Roche Holding AG (ROG.SW) Earnings Call Transcript & Summary

So welcome to our Pharma Day 2025 here in London. It's good to see here full house. I was told we have, I think, a record attendance here on site, and we also have quite a high number, I think, of web participants. So let me quickly take you through today's agenda and make a few upfront remarks before we kick off the event. Regarding the agenda, we will have again 2 sessions. We have a 2 hours morning session focused on strategy and the 2 hours, 10 minutes afternoon session focused on the evolving pipelines of our 5 therapeutic areas. Both sessions include a 30 minutes Q&A at the end, where you will have the opportunity to ask all your questions here in the room and also via the web. Let's start with the morning session. So our first speaker, as you can see here, will be Teresa Graham, our Pharma CEO. She will provide an update on the pharma strategy based on our 5 therapeutic areas, and she will also take us through our well-established on-market portfolio. In addition, and for the first time, Teresa will focus also on our emerging obesity strategy, where we have made significant progress in building a leading portfolio with 2 major deals announced this year, the Zealand deal and just last week, the bio89 (sic) [ 89bio ] deal. The second speaker for the morning will be Levi Garraway, our CMO and Head of Global Product Development. Levi will build on last year's presentation, providing an update on our R&D excellence initiative, which was started now 2 years ago and which has had a tremendous impact on how we manage our pipeline portfolio and how we allocate our resources to achieve long-lasting success and to really make sure that we achieve the best outcomes for most patients. Let me also mention here, and I think you have a little card on your desks as well that we will have a fire alarm going off at exactly 11 a.m. This will be for 30 seconds. And there is no need from your side to rush out of the room. And just to be very clear and to avoid any rumors, I have not been behind this fire alarm to make sure our speakers stay in time, just want to avoid any mistakes here. And following the second -- so following these initial presents and the 30 seconds fire alarm, we will have the 30 minutes Q&A session. On stage, we then will be joined -- we'll have our speakers, but we also will be joined by Karsten Jung, our Global Head, Pharma Strategy; and by Morten Lammert, our Global Therapeutic Area Head for the CVRM franchise, who joined us from Novo. And there afterwards, we will go to lunch. Lunch will be 50 minutes from 11:30 to 12:20. At lunch, you will have the opportunity to meet all of our speakers and also our IR officers will be around. And we also will be joined by our sponsor, our CFO, Alan Hippe. After lunch, we will continue then with the deep dive sessions on our late-stage pipelines. So we have 5 sessions, one each for our therapeutic area. The first session, as you can see here, will be held by Charlie Fuchs, our Global Head of Oncology and Hematology Product Development, who will take us through the oncology/hematology pipelines and who will comment on our news of the day. As most of you have probably seen, we had a top line release out this morning on the positive Phase III evERA results for giredestrant in second-line plus hormone receptor-positive breast cancer in the post-CDK4/2 setting. Second speaker will be our Global Head of Neurology and Product Development, Hideki Garren. Hideki will provide us an update on some exciting pipeline projects, which have recently entered late-stage development. This is trontinemab in early and late Alzheimer's disease and prasinezumab in Parkinson's disease. He will also touch on exciting emerging early-stage assets like the gamma secretase modulator in Alzheimer's disease and the NLRP3 molecule in Parkinson's disease. The third speaker then will be Larry Tsai, our Global Head of Immunology Product Development, who will share with us an update on different B-cell depleting approaches developed for autoimmune diseases like lupus. These are CD20, CD19, CD3 bispecifics being tested or allogeneic CAR-Ts. And he will also provide an update on our TL1A development program, where we are exploring additional indications beyond the IBD and where we have taken the bispecific p40/TL1A into clinical development. Fourth speaker then is Chris Brittain, our Global Head of Ophthalmology Product Development. Chris has also some exciting early news to share. We just got data in-house for several studies and the data are currently still analyzed. There is data for vamikibart, Phase II/III in DME and UME. There's also the Phase III data for satralizumab in TED. These data are planned to be presented in the next few weeks at 2 conferences, ASOPRS and AAO, and we have also scheduled now an IR call for October 21, where we'll cover these data in more detail. And finally, to close with, we will have the presentation of Manu Chakravarthy, our Global Head of Cardiovascular, Renal and Metabolism Product Development. Manu will take us through the significant progress we have made over the last 12 months in building a leading obesity CVRM portfolio, creating a lot of development and combination optionality. And as you have seen, the latest add-on to this has been the deal announcement from last Thursday, acquiring bio89 (sic) [ 89bio ]with FGF21 analog in late-stage development for MASH Stages II, III, IV. After the closing remarks from Teresa, we will have a 30-minute Q&A with all speakers from the morning and afternoon sessions on stage, including Alan. And the event will then close at 2:30, but you are invited to stay around for a buffet reception. Let me also mention one more housekeeping item. As in previous year, we have again prepared a short 10 minutes feedback survey. The link to the survey will be shown to the participants in the webinar 50 minutes before the end of the event. Participants in the room will receive an e-mail roughly 1 hour after the event. We would very much appreciate if you could give us your feedback as we always strive to further improve. Then let me quickly go to my next slide. I just wanted to have this slide in here to remind you that Roche has consistently delivered strong top and bottom line growth over the last decade. This slide summarizes our sales development from 2015 to '24 at constant exchange rates. And what you see here is that we have delivered a 10-year CAGR for group sales, which has been plus 5%. And then if you look at the core EPS level, even a CAGR of plus 8%. Of course, reported numbers look slightly different since the Swiss franc has throughout this 10 years, continuously strength versus all other major currencies on the world. And let me also highlight here that during this period, we had to manage several challenges, especially the CHF 21 billion patent cliff in 2018. And by successfully managing this cliff through in-house innovation, we are now left with a rather fresh portfolio relative to many of our peers in the industry with currently 17 blockbusters on the market. And this brings me to my final slide. As you can see here in light blue, this is the segment of our current on-market Pharma portfolio, which now is expected to deliver growth until '28. So this is -- has been pushed out 1 year. Last year, we had communicated growth until '27. And after '28, actually, we expect this current on-market portfolio to be stable until the end of the decade. So this means our current growth products are expected to always compensate for any generic erosion occurring in this period, and there's no patent cliff forecasted. And Teresa will provide you some more details and an update on this on-market portfolio. You also see here 2 layers on top. In light gray, you see the expected contribution from the current in-house pipeline and in dark gray, additional contribution from future business development. The in-house pipeline, we'll discuss later today. And let me also quickly add here that we have made new epidemiology slides for our pipeline projects available on the IR homepage, so you can download them. To close, let me also quickly comment on the Dia division. As you know, we are quite optimistic on the long-term outlook, as we have a couple of launches ongoing and upcoming, including our unique mass spectrometry solution for the hospital setting. The launch of our CGM solution and our revolutionary -- truly revolutionary SBX next-generation sequencing solution. All of these are clearly blockbuster opportunities just to use Pharma slang here and to characterize the opportunity. And finally, one remark I have to place on group profitability. We have been continuously communicating we strive to keep the group margin at least -- defend the margin and keep the margin at least stable. And with that, I hand over to Teresa. Teresa, please.

