, for example, the CDK inhibitor class. And we know CDK4 is a foundational target there. And yet, the development of resistance to CDK4/6 regimens is a major element of unmet need. And CDK2 overexpression is thought to be one such resistance mechanism. So this is a molecule CDK4/2 inhibition that might have worthy pharmacologic characteristics in this setting based on the initial clinical data. Charlie will walk through the data itself and additional rationale. But overall, we are seeing reasonable progress in terms of our external innovation approach, and this is a key component All right. So I've described three solutions that should enable us to deliver many more transformative medicines. And now I'm going to take a slightly deeper dive into the R&D productivity segment. And one of the solutions here is about setting clear R&D objectives that can elevate productivity. And by way of context, when you look at R&D productivity across the industry, you can see that Roche is industry-leading in annual R&D spend. And the productivity that results is certainly respectable and at the same time, we see an opportunity to optimize that investment in order to boost annual peak sales even further in the coming years. So R&D productivity can be represented notionally as an equation in which the numerator has three components: volume, value success rate. And these together describe R&D effectiveness. And then the denominator has two components, cost and cycle time, which together describe R&D efficiency. And what you see on this slide is that we've identified stringent ambitions for each of these metrics that we strive to achieve by 2030 in order to reach sort of that top-tier productivity. And examples range is -- they range from increases in Phase 0 starts, heightened peak sales potential of pipeline assets, market increase in Phase III success rates and in the denominator driving costs, down substantially and also making major gains in cycle time. And one thing that is important to -- I mean we fully recognize that the productivity components that we're showing here, they're not independent variables. For example, reductions in cycle time also they sometimes come at increased cost. And boosting Phase III success rates may require longer cycle times, for example, to boost a robust Phase II generation. But the point here is to have ambitions that inspire our teams and the broader organization really to think creatively about how do we elevate our R&D performance. So with this framing in mind, let's take a look at some productivity gains that we've already achieved over the past year. And I described the assets that we added to our pipeline through either business development or internal progression, and so those have certainly preserved a robust volume of pipeline NMEs. And then the pipeline additions, together with the application of The Bar have already increased the average peak sales projections of our pipeline assets by over CHF 0.2 billion, as you can see here. Then over the past year or 1.5 years, we've had multiple pivotal clinical trial starts, but our estimates for their probability of success or PTS, are tracking about 10% higher than historical averages for team-assessed PTS. And this is meaningful because aggregate team-assessed PTS, for us, anyway, has proved quite useful as a forecasting tool for pipeline performance. So we feel like our implementation of changes of governance and really our overall emphasis on heightened Phase II success rates, we think we're setting the stage for that to really play out over time. Now on the efficiency side, this past year, we have freed up approximately CHF 200 million that can be directed towards higher return on investment activities. And importantly, while doing so, we've also kept overall R&D spend flat thus far in 2024 and Thomas alluded to that point earlier today. And finally, we've seen initial progress on cycle time acceleration. Now several of the R&D efficiency improvements we've captured come from a range of ongoing initiatives that are specifically designed to evolve our R&D engine. And some of these initiatives that were alluded to earlier, they're really focused on simplifying and harmonizing our system. And the decentralized approach to innovation that Thomas outlined earlier today, certainly brings many advantages. But in some cases, redundancies have accrued over the years that are probably unnecessary. And so R&D excellence provides an opportunity to streamline a whole range of systems from electronic lab notebooks to risk-based quality management approaches that may differ across our solutions. And so we've shown some initial examples of how we've done that streamlining. And of course, as was mentioned briefly, a generative AI, of course, presents opportunities to accelerate various types of document generation. And so we have an example shown here in which an LLM platform spent a clinical study report generation by several weeks, and this is the kind of approach that we and many others are applying to ongoing work, certainly not only across our regulatory organization, but also beyond. Now other initiatives that we have ongoing are streamlining various R&D processes. And so one example here is a major strategic consolidation of our partnerships with contract research organizations, or CROs. And so we've reduced the number of CROs we work with in our clinical operations groups across early and late development by fourfold. And among other things, this simplification can often eliminate the need for recontracting as programs mature and that in turn reduces white space. And so we've already, in fact, we see initial evidence of cycle time reduction after just 1 year. And furthermore, this CRO consolidation should reduce costs again, by as much as CHF 200 million annually in the coming years. And actually, that's over and above the CHF 200 million that I alluded to earlier for redirected investments. So these are just a few examples of R&D excellence initiatives that make our end-to-end R&D engine more efficient over time. And I'll conclude just by briefly touching on the last R&D excellence solution, which is about creating corporate incentives that are fully aligned with these R&D productivity objectives. And Thomas referenced this earlier. The bottom line here is that achievement of several R&D productivity metrics has now been incorporated into our annual sort of performance calculators, performance bonus calculators, et cetera. And these include specific goals around application of The Bar, pipeline value projections, study cycle time and various metrics to increase speed, et cetera. So we will continue to work those kinds of opportunities and those kinds of metrics into our incentives over time. So really, the entire company is being incentivized to enable and support initiatives that boost R&D productivity. So in summary, I have described our progress towards 6 R&D excellence solutions that should help us together deliver many more transformative medicines and while doing so, achieve top-tier productivity during the coming decade. And 1 year in, we can say that four of these solutions have now been implemented and really are being fully embedded into the new business as usual. And then there are two others where implementation is still ongoing, but both of these accessing external innovation and also evolving our R&D engine, these are substantial and their ongoing sort of enterprise priorities that we will remain attentive to. But overall, we're optimistic about the potential of these solutions to elevate our R&D performance for years to come. So after lunch, as Bruno already told you, we're going to shift from sort of end-to-end pipeline architecture to the pipeline itself. And these presentations will be given by the outstanding therapeutic area heads from our global product development organization, and they've already -- I won't go through each of them. They've already been introduced. We also, as mentioned, we have a new Head of Neurology, Hideki Garren, who's not here today. He just is starting orientation today, but but Azad Bonni, who runs neuroscience and our pRED research and early development organization will be presenting in that presentation. So with that, I'll give it back to Bruno and we'll do Q&A.

May I ask the speakers of the morning sessions back on stage. We'll have 30 minutes of Q&A, and you can ask questions here in the room, and we also -- you have the opportunity to send your questions via e-mail. May I ask please to just for the questions for the morning session, just focus maybe on the strategy part and the topics we covered. If you have then more in-depth pipeline questions, I think that's what we can keep for the afternoon session, when we have the experts on the stage.

It's Matthew Weston from UBS. Two questions, if I can, please. One on commercialization, which I know is some way away for elements of the pipeline and also one about portfolio prioritization. So on commercialization, Roche has been very much a specialty care business, but you're now moving forward in some extremely competitive categories, particularly in cardiometabolic and in inflammation. Teresa, I'd love to understand how you're looking to change the commercial organization and particularly how you're going to tackle some of the very significant managed care barriers that some of the existing entrenched competitors will have when you come to market with your assets. And then secondly, Levi, on your applying The Bar to your portfolio, I assume all of your Phase III assets, you just decided that there was no way you could terminate development of those pipeline potential going forward because they were too established. I'd love to know, did you apply The Bar to your current Phase III assets? And if so, did any of them not pass?

So I can start with commercialization. So I think, first and foremost, when you think about when these assets will be reaching market, it is quite likely that the needs of physicians and health care systems, which were already changing as part of COVID in terms of how many people you want in your office, how many folks you want sort of tracing through your clinic. These things are already shifting. I think anyone who looks at the ability, part of the reason that many primary care companies have so many reps is because it's just shots on goal trying to get through the door. I mean that kind of old school share of voice game, I think we increasingly see just doesn't work as well anymore. And so we have already started to think about within our existing portfolio, how to change that commercialization model. It's worked for us exceptionally well. We are prepared to go big if we need to, but we also think that there will just be a different way to commercialize these drugs using technology, using a more focused commercialization footprint than the way it happens today. So that's part one. From the managed care perspective, we're certainly not naive to the fact that there are managed care hurdles that exist in the world. And we have a lot of experience working with managed care organizations in the U.S. and around the world. And what makes me confident that we can do it is, quite frankly, we've done it in the past. And we have been able to take those -- take differentiated assets and to make sure that they get the coverage that is required so that patients have access.

And let me just add to this point that on the diagnostics side, we are the global leader in the space. So we have a lot of access to KOLs, but we also have access to primary care physicians. And having been the GM twice in two different markets, one was Sweden, the other one was Germany. Having worked with my counterparts at that time on the pharma side, they were telling me that, well, without if you have a sales rep in pharma, they don't really get access to doctors in the primary care segment. We don't have the problem on the diagnostic side. There is 0 problems to get access for us on the diagnostics side. So I think we can also leverage the fact that we have diagnostics to get good access to these physicians.

Yes. And to answer your portfolio prioritization question. So yes, we have applied The Bar to our end-to-end pipeline, including our -- all of our clinical assets. And we have, in fact, made decisions in some cases, to stop studies that we did not feel met The Bar. One example was in the tiragolumab space. There were two -- at least a couple of studies, including a Phase III trial that we terminated because we didn't feel like the aggregate evidence, emerging evidence justified that investment. So certainly, there are cases where ethically, it doesn't make sense to stop Phase III studies midstream, but we are intentional about redirecting resources no matter where those resources are, if that is what The Bar has to do.

And I would just add that we had also certain programs where you could still adapt the program. So people actually went and they looked at how we could adapt it to increase the PTS in some of these studies. So it's a mix, I would say. Some studies were very advanced where you cannot change anything. It doesn't make any sense to stop it because the cost is all occurred. Some we stopped because we said it doesn't make any sense and some you could adapt.

I think what I heard a lot about one quick follow-up about the commercialization strategy is differentiation when it comes to managed care barriers. So is that something we should hold you to account and particularly in obesity as we see you develop your portfolio differentiation for you to feel that you can address those managed care barriers when you come to market?

I think we wouldn't have moved forward with these assets. If we didn't feel that they were differentiated. I think they're differentiated from a molecular standpoint. I think they're differentiated from what they could potentially be in combination with other assets across our portfolio. So differentiation is important. You should hold us accountable for making sure that as we see those differentiations continue to reveal themselves that we're maximizing them with our clinical development programs. But I would also say that $100 billion to $150 billion market, there's a lot of room for multiple players.

Sachin Jain from Bank of America. Two questions on The Bar on that actually just follow up on your last comment. So two examples Levi used with bar with obesity. And I think investors is are unclear on the differentiation clinically of either asset. So how much of your Bar application pertains to what you just alluded to, which is size of end market? And how are you flexing The Bar as you chase these big disease areas that you outlined at the beginning, Thomas? The second question is just to get a sense of where your PTS sits for some of your larger assets that you flagged, 7 assets for greater than CHF 3 billion peak sales. You said your team has been fairly accurate in predicting that. So I wonder if you could just loosely share those 7 of which are above Phase III industry average in which it below. So very simplistically, a high probability greater than CHF 3 billion assets that you see?

Yes. So maybe -- so it's two facets of the question. One is, to what extent the size of market factor in -- and the second is kind of a detailed one about PTS. I might defer the detailed question until the afternoon because maybe the presentation will partly give a sense. But on the size of the market, certainly, that's a -- the magnitude of unmet need is a proxy. It can be a proxy for size of market always, I mean, rare disease that have exceptional opportunity for benefit can clear The Bar on that criteria as well. What we would say, in general, is that -- and we're seeing this not just with the IBD segment, but also with obesity. When there are medicines or candidate medicines that are emerging, so let's just take the TL1A, that situation where compared to standard of care, the Phase II data implies that there could, in fact, be a differentiation. That could be a therapeutic differentiation of TL1A. If those results hold up, that could now change standard of care. So that's a differentiation. Now we're not the only TL1A out there, but certainly, we feel like we are very much in a position to be if not first tied for first in terms of launch. So I think that actually is wide open. And so clearly, The Bar is clear for that one. For other areas like obesity, the sense is that this is -- we are in very exciting space, not just a large opportunity, but there are multiple parallel ways in which evolution can occur to allow for differentiation. And so Manu will talk more about that. But of course, the weight loss that's seen today is great, but it's not perfect. There are elements that could be optimized. There are combinatorial opportunities that can be optimized, and we think that we have pipeline assets that with those combinations, there could be differentiation. So we think in a space like obesity, there are paths to differentiation that are highly available to us and others. And we think that with the aggregate of our pipeline and the approaches that we're taking, we can capture some of that.

Maybe just to add to your question, and I'll try to answer the question partly because obviously, we can't tell you every number exactly. That would probably reveal a little bit too much. But what I can say is that exactly what you mentioned, one of the comforting facts that we found was that our scientists are actually very good at predicting whether or not a trial is going to be successful. Whenever scientists say that the likelihood, the PTS is above 50%, I think we had a success rate of close to 90%, right? It's -- when it's below 50%, it becomes more risky. And that's why we have this portfolio committee that we don't only look any more asset by asset. We do that, too, but we look at the overall health of the portfolio that we have a good mix. And it's okay to take a high-risk project forward, projects where we have low PTS, for example, is but it's a high, high reward because there's not been anything for, I don't know how many decades. . So it's okay to have some of those in, but only if you have a high reward on the other hand, what you don't want to have is a high risk and low reward. That's the one part where you definitely don't want to be. So we balance out this risk. And another good example is Gazyva for lupus nephritis before the study read out, the PTS was, I think, 60-something percent. So again, it proved that our people were right because they said, well, it's 60-something percent and the study was positive. I can say TL1A, GLP-1 have very high PTS, right? So these are areas that have very high PTS. So if you have very good and very well derisk Phase II that increases your PTS. And in for example, you don't only have our Phase II. You have the Phase II of another company. And there are 2 companies looking at the same mode of action. So two players right now with long leads versus others. So those are the things that we look at and that people use to assess the PTS, I would say.