So I have to admit I'm a little hurt that this fire alarm was about us not staying on time. So we will have to talk about that, Bruno, later. So thanks, everyone. Thank you, Bruno, and thanks to everyone who's joining us here in London live and also to everyone on the phone, and welcome to Pharma Day 2025. When we were together here last year, I shared with you for the first time our pharma strategy. And at that time, I also made a commitment to you about what you could expect to see from us at Roche going forward. And my commitment to you was that you would see rigor in the science and discipline in the business. And I think what we have to share with you today is going to draw a double underline under that commitment. We'll show you how the pharma strategy is doing exactly what we expected it to do to provide focus and clarity across the entire enterprise. R&D excellence continues to identify efficiencies and to allow us to accelerate our pipeline. As Bruno mentioned, through the course of the day, we're going to share with you how we are consistently applying the Bar across every aspect of our R&D organization, allowing us to make rigorous scientific decisions. We will share our laser focus on the commercial success of our on-market portfolio and how we're thinking about life cycle opportunities in each of these areas. We will show you how we are applying significant financial discipline across the entire enterprise and most importantly, how we are maintaining the culture that has always defined Roche and Genentech, allowing us to attract the best talent and develop the best science. So we have quite a morning ahead of us. As always, there's a lot to talk about, so let's go ahead and jump in. So I'm going to start with outlining a little bit of the progress that we've made since we were last here. So I'm sure all of you have printed out this slide and have it hanging above your desk in terms of what the 10-year ambitions are for Roche. We have committed to delivering 20 transformative medicines, addressing the areas of highest societal burden. We committed to increasing the value of our portfolio by 40% by ensuring that our portfolio continued to provide the best level of innovation with 80% of our pipeline having best-in-disease potential. And most importantly, because it is fundamentally here what we are here to do, we committed to treating 3x more patients with that transformational pipeline. So how are we doing? So in 2025, we're halfway there to our transformative medicines. We've launched 10, and we have more than 10 additional NMEs with transformational potential that could launch by the end of 2029, one of which we just received some very positive data on today with giredestrant, which Charlie will talk to you more about later this afternoon. And this does not include any potential BD deals that might be coming post 89bio. In terms of the value of our portfolio, we have actually overachieved what we had hoped to do. I'm definitely not going to complain about that. We've added 55% in terms of value to the portfolio with the average peak sales per pipeline project. In terms of innovation, we're on track. Today, 67% of our late-stage projects have best-in-disease potential, and that's an increase of 9% from when we first started talking to you about these things in 2023. Now when you look at access, you might say it feels like you're a little bit behind the curve here because we're at plus 40% versus our goal. But you have to remember that when you look at our pipeline, the majority of our large launch products that will treat significantly more patients launch more towards the latter half of the decade. And that's what gives me great confidence that we will still be able to achieve -- that we will still be achieving this goal. It's just a little bit more time shifted towards the back half of the time frame. So you can already see that we're making tremendous progress. So what else has happened since we were last together? You saw at half year that we posted 10% growth with our in-market portfolio, 13% COP growth at half year and 1.7% COP margin growth, discipline in the business. R&D excellence, 26% total portfolio value. 55% of NMEs are now post the bar, and we're fast tracking those assets that we believe have the most potential to help the most patients. Levi will talk a lot more about this in his section. And how are we pulling through the pharma strategy? All 5 of our TAs now have TA strategies that have been aligned to the overall pharma strategy, and we are in execution mode. Our 11 end-to-end disease areas are taking shape, and we will go through each -- we'll go through quite a number of them in the later part of the portfolio. And finally, we'll also be able to share with you a first look at our obesity strategy. So over the last 12 months, a tremendous amount has been accomplished, and we've done it with rigor, and we've done it with discipline. So now let's talk about that on-market portfolio with 17 blockbusters that we have in market today. Let's start, as always, with solid tumors. Our well-established HER2 breast cancer franchise is expected to peak in 2026. No change here with that strong tail. And as Bruno mentioned, no cliff. We also now expect with our positive data in giredestrant to be able to expand into the HR-positive breast cancer segment, again, the largest part of breast cancer overall. And our lung cancer franchise is also stable, but with some exciting potential with divarasib, which Charlie will go in later today. For hematology, we continue to have one of the most established portfolios in NHL with the potential to further improve that standard of care, as Polivy continues to entrench and the bispecifics continue to launch and as new indications are added. We also continue to maintain our leadership with Hemlibra in hemophilia A with a lovely life cycle extension with NXT007 entering late-stage development. And speaking of leadership, Ocrevus remains the undisputed leader in MS. The subcu launch is ongoing, and we are eagerly awaiting the fenebrutinib data end of this year, beginning of next. Evrysdi continues to lead in SMA, and we're excited about the opportunity to potentially launch into 2 very large additional diseases with Alzheimer's and Parkinson's, something Hideki will share much more with you about in his section. In terms of immunology, Xolair food allergy continues to do very well, strong uptake in food allergy and again, no biosimilars expected here until 2026. Gazyva, PDUFA is expected in October. I think you've heard -- many of you have heard me say over the years, I'm a big fan of Gazyva in immunology, and I'm excited to actually have this first indication onto the market. And then, of course, Vabysmo. Vabysmo is their foundational asset in establishing that leading position in ophthalmology, and it is absolutely redefining the standard of care in retinal diseases. And as you will hear from Chris later today, we have one of the most diverse pipelines in ophthalmology in terms of targets, MOAs, devices. We are clearly positioned for long-term leadership here in ophthalmology. And I always find this phrase a little funny, but even though it's not yet in the doughnut, our obesity profile. Maybe that joke plays better in America. We have an emerging obesity profile -- portfolio, and we have one of the broadest obesity profile -- portfolios out there, and we are well positioned for leadership in obesity, something we will talk about much more later today. So let's talk a little bit more about the numbers. We are delivering this best-in-disease portfolio with an amazing amount of financial discipline. If you look at our OpEx development over the last 3 years, we have steadily controlled costs, while increasing sales double digit. And that means that our margin development has been impressive. We focus on this every day. How are we spending our money? Are we spending it in the best places? Are we getting the best return? And are we redeploying those funds in the best possible way? So let's talk a little bit about our portfolio focus and the implementation of the bar. Roche has been and always will continue to be a company that is fundamentally grounded in following the science. But one of the most important things that the pharma strategy has allowed us to do, working in close concert with R&D excellence is to ensure that we are following the science with intention, that we are looking in those disease areas where we can help the most patients, where the science is most fruitful and where we believe we can have the biggest impact. And what allows us to make sure that we're making those decisions in a rigorous fashion end-to-end across our R&D portfolio, it's the application of the bar. So you can see the 5 Bar criteria here. Again, Levi will talk to them in a lot more detail in his section, but the Bar fundamentally defines what makes it into our portfolio and what advances in our portfolio. And it allows us to ensure that the R&D leaders across our entire organization have a consistent way to make those decisions. So what are those -- what does the outcome of those decisions look like? So today, 55% of our portfolio is now officially post bar. And you can see that these assets are really compelling and have significant sales potential. This is truly a rejuvenated portfolio from where we were 12 months ago and certainly from where we were 24 months ago. There are a lot of things on this list that you'll be familiar with, a couple with that you may not, cevostamab in relapsing remitting multiple myeloma. Again, Charlie will talk about this a little bit later today, but this has now been moved into Phase IIIs. And of course, you all saw this morning that CT-388 in obesity has also been advanced into Phase III, and Manu will talk about this a little bit later today. And then, of course, post-closing, pegozafermin for MASH will come into the portfolio as well. So a very nice range of assets across our core therapeutic areas, all with the potential to help a significant number of people and all with significant value. So some of this has happened through business development, and the Bar is also a critical part of how we assess opportunities in BD. So you can see across this slide a number of deals that we've done, all of which closely align to our end-to-end disease areas. 89bio coming in, very exciting addition to our CVRM therapeutic area; Zealand as well, very exciting deal to bring in a best-in-class amylin. But you can see we cover the gambit here, and we're very pleased with the assets -- we're very pleased with these assets and their opportunity to be best-in-class. So now let's take a little bit of a deeper look in each of our therapeutic areas and how we are defining where we want to play and how we intend to win. So as you know, the pharma strategy was introduced last year. And at that time, we defined clearly our 5 therapeutic areas. You can see them here. But I think what's really important to remember about these 5 therapeutic areas is that they constitute 60% of the total global burden of disease. They also represent 80% of where we believe growth is coming from in the pharmaceutical sector in the coming years. So we are targeted in the right place to help the most people. Currently, we have identified 11 disease areas in those 5 therapeutic areas that we are investing in end-to-end, all the way back from discovery to commercialization. This allows us to gain the kind of experience that leads to better judgment and scale and commercialization, which will be critical as we think about moving into the future. So let's start our deep dives as always, with oncology. The focus with oncology today is to strengthen our franchise through a very focused approach. We are focused on our end-to-end disease areas, breast cancer and lung cancer in solid tumor and malignant heme and hemophilia in hematology. And where we are intending to play or where we are intending to win is to find ways to accelerate innovation in the most effective way, depending on where -- which therapeutic area or which disease area that we're in. Breast cancer is probably our most well-developed end-to-end disease area in the portfolio. It's anchored certainly by our HER2 franchise, which, as I mentioned earlier today, is expected to remain the standard of care in the majority of early breast cancer settings. I think we've seen a lot of KOL feedback to this end. And the recent studies sort of indicate there is not going to be a one-size-fits-all solution for patients in breast cancer. Physicians are going to make very tailored and individualized decisions based on the need of these individual patients. And our HER2 portfolio is both well understood. It's well characterized. People are familiar with it, and they're very comfortable with its efficacy and its safety profile. Phesgo will play a big part in how this -- in how the HER2 program actually plays forward. We're currently at a 46% global conversion rate, and we are set on converting as many patients as possible. But of course, that expansion into hormone receptor positive breast cancer is something that we've been eager to do, and the positive results from this morning's evERA trial as announced, will enable that further expansion. So you can see we have a very strong on-market presence, and we have a robust breast cancer portfolio that Charlie will talk to you a little bit about later this afternoon. Moving on to malignant heme. This is another place where we are very much currently a leader. Polivy, first improvement in DLBCL in 20 years, raising the Bar on our own therapy, rituximab era. That's exactly what we love to do. We love to raise the Bar on ourselves. Polivy is establishing itself as the new standard of care. You can see these are the U.S. market shares. They continue to grow. And again, we have no doubt that over time, this is -- Polivy will be the treatment that the majority of patients with DLBCL receive. Our 2 bispecifics, Columvi and Lunsumio are rapidly differentiating themselves in the real world. Much like we expected, their individual profiles allow them to treat and reach different kinds of patients and are uniquely beneficial to health systems in different ways. This will only become more evident as we move into earlier lines of treatment. And finally, as you'll hear more about this afternoon, we are expanding into multiple myeloma with cevostamab and our allogeneic CAR-T programs. Multiple myeloma, very significant patient population, a significant amount of continued unmet need, and we think we have several assets here that could really make a difference. And no discussion of hematology is complete without talking about Hemlibra in hemophilia A, the undisputed standard of care around the world, more than 30,000 patients on treatment currently. We all know that it has around 80% of patients who are not experiencing bleeds without Factor VIII inhibitors, and this is supported by a tremendous amount of real-world evidence and experience. We're very excited to be moving the next generation of this molecule forward with NXT007. And we have just moved that into Phase III, including a trial that will go head-to-head against Hemlibra. We also recognize that in any chronic disease, convenience for patients is extremely important. And so we plan to bring an auto-injector forward not only for Hemlibra, but also for NXT007 to ensure that we can help patients have as convenient a therapy as possible. Moving on now to neurology, where, again, we are already the leader. And our goal is to extend that leadership position. And where we want to actually extend it is into preventative neurology, actually helping patients prevent progression into severe neurological symptoms. We also are very keen to work closely with our Dia colleagues to ensure that we are creating an end-to-end integrated journey for these patients. And this is one of the disease areas, as you'll hear from Hideki later today, that we're probably the most far along in that partnership between pharma and dia. We have 2 end-to-end disease areas, unsurprisingly, MS and Alzheimer's, but we're very encouraged by the data that we have seen out of prasinezumab for Parkinson's and are eager to see what that Phase III data holds. The MS franchise, clearly, the cornerstone of that is Ocrevus, firmly established as the global standard of care, more than 420,000 patients treated globally, and its reach just continues to grow. We are, of course, in the middle of the subcut launch. We now have more than 12,000 patients on treatment. 50% of those are new to brand. And we are rapidly moving into development with our new device, an on-body injector with a high concentration of Ocrevus that will hopefully allow at-home treatment twice a year every 6 months. And again, I think we should never forget when we talk about life cycle for Ocrevus, we are always also talking about extending that convenience. Treat your MS today with subcut 10 minutes twice a year. That's a very compelling message for patients. Launch of the on-body auto-injector would be projected in 2028, and it is our intent to convert as many of our IV patients as possible to subcut and then subsequently to the on-body injector. Fenebrutinib has the potential as a very selective oral BTK to be very disruptive in the MS segment, and we're very much looking forward to that data. Switching over to immunology. Immunology is a really unique area of science. And our goal here is not only to maximize the individual indications that we have with drugs like TL1A, but to actually leverage those mechanisms across different TAs. And so leadership for us in oncology -- I'm sorry, in immunology, not only means being successful in specific disease areas, but how those mechanisms may actually also allow us to grow into different therapeutic areas. Our end-to-end disease areas here are IBD and COPD, but I want to call out here the pan-immuno pathways, TL1A, CD20, CD19, OSMR. These are pathways that we are very early looking at not only in immunology, but how they apply in different parts of the portfolio. Immunology today, of course, Xolair is the star in this portfolio right now. You can see the growth in food allergy just continues. As I mentioned before, no biosimilars expected until 2026. Gazyva in LN showed superiority over the standard of care. Lupus nephritis is a devastating disease, extremely serious. We believe we can help many, many patients with Gazyva in lupus nephritis. And again, that PDUFA is set for October. Moving on to ophthalmology, where Vabysmo is clearly paving the way to a leadership position. We have a broadly diversified pipeline that has significant transformational potential. We intend to be a big player in retinal vein disease for many, many years to come, but would also like to expand into other therapeutic areas, including geographic atrophy and dry eye. Of course, winning in ophthalmology is a lot about how we win commercially today with Vabysmo. And so let's look a little bit at what's happening in Vabysmo in ophthalmology today. So clearly, there are challenges in the U.S. commercial market. The dynamics that we reported at half year are largely unchanged, but Vabysmo continues to gain market share in the branded segment in naive patients. And that is precisely what we needed to do. There has also been new clinical data that was just recently presented that continues to reinforce strong efficacy and demonstrates the ability to get out from a duration perspective to intervals up to 5 months. Chris will talk to you a lot more about the additional data that we have now in ophthalmology. But you can see, again, we have a large portfolio and one that is very diversified relative to competition. And so we are really excited about the ability to be a player in ophthalmology very long term and to maintain that leadership position. And finally, moving on to CVRM. Our ambition here is to be a strong entrant before 2030 with competitive products. We intend to differentiate by using the unique capabilities of Roche, and we're going to talk a lot about that in the next couple of minutes. And our goal is to become a top 3 player. And I want you to know that I am serious about this goal. I believe we have the pipeline, I believe we have the commercial capabilities. And most importantly, I believe we have the will. The end-to-end disease area here, of course, is obesity, but there are numerous places that we are looking at breakthrough innovation, including MASH. So why do I believe that we can do this because I do. A, we've done it before. MS, hemophilia, SMA, retinal vein disease, we know how to enter new markets, we know how to understand our customers. We know how to understand our patients, we know how to understand ways to drive to market that actually allow us to do that efficiently and effectively. And while the disease areas that we are headed into are larger, and we know that they will require us to do things differently and at a different scale, I am just as convinced in our ability to make it happen. So how are we going to succeed? When we were at -- when we were in London last year, we talked about the core capabilities that were resonant within the pharma strategy, and there were 6 of them. All 6 of these are going to be necessary for us to succeed not only in obesity, but frankly, in all of our disease areas going forward. And we have made significant progress in all of these areas in just the last 12 months. I'm going to start with R&D and manufacturing. As you well know, pharma and dia have the full value chain in the U.S. It has always been our belief as a company that you should manufacture your products close to the people who need to use them. We recently expressed our commitment to invest $50 billion into the U.S. until the end of the decade. And that includes importantly, one manufacturing site in Holly Springs, North Carolina, where we have already broken ground and a site in Boston, which is focused on R&D and AI and ML and CVRM. All of our key medicines are already produced today in the U.S. with the tech transfer for the one remaining product well underway. And as you all know, we have a high level of flexibility in our very large and diverse manufacturing chain. And because we have invested so significantly in the productivity of our manufacturing organization over the last number of years, it means when you look at our existing capacity in the U.S., we are at less than 50% capacity, which means we have a lot of opportunity to continue to grow in the U.S. with the facilities that we have and the ones that we continue to invest in. And I call out that when we are a company that actually never left the U.S. We stayed when we acquired Genentech. So that footprint is very much there, and all of the IP for medicines invented in the U.S. is held in the U.S. But one of the things that has been key to many of the investments that we've made in our Pharma Technical organization and part of the reasons that we've been able to see such efficiencies over time is our investment in data analytics and AI in Pharma Technical. We have spent a lot of time thinking end-to-end across Pharma Technical about ways that technology can actually help us speed delivery to patients, avoid costs and continue to make our processes more robust. We have invested significantly in these areas, and we can see those benefits today. Our tech times have dropped. Our output yield is up by more than 10%. We can generate required reports faster than we have ever been able to do before, which frees up time to do many more value-added things. And we've been able to reduce our CapEx because we can actually do more with the facilities that we have. So this is a really practical application of data and AI in a way that has real fundamental impact on our business every day. Related to manufacturing is our investment in devices. So again, you heard me talk last year about the fact that 60% of our current portfolio is going to require a device. We need to be able to manufacture various kinds of devices for different uses at scale. In order to do that, we are moving to a device -- a drug delivery device platform, which will allow us to be able to do this much, much more quickly. We've already identified the first 4, the auto-injector needle safety device, the ophthalmologic prefilled syringe and then our intravitreal device. There will be several more that will be added. But these are going to be critical to ensuring that when we have a product that requires a device, we can get it very quickly into trials. Part of what will allow us to do that is the investment in a device pilot facility in Basel for medical devices and drug delivery components. This is going to give us a platform where we can actually look at how we do this at scale before we actually have to move into big manufacturing facilities. That's the old building, by the way, in case you were thinking it didn't look very impressive. That's going to be replaced with the new building. That's just the site. We are also leveraging AI in different parts of our business. Right now, in the commercial and medical organizations, we are singularly focused on making sure that we have one of the most robust customer engagement models in the industry powered by AI, allowing us to look across the globe at how our customers are reacting, what they're doing, what that means and how we can inform decisions going forward. This will remove a lot of manual work out of the system, which is great, but really what it does is it makes the people on the ground vastly more effective and efficient. And that means we can continue to deliver more medicine, to more patients more economically. These AI solutions will also help us continue to increase our share of voice, which as you enter into more and more highly competitive markets is critically important. But of course, all of this is just so many words on a piece of paper unless you actually have the most talented people in the industry working in your organization dedicated to making change. Culture has always been a significant part of what makes Roche and Genentech, Roche and Genentech. And we are singularly committed to making sure that we continue to be an attractive employer, that we drive to be the most high-performing organization that we can be and that our ways of working continually elevate us in the industry. Our people strategy is critically important to making that happen. And we are constantly looking to make sure that we are identifying the needs of the organization, where do we need critical experiences and competencies that we don't have today and how are we bringing them into the organization. And you'll see a wonderful example of that in a little bit when Morten joins us on stage. So I know many of you have been waiting for this, which is a look at our obesity strategy and how we intend to become a top 3 player in obesity. We firmly believe that our capabilities strongly