Yes. And of course, each study, it's either -- it's binary, either works or it doesn't. But in aggregate, the PTS of the aggregate pipeline, that's as Thomas is saying, that has value. So if the aggregate PTS is 40%, then you -- they're actually -- our teams are very good. In aggregate, we're going to have a lot of failures. But if in aggregate, it's above 50%, we're going to have a lot of successes. So our decision making, and this is coming back to over the past a couple of years in particular, has really been focused on, let's design a Phase II trial that's going to work. And then the team comes back with their PTS and we've been really intentional about forcing the aggregate up. Even though there may be individual instances where we're okay with the high-risk high-reward bet.

But I think all the deals we made have very strong proof of mechanism of action and so on. So those things help, right? So the balance in the portfolio is critical, and I think we moved it in a really good direction.

Richard Vosser from JPMorgan. Just going to retention of talent. You mentioned changes. Could you give us more color on those changes, particularly how that has changed in the last year retention in Genentech or pRED and what you're doing going forward to address that? And then secondly, just back to this transformational medicine and and the size of product on The Bar. How do you guard against the risk that you're looking in exactly the same areas as everybody else? And so that increases the risk of commercial delivery and risk on the project at the back end, not the front end.

Two good questions. The first one on voluntary turnover. So if you look at the voluntary turnover last year, so 1 year ago, we were at 4.9% in voluntary turnover. This year, we're at 4.2%. If you look at industry, we are by far the best company in the industry when it comes to voluntary turnover. Other companies have much higher turnover than we have. So that's the first piece. The second piece is what we decided is that we are going to adapt and reflect our strategy also in our structure. So that's why you see that now in organization, with 5 therapeutic areas. And I think that's important that you have key specialists in each of these areas that are single point of accountability of driving those programs. We're reflecting that across the different parts of our organization. That means that when we had consolidated that, of course, we're breaking up certain pieces. But it also means that sometimes we have to bring in people from the outside to raise the level of what is also a bar on what we expect from people, right? And we do that across the organization to make sure we hire the best people in the industry. And that's the process that we've gone through, and we're still going through because we want to have the best people in the industry because at the end, they are going to make the difference and make sure that these medicines are going to develop and come to the market. Oftentimes, you have some key players that really make the difference. And then the other question to you, but maybe.

I'll start and then maybe Teresa wants to speak specifically on the commercial side. So 1 high-level comment is that it can't be that part of our criteria is we're not going to go into an area because it's competitive because you will not find an interesting area of medicine that is not incredibly competitive. So it has to be that we are going in, and we say, we recognize the scientific opportunity. We recognize that there's unmet need. And then we believe that because of either what we have internally or because of our opportunities in business development are both that we can make a contribution, we can play. We can make -- contribute to the patient impact that can be had. And so -- and that's really what The Bar is about. So there's nothing in The Bar about competition because you would not do anything if it was there. So that's our general approach. There have been many things where we sort of said we've deferred because we sort of said, well, actually, yes, one could go bring this thing in, but maybe there's not something such about Roche that will allow us to bring differentiated impact. But certainly, for the transactions that we have made, and I think Teresa summed up very nicely, we feel confident in our ability to not only play, but ultimately contribute meaningfully over time.

Just to say, and fundamental to The Bar is this idea that you are bringing a transformational medicine. If you're bringing a transformational medicine, you're by default, bringing one that's differentiated. And so that differentiation allows you to compete even in the most competitive market. I mean, when you think about some of the markets that we've entered that have been absolutely dominated by particular companies or particular products. If you bring something that has better efficacy, that is safer or more tolerable, that provides a different kind of convenience option for patients or a different kind of delivery option that helps, for example, health care save money. These are all things that allow us to compete smartly. And I think this is where a lot of our experience over the last couple of years, we really intend to bring to bear with the pipeline products that are coming in. What are those aspects of differentiation? What really matters to patients, what matters to providers, what matters to health care systems and how do you craft a commercial strategy that actually allows you to do it with maximum impact and minimal investment.

Yes, add one more thing here. I mean some of the programs that were stopped was, well, actually, we're behind, and there's no meaningful differentiation. So then you just stop and you shift effort. Now when you go to the research area, right? So in research, when you look at new foundational targets, their goal is by the time it goes into more clinical stage, they have to have proven that this is the foundational target, right? I mean if you look for foundational target, that's one of the ideas on how can they prove that this medicine is differentiated, address the foundational target. And the same we do when we look at external programs. in early stage. Are there programs out there where we are not working on no one else is working on, but this could prove to be a financial target. So you kind of apply it over the time period. And if it doesn't, do what it's supposed to do, you definitely don't go into Phase III.

Okay. The next question, we take over here, Peter.

Peter Verdult, Citi. Two questions. Just given what we've heard today about R&D strategy and The Bar. I'm going to ask to raise the same question I asked Manu at How strategically important is it for Roche, given that you want to go big in obesity to get an amylin targeting agent into your portfolio as quickly as possible? So that's question number one, do you have anything internal. And then secondly, and I'm sorry to come to this topic, so I'm sure your Board answering the question about capacity. But just to make sure we're all on the same page. Roche -- sorry, Novo or Lilly when you talk to them, they're actually putting numbers. Their scaling ambitions are 50 million to 100 million patients. I hear what you said about being able to scale within your budget, the technological advances you're making, but is that the sort of scale of your -- Roche's ambition when you get to the end of the decade to be able to be similar -- to be able to serve a similar population.

Maybe we defer the Alnylam question to the afternoon, not to pump, but Manu will undoubtedly have plenty to say about that, but maybe the capacity one.

Once I see the wonderful Phase III data that I am positive that Manu is going to deliver to me. I will be able to give you a much better answer as to what my aspiration is with the number of patients that I want to treat. But I will say that our aspiration is to reach as many patients as possible with our medicines. And I think we consistently look at what do we believe the peak potential is for any medicine that we have and we make sure that we have capacity somewhere in the network to accommodate it.

But clearly, I mean in the transition time, there is a transition time as well. We have had conversations with CMOs. So we know that there is enough capacity that's coming, and we are reserving that capacity.

Okay. Let's go over there.

Peter Welford for Jefferies. Two questions, sticking to The Bar. Firstly, I didn't necessarily look and apologies if I missed this. But bar necessarily seem to include within it your own internal capabilities, both in terms of manufacturing, commercial angle. So I mean, I guess, is that built into just to understand that the -- and equally, the portfolio effect I mean does it consider, and I guess this sort of relates to Peter's question in the sense it could make sense to have a lot of some assets that may make a lot of sense with other assets. So how do you sort of account for that? And I guess related to that for the obesity, are you confident you can succeed in obesity with only focusing on obesity within cardiovascular medicine? Or do you think you actually need some other Part D diseases within that to actually be able to then go to payers and succeed? And then just very quickly, have you now applied this to your pipeline? So are changes we see from now, obviously, it's an ongoing basis, but it changes from now more going to be based on success failure, et cetera, rather than applying, if you like, your big thing read through this.

Yes. So a number of facets there. So the first question was really about where does manufacturability and developability fit in? And actually, under the criteria of worthy pharmacologic characteristics. So there's the characteristics of the molecule, but then there's also characteristics of can the molecule actually be generated, what are the COGS, but also from a standpoint, do we trust ourselves that we have the ability and capacity to deliver it. So that's all part of worthy characteristics. It has to be not just an active molecule, but it's going to be something that we can deliver to the world feasibly. So that is that question. I'll go back to the third question because it's straightforward, which is, yes, we have applied The Bar into end, certainly for all of our clinical assets, and now it's working its way through research. There are some tweaks about how to apply it in research because, of course, there, it's really about is there a feasible path. I mean not everything will have already landed that we know for sure is foundational target and people, as Thomas has mentioned earlier. But we have definitely applied it across our clinical portfolio, and we will continue multiple times a year to update that application. So -- but now to your question, so certainly, there's much now that's in play, and we can say, yes, it will work or it won't. But there's also an element where sometimes when we apply The Bar, the relevant question is, the term we often is the crux. What is the most important -- what's the most important next data, our next analysis that will tell us yes or no because not every criteria is already fully applied at any given point in development. There will be some criteria. Well, actually, we don't really know until we get the true concept data in Phase II or until we get this in data in Phase I. But we always know what is the gating experiment that will tell us yes or no for a criteria. And that's how we are determining in real time, whether or not an asset should stay or go or be deprioritized.

Just the topic of path to value. The path to value is always a business case. The business case always includes commercialization, includes manufacturing. You calculate NPV just as you calculate an NPV also when you look at external acquisitions, right? So you always do a fall in cost calculation, and that includes -- do you have to address new markets, et cetera. And obviously, if you have like CDK4/6 and you have things like trontinemab and list in your portfolio, then you have other kind of synergy effects as well. Then to your question around obesity, I mean the other reason why, not only because of the amount of people that are affected by obesity, we believe it was strategically important step for us to acquire the GLP-1 It's also strategic because they play a role in multiple disease areas across actually all the five that we were just talking about, right? It's playing a role in immunology. It's playing an all in ophthalmology, potentially in neuroscience. So we need a backbone that we can combine other medicines with. There is a lot of excitement and potentially combining it with an right? So there is this -- we don't want to be locked out from entering all these other diseases in the future because we don't have a backbone. I think that would have been a huge strategic mistake if you ask me. Just to put the point there that as well.

Couple of questions. First with The Bar still. How substantial is the change? Like are the five criteria completely new? How much were they already present? Is it the end-to-end nature that's really the difference here. So what's the amount of change in The Bar? And then secondly, on -- I saw on the slide on AI, specifically in commercial, a mention of some revenue gains this year, CHF 500 million to CHF 700 million, I believe. Could you put some context around that? Is it higher than last year? Where are they coming from? Assets, regions? And what are you assuming going forward given your revenue ambitions you've highlighted today?

So I'll start with The Bar. Thanks for the question. So as I mentioned, it's not as though these criteria are regulatory. They come down from the sky. They're actually -- you can look at them and they intuitively makes sense. But I would say that maybe the biggest difference is to be intentional for every program we sit down and so let's go through criteria by criteria and have the honest conversation. Is there a there, there, or not? And because sometimes, there may be reasons why a program has stuck around, and it may or may not be because there is an outstanding business case or that there's an outstanding differentiation case. But this is really now let's call the question. And if there's a plausible rationale for why it could land, great. But let's be clear about what that is and what we're going to know about it. And if there's not, let's call it. And I think you can see that we called a number of NMEs in the past 9 months. So I would say, although the concept is not a radical from to, the application has had a meaningful impact.

I mean having talked to all R&D organizations across the board, I mean, everyone has something right? They didn't really apply the same kind of methodology, but some of them had something similar like to the 5 Rs that AstraZeneca introduced a number of years ago, et cetera. So there was no, I would say, one approach to everything in the entire company. And there were others that were following the science, and that was good enough. So -- but the issue is that if you are not effective in decision-making, what actually happens is that you become slower, right? And what actually happens is that you get too much risk in your portfolio. What happens is that you cannot reallocate the money to or promising things. And that's what we are much more intentional about and having the same kind of assessment throughout the organization. And what we have reintroduced, which we took out probably 4 or 5 years ago, is so-called development boards. And these development boards are some of our best people that we have in the entire company, and they give advice and challenge project teams on their project work. And with that, what you actually do is you also increase the PTS because you have people who have a lot of experience in developing these medicines, they can give advice on how they should design the study, et cetera, et cetera. But they will also challenge the team, okay, and say, this program doesn't make any sense because scientists, and that's good because they're really believers in their own program, they will never stop their own program, right? So I think this more systematic approach is really effective, I would say, right now.

One thing to add to that, because you could listen to what Thomas said, I said, well, why were those taken away -- and there are -- the other way to be slow is to be very heavy handed in your bureaucracy and your governance. And so by bringing these things back, we've been -- I mean, there's a whole series of conversations about how do we make it nimble? How do we make it so that it's not a burden to the team to have to go through these things, but it's enabling. So that's been a big part of the architecture in recent months.

And to answer your other question, that primarily is the result of the full year -- first full year implementation in the U.S. of what we call next best action. So this is a mechanism by which when field representatives put information in our CRM system, they are presented with what a most reasonable next best action would be with a customer. So that additional revenue is the first full year realization of that program being in place primarily in the U.S., and it is being rolled out globally.

Emily Field from Barclays. A question -- another question on PTS. And we talked at Pharma Day last year about at least the Phase III success rate being somewhat depressed due to perhaps too quick acceleration into Phase III and not running best enough Phase II. So I was curious how much of the increase in PTS is due to some of those changes or more so if it's a result of the constitution of the overall portfolio in terms of molecules? And then a question on the recent closure of the Genentech Cancer Immunology Research Unit. I believe this was to another unit of GRE, but just wondering, from a higher level, if you change your thoughts towards the broader I-O opportunity in oncology? And if so, how much of this was driven by tiragolumab?

I can answer the second question. So I'll answer the second question. So in Genentech, we had basically two oncology groups. One was the cancer immunotherapy group and the other one was the molecular oncology group. In fact, we know more today that if you look at the tumor microenvironment and all these different things, actually, those two are very much overlapping. And so we felt it's better to actually have it in one group instead of having two separate groups addressing that. So I mean, TIGITs, definitely, based on TIGITs data, people had a high hope on TIGIT. But there are other things programs that we have in-house, like the personalized cancer vaccine and other areas where we do believe that cancer immunology will play a significant role. But again, I don't think it makes a lot of sense to have two separate groups working on these topics. You can use the synergies much better in this way.

Yes. And just specifically on the PTS question. The short answer is there's no single -- there are a range of things. But for example, in some cases, the design was to really focus on the patient population where we know from our clinical data that benefit is likely to be maximal as opposed to speculating about other segments that might make the market larger, but we actually don't have the same data. That would be one example. Another example was, in fact, we have, in some instances, weighted several months for the complete data set to inform so even though you might want to go faster because -- but if you don't have the data to really guide the design, then it's risky to go forward. So that was another example. So there are examples like this where we think about the elements that predict success and ensure that the teams have all of those pieces and not to rush without the essential pieces.