position us to deliver in obesity. And that there are 5 capabilities that are going to be critical in order to make that happen, that we have a best-in-disease portfolio, that we're able to leverage the synergies across our TAs, that we have an appropriate manufacturing and supply chain, that we have a highly efficient and effective global commercial footprint and that we are maximizing our partnership with dia to create a meaningful end-to-end patient journey. Now Manu is going to talk to you about the end-to-end patient journey, so I won't make you listen to that twice. We've talked a little bit about the global commercial footprint, and we've also talked about manufacturing and supply. So in my talk here, I'm going to focus primarily on how we believe the obesity market looks today, how we think it is going to evolve and fragment and then why we believe we have a right to win in this space. So let's start with the obvious. Obesity is different from the other areas that we're in at Roche. The patient is the key decision driver. There's actually a multitrack system for how patients get their prescriptions. So you're not talking with just one type of physician, you have to talk with multiple types of physicians. In many parts of the world, obesity isn't even established as a chronic condition, which means there is no reimbursement. But yet it is of unprecedented size and scale, something that we have not seen in the industry before. And there is a deep amount of heterogeneity and fragmentation that results from all of these components. So let's start by actually -- let's start by looking a little bit about the patient journey. In the U.S. today, 55% of patients are actually the ones showing up at the doctor's office and asking to be put on an anti-obesity medication. And they do that for a variety of different reasons. It may be about their health and making sure that they can address things that are physically troubling. It could be emotional and about their psychological well-being or it could be that they have a lifestyle goal that they wish to achieve. But the reality is every patient shows up for a different reason with a different ask of their physician. And they show up to different kinds of physicians. 88% of the time in the U.S., they show up to their primary care physician. The rest of the time, they're showing up to an endocrinologist or some other kind of specialist. And why is this actually so important? Well, it's so important because depending on the kind of physician you are, you're going to ask a different set of questions about why that patient is there. And you're going to care differently about the treatment that you select based on how you're evaluating that patient and any potential comorbidity that they may have. If you go to an endocrinologist, chances are first thing they're going to care about is diabetes, then cardiovascular, then potentially renal, probably true for GPs as well. Cardiologists, mostly going to care about the heart. And then they'll also think about type 2 diabetes and renal involvement. But what that means is that every patient is on a different journey and every physician is going to have a different set of questions. And even when they align on the fact that an anti-obesity medicine is appropriate and they make the selection as to which one they're going to go on, there is actually no guarantee that, that prescription gets filled. Again, focusing on the U.S. just because this is where the most data is available, obesity is already identified as a chronic disease. Reimbursement is available, but 33% of the time, a patient who has been deemed appropriate and received a prescription will actually not get a drug reimbursed. They will have to pay out of pocket, which means there is a significant out-of-pocket component to this market, not only globally, where I think is where we relatively always talk about it, but also in the U.S. So when you're talking about a cash market, that is also a different thing that you have to think about commercially. Now we also mentioned the size and the scale of obesity, which I think everybody understands, but I think this chart does a great job of identifying how many people in the world today are actually eligible for treatment. 51% of the global population will either be overweight or obese by 2025. That is truly an epidemic. That is a massive amount of people who are at higher risk for significant comorbidities and mortality. And yet today, with the treatments that we have, we see a relatively small amount of people with obesity are actually being treated, about 10% or 15% and the mean BMI of those patients being treated is 39. So you have a relatively small percentage of your most heavyweight patients being treated, leaving a tremendous amount of potential opportunity for patients who could benefit, but for whatever reason, are not receiving therapy today. This leads to a market which is exceptionally fragmented. And there are many different ways in which that fragmentation could actually present itself in the commercial setting. Many different drivers of why a patient or a physician would potentially choose any given therapy. But I want to start by talking about comorbidity management because from a human health perspective, this is a very significant one. And we know that patients with higher BMIs have many more comorbidities. Over 70% of patients with just one -- 70% of patients living with obesity today have already one comorbidity, and that number dramatically increases as BMI increases. And so what does that mean? It means that obesity is a major risk factor for over 220 different diseases. All of these diseases have significant impact on human health. And it should be noted that we are one of the only companies that has treatments in a lot of these diseases. So not only do we have the ability to help patients with overweight or obesity, but we also have the opportunity to look across our therapeutic areas and see how we could potentially combine different therapies together to actually address some of the most significant health needs that patients have. That is something that is materially different about our portfolio relative to the rest of the industry. And that patient-centric approach is going to be really critical moving forward. So these are just 3 different types of potential patients who could show up at a doctor's office. There's the patient who is overweight and eligible for an anti-obesity medication, but is probably not morbidly obese, but still eligible. There are people who have an early sort of diagnosis of obesity, Class I with some comorbidity. And then there are Class II to III that have high-risk obesity. What these patients are looking for and what their physicians need to treat them with is very different. And if you -- just to orient you to this slide, if something is bright green, that means it is of highest interest to that patient. So unsurprisingly, if you think of depth of weight loss, that's actually most important to people who are at highest risk, for the people who are the heaviest who need the most weight loss. But they're not as interested in how quickly they lose it because they're on this journey for a longer period of time. For those people who are potentially looking to lose less weight and have fewer comorbidities, you can see that speed to weight loss is much more important. Tolerability is much more important. Convenience is much more important because they have a very different set of treatment goals than the people on the other side of the spectrum. And what's exciting for me is that our portfolio allows us to address all of these patients. Now it's undeniable that incretins have unlocked a new era in the treatment of obesity. If you look in the past decade, this was a relatively smallish market at less -- at about $6 billion. But we hit an inflection point with the GLPs coming into the market in force. And we're now looking at a significantly larger market a significantly larger market and significantly more options for patients -- or more options for patients. But the reality is that in the real world, there is still a lot of unmet need. Treatment persistence, as you guys know, is a big problem. The share of patients who are able to get to that higher dose -- highest dose and be able to experience all the weight loss they want to see, not able to be done so much. And actual weight loss is often below target because of those 2 things. So whatever comes next is going to have to address that remaining unmet need. And we've identified 6 things that we think are going to be really critical to whatever comes next to addressing that unmet need, tolerability. We all know that nausea and vomiting are major drivers of discontinuation, particularly as you think about those patients who are in the lower -- have the lower desire for weight loss spectrum. The ceiling effect on weight loss. Most patients plateau after 12 to 18 months. They never get to their target weight. Weight maintenance, even if you lose the weight, once you stop treatment, the weight comes right back. And because it's not -- and because many patients don't find existing treatments tolerable, it's harder for them to stay on longer term. We've talked extensively about the comorbidities and the need to treat those as well as to treat the underlying weight problem. Lean muscle mass loss, again, you guys know this, 40% of weight loss comes from muscle loss. That's less optimal, clearly. We want to find ways to preserve that lean muscle. And then less talked about, there's about 20% of patients who actually have no or suboptimal response to these treatments. And so the existing treatments actually aren't working for them and that's where our portfolio comes in. Our differentiation potential relies on having that breadth of options to address all of the different patient needs. From petrelintide to CT-388 and monotherapy to all of the different kinds of combination therapies, we can cover the breadth of this unmet need completely. And that's not even talking about the opportunities to actually look forward into ways to combine to address comorbidities. So to sum it up, our capabilities strongly position us to deliver here from multiple pipeline assets with best-in-class and best-in-disease potential to the ability to leverage the synergies across the portfolio, our global robust manufacturing network, our presence in more than 150 countries around the world with our global commercial footprint and of course, our very unique ability to leverage our pharma and dia connection, we believe that those capabilities in total, executed correctly will allow us to become a top 3 player in obesity, and we are committed to making that happen. Now to close out on future growth opportunities, these are the new 8 NMEs that are new to Phase III in 2025. I think we've talked about all of these, again, just to call out the addition of pegozafermin in MASH, our newest addition after closing and cevostamab in relapsing remitting as well as CT-388 moving into Phase III. You've all seen the consensus slide before, but just to reorient you to it, after half year, we went and took a look at what the consensus was saying. In 2024, this is sort of where people believe we are in terms of sales -- or where we were in terms of sales. In 2029, if you look at consensus, it looks like we have a gap of about CHF 6 billion related to loss of exclusivity. This is primarily Xolair, Actemra, Perjeta and Kadcyla. But if you then look at where consensus says we have growth opportunity in that same time period, consensus says we can grow by CHF 12.9 billion. There is a lot of opportunity in our pipeline. And by the way, there is a significant number of things in our pipeline, including many of the things that I've talked to you about today that aren't even included in consensus in a meaningful way today. Our cardiovascular and metabolism assets in general are not yet included in models. There are a number of things in the oncology, neurology, immunology and ophthalmology franchises as well that are currently not represented. And so we believe the true value of our pipeline is actually quite underestimated. And why do I say that? Because by 2030, we have the opportunity to launch up to 18 new NMEs. And that includes 15 NMEs with blockbuster potential. We are well set up within our 5 therapeutic areas to continue to diversify and add leadership in the areas that we know will matter most to patients. And importantly, we have the skills and capabilities and resources in order to ensure that we will make those launches successful and that we will reach the number of patients across the world, who deserve to be reached. Before I turn it over to Levi, I just want to reiterate what I started with. As an organization, we are committed to bringing transformational medicines to patients. And we are committed to doing that in a way that is uniquely Roche. I am committed to continuing to deliver rigor in the science and discipline in the business to ensure that when we're standing here next year and we're able to share the advancements that we've made, we're continuing to make progress at an even faster clip than we have today. So I hope you'll agree, a lot has happened in 12 months. We're very pleased with where we are, and we're also very excited about the opportunities ahead. And with that, I will turn it over to my colleague, Levi Garraway, to talk to you more about R&D excellence. Thank you.