And importantly, speed matters. Even though that the internal development process is long, process, I mean you have to be very, very fast in the beginning so that you don't get in a situation where you have to take your cuts, right? So you have to go really fast. And that's what we're really focusing on, how can we accelerate the whole process from the very beginning because it's a competitive world out there.

Okay. I think with that, we are already at the end of the first Q&A session. Unfortunately, but you will have the opportunity to ask the questions during lunch or later on. We will have 15 minutes lunch break and then we will meet back here at 12:30. Please be in time. So we still have a lot to cover today. Yes, bon appetit. [Break]

I'm Charlie Fuchs and I'm the Global Head of Hematology/Oncology product development and I have the privilege of kicking off the second portion of our day that is the journey through our portfolio with my privilege to share with you some key highlights of our hematology/oncology portfolio. Part of the reason I chose to come here about 3.5 years ago was the very rich legacy that Roche and Genentech has in transforming the therapeutic landscape and improving the lives of patients with cancer and blood disorders. Today, our strategic pillars include advancing best-in-class precision medicines such as inavolisib and divarasib leveraging novel modalities and technologies, including, as I'll describe further, our entree into the next-generation off-the-shelf allogeneic CAR-T therapy as well as next-generation antibody drug conjugates, leveraging our broad portfolio for rational and high-impact combinatorial therapy, including the addition of Columvi to now the best-in-class Pola-R-CHP regimen in the first-line setting of diffuse large B-cell lymphoma as well as our combinations of our growing portfolio in hormone receptor positive breast cancer. And no less importantly, accelerating all of these assets and combinations into the curative setting of cancer, including our successful ALINA study, which documented the benefit of Alecensa in the curative setting of ALK-positive non-small cell lung cancer and our ongoing work, adding our best-in-class SERD giredestrant in the curative adjuvant setting of HR-positive breast cancer. We have a privilege in service of this -- of these strategic pillars to advance one of the richest and broadest portfolios in oncology which uniquely leverage a series of technologies that Teresa outlined earlier today, such as small molecules, a gamut of novel protein engineering, neoantigen vaccines, cyclic peptides among others. And we're equally privileged to have a broad array of novel molecules in hematology, targeting a series of malignant hematology conditions, hemophilia A as other important unmet needs in -- the slides changed. There used to be -- sorry, in my deck, the next slide was our hematology portfolio, and I wasn't looking down. So turning actually to our breast cancer portfolio. namely, Roche, as you know, really wrote the book on targeted therapies for breast cancer, improving the lives of patients with HER2-positive breast cancer. But we remain committed in this space now in HR-positive hormone receptor positive breast cancer, which represents 70% of the market and doing so through a series of interventions our best-in-class SERD giredestrant, which we believe can be a new backbone for endocrine therapy. Our play now with the acquisition of the CDK portfolio, a next-generation CDK from Regor Therapeutics as well as novel targeted therapies, most specifically our best-in-class PI3K inhibitor, inavolisib. Endocrine therapy remains the backbone for HR-positive breast cancer, but there continues to be a need for more effective and better tolerated therapies. For instance, in the adjuvant setting, 50% of patients stop their endocrine therapy or are not consistently using it. Moreover, among those patients, 30% will go on to develop progressive metastatic disease. giredestrant shows the highest potency of SERDs currently in development as well as fulvestrant. Moreover, it's combinable at full doses with all available CDK4/6 inhibitors, and it avoids any of the serious toxicities that have been described with the other drugs, including no evidence for ocular toxicity and no evidence of any dose-limiting toxicities. In our window of opportunity giredestrant study, we compared in that neoadjuvant setting, giredestrant2 an aromatase inhibitor, showing statistically significant greater suppression of Ki-67 both when both drugs are compared as monotherapies and as well when the 2 drugs are compared in combination with CDK4/6 inhibitors. As you also know, our Phase II acelERA study in the second and third line settings of metastatic HR-positive breast cancer. Giredestrian did not achieve a statistically significant improvement in progression-free survival compared to the alternative AI fulvestrant. However, we've now come to realize in those patients with multiply treated endocrine therapies. The majority of those patients have tumors that are no longer dependent on the estrogen receptor and, in fact, driven by other oncologic pathways, pathways that are insensitive to any perturbations of the estrogen receptor pathway. But there was one unique subset in the acelERA study. Those patients with ESR1 mutations, those tumors that we believe are dependent on the S receptor, and in ESR1 mutants we saw a hazard ratio of 0.6, that is a 40% improvement in progression-free survival among those patients randomized to giredestrant to understand that phenomenon, we conducted this transcriptome analysis of various subgroups of breast cancer. And as you can see, in the multiply treated ESR1 wild type patients in the green, those tumors are no longer dependent on than the estrogen receptor pathway. And therefore, predictably insensitive to any estrogen directed therapy. However, for the ESR1 mutants, they show a transcriptome depending on the S receptor. And in fact, in that subset, giredestrant proved to be a superior therapy. And further, when you look at patients with either early breast cancer in the adjuvant setting or first-line metastatic, we see a similar pattern of estrogen dependence consistent with ESR mutants. And that pattern gives us greater confidence in our ongoing studies of giredestrant in both the adjuvant and first-line indications. Our ultimate plan is to make giredestrant the next standard of care backbone across all indications for HR-positive breast cancer. Our first-line persevERA study in combination with a CDK4/6 inhibitor, we'll be reading out next year as well as our giredestrant plus everolimus, evERA study will also read out in the second line next year. We've initiated as well a first-line endocrine-resistant trial, the PIONEER study, which actually as well allows for a choice of CDK4/6 inhibitors. We are also the leading adjuvant study with lidERA, which is comparing giredestrant to an alternative aromatase inhibitor in the adjuvant setting. And finally, we are conducting a study of giredestrant in HR-positive HER2-positive breast cancer. And we believe this [ comparative ] studies could make giredestrant the standard of care across all estrogen-dependent breast cancer. Beyond giredestrant is our best-in-class PI3K inhibitor, inavolisib. As you know, we've known about PI3K mutations for decades, mutated in 40% of HR-positive breast cancer and 30% of HER2-positive breast cancer. However, despite our understanding of the pathway, we've been unable to really meaningfully attack it therapeutically because the available molecules were largely ineffective, poorly tolerated and patients couldn't stay on the therapies, including a high rate of discontinuation with the current commercially available PI3K inhibitor. In contrast, inavolisib is differentiated as a far more potent molecule for the alpha subunit and as well has a unique mechanism of action of degradation of a mutant alpha subunit, allowing greater selectivity, tolerability and efficacy. And the proof has been in the recent readout of the INAVO120 study, in which in the first-line setting, the addition of inovalisib to palbociclib and fulvestrant conferred a 57% improvement in progression-free survival with medians of 15 months versus 7 months as well, although overall survival remains immature, we see a hazard ratio of 0.64. Inavolisib was extremely well tolerated, discontinuations were in the mid-single-digit range. And on the basis of these data, the FDA granted breakthrough designation for inavolisib, and we await the PDUFA date for inavolisib in November with applications across global health authorities. As well based on these data, we're advancing a broad portfolio of opportunities for inavolisib beyond INAVO120, INAVO123 is looking at the first-line endocrine-sensitive indication. We also have a head-to-head comparison of inavolisib against the current commercially available PI3K inhibitor in CDK experienced patients. And finally, we're looking at the molecule in HER2 positive PI3K-mutated patients. Finally, as Teresa mentioned, we're looking at other tumors that are PI3K mutated, and we're looking at the utility of this in the adjuvant curative setting of PI3K-mutated breast cancer. Further rounding out and creating synergy in our HR positive portfolio has been our today announced acquisition of the CDK portfolio from Regor Therapeutics. As you know, CDK 4/6 inhibitors really have transformed the landscape of both metastatic and adjuvant therapies for HR-positive breast cancer. However, there continues to be an unmet need for more efficacious and better tolerated therapy, specifically inhibition of CDK 6 has been associated with the unwanted adverse events and toxicities associated with that class of molecules, whereas CDK2 appears to be an important mechanism of resistance. The lead molecule in this portfolio is RGT-419B, which, as you can see, is a highly potent CDK4 inhibitor, but also has therapeutic inhibition of CDK2, that resistance mechanism, which is not present in the 3 commercially available molecules, also rapidly behind this is RGT 587, which is a highly potent, highly selective CDK4 inhibitor, which is brain penetrant and Phase I ready. Regor has been conducting a Phase study of 419B, that is the CDK 42 inhibitor as a monotherapy in patients who had previously progressed on a CDK4/6 inhibitor. What they find is that 419B can be dosed continuously with acceptable tolerability. It has a favorable PK profile with sustained target coverage of both CDK 4 and CDK 2. And as a monotherapy is demonstrating durable responses in these patients who have progressed on the available CDK4/6 inhibitors. On this basis, we believe that this unique CDK 42 inhibitor has the potential to be a best-in-class next-generation CDK inhibitor for HR-positive breast cancer. We look forward to sharing the expanded data from the monotherapy study. We as well will be initiating studies combining the agent with aromatase inhibitors, giredestrant inavolisib as we accelerate this towards a potential registration process. We -- as you heard earlier today, this year, we announced the results of Skyscraper 6, that is our first-line study of teragolumab plus Tecentriq and chemotherapy in nonsquamous non-small cell -- non-small cell lung cancer which did not meet either its primary endpoints of progression-free overall survival. On that basis, we decided to stop the Skyscraper 15 and Skyscraper 5 programs, but we are continuing to see the results -- waiting the results of our completed studies Skyscraper 1, as you know, is in PD-L1 high non-small cell lung cancer, Skyscraper 3, Skyscraper 7, and finally, Skyscraper 14, the latter in first-line advanced hepatocellular carcinoma. Beyond tiragolumab in lung cancer is what we believe are best-in-class G12C KRAS G12C inhibitor, divarasib in preclinical studies, divarasib is 5 to 25x more potent and 10 to 15x more selective in vitro compared to the commercial available agents adagrasib and sotograssib. At the recent World Lung Conference we updated the Phase II monotherapy data in second-line non-small cell lung cancer. And at the targeted dose of 400 milligrams, as you can see, we had an overall response rate of 59% and a median progression-free survival in excess of 15 months. This compares favorably to the data for the commercially available molecules, which have response rates in the range of 30% to 40% and a median progression-free survival of only 5 to 6 months. On the basis of this, the FDA has granted breakthrough designation in the second-line setting for divarasib, and we are launching a head-to-head second-line study of divarasib compared to dealer's choice of adagrasib or sotorasib as well, we're accelerating first-line combinations of divarasib with the anticipation initiation of a first-line registration study next year. Turning now to our hematology pipeline which covers a broader wave of molecules for malignant conditions as well as several benign conditions, including most notably hemophilia A. Teresa talked about our broad portfolio for B-cell malignancies and describe the strong uptake of Polivy in the first-line setting of diffuse large B-cell lymphoma based on the progression-free survival benefit in the POLARIX study. We are looking forward to sharing the updated 5-year overall survival for POLARIX at an upcoming meeting. Beyond Polivy are our 2 CD20 CD3 bispecifics, Lunsumio and Columvi approved for the third-line relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma, respectively. As you can see on the right, we have an aggressive portfolio of moving both molecules into earlier lines of follicular diffuse large cell, mantle cell and other indications and in combinations with currently available agents for these B-cell malignancies. For instance, we recently reported out the results of the Phase III STAR GLOW study, in which patients who were randomized to the addition of Columvi to the GemOx regimen experienced an approximately 40% improvement in overall survival and a 60% improvement in progression-free survival compared to the R-GemOx control arm. Moreover, the Columvi GemOx regimen was well tolerated with cytokine release syndrome being limited to largely grade 1 toxicity. On this basis, the Star glow data have been submitted to global health authorities, including the FDA and EMA. At the same time, we recently updated the Phase Ib/II data for our chemotherapy-free combination of Lunsumio and Polivy which, as you can see, demonstrated an overall response rate of 59% and a complete response of 46% in the second-line relapsed/refractory diffuse large B-cell lymphoma setting. On that basis, we initiated and conducted the SUNMO study comparing Lunsumio Polivy to Rituxan-GemOx and the results of the SUN MUD study are anticipated next year. Finally, turning to the first-line curative setting. Certainly, the Pola-R-CHP regimen appears to be a best-in-class regimen in the first-line setting. But still we are committed to further enhancing the rates of cure in diffuse large B-cell lymphoma. At ASH last year, we provided updated data for the addition of Columvi to both the Polivy R-CHP regimen as well as the original standard R-CHP regimen. And for the combination of Columvi Pola-R-CHP, we see a response rate of 100% with a complete response rate of 92% and highly durable responses with very acceptable toxicity and relatively low rates of cytokine release syndrome. Of note, this combination of Columvi Pola-R-CHP, compares favorably to the less efficacious combination with our R-CHP. And that's important because it really confirms the benefit of Pola-R-CHP, not only on its own but in combination with the bispecific. On that basis, we launched the SKYGLO study which compares the standard now Pola-R-CHP, to Columvi Pola-R-CHP. And to be clear, this is the only study in which a bispecific is being added to that Columvi Pola-R-CHP regimen, which we think has the opportunity to give patients the best chance for cure for diffuse large B-cell lymphoma. Rounding out our portfolio for hematologic agencies has been our entree into CAR-T therapy, cellular therapy with Poseida Therapeutics. As you know, CAR-T has transformed the landscape of hematologic malignancies, but they're highly complex. They rely on patients to undergo Pheresis for the cells to be manufactured, resulting in delays the need for bridging therapy. And no less importantly, the fact that these therapies typically can only be delivered at high-profile tertiary care centers. As a result, among patients eligible for CAR-T, only about 20% will actually receive CAR-T therapy. We believe this partnership with Poseida allows us to truly scale CAR-T therapy to a much broader population, namely using donor-derived healthy stem cell memory T-cells, we can use a much more robust pool of T-cells compared to heavily pretreated donor-derived T-cells that are available off the shelf, we're also leveraging Poseida's unique gene editing technology, including their piggyback insertion technology, which allows for the delivery of multiple cars in a single step with great efficiency and without the need of viral delivery systems as well as their proprietary cast Clover gene editing technology which allows for multiple knock-in and knockouts, thereby preventing both graft versus host and host versus graph as well as improving efficacy and tolerability. Ultimately, we believe this off-the-shelf immediately available CAR-T approach will allow us to truly democratize cellular therapy. Our lead program is a BCMA allo CAR-T currently in Phase I in relapse refractory multiple myeloma, and that program is now demonstrating a 91% response rate in heavily pretreated patients with multiple myeloma. On that basis, we were actually granted an RMAT designation by the FDA, which goes beyond breakthrough designation in that it allows for accelerated approval based on proxy surrogate endpoints. We also have a CD19, CD20 dual CAR program in non-Hodgkin's lymphoma, B-cell malignancies that's currently ongoing. Turning now to benign hematology. There's a slide missing on PiaSky, but -- or it was in my deck, sorry, but it's not in this. Turning finally to our benign hematology portfolio, namely NXT007 but for starters, as you know, hemlibra truly transformed the landscape of hemophilia A. -- principally as compared to what was typically the administration of intravenous Factor VIII. That bispecific hemlibra have given patients the chance to achieve a greater life free of the typical manifestations of bleeding with 0 bleeding rates in the range of 80% to 90%. So ultimately, hemlibra really has set an extremely high bar for the treatment of hemophilia A. It is on that basis that we designed NXT007, which optimizes hemlibra in multiple ways. Firstly, changes to the binding domain with far greater affinity for Factor IX, thereby increasing potency of the clotting cascade as well as changes to the Fc domain thereby improving the half-life. In fact, NXT007 is 30x more potent than hemlibra and an in vitro assay indicates that NXT generates thrombin in the range of patients without any evidence of hemophilia. We believe that this drug has the potential to allow patients a life completely free of any clinical manifestation of hemophilia A. There is an ongoing Phase II study, and we will be sharing the results of that program next year. So in sum, we actually have a number of important readouts, which are not in the slide that I thought was coming next, but includes are readouts for giredestrant for tiragolumab for -- I didn't get a chance to share with you our C5 inhibitor PiaSky in various indications, including hemolytic uremic syndrome and sickle cell disease, and ultimately, I think, a lot of exciting news to follow in the hematology oncology portfolio. So I thank you for the opportunity to share all this. And now let me turn to Azad Bonni Kapani, who is going to -- our Global Head of Neuroscience and Rare Diseases, who will share with us the exciting developments in our neuroscience portfolio. Azad?

Thank you, Charlie, and good afternoon. So I come to you from pRED, as Charlie mentioned. And Today, I'm going to give you an update on our portfolio in the space of neurology. And in the spirit of 1 pharma strategy and end-to-end R&D excellence, it will be about both the early and late stages. Now as you heard earlier from Teresa, when it comes to launch products, we're actually already -- we already lead the field in this space, in neurology. And so to match and exceed this success in R&D, what we're doing is to actually -- to take advantage of advances in human genetics, advances in disease biology understanding and also in therapeutic technologies to establish an industry-leading portfolio. And today, what I'm going to do is to give you some highlights on some projects in the following disease areas, as you see on the slide, including MS, neuromuscular disorders and neurodegenerative diseases with some of the examples shown below. Now in terms of our portfolio in clinic, shown on this slide, I want to make 3 points. One is that we're actually interested in a number of disease areas, including those that I just mentioned. The second point is that as you can see on the lower left corner there, the Legend, we're actually using diverse and innovative technologies in the clinic in these projects. And the third point, which is not on the slide, and that is that we actually have a large portfolio of preclinical research projects that feed the clinical portfolio. So let's go to the projects. Now building on the success, we'll start with MS and building on the success of Ocrevus in MS. Let's focus on our intention now on fenebrutinib. Fenebrutinib targets the nonreceptor tyrosine Kinase BTK. BTK activates the immune cells in the periphery and within the central nervous system and in particular, B cells, myeloid cells and microglial cells. And that's important and makes it an attractive target for MS because with this, you can see that you can address both the relapsing as well as the progressive aspects of the disease. Now in clinic, we've already -- as shown on the left-side panel, we've already completed the Phase II FENopta study, and I'll tell you about this shortly. Also, we have completed recruitment of 3 Phase III trials, including 2 in relapsing MS and also in primary progressive MS, where notably the comparator arm is ocrevus. Now Fenebrutinib stands out among the BTK inhibitors out there because it's the only nonreversible -- non-covalent reversible inhibitor of BTK. In addition, so shown on the middle -- in the middle panel, fenebrutinib is quite potent. And Also, it's brain penetrant. And as shown on the right side, it's quite selective relative to other BTK inhibitors. So with all of these pharmacological properties, Fenebrutinib has best-in-class potential among BTK inhibitors for MS. And also, as an oral agent, of course, it has the potential to be best in disease in the oral market for MS. Let me tell you a little bit about the FENopta study. So on the left side, you see the results from the double-blind period. And here, what you see is with the primary endpoint of gadolinium ENHANCE T1 lesions by MRI, you see with fenebrutinib, there is a rapid reduction of these lesions by week 4. And actually by week 8, you can see and this is sustained at week 12, there is deep suppression of these lesions. And we see a similar effect on key secondary endpoints as well that include enlarged or new T2 lesions. In a subset of patients where we examine the concentrations of fenebrutinib in CSF, we see actually that fenebrutinib reaches levels of near maximal inhibition of BTK. And that's important for a couple of reasons. It shows that it's brain-penetrant, highly brain penetrant. The other thing is these are where in the CNS, there are immune cells that are thought to be responsible for disability progression. So that bodes well for that aspect of MS. The safety profile of fenebrutinib in FENopta has been consistent with previous studies in non-MS indications, which is a favorable safety profile. And so far, up to 2,700 over 2,700 patients have been dosed with fenebrutinib. Now the results of the open-label extension of FENopta shown on the right side, the right panel are equally -- and here, what you can see is that actually by week 48, 96% of the patients are free of relapses. And that's the annual relapse rate of 0.04 that you see. In addition, 99% of patients are free from Enhance T1 lesions. And so now, of course, we're waiting for the results of the Phase III trials with the initial readouts coming in 2025. Now let me move from MS to neuromuscular disorders and start with SMA or spinal muscular atrophy, where as you know, Evrysdi has really transformed the care of patients with SMA. Evrysdi, of course, addresses the proximate cause of the disease. And here, now what we're trying to do is to see if we can build on that by combining it with an agent that should lead to an increase in muscle size and function. And this is where GYM329 comes in. GYM329 is a monoclonal antibody deploying the technology of the sweeping and recycling technology that makes it much more potent for soluble factors in circulation, in this case, targeting latent myostatin and this pathway that's regulated by myostatin is put-a-brake on skeletal muscle growth and strength. So the idea then is to combine it with Evrysdi to see if we can get further benefits. There is already evidence for GYM329 preclinically in mice shown on the right side. And currently, we're in a Phase II/III trial, the MANATEE trial in the first part we're looking for the optimal dose and then in the second part, this would be where we would study the effects -- the efficacy in addition to safety. And then a couple of words about Elevidys in Duchenne muscular dystrophy. As you know, Duchenne is a devastating neuromuscular disorder, results from mutations of gene encoding dystrophin and Elevidys represents a gene therapy approach, a single intravenous dose delivering microdystrophin for expression in muscle cells. And from the EMBARK trial, you can see on the left side that although there were improvements on the North Star Ambulatory assessment score, the NSAA, this did not reach statistical significance and was not met. However, on key secondary endpoints that are clinically meaningful in a whole number of these were met, including time to rise, 10-meter walking test, the Stride Velocity 95th centile and time to ascend 4 steps. So combined, all of this together provides a positive benefit risk favorable profile for Elevidys, and this has actually received overwhelmingly positive feedback from key opinion leaders. And as you know, perhaps through our partner, Sarepta, it has been approved in the U.S. and now through Roche, in 6 other countries. And now we're actually -- we believe that this is going to be relevant for patients beyond the ages of 4 to 7. And so therefore, we have trials shown on the left -- on the right side extending the age as well as going into nonambulatory patient population. And now let me move to the early development portfolio and focus on neurodegenerative diseases. I'll start with Parkinson's disease where, as you know, there are symptomatic treatments, but as of yet, no treatment to slow the course of the disease. And this is where prasinezumab comes in. And you heard about this from Thomas earlier, prasinezumab is a monoclonal antibody that targets aggregated alpha-synuclein extracellularly, and the idea is to mitigate the spread of aggregated alpha-synuclein and further degeneration of dopaminergic neurons. In the Pasadena at Phase II trial, although the primary endpoint was not met, we saw really interesting signals suggesting that prasinezumab on an established motor scale that prasinezumab slows motor progression. And this was corroborated with evidence on innovative digital readouts that gave us the confidence to move to a Phase IIb trial, the PADOVA trial, which I will tell you a little bit about shortly. In the meantime, we've done further analysis, including as shown on the right side, open-label extension on the same scale, MDS UPDRS part 3, where we see that for up to 4 years that actually patients remain stable. For a specialist, looking at this list looks quite striking. Now here, we're -- it's an open-label extension, and we're comparing it to a natural history cohort that's the gray bar that comes from PPMI. So the other sort of analysis we've done is actually in pre-specified populations in Pasadena shown on the left side, where we look at, in this case, 4 populations. And in each -- this is a Forester plot. And what we see that in each case, look at the very bottom one, in each case, we see that actually prasinezumab has a greater effect on patients that are expected to progress faster. So this is just giving us more evidence that actually prasinezumab may indeed have an effect on motor progression. But the proof of the pudding will come in Padova. And that is the trial that's shown on the right side, it's fully recruited. The readout is expected later this year and will be -- the results will be shared in '25. Here, we're actually focusing for the primary end point on motor progression using a time-to-event type analysis. Now let me move to Alzheimer's disease, and which, of course, as you know, is the most important -- one of the most important public health challenges of our time. There's been a lot of work in this. We're interested in many -- a number of targets like the rest of the field. But of course, one target that has been studied for quite a long time is amyloid beta where -- as you know, in the last couple of years has emerged as a clinically validated target. Yet there is a lot of room even with amyloid beta for improvement, both on efficacy and safety. And here's where we come in with trontinumab. This is a novel antibody that targeting amyloid that deploys a technology that's been developed at Roche for the past 15 years. that's called the Brainshuttle technology. This is going to be relevant, not just for Abeta, not just for Alzheimer's, but actually for many indications in neurology. And so to help you understand how -- and myself as well understand how this works, I'd like to show you a video now. [Presentation]

Great. So now that you've seen the video, I'm going to skip the left panel because now we understand the mechanism, I'm going to go right to the middle panel and tell you about the results of trontinumab in the Phase IIa trial in Alzheimer's disease. And here, what we see is with these 4 doses, a dose-dependent reduction of amyloid load as measured on PET scans. And we have also here analyses with the last dose, the 3.6 milligrams per kilo, shown in the purple at 12 weeks where you can see a rapid and robust depletion of amyloid. And in fact, in this cohort, about half of these patients are already amyloid negative, and many of these are deeply amyloid negative. And so this is really exciting for a couple of reasons. One, it takes conventional antibodies several months to reach this level. And here, we're seeing it in a matter of weeks. Why that is important is that there's been evidence in the literature that the faster and the more deeper that you deplete amyloid, the more likely it will lead to a beneficial effect. So this is one major reason. We're seeing rapid and robust depletion of amyloid in -- with trontinumab. The other reason we're actually quite excited about trontinumab and shown on the right side, and that we speculate is because of the route of entry of the antibody is that we're actually seeing less of ARIA, which is this major adverse event with anti-amyloid antibodies which stands for amyloid-related imaging abnormalities. And so this is really exciting because now we have with this combination of potential better efficacy, better safety on really the potential to be best-in-class anti-amyloid. So I do want to say also that there will be an update on this in 1 month's time at CTAD. Now let me move to the last molecule slide, and I will take you through this. So let's go through the -- let's look at the left side first, the left panel. So whereas with Trontinimab, we're focusing on targeting the plaque, which is shown in that red globe there. We're clearing plaques with this new molecule secretase modulator is focused on the production of the -- on the other side of the amyloid cascade. So on the production of amyloid beta peptide. So gamma secretase is a protease that cuts amyloid precursor protein and together with beta secretase leads to the production of A-beta peptides. Now what's really interesting about gamma secretase, it acts processively. So it's sort of like think of a chef cutting a piece of meat, chopping a piece of meat. So it cuts it in multiple sites. So you get different species of A-Beta peptides. There's the Abeta 40 and 42 that are amyloidogenic, they're considered harmful. There are also other species, including 37 and 38 that are not amyloidogenic and are actually thought to be beneficial. Now previous attempts are targeting gamma secretase acted like a sledgehammer. They would inhibit gamma-secretase, they were not very selective, and so they actually did not lead to beneficial outcomes. And here, what we have is a new molecule that acts very incisively binds to gamma secretase and modulates it so that you get less of a beta 40 and 42, less of the harmful peptides and more of the 37 and 38 -- and then the middle panel, you see that actually in healthy volunteers, we see in CSF a reduction of a beta 42 and 40 and a concomitant increase on the right side of that middle panel, an increase of 37 and 38. And currently, we're now in a Phase II study, where it's focused on safety, tolerability, pharmacological properties, PK and PD. And this is in a population of people who are accumulating amyloid. So they're either actually cognitively normal or have minimal cognitive impairment. So we're very excited about this molecule as well. Let me end with the patient journey. This will be my very last slide. And actually, this is a concept that Thomas referred to. And here, I'm going to -- it's going to be really important for us. for neurology in general with chronic diseases. And here, I'll just illustrate it for Alzheimer's disease. So we already have approved a CSF test for diagnosis of Alzheimer's disease. I would say, even more excitingly, in development in diet, there are tests that are plasma for plasma biomarkers, including pTau and APOE4 that have a high negative predictive value, which means they can be used to rule out the diagnosis of Alzheimer's. In addition, we have pTau217 that are being developed with very high positive predictive value so they can be used to rule in the diagnosis of Alzheimer's. So in the future, of course, this could be used across the journey, but especially you could see it happening early in the process for people who are at risk, for example, for developing Alzheimer's disease. And the idea over time because once we have therapies that are now in development that you can match this so that a person comes in, they're at risk for Alzheimer's disease. These tests are done and the treatment is given to prevent the progression into symptoms. And then once you treat them, we want to have additional tests to monitor that, either with digital readouts as well as additional fluid biomarkers. So this is actually a future that is within reach. And I think it's a future that will really transform the way we care for patients with Alzheimer's disease as well as other neurological diseases. And with that, I will turn it over to Larry to tell us about immunology.