Well, good morning, everyone. It's always a privilege to have the opportunity to describe our pipeline progress to the investor community. So as Teresa mentioned, I'll provide an update on R&D excellence, which actually we first rolled that out here at Pharma Day a couple of years ago. And then after launch, of course, our 5 therapeutic area heads will provide deeper dives into specific programs. Now by way of reminder, our overarching objectives for R&D excellence are twofold. So first, we want to deliver many more transformative medicines to the world. And second, we want to become one of the most productive R&D engines in the industry as measured and evidenced by top quartile performance. And here are the solutions that we've been implementing over the past 2 years to achieve these objectives. And 3 solutions, which are shown at the top of the slide, are focused on expanding the transformative potential of our pipeline. And I'll delve fairly deeply into each of these. Two other solutions are about improving the efficiency of our R&D engine, and then one is focused on incentivizing the organization to perform in this way. Now in addition, streamlining our system landscape and our data foundation, of course, that's also necessary to make sure everything works well. And that effort has essentially become a seventh R&D excellence solution. So I'll touch on that briefly at the end. Now a key premise for R&D excellence is that if you want to deliver transformative medicines, you need a pipeline that consists exclusively of assets that are capable of becoming such medicines. And of course, that's easier said than done because most therapeutic candidates fail. But on the other hand, pharma R&D pipelines do obey the power law. So that means that although most fail completely, some become medicines that are so impactful that they truly transform the lives of patients. And so we must intentionally identify candidates with that type of potential wherever they might be found along the R&D continuum. And that's where the Bar comes in. So the Bar is an evaluative framework that we developed a couple of years ago to describe the essential characteristics of transformative medicines. And we've now applied the Bar end-to-end across our R&D pipeline. And so that has allowed us to identify and prioritize assets that do have transformative potential, but also to attrit and deprioritize those that do not. And the Bar consists of 5 criteria, which I'll come back to actually several of them over the course of this presentation. And none of them are particularly surprising in and of themselves, but each of them must be met if a medicine is going to have transformative impact. So first of all, the drug must answer a clear unmet need, and that need would have, of course, become addressable through advances in disease biology and understanding. And second, it must engage a foundational target. So that means a protein or pathway that drives disease pathophysiology or the salient clinical manifestations. The third is that the asset must possess worthy pharmacologic characteristics compared to other contenders that are out there. And fourth, it must be able to achieve meaningful therapeutic differentiation. And finally, the medicine must unlock a path to value. And first and foremost, that's value for the patients being treated, but also value for the company that delivers the medicine to the world. And so adoption of the Bar end-to-end has now become business as usual across Roche Pharma R&D. Now one way to visualize the impact of the Bar is through our pipeline evolution at the NME level. And 2 years ago, our pipeline consisted of 81 publicly disclosed NMEs. So you can see that on the left. Today, we have 20% fewer NMEs, 65 instead of 81. But we've been quite active in sculpting our pipeline during that interval. So on the one hand, the initial application of the Bar in 2024 brought a fair bit of pipeline attrition, and we expected that. However, we've also achieved many pipeline additions either through our internal pipeline or from business development deals. And those pipeline additions are starting to mature nicely, especially in our late-stage pipeline. As you just heard from Teresa, we're on track to progress quite a large number of NMEs into our Phase III portfolio in 2025. We've actually done 8 thus far, and there might be still other opportunities before the calendar year ends. So having applied the bar, although we have fewer overall NMEs today than we did 2 years ago, the quality of our NMEs seems to be increasing as we had hoped. And 2 examples specifically illustrate this point. First, the percentage of projects that we believe could have best-in-disease potential has increased to 67% of pipeline projects, up from 58% just 18 months earlier. And also the projected average peak sales per pipeline asset has increased by more than 60% to CHF 1.3 billion. And in keeping with average peak sales estimates, overall portfolio value estimates have also increased significantly. Now one of the most important questions that we can ask is whether application of the Bar is improving our success rates. And of course, it will be several years before we know for sure, but one possible leading indicator is the impact on team assessed probability of technical success for our Phase III trials. And so here, we're looking at a plot of pipeline projects for which the decision to initiate pivotal trials happened prior to application of the bar. And team assessed PTS is shown directionally on the Y-axis, adjusted net present value is shown also directionally on the X-axis. Now for obvious reasons, we're not disclosing the actual names and values. But the graph shows that several of these projects had either a team assessed PTS or an adjusted NPV that was lower than we would like to see. And in some cases, actually both of those things were true. So that -- those are the dots in the lower left-hand quadrant. All right. Now let's overlay the projects that underwent pivotal trial go decisions after introduction of the Bar. These are the dark blue dots. And you can see that a much larger proportion of these Phase III projects has a team assessed PTS within our target range, so above the center horizontal line compared to what we were seeing before application of the Bar. And most of these projects have a much more robust adjusted NPV than what we were seeing before. And actually, even for the couple of cases where the PTS still seems maybe kind of border line, they're actually -- there are sometimes additional upcoming data cuts that could push the final assessment upward. So it's still early days, but we can already draw 2 conclusions from the results that I've just described. First, adoption of the Bar has been successful. And second, it appears to be having the desired effect, both on pipeline quality and the potential for future Phase III trial success. All right. Another important R&D excellence solution was to reconfigure our portfolio management and governance so that it would be centered entirely around executing the Bar effectively. And implementing this solution has required multiple changes, one of which was to establish cross-cutting review boards. So these are panels of functional experts who provide critical assessments at key points along the molecule journey. So we have development boards. They focus on asset strategies and clinical development plans. And then we have business boards, which assess key commercial drivers and risks. And all of these review boards are jointly chaired by leaders from early-stage and late-stage R&D. So that ensures the end-to-end cohesiveness that we're looking for. And these boards have been highly successful. So teams are benefiting from rigorous reviews, but they're also preserving the speed necessary to ensure that programs are competitively positioned. Now another change, which is summarized along the bottom left, involves the creation of what we call one asset teams. So once a molecule demonstrates proof of concept, so in Phase Ib, for example, we form a single team that will guide that asset through the remainder of its development and eventually its life cycle. And the team has membership from both early and late development and the membership evolves over time with the needs of the asset. Now we've also created an enterprise-level pharma portfolio team that includes several members of the Corporate Executive Committee, including several people who are here today. And this group meets regularly to make holistic assessments of our end-to-end portfolio health from research all the way through late-stage development. And this can include composite assessments of the Bar. You can talk about volume at various stages, risks, strategic fit, et cetera. And these frameworks inform broader strategic considerations to shape the near-term or the longer-term shaping of the pipeline. Now this is the changes to portfolio management and to governance, this is all well and good, but how do we know that these are evaluating the quality of our decision-making. And again, the ultimate proof will be in the delivery of transformative medicines. However, we can give you at least a flavor of the thought process around some recent pivotal go decisions. Now one thing I want to emphasize first off is a desired outcome of reconfigured end-to-end governance is to ensure that we generate early clinical data sets that are sufficiently robust to inform optimal Phase III decisions. So in the past, sometimes competitive pressures to move quickly made it challenging to fully derisk certain programs early in development. And so that meant that our Phase III pipeline was carrying extra risk, and we unfortunately saw that play out with more disappointments than we would like at times. But going forward, one goal here is to generate enough data early on to learn not only whether to do a Phase III trial, but also how to design one that is maximally likely to be positive. So zilebesiran on this slide is a good example. Our partner, Alnylam, completed 3 Phase II trials of zilebesiran in hypertension. Now Manu is going to discuss the trials this afternoon, but it's actually unusual to have that much Phase II trial data available, but we were actually quite glad to have it. Now when the first trial, KARDIA-1 read out, we gained confidence that zilebesiran engaged its foundational target, angiotensinogen very effectively. So that's obviously a Bar criteria. And then the second trial, KARDIA-2, taught us that zilebesiran could lower blood pressure meaningfully when combined actually with 3 different types of blood pressure medicines, but its effect was particularly pronounced in combination with a diuretic. So KARDIA-1 and KARDIA-2 taught us that zilebesiran had worthy pharmacologic characteristics, another Bar criteria. But there were still important unanswered questions, including the right dose, whether zilebesiran would work safely in combination with multiple medicines and the exact population of patients to study in a cardiovascular outcomes trial. So we ran KARDIA-3 to help resolve those questions. And in KARDIA-3, the zilebesiran effect on blood pressure was greatest once again in the subset of patients, who are on a diuretic. But very importantly, we also learned that zilebesiran works best in people whose hypertension is clearly uncontrolled at the time of enrollment. And this actually makes sense because if your blood pressure is already adequately controlled, you don't really benefit from adding another medicine. And of course, if people whose blood pressure is already adequately controlled, make their way into a clinical trial, the risk of a type 2 error increases. So that means you falsely conclude that a blood pressure medicine is less effective than it actually is. So the big picture is because of the full KARDIA Phase II data set, we can feel confident in the ability of zilebesiran to achieve meaningful therapeutic differentiation when studied with the right treatment combination and in the right patient population. In other words, the robust early clinical data here has taught us how to design a Phase III trial that has a good chance of working. Now prasinezumab is another example of the importance of having a robust Phase II data set to guide both decision-making and design of a confirmatory Phase III trial. And for context, there are no disease-modifying treatments for Parkinson's disease and really only a few options for symptomatic relief. So the unmet need is very high. Now the first Phase II trial we conducted, which is the PASADENA trial, was suggestive of possible benefit, but it was hard to be sure that those results by themselves weren't simply due to chance. So we did another much larger Phase II trial, the PADOVA trial to further explore the signal that was seen in PASADENA, but also to assess how prasinezumab might perform in combination with medicines such as L-DOPA, which are commonly used for symptom relief in Parkinson's. Now Hideki is going to describe these data this afternoon, but the results were certainly supportive of the hypothesis that prasinezumab could bring a meaningful therapeutic benefit and the effect was even more pronounced in combination with L-DOPA. So when you take the entire Phase II data set together, prasinezumab shows a consistent efficacy signal. It looks safe, and we learned that combining prasinezumab with standard of care L-DOPA has a reasonable chance to show clinical benefit in a well-powered Phase III trial. Now of course, early clinical data sets don't always need to be that large to be highly convincing, and trontinemab provides evidence for that. Pathologic beta amyloid, we all know, clearly, it's a foundational target. And yet the existing treatment options have still barely made a dent in the unmet need surrounding Alzheimer's disease. Hideki, again, will describe the data for trontinemab later, but already even in Phase Ib, it became evident that trontinemab possessed worthy pharmacologic characteristics that offer the potential for meaningful therapeutic differentiation because we're seeing rapid and deep clearance of amyloid plaques, more than 90% of patients have become PET negative after several months. And the safety profile is encouraging, less than 5% incidence of ARIA-E after 28 weeks. So -- based on the Phase Ib/IIa trial results, we already felt confident to ungate Phase III trials, both in early Alzheimer's disease, but also in the preclinical Alzheimer's disease setting, where we'll see if we can prevent or delay progression in patients who have beta-amyloid plaque deposition, but do not yet show symptoms of cognitive decline. So hopefully, these 3 examples make it clear that configuring our decision-making around the bar and ensuring robust clinical data are enabling a data-driven approach to design confirmatory Phase III trials that have a good likelihood of being successful. All right. The next R&D excellence solution, I'll touch on briefly, involves accessing the best external innovation. And when the concept of the bar emerged 2 years ago, a vision that we had was that we would invest in candidate medicines that cleared the bar wherever they might be found, whether from our internal pipeline or the external biopharma landscape. Now for this to be feasible in practice, we needed to make several adjustments in terms of how we support pharma partnering across our organizations and vice versa. And although we're certainly not done, it's fair to say that the business development results thus far speak for themselves. The clearest example, of course, is in our cardiovascular, renal and metabolism therapeutic area. And as you've already heard, this progress was, of course, anchored by partnerships with Alnylam and with Zealand and through acquisitions of Carmot and now 89bio pending successful closure. But equally, our other therapeutic areas have also been enhanced as evidenced, for example, by the Zion and the Rigor -- Rigor and Poseida deals in oncology. And Poseida, by the way, also opens a potential door for allogeneic cell therapy in multiple sclerosis. And then we have acquisition of Telavant, which brought afimkibart into our immunology therapeutic area. And then there is the AntlerA deal, which boosted our ophthalmology pipeline. And so overall, we're leveraging internal and external innovation to architect a pipeline that is enriched with candidates that can become transformative medicines. Now in my remaining time, I'll highlight our progress on the second overarching R&D excellence objective, which is to achieve top-tier productivity. And here, one of our solutions involves embracing ambitious productivity objectives. Now just to remind you, there are 5 key components of R&D productivity. You have volume, value and success rates on the one hand, which defines the effectiveness of an R&D engine. And you have cost and cycle time, which describes the efficiency of the engine. And the bottom line here is that we remain on track towards our 2030 ambitions for each of these components. For example, we've added 29 assets to our pipeline since we launched R&D excellence, including 12 thus far in 2025. I already described the increase in average peak sales for pipeline asset. On the efficiency side, we've reallocated approximately CHF 1.2 billion towards programs that meet the bar and also to other productivity initiatives. And we've done that while keeping our overall R&D investment flat since the end of 2023. And we're on track to achieve a significant acceleration in our end-to-end cycle times. Of course, we can't yet quantify Phase III trial success rates, but I've shown you that the team assessed probabilities of technical success have already increased substantially. So based on progress across these 5 components, our R&D productivity seems to be moving in the right direction. Now the ultimate proof for increased R&D productivity will require a meaningful reduction in R&D spend per NME launch, and it will take years to show that conclusively. However, we do see some preliminary evidence that this might be starting to happen. In the graph on the left of this slide, we're looking at R&D spend per NME launch for Roche together with 11 peer companies, and we're looking at this across 2 adjacent partially overlapping 5-year windows. And overall, across the peer group, the average spend per NME launch has increased from the 2018 to 2022 window to the 2020 to 2024 window. But Roche, shown in the middle of the graph, is pushing against that trend. If anything, our total R&D spend per NME has decreased slightly from one window to the next. And remember, R&D excellence didn't kick in until the last year of the second window. So this suggests that even a single year of productivity improvement has already had an impact. Now the graph on the right of the slide illustrates that our internal reallocation has produced a markedly increased proportional investment in high-value R&D programs. Now I should point out that many of the so-called lower-value programs are actually line extensions, and we certainly need to be committed to line extensions to realize the full value of NMEs. But overall, we are starting to see qualitative and quantitative productivity gains from R&D excellence. Now last year, we created an internal fast-tracking mechanism for a few programs with exceptionally high potential. And this, by the way, is not to be confused with the FDA, Fast Track Designation. But this approach has been quite effective for us. And you could see that the reductions in projected time to filing range from 6 to 9 months to as much as 21 months compared to original expectations. And there are a wide range of interventions across these programs that have contributed to the acceleration. And I won't read through them all here, but they're listed on the slide. But what's really nice about this is that the learnings from this program are becoming best practice across our pipeline regardless of whether the program receives a special designation. All right. There are several additional ways in which we are evolving our underlying R&D engine to make it more efficient and more cost effective. For example, resource optimization. So a moment ago, I mentioned the extensive reallocation toward higher-yield investments over the past couple of years, which amounts to more than CHF 1 billion since the beginning of last year. Now we've invested over CHF 600 million of that savings to fund programs that we brought in through business development. And then an additional CHF 70 million was deployed to ensure pull-through of the Fast Track programs that I just described. But furthermore, CHF 370 million has been deployed towards future capabilities, some of which I'll describe further in a moment. But all of this sums up how we have aggressively funded programs that clear the bar, all while keeping our overall R&D spend flat during the same interval. Now a year ago, we described to you how we were radically simplifying our outsourcing model to help make our clinical trial infrastructure more efficient. And 12 months later, that effort is starting to bear fruit as measured by accelerations in trial start-up times or improving the site experience and annual cost reductions, which include CHF 100 million of savings since 2024. And we expect in the fullness of time that this will deliver up to CHF 300 million in annual savings by 2030, and that will provide additional resources that can be reallocated to support future transformative programs. Now lastly, I'll say just a few words about how we're assembling a systems and data foundation to enable future R&D productivity enhancements. And -- as you might imagine, we expect generative AI, Agentic AI and other automated platforms and analytic platforms to have a significant impact really across most elements of drug discovery and development. And one specific use case from the development side involves content generation at scale. By now, it's self-evident how this kind of work can be enhanced markedly by generative AI. And so what you're seeing on the slide are multiple content generation elements where AI is actively being deployed to produce efficiency gains. And of course, one can step back at a meta level and orchestrate all of this with -- through agentification, for example. But now we're moving far beyond content generation. We're mapping out many diverse workflows across our drug development continuum that might benefit in the future from Agentic AI applications. So in the fullness of time, these types of efforts could bring many efficiencies, and they also should augment the capabilities of our broader workforce. Now we have many AI and machine learning initiatives ongoing on the drug discovery side as well. And one of these, which is called lab-in-the-loop has been championed by Aviv Regev, who leads gRED. And the key concept behind the loop is the iterative learning that becomes possible when, for example, screening data or perturbation-based data at scale is leveraged recursively to train models. And in turn, the incorporation of such models can enhance target discovery, target enablement, lead identification, lead optimization and other downstream efforts. So overall, these applications should lay the groundwork for a data foundation that can help drive improved productivity across the R&D continuum. All right. So in summary, 2 years into our R&D excellence initiative, the majority of solutions seem well along the path to being embedded in a new business as usual. Now we still have a lot more work to do, and some of these are still closer to the beginning than to the final outcome. But we believe this initiative could push us to top quartile R&D productivity by 2030. But most importantly, R&D excellence is really fortifying our pipeline with many candidate medicines that truly have transformative potential. So with that, I'll stop and either we'll have the fire alarm or we'll have some Q&A first.