All right. Thank you so much, Azad. I don't have any slick videos to show you, so just warning ahead of time. But nevertheless, I'm very happy to be here today to talk to you a little bit about our immunology strategy and pipeline. Roche has a long legacy of innovation in immunology and in the 2-plus decades since Rituxan was first approved for the treatment of RA. And XOLAIR was approved as the first biologic for the treatment of allergic asthma. Our understanding of immunology has really grown by leaps and bounds. And that's created a lot of new opportunities for drug development, but it's also created some new challenges as expectations for efficacy have continued to rise and competition has intensified. We feel that we have an immunology strategy though, that will position us well to continue to lead innovation in immunology over the coming decades. And that strategy consists primarily of 4 components. First, optimizing pathways, including improving unknown pathways and identifying novel pathways with transformational potential. And we have examples of this, including Gazyva and Lunsumio, which are next-generation anti-CD20 molecules with enhanced B-cell depletion and Selnoflast an LRP3 inhibitor with the potential to be the first new oral asthma met therapy in about 25 years. Secondly, combinations, which target multiple pathways to raise the efficacy ceiling. And here, we have early-stage programs in inflammatory bowel disease and inavolisib COPD. which combined orthogonal, validated and novel pathways that are relevant to these diseases. Thirdly, endotypes, which can identify patient subsets to improve efficacy and guide therapy. Examples here include Astegolimab, which while directed at an all-comers COPD patient population does have the potential to address the historically most difficult to treat low eosinophil patients -- and anti-TL1A in IBD, which is also directed at an all-comers IVD patient population, but it's exploring biomarkers, which may predict better responses to treatment in subsets of patients. Finally, last but not least, our ultimate goal is cure or long-term remission for immunologic diseases. And here, we have a CD19 CD3 T-cell engaging bispecific monoclonal antibody which may act similarly to cell-based therapies directed at CD19 that have shown the potential to achieve functional cure for a large range of autoimmune diseases. This is something that we're particularly excited about when we think about the future of immunology treatments. When we look across our full immunology pipeline, we see a whole range of additional programs with transformational potential that support the immunology strategy and our ambitions. And I'm going to spend the rest of our time talking about just a few of these in more detail. I already mentioned Xolair, 20 years young and still delivering new innovation for patients. xolair, as you probably know, is in anti-IgE antibody that is approved for the treatment of allergic asthma, chronic spontaneous urticaria, nasal polyps. And now is the first and only FDA-approved medicine to reduce allergic reactions to multiple foods. Food allergies continue to increase in prevalence with about 17 million adults and children affected in the United States alone. About 50% of these patients will actually have severe reactions that result in about 30,000 emergency room visits per year. And as a parent of a child with severe food allergies, I can personally attest to the long-lasting psychosocial, emotional and developmental impacts that these severe food allergies can have on patients and their families. The approval in food allergy was based upon the results of the Phase III OutMatch study, which demonstrated dramatic improvements in ability to tolerate an oral food challenge to known allergens, including peanut, milk, egg and cashew. And I think these data point to part of the unique value story for XOLAIR, it doesn't matter how many things you're allergic to, it doesn't really matter what they are. It's one treatment. Early uptake has been quite strong with about 15,000 patients treated in the first 4 months since launch. Shifting gears a bit. decades of effort have also positioned Roche well for a strong future in immunologic kidney diseases, including lupus nephritis, membranous nephropathy, idiopathic nephrotic syndrome and IgA nephropathy. And in each of these diseases, Roche has a Phase III program that's expected to read out in the next few years. I'm going to spend a little bit more time talking about lupus nephritis. Lupus nephritis, if you don't know, is a severe and dreaded manifestation of systemic lupus. About 50% of lupus patients will develop lupus nephritis within 5 years of their diagnosis. And about 1/4 to 1/3 of those patients will go on to develop end-stage kidney disease. Lupus nephritis is also associated with increased mortality about 6x that of the general population. We recently announced the positive top line results from the Regency study of Gazyva in lupus nephritis. As I mentioned earlier, Gazyva is a next-generation anti-CD20 antibody with enhanced B-cell depletion and less dependence on complement for cytotoxicity which means that Gazyva particularly well suited to treat patients with a disease like lupus nephritis where complement levels may be reduced. The Phase III Regency study results showed that a higher proportion of patients treated with Gazyva compared to placebo on top of standard of care therapy achieved a complete renal response at 76 weeks. Complete renal response is an important endpoint because it's correlated with sustained preservation of kidney function as well as delay or prevention of progression to end-stage kidney disease. Key secondary endpoints were also supportive of the primary endpoint and no new safety signals were identified. We will be filing this data with global health authorities and presenting it at an upcoming medical scientific conference. Turning to gastro immunology. Tumor necrosis factor like cytokine 1A or TL1A is emerging as an exciting new pathway relevant to inflammatory bowel disease. IBD affects about 8 million patients worldwide and about 80% of them will not achieve lasting remission with currently available therapies. TL-1A also has potential relevance across a whole broad range of immunologic diseases because it sits upstream from some key pathways, which modulates Th1, Th2, Th17 and fibrotic responses that are relevant across multiple disease indications in gastroenterology, rheumatology, pulmonary fibrosis, dermatology, et cetera. Our Phase III pivotal program in inflammatory bowel disease is underway at this point with first patients enrolled achieved in our ulcerative colitis studies as of earlier this month and first patient in expected in our Crohn's disease studies in the first quarter of 2025. We're continuing to explore additional indications to achieve the full potential of this molecule is a pan immunology molecule, and we're expecting to be able to update you with some details in the first half of 2025. As I mentioned, the Phase III program in ulcerative colitis is underway with the AMETRINE-1 and AMETRINE-2 studies, and the first patients have been enrolled in those studies. These studies, of course, were designed based upon the robust safety and efficacy data from the Phase II TUSCANY-2 study in ulcerative colitis, which showed sustained clinical and clinical remission and endoscopic improvement from the induction phase through the chronic maintenance phase with treatment. And we'll be presenting an updated analysis of these results from the Phase II study at the United European Gastroenterology Conference later on this year. AMETRINE-1 is a treat-through study, meaning the patients move seamlessly from induction to maintenance and into the open-label extension portion of the study without requiring rerandomization. AMETRINE-2 is an induction only study, meaning patients move from the induction phase into the open-label extension directly, again, without requiring rerandomization. And this study design is particularly appealing to patients and to clinicians because it minimizes the time that patients are on blinded placebo. Both studies are directed at a broad all-comers IVD patient population, including patients who have not responded to more than 3 previous advanced therapies. So some of the most refractory and difficult-to-treat patients, but they're also exploring a biomarker test, which may predict better response to treatment. COPD, astegolimab is our first-in-class anti-ST2 monoclonal antibody in COPD. COPD is, of course, the third leading cause of death worldwide affecting approximately 450 million patients globally. ST2 is a receptor for IL-33, which is an alarm in cytokine released in the lung in response to not just stimuli, including cigarette smoke and viral infections. And in the Phase IIa COPD STOP study, astegolimab treatment was associated with a 22% numerical reduction in acute exacerbations accompanied by significant improvements in symptoms and forced expiratory volumes. And I should note here that treatment effect seen in COPD staff was actually similar to the treatment effect seen in other Phase II studies of compounds which directly target IL-33 rather than targeting the STT receptor. COPD has historically been a very difficult disease to treat. And 1 of the key reasons for this is the heterogeneity of the disease. A treatment that might be effective for a patient who has chronic bronchitis might be completely ineffective for a patient who has severe emphysema despite both patients having COPD with similar levels of airflow obstruction. One approach to this heterogeneity has been to segment patients based upon their eosinophil levels like we do for asthma. And not surprisingly, repurposed asthma medications have seen some success with this approach. Unfortunately, it only addresses about 20% of the patient population of COPD who have high eosinophil levels. Another approach has been to segment patients based upon smoking status. But in contrast, astegolimab has the potential to address a broader range of COPD patients regardless of their eosinophil levels and regardless of the smoking status because its mechanism of action addresses both eosinophilic and neutrophilic inflammation. And our pivotal program, ALIENTO and ARNASA, the 2 studies well underway with results expected in 2025. Another novel pathway that we're very excited about is NLRP3. An NLRP3 is a multiprotein complex that triggers pyroptotic cell death and has been implicated in multiple disorders across different therapeutic areas. Selnoflast is an orally active, potent, selective and reversible NLRP3 inhibitor that's currently in a Phase Ib study of moderate to severe asthma. NLRP3 inhibition has -- was shown to reduce airway inflammation and hyperresponsiveness in preclinical models of steroid-resistant asthma. And that's why we believe that Selnoflast has the potential to be the first new oral asthma therapy in 25 years. Selnoflast is also being studied in other Phase I studies of Parkinson's disease and coronary artery disease, diseases in which inflammation is [ felt to ] play a key role in disease progression. So I'm going to turn for a few moments then to infectious diseases. Infectious disease is not part of the immunology and it's not one of our 5 therapeutic areas of focus. Nevertheless, it is a part of our societal commitment to the global health security. Looking back over the last few years, one of the things that we're most proud of as a company is the role that we played in combating the global COVID-19 pandemic, and that spans across pharma and diag. And we believe that we should continue to aim to deliver curative therapies for infectious diseases that represent some of the highest unmet needs in the world. And in doing so, continue to contribute to preparedness for the next global pandemic. In that context, we recently announced the results of the CENTERSTONE study, which showed that a single treatment with Xofluza can reduce transmission of influenza from an infected person to their household contacts when only the infected person is treated. This is the first time this has ever been shown for a respiratory antiviral and it has important implications for personal and public health because influenza continues to represent a serious threat to public health and a significant burden on economies and health care systems, with 1 billion cases annually and 650,000 respiratory deaths. In addition, antimicrobial resistance is increasingly recognized as a silent pandemic that is expected to claim more lives over the next 30 years in cancer as current trends continue. Despite this, there are significant challenges, both scientific and commercial to the kind of sustained development efforts that are required to win this battle against the [ bugs ], particularly what we need is novel classes of antibiotics with new mechanisms of action. And as Thomas alluded to this morning, none has been marketed since 1968. It's been a long time. Roche currently has 2 novel mechanism of action, antibacterials and development, Zosurabalpin is a neurospectrum macrocyclic peptide, which blocks gram-negative transport of Lipopolysaccharide, and this molecule actually has high in vitro potency against acinetobacter baumannii, including carbapenem-resistant strains, which are the highest threat pathogen according to both the WHO and CDC. We also have RG6436, which is a broad spectrum LepBi inhibitor with high in vitro potency against carbapenem-resistant enterobacter cloacae and Pseudomonas aeruginosa. LepBi is a type 1 signal peptidase that cleaves and activates bacterial pre-proteins. And both of these molecules are in Phase I development, but we're looking for opportunities to accelerate these programs in order to bring them more quickly to the patients who need them the most. And with that, I will close my section, and I will invite Christopher Brittain, the Global Head of Product Development ophthalmology to the stage.

Great. Thank you so much, Larry, and good afternoon, everybody. So it's a great pleasure today to be able to talk to you about the ophthalmology pipeline for the next 10 minutes or so. For those of you who were here last year, I talked a lot about the momentum. And today, I'm going to talk a lot about momentum and execution. Last year, when I mentioned momentum, we had 1.5 million vials of Vabysmo in the market. Today, we have 5 -- over 5 million vials of the Vabysmo in the market. So real momentum -- it's really been going strong on the ophthalmology side since we last spoke. As Thomas talked about earlier today, stopping, preventing and curing is kind of one of the backbones of our strategies at Roche. And the ophthalmology pipeline is really continuing with that in mind. And here, you can see we have several approaches. Today, our therapies such as Susvimo and Vabysmo are really aimed to improve vision in patients who've already suffered from some form of disease. And oftentimes, 40% to 60% -- 40% to 50% of patients, despite the best available treatment still don't return to driving vision in their treated eye. So those are in the middle there. We, therefore, really want to aim to treat patients earlier in their disease spectrum, and that's prevention. And examples here are going to be looking at treatments for intermediate AMD, diabetic retinopathy. On the later stage of disease, we have the opportunity to restore vision for patients who've already lost it and whom the currently available therapies do not work. And we have a couple of examples, one of which I'll talk about later, which is OpRegen, but optogenetics is another disease there where we're looking at restoring vision for those who are currently would be blind or considered blind in many instances. To execute on this strategy, we have 3 broad pillars starting with extended durability and future technologies. And the best example of the extended durability is the Susvimo and the Port Delivery Platform, we really believe this is an important platform for us. And although I'll talk a little bit more detail about it later, currently Susvimo can provide treatment every 6 months. We really see future technologies, future molecules going into that platform, being able to go every 9 months, every year and beyond. While I'll talk a little bit about cell therapy later with OpRegen, obviously, I've just mentioned the fact that we have other novel technologies in the form of gene therapy. And here, we're looking at novel kind of second-generation capsids to treat blinding conditions with what we call optogenetic technology. So replacing -- converting viable retinal cells into photoreceptors. The second column here is around novel mechanisms of action and new indications. Part of our strategy at Roche in ophthalmology is to look at the mechanisms of disease. So examples here, we have the leading technologies in the vascular stability with our VEGF-ANG2 pathway knowledge. We're looking at inflammation with our IL-6 and vamikibart. Many of you will be aware that we acquired an asset through the Sema-3A partnership a number of years ago, which is addressing retinal ischemia. And I'll talk a little bit about later about our wind pathway, which addresses both ischemia and potentially vascular stability. So all these, as you can see, really address inflammation atrophy, ischemia and vascular stability. And finally, you've heard a lot this morning about digital capabilities. So ophthalmology is no different, if not possibly what are the leaders within the organization. And what we found is we're really capable of integrating Omics clinical imaging data and this is providing not only insights in terms of disease understanding, but it's enabling us to develop disease algorithms. And a good example of one of these algorithms is actually with a single fundus image, we can predict the rate of disease, we can predict 50% of the next year's rate of progression of disease in patients with geographic atrophy. And then the last piece there is we've -- in the U.S., we've had a controlled U.S. commercial launch of our myVision track monitoring tool, which has the potential to be an accessible and effective and low-cost wave tracking disease. So we talked a little bit about Susvimo and Vabysmo. The momentum with the Vabysmo, I've already mentioned the 5 million vials, but we've also been approved now in over 100 countries. So that's going incredibly well, and you've heard about the pre-filled syringe already. On the Susvimo side, the relaunch is going nicely. And we're getting good feedback from physicians, and we've already had reimbursement from a number of U.S. reimbursement organizations. And then in Phase III, which I'm going to highlight in a minute, is going to be around kind of Enspryng in thyroid eye disease and where we are and how we've executed that since we last spoke last year and also vamikibart for patients with uveitic macular edema. So as a reminder, vamikibart is an IL is an intravitreally injected IL-6 targeted therapy, with a modified FC region to reduce systemic exposure. Based on the Phase I data where we had about 30% of patients were able to have a gain of approximately 15 letters or 3 lines of visual acuity over a 3-month period. Since we spoke last year, when we were announcing our launch of this into Phase III, we've already completed enrollment in 1 of our Phase III studies called MEERKAT. And by the end of this year, we expect to complete enrollment of the second Phase III study called SANDCAT. So for me, this is really a real validation of the unmet need by which I mean the desire by physicians to have a therapy which targets inflammation, which is not a steroid. Steroids have horrible side effects in the eye cataract, intraocular pressure issues, permanent glaucoma which surgeries can be required. So really exciting progress and execution on the vamikibart side. Enspryng is our therapy systemic subcutaneously delivered thyroid eye disease treatment, which is currently in Phase III also, going very nicely, 2 studies, SatraGO-1 and SatraGO-2. As a reminder, IL-6 is a key mediator of inflammation and really drives fibrosis in patients with thyroid eye disease. The opportunity here with Enspryng particularly is that the currently available therapy, which is only available in a small number of countries has side effects, which include hypoglycemia, fetal toxicity, menorrhagia, and issues with menstruation in up to 1/4 of women, so hopefully, when you see the thyroid eye disease affects about 5x as many women as it does men, there's an enormous amount of unmet need in this disease area. So we are really excited to be able to move these studies forward and they've been [ recruiting ] very nicely. Coming back to Vision restoration, which we talked about earlier. The OpRegen program is ourself, is our allogeneic cell RPE cell therapy, so retinal pigment epithelium, and it's injected under the retina. The Phase II study continues very nicely, and we've been able to share now 2-year data from our Phase I program, which is very reassuring in that, not only do the patients continue to have preservation of their visual acuity, but probably more importantly, the anatomy is also maintained out to the 2-year point. As you can see on the graph on the right side, that's showing the mean increase in area of retinal pigment epithelium. So the left-hand side of the right graph shows, when you inject these cells in the right place, i.e., under the retina where there is atrophy, the cells really go there and stay there, and that area of actually does not increase in size over that 2-year time point. So a really exciting program and lots more to come in that in the future. Returning to the Port Delivery System Platform, zifibancimig is our second therapy now officially in the port in clinic, zifibancimig is our bispecific VEGF-ANG2 molecule. It's in part 1 and part is -- entered part 2 and part 3 as you can see in the graph of our BURGUNDY trial. And Part 2 is comparing a low dose versus a high dose and Part 3 is a larger subsidy comparing a low dose or high dose and Susvimo. The goal here is to see how long we can extend the durability of treatment for with this bispecific molecule. Importantly, Port Delivery is a platform, as I said previously, and the opportunity here is we actually have 3 DutaFabs in total, which can go into this platform and 2 other preclinical molecules, which could also expected to enter the platform. So we're really excited about this, and it's going to be not just neovascular AMD and DME, but multiple diseases. And you heard a lot about our AntlerA acquisition this morning from Teresa. So I'm delighted to be sharing just a few seconds of information about this. But as a little bit of a background, the wind pathway has been known for many, many years, and it plays a really important developmental role in developing the retinal vasculature within the human and within animals. It supports retinal vasculature development and also maintenance of the blood retinal barrier. So therefore, it has a role in potentially in both ischemia and in retinal vascular stability. And the exciting thing about the Ant farm, which is what we discard this picture of multiple bispecific molecules, which this acquisition of Antler provide us with, is that we can have multiple -- is basically -- it's -- the evidence has really grown over the last couple of years. Number one, we have genetic evidence, so there's a variety of human diseases, one called Familial Exudative Vitreoretinopathy where deficiencies in the pathway result in disease blinding diseases in childhood for the age of 5 years. Secondly is preclinical models, whereby we've shown the knockouts of various elements of the pathway result in ischemia and retinal leakage and vision loss in animal models. And thirdly, we've seen a clinical proof of concept with a competitor molecule. So all in all, a really exciting time, and we're looking forward to bringing this into the clinic. So with that, I'm just going to close by saying, have you seen today that we're really building on the momentum with Susvimo and Vabysmo. We've got -- we've built the momentum and executed on our Phase III studies with thyroid eye disease and uveitic macular edema and we've really executed now on building -- continuing to build our pipeline out with addressing multiple mechanisms of action from addressing ischemia, fibrosis, inflammation and atrophy and vascular stability. So with that, I'm very happy to pass on to our last speaker, Manu Chakravarthy, Head of our Cardiovascular, Renal and Metabolism Product Development.

Thanks, Chris. I know I stand between you and the upper row or the drink so we'll try to make this efficient and quick. So let me just start with this slide because it sort of encapsulates really the genesis of why CVRM at Roche. Both cardiovascular, renal and metabolic diseases are considered interdependent. And in fact, the American Heart Association recently actually called this the CKM syndrome, Cardiovascular-kidney-metabolic syndrome. And it underscores the fact that all these things likely have a common driver and that happens to be obesity or adiposity and in fact, individuals have a BMI greater than 40 -- 30 will carry more than 40% elevated risk of overall mortality. So it's clearly not a by standard. It's really a driver of many of these interdependent diseases. Of course, I mean, from a patient perspective, it's really amazing and it's really thankfully, there's some really transformative frequence available today. But in the field of CVRM in general, there are significant unmet needs that remain and I'll try to encapsulate some of those. Quite honestly, that's what gets me up in the morning. It's just all these needs. And to me, personally, I felt this is what I was drawn to Roche for is, no better place to do this than in a company that you've heard already is interdependent on both the therapeutics and the diagnostic side of things. So in terms of the strategic pillars that we're trying to build in for CVRM at Roche, it really includes the backbone of the incretins that was acquired through Carmot, CT-388/868/996. But also to take that and build upon the other needs that clearly exists in the field, which we all know that, of course, yes, we need to address obesity, but obesity comes with other related mobilities like hypertension, heart failure, chronic kidney disease. And even as you heard from Azad neurodegeneration, Alzheimer's, Parkinson's, and even diabetic retinopathy. So these are all interrelated and one could argue that that's where the differentiation opportunities at Roche really lie. Obesity is going to be heterogeneous. It's going to be a segmented market. And so we have to be mindful of where the combinations are. And so another strength that we're trying to bring forward together at Roche's to be able to leverage the internal pipeline with GYM329 that you heard again from Azad. There's also CT-173, which is our PYY, I'll tell you a little bit more about today. And then you also heard from Larry about Selnoflast NLRP3 could be potentially a great combination to address the vast spectra of ASCVD or atherosclerotic cardiovascular disease. And then probably, one could argue, the true sort of the strength at Roche is really to marry the therapeutic and the diagnostic approaches. And there's no better therapeutic area that lends itself to our diagnostic than CVM. You already have the continuous glucose monitor that's already used as standard of care in diabetes. The SmartGuide AccuChek from Roche is at the leading edge of that. There's already detection tools available that we need for heart failure, MIs and even lipids. So when you bring it all together, it provides us the type of pipeline that will allow us to address this incredible challenge. So this is the cardiometabolic pipeline as it stands today. I'm going to give you brief snippets of each one of them. I'll spend a little bit more time on CT-173, the PYY analogue since that's a little bit new, but many of you were at the EASD and other events that we've had. And so you've already seen little snippets of this, so I'll go through them relatively quickly. And we will highlight exactly where each of these assets are in their development. So one of the questions that I always get is Roche too late in obesity? I think some of the questions were already asked this morning. So my answer to that would be wholeheartedly no. There's a lot to do in this space. And I think, as I said before, it's not only a large market, but actually when you think about the unmet needs of people living with obesity, it's numerous, okay? So when you really think about the full spectrum from -- yes, you need to reduce body weight, but there's so much more than that, right? So you have to think about, can you improve tolerability? Can you get to a deeper and more sustained weight loss? Can you get to a better quality of weight loss? Can you maintain that weight loss? These are fundamental questions that the field is yet to answer, and Roche is well positioned with its pipeline. And so when we actually constructed the pipeline, the whole intent was actually to try to figure out where the monotherapies and the dual therapies and the combination therapies can all play. The advantage that we also have is the modality. So there's injectables and orals. And so another question that comes up all the time is how -- and why do you need both. We certainly know that patients are in different stages of their journey. Some people like needles, some people don't. So having that optionality becomes really vital and very few portfolios, at least that we are aware of, really carry all those options. So before we go into each of those assets, one of the things that sort of just remind ourselves is how are they actually designed. So we, of course, knew about the incretins in our Carmot. So it wasn't like we were just entering this field completely blind. But one of the critical questions that actually still remains unknown is how do they actually work. As seemingly simple as that question is, it's actually still not fully delineated. So one of the insights that Carmot was able to provide was to actually focus the design of these molecules. -- in such a way that we could maximize the efficacy while improving upon the tolerability. And 1 way you could do that is by what is called biosignaling. So most molecules that's there right now in the marketplace or even the natural hormones like GLP-1/GIP. They signaled through both cAMP or cyclic AMP and beta-arrestin. We knew from the literature of that -- if we could favor the signaling through cAMP and eliminate beta-arrestin, which is thought to be the off signal, then the hypothesis was that we would prolong the efficacy and the tolerability -- and our preclinical data to date suggests that, in fact, that is the case. And of course, as we go through and mature our clinical pipeline, we will continue to support that clinically as well. And there are other data not from [ CAR ], but including from Bob Lefkowitz. -- who was -- actually who have got the Nobel Prize for G-protein-couple signaling. And others actually showed that, in fact, by biasing you will have greater efficacy and improved tolerability. So CT-388, very quickly, again, many of you were at the EASD. So I'm not going to belabor on each one of them, but just give you the highlights. So we reported on the 24-week data strong weight loss, very robust. The overall profile is actually in line with the incretin-based therapies for this stage of development. Now we're -- achieved the first patient in for our Phase II study. So it's a multi-arm, dose-ranging study to really understand the tolerability and the starting dose. So that study is underway already, and we are about to embark on the second Phase II in people with obesity and diabetes. 996 again, is also presented at EASD. So again, as a reminder, this is an oral synthetic highly potent, small molecule. The Phase I data continues to, again, tell us that we have a very potent selective molecule roughly around 7% weight loss in 4 weeks. And again, when you compare it to other molecules in the stage of development, the AE profile, the tolerability profile is very much in line, very consistent with that. Very reassuringly for us. We saw the plasma half-life in the 17- to 22-hour range, which comfortably puts it in the once-daily regimen, which we believe is a must win or a must-have for a true competitive molecule in the obesity and diabetes space. So the main things there are -- we're about to start the Arm 3, which is obese type 2 patients over a 4-week duration. And then we are planning already based on the reported data Phase I initiation in 2025. CT-868, a very exciting program because it's, in our view, the first-in-class and potentially best-in-class for type 1 diabetes. So while a lot of people focus on type 2, they get a lot of attention there. but patients with type 1 often get forgotten. And this is an opportunity to really transform that care. So there's a Phase II in type 1 patients underway. We'll have the data in 2025. But the proof of concept that 868 is a very potent glycemic control agent comes from our type 2 study, which we did over 26 weeks. And you can see a nice dose-dependent decrease in the A1c of almost 2.3%. To the best of our knowledge, that's about as steep as A1c reductions can be. And over 70% of people were no longer diabetics at the end of their 6-month period. So 173, so this is our long-acting PYY analog. And the data, so far, of course, is preclinical, but very exciting. So when you look at the data on the left, what you see on the green curve, is a combination of CT-388 plus 388 -- sorry, 173, which shows you this very deep and fairly sustained reduction in body weight, way above and beyond either agent alone. So potentially synergistic response. On the right is equally exciting data, which actually shows that once you achieve the plateau, which many incretins do get on to the plateau, and then on the plateau, when you treat these animals that are overweighted or actually in obese in this case, you actually drive even further weight loss. So this is very exciting for us because this is actually telling us potentially that there's an opportunity to maybe reset the body weight set point. And that has been always the sort of the big question in the field is, can you actually reset the set point and perhaps with agents like this, there is an opportunity to do that. And then switching gears quickly to Zilebesiran. And why do we really care about this, right? I mean one could say about hypertension, I mean, don't we have enough drugs already? It's true. But -- what was striking at least to us when we looked at this epidemiologically is that more than half of the adults in the U.S. with uncontrolled hypertension are actually unaware that they're even uncontrolled. And that leads to up to threefold increase in overall mortality. And that's a significant problem, right? And that's pretty much unmet. And so when we think about Zilebesiran, it's paradigm shifting, because this is the agent that actually inhibits angiotensinogen, which is the most upstream of the modulators of the RAS pathway, a highly validated pathway in the field of hypertension. And in -- this medicine in partnership with Alnylam that we're working towards has the potential to be really game changing because you can give this as a single shot just twice a year and then really get to this very sustained blood pressure lowering. And the proof of that is comes from our KARDIA-2 study where we show both in the primary endpoint and the secondary endpoints. So the primary endpoint is ambulatory blood pressure and the secondary endpoint is office blood pressure. And then what's remarkable about this study is that all these patients were treated with true standard of care, including ARBs and ACE inhibitors, which is, of course, used quite a bit. And so even on top of ACE inhibitor or an ARB, you still see statistically significant clinically meaningful changes in blood pressure lowering. So this tells us that there's a really significant opportunity here to improve the care and so we are embarking on a pretty extensive development program. So there's the 3 KARDIAs, KARDIA 1, 2 and 3. We're actually just in the midst of KARDIA 3, Cohort A of KARDIA 3 is fully enrolled Cohort B is enrolling currently, and that's a high-risk CBD population with CKD as well. And so -- the goal is that we would read out on KARDIA 3, and that will help us then design our or embark on our CVOT study, which we will have ready as part of our launch package. So just to conclude then, given the fact that these are probably the biggest diseases, as you heard from Thomas this morning, Roche is well positioned to address these interdependent diseases with a core foundation of not only the incretins, but a lot of the other molecules that we have in our therapeutic space. So let me invite Teresa to the stage to bring us back home. And we'll be open to questions after that.