So I would ask -- as we have now 40 minutes for Q&A. So the speakers did an excellent job in keeping the time. We will be interrupted by the fire alarm at 11. Please stick to questions which are -- were covered in the morning sessions. You still have the opportunity then -- for drill down on details when it comes to pipeline or to data questions. Start here before Richard, please.

Richard Vosser from JPMorgan. Maybe one question on the bar on zilebesiran and then one other. So on zilebesiran, you gave an example of all the criteria at the bar, but I'm wondering about competition. When I look at KARDIA-3, the blood pressure lowering is a little bit lower than some of the other agents, maybe the aldosterone inhibitors. So just how do you factor in competition when you're looking at that to go into Phase III and push forward? And then one on R&D spend. Clearly, very good reallocation over the last few years, but we're looking at a significant step-up in Phase III development going forward. So just thoughts on how R&D spend can develop from here? Are we looking more at low single digit or growth in line with sales from now on?

So maybe I'll start. And of course, we'll have a lot more in-depth discussion on zilebesiran this afternoon, but a couple of high-level points on the competition. So the first point, and actually, I'm glad you brought up because it's worth mentioning the entire premise of zilebesiran is that you can dose it twice per year -- and because it's an RNAi, you get 24/7 coverage of blood pressure for that twice per year dosing. So including nocturnal control, which is something that orals -- so the whole issue is with oral. So one thing is, of course, the -- you don't necessarily get nocturnal control, you don't get that 24/7. But the other issue is the adherence. A major reason why many patients are not controlled is because it's hard for them to take 2, 3, 4 orals multiple times a day. So we think that, that will set zilebesiran apart. So -- but we'll talk more about that this afternoon. In terms of big picture R&D investment, certainly, as you've seen, I think one important lesson for R&D excellence is that we have now really worked the discipline around making the trade-offs that are needed, but then also maintaining overall fiscal discipline. So that will continue to be a major effort here -- to a first approximation, the idea is to make the trade-offs that we need within R&D or within other elements of the P&L, but to maintain tight margin discipline. And I'm sure Alan will have more to say about that this afternoon.

Yes, Sachin Jain, Bank of America. One question on obesity and then one on the pre and post Bar. So on obesity, since you did the Carmot acquisition, the commercial landscape seems to have changed a fair bit as we observed it. So just two questions. One, the price point at which you expect to launch at, has that materially changed given the changing landscape? And secondly, how do you think about the split of the eventual market cash versus reimbursed given that is also changing? And then on your blue dot sort of bar, pre and post Bar, I'll chance my on this one pre-Bar asset, which is in the upper right quadrant, both large peak sales and high probability, any sense of which that is? And then the one I'm more interested in actually is the post Bar, you have one in the bottom left quadrant, so small and low probability, why would you do that?

Yes. Thank you for that question. The first part being the evolution of the market since Carmot acquisition. I think we all agree that this is a very volatile and evolving market, but we are way within the bookmarks that was part of the initial acquisition. So the price point and the volumes is within what we have anticipated even though it's evolving faster. To the split between cash and reimbursement, I think that will have significant differences across the different geographies. And you will see all three ways of funding AOMs continue to grow with a growing market. So we are building in optionalities in our go-to-market plans, ensuring that we can cater for different future outlooks and make sure that we only make the decisions when really needed to ensure that we can meet the patients where they are and tap into whatever health care system evolution that we will see over the coming years.

Great. So on the pre and post Bar -- so I'll just -- so first of all, for obvious reasons, we're showing directional to give a flavor of how the decision-making has changed. So we're not going to comment on exactly which dot was where. But I will say that one of the programs that we moved into Phase III is an antibiotic. And we do that because of our commitment to society. It doesn't necessarily fit the path to value in the same way that the others do. So I'll leave that with you as you will.

Matthew?

It's Matthew Weston from UBS. Two questions, please. Obviously, Teresa, one thing you highlighted was the excitement around the giredestrant press release this morning with evERA. And in the PR, you highlight that you saw efficacy in the ESR1 subgroup and in the total population. Can you give us confidence that there is actually some efficacy in the non-ESR1 patients or whether or not it's just those mutant patients that are driving the efficacy? And I ask because we've increasingly seen the FDA focusing on subsets of patients and only giving a label for where the efficacy is. And then the second one also for you, Teresa, was Vabysmo. And again, you highlighted in your comments the strong market share and market leadership. One thing we've all been looking for from Roche is contribution to the patient Charitable Access Foundation program so that you can cement that, help patients get access and bring Vabysmo to more people. Can you give us any comments as to when we can expect Roche -- can we expect Roche to contribute to the cap? Could it happen in '25? And would you see that as a way of accelerating Vabysmo uptake?

Sure. So maybe I'll start with the cap question and then Levi, I'll let you answer the evERA question. So I'm unfortunately going to give you a somewhat unsatisfying answer to your question because as you all know, the -- as part of our charitable contributions, we do provide donations to co-pay assistance funds. However, those donations are made by a separate part of the organization and are completely firewalled from the commercial organization. So it would be inappropriate for me to comment what their plans are and how they plan to contribute because that is -- it is and has to be separate. That having been said, I think what we have previously communicated is that we will always attempt to do what's right.

So what I can't do is comment specifically on the results of the evERA study. But what I can -- I mean, they'll be presented at an upcoming meeting, and we look forward to all that. But what I can say is, at a high level, what we -- everything is on thesis to what we have said actually multiple times, including I, myself, have said at this event in years past, which is that if a breast cancer is dependent on the estrogen receptor, giredestrant can perform. And that continues to be the case. And that is the case regardless of whether or not there happens to be an ESR1 mutation. So that is all on thesis. Now of course, as you go through later and later stages, by definition, you can have reduced dependence on the estrogen receptor. But if there's dependence on the estrogen receptor, giredestrant can perform.

James Quigley from Goldman Sachs. I got 2 questions, please. So first of all, on the balance between internal R&D and external R&D. So of the 65 assets you have in the -- or 65 NMEs in the pipeline, how many of these were externally sourced? And how has that changed relative to Q3 '23, I think it was -- you had 81 assets in the pipeline. How will this then change or how will this develop further over time? And what does that mean for your internal research spend? That's question number one. And question number two, picking up on the comment, Teresa, on new areas and Roche has done this before. And across MS, across Hemlibra, and obviously Vabysmo, I think it's fair to say with those 3 assets, you are head and shoulders above the competition. So moving into those areas maybe was made a little bit easier from that respect. So as you move into obesity, as you move into CVRM, are you confident that you have the same head start that you have relative to the other competition?

Yes. So I'll start. So I don't -- it may be that Bruno has the exact numbers and can speak to those. But I can speak kind of higher level, which is that, as I mentioned in my talk, the concept of the bar is that we will go after assets that clear the bar wherever they are. And it's great if they're internal. But if they're not and they're external and they clear the bar and they otherwise are fit, then we'll go after those. So to a first approximation, we haven't been sort of keeping tabs and using that as a guidepost to whether we go internal or external. Obviously, we certainly -- by the way, giredestrant is a homegrown molecule. Inavolisib is a homegrown molecule. Trontinemab came out of [indiscernible]. So we're very pleased with our internal pipeline and its ability to generate medicines like this, but we're not constrained by that to a first approximation in terms of where the exciting medicines might come from.

But the ratio is very stable at 60-40. It has not changed despite the turnover. It's 60% external, 40% internal. What has changed, though, is that we have more late-stage assets. So therefore, it might become more visible. Normally, we have a lot of stuff which gets onboarded as preclinic or Phase I and you will have recognized.

And the question on best-in-class obesity, would one of you gentlemen like to do that?

I'm not sure I fully got the question.

So the question was in -- when we entered prior disease areas, we have entered with really best of disease...

So we are having a growing portfolio of late-stage assets that we believe have the best in disease and can be differentiated when it reaches the market and the patients. We will do that based on some of the capabilities that Teresa talked to through combination opportunities and by being determined and curious about this growing market. So our belief is that many of the late-stage assets we have will translate into differentiated assets that have a clear role to play in the evolving obesity market.

And I think if you sort of break them down more specifically, certainly, CT-388 has potential, petrelintide absolutely has potential to be best in disease. Pegozafermin -- it will roll off the tongue next time, I promise. Again, for MASH, it is the first to move into the Phase IV -- I'm sorry, the F4 population, which is the most serious form of MASH. So I think we have assembled a pipeline which both in monotherapy and combination has the potential to be truly differentiated.

Conscious I may have the fire alarm slot, but I'll start. It's Luisa Hector from Berenberg. I have a couple of questions really on timing and efficiency. But starting with your 3 fast-track assets, which you highlighted last year, could you say a little more on how they have been accelerated versus other assets? And is 3 the right number? Might we expect to see more? And then on efficiency and timing again, you have 8 new NMEs entering Phase III this year, but half of those don't start Phase III until next year. Is there a reason for this? Is this perhaps not the best way for us to gauge timing, speed to market, et cetera, as you push through with the efficiencies?

So to the first question, there we chose 3 programs that we felt like had particular exceptional potential for impact for the -- obviously the value of the company, et cetera. But actually, it's not as though those are the only 3 where we put all of our resources into. Actually, the learnings, as I mentioned, really -- I mean, we have many programs that are moving robustly. But I will say that it was highly instructive to pick 3 and to ask our teams to really think outside the box of what would it take to accelerate. And there are a range of -- so there's not one single thing, but there are a range of approaches that we're taking. So they range from, for example, very tight partnership between our medical affairs colleagues and our clinical colleagues in parts of the -- in geographies where we really took that to another level. In other cases, there were close collaborations on the manufacturing side to make sure that things could be gated appropriately. In other cases, it was about can we take interim looks and have discussions with regulatory authorities and move things. So there are a whole series of creative approaches that led to the acceleration. Now the second question that you asked, can you just remind me the...

Yes. So we're one of the fast track assets and then 4 of the 8 NMEs you highlight for Phase III don't start until next year. So why?

So actually, historically, internally, we used to get very excited about when is the first patient in to a study. And you would then move heaven and earth to get the first patient in as quickly as possible. But actually, it turns out that's not the relevant metric because very often, you could say, okay, great, we've got the first patient, and then you get through 2 or 3 months before you've enrolled enough sites. So really, the relevant metric is when do you get a critical mass of sites stood up. Once you have that, the hockey stick -- you get to the long end of the hockey stick. So that's really what we're focusing on. So the time that the Phase III trial starts is less important than the time that enrollment finishes.

And I just want to double down on something Levi said because I think it's really important. Every single one of the fast-track assets, those teams are actively sharing their learnings back with all of the other teams. And so just the synergistic effect on the portfolio is actually pretty cool to see.

And maybe one to add on just to avoid confusion. When we show the appendix slides, for example, with the trials listed, then that -- we put it in there when it's first patient in. So what we have communicated today is when we have taken the internal decision that we will move an asset on. So there's just a couple of months, 1 or 2 quarters in between normally.

It's Michael Leuchten from Jefferies. Just if I could go back to the obesity question in terms of channels. Given the interdependence of pricing in the U.S. between the different channels, government, commercial and cash, how much flexibility really is there in the DTC channel? Like is there a scenario where you could price in the DTC side really low, say, $100 and then protect pricing in the other channels? Or is that not possible because of the set interdependence? And then a question for Teresa on NXT007, [ 5 billion peaks ] on the slides. Can you just talk about how that fits with Hemlibra? Is that total cannibalization? Is that additional revenue potential in pockets? Like how do we frame that 5 billion versus what Hemlibra does deliver?

I mean -- maybe I'll just take that one to get it going. So in terms of 007, that we would anticipate cannibalizing all of Hemlibra. I mean if we can beat Hemlibra, which is the current standard of care, we would clearly want to shift patients on to the most appropriate therapy. I think we should also remember there remains a significant number of particularly more mild and moderate patients that are not yet on prophylactic therapy. So I think when you have a drug that potentially has the profile of NXT007, not only do you sort of take the Hemlibra share, but you can then also very credibly think about expanding your market.

I think it's probably too early to comment on the exact price point. So I'll refrain from that. What I do say and I would like to comment on is the ability to also differentiate in a cash paying segment. We clearly see that their willingness to pay also for premium solutions in that channel. So we will maintain, as I started out saying, the optionality to make sure that we are ready to offer where patients expect us to be.

Sarita from Morgan Stanley. Just a question on prasinezumab, and you mentioned the Bar across 2 trials, both of which didn't meet the primary endpoint, we saw a variety of findings, better efficacy in L-DOPA patients, better efficacy in MAO-B-treated patients, diffuse disease and then running the trials for longer over 104 weeks potentially. So what drives the confidence that these findings across 2 trials, various findings are not due to chance? And then a second question on fenebrutinib in PPMS. Could you confirm if you've changed the endpoint to noninferiority to Ocrevus in PPMS? And are you able to do so, so close to trial ending?

So for prasinezumab, the -- so as I mentioned, after the first study, we were not convinced that the findings that we're seeing were due to an efficacy versus chance. But after the second study, which was much larger -- so it was much larger, number one. Number two, it was corroborated with additional biological correlates of activity of prasinezumab. So then it looked like -- this is probably a real finding, and it's just a matter of can you power the study appropriately in Phase III. So hopefully, that addresses that question, but we'll talk a lot more this afternoon about the data. The second -- to the second question, we cannot comment right now on discussions around what we might or might not do in PPMS within.

Emmanuel Papadakis, Deutsche Bank. Maybe just a couple of questions on your obesity strategy. Just interested to understand how you think the future market will segment in terms of oral injectable? And then also in terms of incretin amylin monotherapy versus combinations, I understand there's many things still to be determined, but how are you expecting that will play out and how are you going to reflect that in your clinical development program, particularly in terms of time lines?

Yes. Thanks for that question. I think Teresa with her distribution of BMI clearly shows that there are two ways to truly expand the market, is treating more of the patients that are currently receiving GLP-1s or GLP-1 incretin market. And then the big opportunity to address an unmet need is to also engage patients much earlier in the disease. Teresa called out that the average BMI for patients eligible and using AOMs today is 39. So it means that we have almost 10 BMI increments where it's not sufficiently being used. Why is that? That was a heat map in terms of what is important to the different patient segments. And there, clearly, we see that those with lower BMI in the what we named the label prevention or early treatment, they value the tolerability and the convenience and are ready to trade in some of the last few percentage points on efficacy. We see both amylin with petrelintide and a more tolerable profile to have an opportunity for monotherapy there as well as in combination with incretins and then play in the high efficacy. But we definitely also see the opportunity for a significant share of the market, you can say, having a preference for daily orals over weekly injections. The exact share, I think, is difficult to comment on. But I think what we need to remember is that this market will be significant. So even a small share represents a large number. So there's plenty of opportunity for oral GLP-1s to play in the early space and into the -- into maintenance potentially for the amylin and petrelintide to establish itself do the combinations with incretins, et cetera, the market will be very heterogeneous and there's not one solution that will fit all patients they are very different.

Maybe just to add one factoid on top of that. I think we generally -- sometimes we assume that patients just prefer oral treatment. But many patients would actually prefer a once-weekly injection to an everyday oral because it's just more convenient for their lifestyle. There's actually only a relatively small subset of patients that are truly needle phobic. They just won't touch a needle. The vast majority, particularly if it's a simple subcut injection, are more than willing to do that, and it just is easier than taking a bunch of pills. So we shouldn't always assume that oral is necessarily going to be the winner. I think you're right. It's just going to be a mix depending on preference.

And I think mono is also coming back with a little more details on how we see that market pan out.

There's one over in the corner. I don't know, but he's behind you...

Naresh Chouhan from Intron Health. Just one going back to the R&D spend, please. You've got one of the highest spends in the industry. You've just shown that you've cut some of the assets and want to reduce cost per NME and drive efficiencies from time lines and AI. Help me to understand why we shouldn't expect R&D to fall in absolute terms, as a victim, please? And then secondly, on your obesity programs, how is the evolving landscape -- or has the evolving landscape -- commercial landscape reduce the size of the clinical program you anticipated maybe a year or 2 ago?

Maybe I'll start on the R&D side. So one major consideration over the next couple of years is the fact that we have indeed moved already 8 NMEs into Phase III. Some of those Phase III programs could be robust, including CT-388 and we haven't moved petrelintide, these are significant programs. And so we moved 8. We expect maybe a few more in the next several months. So that we -- in order to make those successful, we have to invest behind them. So that will be an important consideration that will require some additional fiscal discipline and trade-offs over at least the next 2 or 3 years.

And maybe on the perspective of how does the perspective of the commercial ecosystem evolve is obviously, we are observing what happens. We know that patient segments start to fragment and has very different patient preference and our CDP. So clinical development plans actually reflect this. And we'll use the portfolio we have to do the right combinations based on the patients safety observing emerging already there.

Luisa Hector again from Berenberg. Maybe to follow up on obesity. Have you debated simply trying to get to market on weight loss data as quickly as possible? And how critical are the CVOT, the comorbidities? And will they just be assumed as a given, given other drugs have that data?

Yes. So clearly, one of the lead indications will normally be chronic weight management. That's where the guidance to industry is relatively clear in terms of what is expected. And you will probably also see in many of our assets that that's where we will have the first indication. Expanding into adjacent TAs and indications really also a function of where do we see that product play a role in that evolving landscape. If we are in the high-risk segment, you are expected to also demonstrate the benefits on comorbidities, whether it's CVOT or into MASH or chronic kidney, et cetera. So there, you will probably see a growing, you can say, pool of evidence to support commercialization of those assets. Whereas in the other end of the spectrum, it might be that it is not the, you can say, cardiovascular metabolism that will drive uptake and preference for a certain product, but actually more being other endpoints. And we are exploring what could those other endpoints. And that's where we believe that many of the capabilities from other parts of our end-to-end DAs and TAs will help us make sure that we can make some strategic choices that will set us apart.

May we capture some questions over there before we do a second round?

Justin Smith from Bernstein. Just quickly on the BTK, Teresa, you used the word disruptive. Was that with reference to the entire market or just to tablets? If it's both, could you just help us understand where you would expect to take share from biologics and ABC?

Yes. I mean I think that fully depends on the data, right? I mean if we see -- if what we see in the Phase II plays through to the Phase III, certainly disruptive in the oral space, but potentially disruptive in the IV and subcut space as well. It looks like at least in Phase II, the efficacy is looking pretty good.

And today, just remember today, more than 1/3 don't have access to disease-modifying therapies in that space. So if an oral that would allow way more access for those patients.

Yes, absolutely. Good add.

[indiscernible] from ZKB. So also on obesity, you talked about that patients are willing to pay a premium also in the cash pay market. Do you have already some understanding of what is really needed that the patient is willing to pay a substantial premium to like cheaper solutions? And then a second question more on strategy. Would you assess that most of the internal transformation work is over now and that you are in full execution mode, but also could mean that we could see an acceleration of external deals being announced in the future?

Can I go first?

Yes.

Yes. Okay.

So I think we should try to look 10 years back and see what was the cost for medicines and relative to effectiveness of those treatments and where we are today. And that means that the price point is coming down per kilogram weight loss, et cetera. That gives room for optimizing the treatment journey through a seamless engagement and patient support solutions that could be provided by some of our colleagues in diagnostics and other places that would give a holistic approach to care and thereby also warrant a premium to a generic version of an alternative product. I think there will be significant opportunities to explore that in the years to come. And I think we have only seen the beginning of how patients will engage with telehealth, online pharmacies and direct-to-consumer channels.

And maybe on the internal transformation question that you asked. So certainly, there are several solutions that I described where I would say -- I mean, done is always a tough term, but we are very much into the embedding into -- this is just how we do business. So those things, the cycle kind of -- the circle comes to closure. But there are one thing that if Thomas were here, we always -- he would remind us that productivity is never done. It always continues. And actually, there are still real opportunities that we see to continue to achieve productivity gains, and we're going to go after that. So that's the first point. The second point on the internal versus external balance certainly, we are -- again, we're happy with the progress that we've made, including how harnessing these kinds of capabilities can boost our internal productivity. But it's also the case that the amount of external -- the amount of innovation in the great white world is going to be far greater than what we can do in-house. That is one thing that's not changing. So I would expect to continue to see a balance between external and internal. It may be that we don't have to do as many late-stage deals as we have done, although if we see something that clears the Bar, certainly, we'll evaluate it. But certainly, across the continuum of our pipeline, we would continue to have external augmentation.

If I may just add one comment to your question. Obviously, we're talking about getting ready for obesity portfolio or the future portfolio. That work is at full swing. We are laser-focused to make sure we understand how this market evolves and we get the capabilities in place, as you've seen in the slide. So you could argue there's still clear execution there, but there's still also capabilities to build.

Any questions from that end? Yes, please add on.