Okay. All right. So I hope what we've shared with you here today gives you a strong sense of progress from where we started at the beginning of last year. And to just sort of sum everything up, we're in a place where that young best-in-disease portfolio will continue to provide growth over the next several years. We have a number of exciting readouts coming from our late-stage pipeline, 12 Phase III readouts next year, including a number of Phase I and Phase II readouts for some of our earlier-stage pipeline assets. A tremendous amount of work going on in the R&D organization to ensure that we're able to accelerate the time line in which we're bringing transformational medicines to patients and increase our response -- success rates. And then, of course, the strategy to help make sure that from an end-to-end perspective, we are applying rigor and science and discipline and business to ultimately meet our ambition of delivering 20 transformational medicines to patients by the end of the decade. So we've covered a lot today. I suspect you have a lot of questions. So I'm going to bring all of our presenters back up to the stage, including Alan Hippe, our CFO, and Bruno, and we will get started on our Q&A. And then you actually go get to have an apero.

Let's immediately jump into the second Q&A session. And Sachin, you go first.

Sachin Jain from Bank of America. I'll take a couple of questions, please, on some Phase III reads due next year. So firstly, on fenebrutinib. I wonder if you could just reappraise of your level of confidence in RMS given we've now had 2 failed molecules? So 2 specific questions. One, given what you've learned from other molecules, are you thinking about changing the primary endpoint from relapse rate progression? And then secondly, the Phase II data, how do you think about that $0.04 being reflective of Phase III, given it was an open-label extension and a very early stage population. And then I had a follow-on [ SERD ].

Sure. So we're actually quite confident about fenebrutinib despite the sort of the results you mentioned. Fenebrutinib, as I mentioned, is really actually quite differentiated. And it really comes down to the pharmacology. So because of the pharmacology that I mentioned, it's non-covalent, reversible, quite potent, and so it has a good sort of benefit safety profile, and it really comes down to the dose then. So actually, we're using an high-end efficacious dose of 200 milligrams twice daily. And so I think that the dose is going to be really important. And I think the FENopta results actually sort of bear that out. So it's not just in the double line period. But as you alluded to also in the sort of the open label, yes, it is open label. Nevertheless, they are quite striking results, both in terms of clinical relapse as well as the MRI results. So we're confident. Obviously, we need to await the results of the Phase III. So I think that's very clear.

If I could take one of the [ SERD ], please. So part of a description of your confidence success is endocrine sensitivity and frontline and adjuvant related to ESR-1 mutant. So it's hard to see from the chart does endocrine sensitivity very much between frontline and adjuvant. I'm just trying to get a sense of which population you're more confident in and front line fails or succeeds next year, how that impacts on adjuvant probability?

Yes. Well, I think what I wanted to address was the findings from AcelERA, which I know we're -- we're really -- the overall intent-to-treat analysis was we didn't see the giredestrant meeting its expectations on PFS, but then recognizing that probably up to 60% of those patients had endocrine insensitive disease. That transcriptome analysis that I showed you looked specifically at the ESR wild type and mutant wild type being estrogen independent mutant continuing to be dependent. If you look -- if you line up both early breast cancer, those eligible for adjuvant therapy as well as frontline metastatic, their profiles match the later line ESR-1 mutants in terms of their dependency on estrogen receptors. So certainly, based on that transcriptome analysis that would further our confidence both in the adjuvant and first-line metastatic settings.

Yes, I agree. I would just add what Charlie said. So essentially, we know that in the frontline treatment naive and in the adjuvant ER-positive breast cancer, they are endocrine sensitive. So that's pretty clear. But in addition, we didn't show it this year, but we showed in the past, we had a neoadjuvant window of opportunity study where we actually compared giredestrant to aromatase inhibitor and those kinds of studies have often been predictive of what will happen in the adjuvant setting. So that's an example where it's perhaps a proxy for the outcome that we have to do the experiment, but what we hope to see in the adjuvant setting. In addition, obviously, a difference between the adjuvant setting and the frontline metastatic setting is that we're testing in combination with the CDK inhibitor, but there's also equipoise for the idea that if we increase the impact on the estrogen receptor in that setting, there could be a benefit. And actually, there's some clinical trial design elements that may skew us in favor of that. So obviously, we have to wait and see the results, but there's reason to believe in both the adjuvant and the frontline metastatic setting.

And fact that neoadjuvant studies that I mentioned earlier that Levi's referring to, we showed superiority for giredestrant over in AI, both in the monotherapy comparison and in the comparison with the 2 drugs were combined with a CDK inhibitor.

Richard Vosser from JPMorgan. Just following up on the SERD, I think in that window of opportunities, say, there were a number of cases of bradycardia and an MI as well. So do you feel that you've got a safe enough product for the adjuvant and in particular, but also first line. So that's the first one on SERD. And then secondly, on the PADOVA trial. You highlighted the benefit from PASADENA from fast progressors. So I suppose the question is what proportion of patients do you think you've enrolled to enrich that in PADOVA in terms of fast progressors? Because on the face of it, the population looks pretty stable from what you've shown.

So across the entire portfolio of guradestrin studies, we're not seeing meaningful issues in bradycardia or other dose-limiting toxicities and that patients are staying on -- and in terms of the IDMC reports from that portfolio, we're not hearing any safety concerns.

So I can take the PADOVA question. So yes, actually, in the PADOVA, we have -- these are patients who are -- yes, they are Stage 1, 2. They're actually already on L-DOPA treatment and now on MAO-B. So they already are -- there is a good sort of representation of patients who will be faster progressors. So we're actually -- the other thing we're doing, as I mentioned, is focusing on the motor progression and looking at time to event.

It's Peter Verdult from Citi. Just 2 questions for Azad. Just coming back to Sachin's question on fenebrutinib. [ AcelERA and EVO ] look great on lesion reduction for the first year, but then there's waning effect when you look at all the other data, I know you've shown some really impressive data up to 48 weeks. But have you got -- have you seen -- is there anything you have in-house beyond that? That gives you the confidence that you're not going to see something similar as it relates to that waning effect? That's question number 1.

Okay. Well, I think I will sort of highlight another aspect of the pharmacology. It really does come back to the pharmacology. So without commenting on sort of the other drugs, we're using a dose that's highly, we believe, efficacious. And now we can afford to do that because of the pharmacology an aspect that I didn't mention also is that although it's reversible and no-ncovalent, it actually has a slow dissociation rate from BTK. So we think that actually that could -- I mean, it's speculative, but that, that could help explain sort of the longer the duration of the effect. So again, of course, it is open label, but it's going out to 48 weeks and sort of the results are quite striking. So we do have to await the results. But the results of the other BTK inhibitors do not diminish our confidence in the potential result. Again, we have to wait for those results. But I think it's a different construct in terms of the other BTK inhibitors, how they went from sort of earlier studies to Phase III. As you know, in one of them, for example, the dose was reduced, whereas here, we have stayed with the 200 milligrams twice daily.

Very fair. And then the second question is, maybe [indiscernible] my arm here. Just your level of enthusiasm for bepranemab, the - anti-tau, so I believe that there is a symposium at CTAD, bepranemab, the - anti-tau?

Yes. So what I can say about that is that this is a collaboration with UCB. And so there will be, as you said, an update. If you have further questions, I think we would direct them to UCB.

Just your general enthusiasm of antibody targeting TL to as a strategy.

As a more general question. So I think that this is tau, of course, beyond Abeta is one of the sort of the second hallmark of the disease, described since Alzheimer. We -- there are many ways of going about tau, including going after it intracellular. There has been evidence for extracellular tau. There have been a number of antibody approaches. People think that this mid-domain region of tau that's targeted by this antibody is sort of would be the most optimal way.

Emmanuel, next.

Emmanuel Papadakis, Deutsche Bank. Maybe one asset-specific question of readout next year. Astegolimab, you put a $3 billion-plus target on that. Perhaps you could give us some idea on whether that's a reflection of your perspective on market potential or molecular differentiation will obviously, have just had 1 molecular [ reading ] in that space, we have several more reading out next year. So just perspective on both of those would be interesting. And then a question, a follow-up from this morning in the R&D session, a couple of things that jumped out from your platform capabilities modalities slide, you had next to next ADCs, obviously, the industry has been moving in the other direction. So is that a deliberate decision to disinvest in that modality, we just think other opportunities fulfill the same function. And then Conversely, you seem to have more accumulation of more small molecules, again, industry moving in somewhat in the other direction. Is that a function of the opportunities that you have in hand? Or are you expecting some change in IRA that would make that rationale?

I can start to answer the astegolimab question from sort of a clinical and scientific perspective, and then I can hand off maybe to Teresa to talk about the commercial opportunity. When we look at this first generation of biologics for COPD. These are, again, largely repurposed asthma medications, and they are directed at patients who have high eosinophil levels, the highest levels of eosinophil levels again, which is really a subset, a minority, maybe 20% of the overall COPD patient population. So we think that really kind of that's the low-hanging fruit. And really, the most important patients to treat are those who do not actually have high eosinophil levels. Those are kind of the historically most difficult patients to treat, 80% or so of the patient population. astegolimab, again, because of its mechanism of action, is targeted not only in patients who have high eosinophil levels, but those who have low eosinophil level as well. So we think it is a much broader patient population that actually is targeted by astegolimab. I don't know if Teresa wants to add.

And that is why we actually believe it has a higher market potential because it's just targeting a much larger group of patients.

And I can take your question about antibiody drug conjugate. And others can chime in. I think that in many respects, this organization launched the field of antibody drug conjugates with KADCYLA and POLIVY, and I think it's a bit of a roller coaster. The molecule is really falling out of favor a decade ago and then with renewed interest. But I would say even in the results we're seeing this year. I think what we're learning is that it's a challenging space. Preclinical models of this class of drugs are not particularly predictive of clinical results and that in certain circumstances, it's empiric is that the science is not clear that there's a specific target linker and payload that can add up to a clearly winning molecule. That doesn't mean we've retreated from ADCs absolutely not. As you saw, we made a deal with MediLink. But I think we're watching, we're really watching carefully as we develop in that space. Recognizing that I think the approaches have been more empiric than scientifically driven in terms of understanding design and preclinical work but that we continue to be interested. And beyond, obviously, the ADC that we have with MediLink, we're continuing to develop antibody drug conjugates with novel payloads internally. So it's a space we're interested in, but we realize it is not as easy as 1 might think, given the difficulties predicting our clinical outcome.

Yes. Just one final point on that. In general, from an R&D excellence lens, the first question we would ask is, is this a foundational target? And then the question would be what would -- what is the optimal modality to kind of engage the target. And I bring -- it sounds kind of obvious, but we don't do it the other way around. It's not like, oh, what's the foundation of modality and then go searching for target. So I think that's going to be a guiding principle for us. And the good news is there are -- I mean, ADCs is one, but there are many now modalities that are at our disposal and of course the industry, so I think it makes sense to start with the target and the disease and then pick the right modality and ultimately, that may require iteration on how to actually leverage that modality.

And then I think your other question was on -- what I believe suggests was a greater expansion of small molecules and whether it be in hematology, oncology or really across our therapeutic areas, I'm not sure I would characterize our portfolio as a greater interest in small molecules. I think what we have is a broad array across modalities and technologies really to the point that Levi just made about given the target, what is the best way to confer a therapeutic effect and the best outcome for patients in terms of the effect on IRA, I defer to Teresa.

Yes, I just wanted to add, there is also a class between the small molecules and the antibodies, which is specially peptides, right? And so Jill has really mastered that technology. And it's quite interesting because one of the issues with the small molecules is although you can get into the cell, you may not create the binding affinity. So you have to target something that has a pocket in order to create the kind of binding affinity. Now the cyclical peptides, they can actually to confirmation and change, get through the membrane and create the pockets. And I think that will enable us to target targets in the cell that today are very hard to target. And I think here, we have a leadership position in terms of that modality.

And then from an IRA perspective, I think it's just important to make sure that as you're developing small molecules, you're doing it wisely in terms of thinking about how your development program is unfolding, how you're thinking about the indications given the constraints that we know that the IRA conveys. Let's also remember that there are a lot of people who live outside of IRA affected populations, and small molecules are actually very, very useful for getting drugs to places where things like cold chain or IV capabilities just aren't possible. So I mean, I think we do need to really follow the biology here and pick the modality that's going to work for the biology and then you figure the rest out.

Astegolimab, just to be clear. I understand you think there's more potential beyond the eosinophilic IL patients. But I was asking more in terms of differentiation with the other IL-33 and ST2 molecules that are reading out next year. Is there anything you particularly highlight there.

Yes. Sure. Happy to talk more about that. Obviously, astegolimab is the only molecule that's targeting the ST2 receptor as opposed to targeting the IL-33 ligand. And in terms of what difference that will make in terms of clinical outcomes that remains to be seen. But I think if we look at the other 2 nearest-term competitors, again, both IL-3 ligand inhibitors, one is actually significantly behind in terms of their launch time lines. And the other 1 is targeting actually a more narrow patient population. In that case, they're segmenting based upon smoking status, whereas again, astegolimab is actually targeted at a broad patient population regardless of eosinophil levels and regardless of smoking status.

I mean essentially Astegolimab allows to go after the entire population. And that is a very significant group of patients. There's probably also a group of COPD patients who are just undertreated and not seeking treatment right now because the treatments aren't very good. So I think you'll both see -- we have an opportunity to go after a much bigger slice of the pie, and I think you might also expect the pie to get better.

Simon, please.

Simon Baker from Redburn Atlantic. Two questions. One, firstly, on more organic oncology modalities. Another one missing from the slide is radiopharma. I'd just be interested to get your perspectives on that. And then one for Azad, on multiple sclerosis. There's been a lot of work this year on the potential involvement of Epstein–Barr virus infection in MS. I'd be interested to get your thoughts on whether you see that as an opportunity or a threat to the MS franchise?

So is this working? Yes. So specifically on radiopharma, you as I mentioned at the beginning, we have engaged in a partnership with PeptiDream on novel targeting radio conjugates. And that certainly is a continued active area investigation. I think it -- there's the field of radio conjugates in general is an evolving field. That's certainly an area we're interested in, and that's an investment we are advancing as we continue to follow the field.

With regards to your second question about EBV, I think that's a really interesting development scientifically. We do not see it as a threat. The B-cell targeting approaches, for example, with OCREVUS, targeting B cells and B cell depletion. Most people think that actually, a lot of the way that the B cells work is more from an antigen presentation rather than autoantibodies, although that can be also involved with EBV, that is something the idea is that there would be auto antibodies to specific proteins. So I think it's a very interesting idea. There's a lot of interest in following up on this. One of the challenges will be, of course, a lot of people get EB virus, but only a few people get MS from that. So figuring that out is also going to be important. And that's really all of that means that it's going to be an opportunity. for us to build on.

Can you please pass it on to Luisa.

Luisa Hector from Berenberg. A couple of clarifications. On the 20 transformative medicines by the end of '29, I think that you said that started in 2020. How many have you launched so far? And Thomas, you also mentioned R&D flat next year. I just wanted to check that as a percentage of sales. And then lovely to see you all there, and thank you for your presentation. I'm wondering if all of you are poll voting over your bars very well with your internal assets and you all see exciting external assets. Is it Alan that gets to say no, we can't afford it? How is that final decision come to end -- come to be made?

So let me answer the first question around R&D flat. That's an absolute flat. So in percent, it will come down. So in percent of sales, it comes down. So similar as you can see it this year. So we just want to make sure that we make sure that our engine works extremely efficiently. That's the first thing. The second thing is when we assess the targets, I can tell you we have very -- often very late night calls -- many people in this group are then on these calls, depending on the topic plus then the scientists and so on, and then you get kind of an evaluation, how strong is the data and you get the financial component in. What does it mean in terms of what's the purchase price? Does it make sense from an NPV perspective and I would say we look at -- I don't know how many companies every year, but probably in the hundreds, if not thousands, and we say no to 99.9999%, right? Because we have to be firmly convinced that the science is strong. The data is strong. Oftentimes, we actually take the antibodies or these molecules in, we test them in-house to make because we don't only rely on other people's data. right? So we really do very thorough due diligence. And then if it also makes sense financially, then we say, okay, this is a good one. It makes a lot of sense, and then we go forward. So we are very, very disciplined. And I think it's a very strong team approach from key experts across the organization, maybe from people here, but also from finance, et cetera. So I mean the way we define transformational medicines, it's important to keep the bar high. If you look at how many we've launched per year, we've been launching 2 a year. But if we say what we consider transformation, then we would say we've launched 7 transformational, which still needs 13 to the end of the decade to launch. So the bar is high.

Peter?

Just 2 quick ones, please. First, just as a continuation of Louise' question actually, just to be clear on the R&D budget. So 2025 is flat in absolute terms, looking beyond 2025. Because it sounds like Manu's basically got an open checkbook. Not this respective -- everyone else is this kind of managing it, but equally, the pipeline is getting bigger, trial biomarkers are getting bigger. Can we just try to understand is R&D long term? Should we consider that a source of leverage or not? I guess is one view, Alan. And then secondly, just curious why the decision was made IBD and COPD is the focused disease areas. And I say that just because there's a lot of other areas in immunology, which a lot of people throughout this growth, HS, atopic dermatitis, you're not looking at and equally asthma, we've heard several times today. And actually, you're in asthma already, and yet you're not mentioning that. So curious what the decision was for IBD and COPD?

Alan, do you want to do the first question first and...

Sure, I'll take that. No, look, I think we have said 2024, '25, I think we keep R&D [indiscernible] I think that's really what we bring to the table at this stage. I think everything else, I think we have to look at and see how things develop. But I would argue that's already pretty strong commitment because it requires that we really reprioritize within the R&D budgets quite a bit. We have done quite some M&A transactions. And I think that certainly means we have to bring these things into the budget, if you like, and have to make room for it. How we did that, I think Levi went through it and said, okay, what did we do with the compounds and whatever. So I'm very confident that we can achieve this. But I think really, this applies to '24, '25.

Yes, let me just give 2 examples that we've shown you today. I showed you on how we became much more focused on our digital portfolio in the 4 segments. These are segments that enhance our products, both in pharma and diagnostics. So we're not venturing into something completely different. And with that, also harmonizing the platform, and so we saved $170 million. Now the other example that Levi brought up is on how we reduce the amount of CROs, we end -- work with them more end-to-end so that we reduce the white space. We talked about savings of $200 million. And so I can give you a couple of more examples, not all of them are public, where I can see that we have an opportunity to take money out of the system without actually not making smart decisions in terms of investments. So it's a way to reprioritize the money and be very diligent with how we spend the money. And I call those internally, no regret moves where we don't regret actually making those moves, and it will actually, I think, help the organization because if you do a lot of things and you don't focus enough, you actually slow down and by really focusing, you can accelerate, right. And there are things which we can do in a much more efficient way, and we take that one by one and make sure that we implement that. And that's over this time period. And with that, we prioritize the money to programs that we were just talking about, Tier 1A and so on and so forth.

And just on the disease question. So the 11 diseases that Teresa described this morning -- these are diseases where we feel like as a company, today, it makes sense to have end-to-end investment across the value chain, starting all the way from research, early development, late development, commercial, et cetera. And so -- but it doesn't mean that if there is an opportunity that target or pathway opens up in another disease that we're not going to invest there. So I think COPD or an asthma is a good example. I mean if we astegolimab, hopefully, it works. But there are other targets and pathways that are in our pipeline and that are of interest to us that could be relevant to COPD, so regardless of what happens with the as, I mean, we're very confident. But regardless, there are other opportunities, and we feel like because of that, it merits sort of an end-to-end investment. But we're not -- in no way is this sort of an implication that, oh, we wouldn't do something in asthma because it wasn't on that list. This is really about a framework for a prioritization of investments because you can't invest equally end-to-end across the value chain in every single disease even with the large investment like ours.

Okay. I think we have time for 1 more final question. I think Jo, I promised you one question. So.

Thank you. I've got one big picture question. A couple of clarifications and a challenge for you. So my first question is just a simple one. You've talked about having the backbone of therapy, particularly in things like obesity. When might we see an amylin on your development program. My main question, though, is to invite Alan and Thomas to be a bit more ambitious in terms of the growth rates going forward. So I think every other drug company that has the ability to say that it doesn't have major patent expiries before 2030 is telling us what its growth rate should be between now and 2030. You've done 5% recently in a time frame when you've had some big patent expiries that you've had to absorb. And you're telling us about this great pipeline. Can you put your money where your mouth is and give us some idea of what you think a target growth rate top line should be between now and 2030 for you considering your base business, what you can do perhaps to be better than that $6 billion of headwind, maybe you're reformulating things into subcut, et cetera, and making them grow longer? Just give us some idea of that growth rate going forward. And just while you're thinking about the answer my clarification question is prasinezumab. I believe you said that the data was at the end of this year, but we would hear the results next year. Do we get the top line this year and the full data next year? Or is it just so close to the end of the year when you actually get it that we may not hear prasinezumab until early 2025. And my challenge to you is when you next come back, can you bring more women?

Let me answer 2 questions first regarding more women. Just to say that if you look at the Corporate Executive Committee, which is the most senior team in Roche. We have more women and men on the team. So you can look at the website. You can see that we have more women and men. So if you take a selection of 5 or 6 people or 7 people, then it's not representing the entire company. I just want to say that. Also, when we look at metrics on D&I versus other companies, or the other pharma companies, we are pretty much on top of that list. Just wanted to put that into perspective. Now I know that there are companies that give out certain targets, some starting with 8 in the beginning. And then they have a sudden trials and sales and then everyone questions that, right? And we've had, I would say, a number of discussions with also investors and analysts where we said, okay, you want us to put out a target. Now most of them say, it's actually not very credible because you know that all the events are binary. And so you don't know exactly how things are going to develop. When you look at the graph that I showed at the beginning in terms of the consensus, we showed you that we believe that some of this is right. We believe that the CHF 7 billion seems to be ballpark the right figure in terms of biosimilar erosion over those 5 years period. When we talk about the 17 point-something billion, we believe that makes sense, except that there are other assets that are not in there yet. So you're already a net increase of CHF 10 billion and diagnostics will add at least CHF 1 billion every year after that. So you get a little bit to the ballpark where the middle ground is but we don't give, and we've never done that we give out a multiyear guidance. right? And again, we've discussed this multiply internally. We have discussed it externally. We don't -- what we give as an indication is the spectrum of what we believe that can happen. And you can see that we don't have a clear situation. And all the assets basically that we are launching will build on the growth momentum that we have. And that we can commit to. And then we'll see each trial that comes out. I mean we have very clear visibility for the next 3 years. But after that, it's really dependent on the readouts.

Can I chime in here.

Yes.

So I would argue, I think we -- compared to standards we have said in the past, I think we've said quite a bit already. I think, first of all, let me start with 2024. We have upped the guidance, I think, for 2024 at half year on the EPS side. I think we have said that we think kind of that momentum you can also expect in 2025 and -- and Thomas has even today said in his presentation that the margin that we achieved in '24 to the EBIT margin that we would like to defend that perhaps even improve it in 2025. I think we have said this. He said, that pharma will grow until 2027, '28, I think that was also something which was mentioned. And I think once again, you made the point about diagnostics, where we now with the 3 new technologies and do 3 new platforms that we bring to the market, that we have high expectations here, mid- to high single-digit growth for the foreseeable future. So I think there is much more granularity in these perspectives, if you like, compared to the past. And I can say that with conviction.

I can help answer that amylin question real quickly. So in the graph that I showed you, I mean, the unmet need of obesity, we certainly think that there is more room for other modalities. So -- it's not a question of if we should have 1 XY or Z. It's more about when is the right time to bring the right combinations and for what reasons are we doing that. So we believe that the current backbone is actually quite important. We need to prosecute on that first. The advantage of having a GLP-1 is a backbone is it's a very well validated mechanism, as you know. If we bring something else, all that validation has to go through yet again. But having said that, we are very open to looking at all things, whether it's gut hormones, whether it's modulators of energy expenditure, whether it's things that can be exercised in the medics, et cetera. So it's not a the pipeline that I showed you is just a snapshot in time for today. But we certainly expect that over the course of our building of this franchise, we will bring what is necessary or develop it internally if necessary.

We always guided for the fourth quarter. That's when we will have the data. And in case it would be material event, we would have a top line release data then to presented next year.

For the 2025, that was for sort of once we have the full picture and presented at scientific meeting.

I think with that, we are at the end of the second Q&A session and the broadcast part of the event. You still have 30 minutes with the management team at the upper row. Let me also take the opportunity here to thank all the many people who contributed to really make this event happen. I think it was a very busy September. So we really started when everyone was coming back from holidays. And from the IR team, I have to call out a couple of people, Jan-Philipp Schwarzhans, [ Jan Bayar ], who managed the morning sessions. And then for the afternoon sessions, we have[ Lauren Karl ], [ Manita Tang ], Richard Sally, Sabine Borngräber and Julia Bayer, who were managing all the afternoon sessions. And then from the back office as well, Melanie Wolf, Beatrice Hau and Eva Losert, who did all the event organization. There's, of course, many other people in the organization who continuously contributed in the last 4 weeks, which I could not all name now because it would be a long, long list, but also a big thank you to all the other silent contributors. And with that, I think we close the event. Thank you.