Yihan Li from Barclays. So the first question will be on your obesity franchise. So a message from EASD conference last week is that the potentially involving trial design standard with future obesity trials might likely require active comparator arms, for example, like semaglutide or tirzepatide versus the placebo. So I know it is still in early days. I'm just wondering like what you think about it? And any implications of your trial design as you are aiming to achieve the top 3 players in the obesity market? And a second very quick question on your oral SERD. So congrats on the top line this morning. But we note the persevERA, like first-line data is now pushed into the first quarter next year. So just wondering any commentary on this delay, please?

Yes. So I'll just briefly take the second one. All of these studies, given that they're event-driven, we have to wait for events to play out. So there's nothing particular to read into that, except that it's event-driven. On the first point, I would say we'll have time for a robust discussion on this in the afternoon. But suffice it to say, on the one hand, there's not a categorical requirement that we do studies against active comparators. But certainly, if it becomes appropriate to do that, we are prepared to do that in certain settings. But we'll talk more about that this afternoon.

Then we do a second round here in the front row?

It's Matthew Weston at UBS again. Teresa, MFN.

I thought I was going to -- you were so close.

You're not going to get away with it. I'm sorry. President Trump's letters required or requested a response from the pharmaceutical industry by the 29th of September. I'm not expecting you to tell us what Roche will say. But I would be very interested in your view as to what investors should expect over the coming months. Do we think that this is a period where the industry has a clear view as to what it can offer or companies have a clear view as to what they can offer, I should say? Or is this a period where investors should probably expect kind of noise, volatility and some ongoing uncertainty before some very difficult or different views come together in a compromise in due course?

So I think we are all aware of the significant conversations that are going on in the wider world today about MFN. And I'd just like to say a couple of things. One, which is just to reiterate some comments that I made earlier in the morning, which is that we, as Roche and Genentech, are committed to the U.S. We have a substantial presence there. We have over 25,000 employees. We have 13 manufacturing facilities, 15 R&D centers. We've made a $50 billion committed. We are committed to the U.S. market. We have also said over time that we share the goal of making medicines more affordable for U.S. patients. And yet, I think we all know that the complexities of the U.S. system mean that about 50% of the cost of innovative medicine actually goes to a middleman. And so I think the industry is in active conversations as are we with the administration to try and define what passes forward actually allow us to solve the ultimate goal, which is to help make sure that more Americans have access to the medicines that they need.

And is it going to be noisy or it's all going to become clear?

I think it will all become clear.

Sachin Jain from Bank of America.. I'll take 2 on topics we've discussed. So one, a follow-on from Matt's question around evERA. I guess the simple question is, has it changed your view probability success of persevERA, I guess, was the background to the question. The reason I'm asking it is you say whilst the data is on thesis, I think there's been mixed messaging on probability of success of persevERA across the C-suite. So just interested in your thoughts there. And then on FGF21 and 89bio, I wonder if you could talk about that relative to Bar, again, following to James' question, a lot of commercial assets, competitive landscape at the time of your launch. How do you think your asset is differentiated?

So for evERA, I would say that the results that we're seeing reinforce the thesis, the biological rationale that we have believed in and talked about on many occasions for giredestrant. We can't comment on a particular probability of success. But certainly, we're very pleased with the data, and we look forward to presenting it. So that's what we can say now. On FGF21, certainly -- I mean, I can speak to the scientific criteria. Maybe I'll let my colleagues speak to the business criteria. But certainly, from a scientific standpoint, we have a very large unmet need in MASH. And actually, that will be true regardless of how -- of the penetrants of GLP-1. We expect that to be -- remain a very large market. And actually, now that there are therapeutic solutions coming out there, the diagnosis of MASH could actually grow. So the addressable market could actually grow effectively. So clear unmet need, a large opportunity. The FGF21 data itself, that was, of course, a linchpin for us in terms of being enthusiastic about this opportunity. The Phase II data that was seen, the effect on fibrosis, the ability to achieve resolution. Certainly, that data was for F3, but then also we know that the class can have activity kind of across the board, including F4. So that's a therapeutic differentiation that we don't really have, particularly F4 is that the GLP-1s are not likely to play a major role in F4, and we can discuss more on that with Manu this afternoon. So from a scientific criteria, it actually checked all the boxes from a Bar standpoint. And maybe I'll let my colleagues speak to the business side.

Which makes it relatively easy because the fact that this is a potentially transformative medicine, which has a huge potential for patients, clears the Bar. And if you see just the numbers, the market right now is like CHF 2.5 billion approximately. We expect it to go easily above [ CHF 10 billion to CHF 20 billion ] in the 2030. So there's opportunity for patients there.

And maybe just to reiterate -- I mean, I think the incretin solve or attempt to address this sort of the -- through the -- addressing the underlying metabolic condition, the FGF21 analog actually goes straight towards the inflammation of fibrosis. So it's a very different way of actually attacking the disease.

Maybe also to let me add here again, we have in the appendix the updated epidemiology slides and -- based per molecule. So there you will see, for example, for giredestrant, all the different lines of treatment with driving mutations on top. You will find the estimate for what zilebesiran could do as the Phase III trials are designed, what patient population they would go after. So it's maybe worth to have a look there as well. And for MASH, I think we'll find something as well. And assumptions in there, of course, that this will change over time, the standard of care will change.

Richard Vosser from JPMorgan. Just a question on the devices. You mentioned the pilot -- the pilot facility coming on -- coming or being built now. So what comfort can we have that there will be devices for the GLP-1 and amylin franchise, given we've seen, obviously, that's been the biggest bottleneck for current players. I can imagine [ NX07 ] , you can have a device for that for the future, but just thoughts there. And maybe aligned to that, obviously, [ $750 ] million, I think, spent on a peptide facility in the U.S. You will have CDMOs, but thoughts on that capacity as well.

Yes, absolutely. So I think we've always said that with CT-388, our clinical trial and initial launch will be a balance of internal and external supply. That remains the case. We will ultimately bridge to primarily internal supply chain eventually. But that really was the purpose of building Holly Springs was to make sure that we had that large volume throughput device facility. And so I think you can be very confident that we will be entering with devices in the places where devices are necessary.

Maybe we take a final question before heading to lunch.

Kirsty Ross-Stewart from BNP Paribas. Just on the FGF21 deal that you've done, does that change the nature of your collaboration with Zealand given their interest in MASH and [indiscernible]? Just interested on the logistics there. And then just maybe a clarification on R&D spend. You've highlighted multiple new Phase III programs requiring investments. So can I just clarify what you mean and what you can commit to in terms of R&D spend on an absolute basis? So can the current rate be maintained? Or is it fair to expect this to grow in absolute terms over the midterm?

So on the -- on the FGF21 -- sorry, can you just repeat the first part of the question?

The nature of the partnership with Zealand?

Yes. So high level, we are really excited about our partnership with Zealand, and we're excited about the FGF21. We actually think that there's certainly no fundamental disruption or alteration. If anything, it just opens additional opportunities, including additional combinatorial opportunities. And actually, that gives me a chance to emphasize something that I didn't in the last question, which is that the characteristics of pegozafermin, very safe. So a little bit of nausea diarrhea, but not a lot of dose-limiting toxicity. So that implies -- we don't know for sure, but that implies the possibility of combinability with other assets. So we think, overall, this is a net add for all parties. Now on the R&D side, I think once again, we -- this is probably not the place where we can say specific numbers. What we can say is, number one, we are -- we've gone out and done these deals. We've made these investments. We've applied the Bar. So we're certainly committed to driving these programs through Phase III. And we're also committed to fiscal discipline, and we have evolved practices to do that. We see other opportunities to do that, but we'll work together to make that happen. I don't know, Teresa, if you want to say anything from a P&L standpoint on that?

Yes. No, I mean, I think...

And we have been saying before, we want to defend the margins. And I think there's more room for reallocation of resources. So you should not expect because we have now a wave of Phase III studies that you will see the R&D expenses go down.

I mean, as Levi pointed out, we've been planning for this. So this isn't...

Okay. I think with that, we end our first session, and then we're heading into the 50 minutes lunch and then see you later.

Okay. Thank you.

Thank you. [Break]

To lead the hematology/oncology product development. And I'm here to kick off the afternoon session where my colleagues and I will be sharing with you the highlights of the portfolio across therapeutic areas beginning in my case for oncology and hematology. Roche has a long history of 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 our PI3K inhibitor, Itovebi and our KRAS G12C inhibitor, divarasib. We're advancing high-impact combinatorial therapies. And as you'll see shortly, we have a growing number of combinations to address non-Hodgkin's lymphoma as well as our growing portfolio of combinations in hormone receptor breast cancer. We're investing in new technologies and novel modalities such as next-generation off-the-shelf allogeneic CAR-T therapy as well as molecular glue degraders. And we're focused on seamless end-to-end investment from discovery science through commercialization in key disease areas, namely lung, breast, hematologic malignancies and hemophilia to deliver differentiated, high-impact, high-value therapies to patients across the globe. Our organization also has a strong legacy of pioneering new drug targets and technologies. Today, we have a highly diversified portfolio in hematology/oncology, ranging from small molecules, antibodies, antibody-drug conjugate, fusion proteins, peptides, gene therapies and next-generation CAR-T. We also recognize that innovation in cancer therapeutics requires a constant hunt for novel modalities being developed externally. Highlighted here are some of the key deals we've made over the last couple of years mentioned earlier, the CDK portfolio acquired from Regor, the HER2 TKI partnered with Zion Therapeutics, the CAR-T program through our acquisition of Poseida and antibody-drug conjugates from MediLink and Innovent. This broad array of technologies is reflected within our portfolio of agents in development for solid tumor malignancies from Phase I through registration with a particular focus on the end-to-end development in lung and breast cancers. Turning specifically to breast cancer. Our organization really is proud to have launched the field of targeted therapy for breast cancer in transforming the lives of patients with HER2-positive disease. We continue to address the unmet needs of patients with metastatic HER2-positive breast cancer. Specifically, 50% of patients with HER2-positive disease will ultimately develop brain metastasis. We're therefore advancing ZN-1041, a highly potent, well-tolerated brain-penetrant HER2 TKI that has shown high response rates, both systemically and within brain metastases in Phase I investigation. Today, though, a major focus for our organization, as you heard earlier, is hormone receptor positive breast cancer, which represents 70% of patients. There remains an important unmet need to reduce the risk of disease progression or recurrence and foster greater tolerability of these therapies. We're tackling HER-positive breast cancer by targeting well-validated signaling nodes that are critical for tumor development and resistance with our best-in-class SERD, giredestrant, our recently approved PI3K inhibitor, Itovebi, and our acquisition of the next-generation CDK inhibitors from Regor Therapeutics. These novel CDKs have the potential to become best-in-class molecules, overcoming resistance mediated by CDK2 adaptation and reducing toxicity often mediated by CDK6 inhibition. Our lead molecule, GDC-4198, is a potent inhibitor of both CDK4 and CDK2. Among patients who have progressed on a CDK4/6 inhibitor, 4198 monotherapy demonstrated durable objective responses with acceptable tolerability, favorable PK profile and sustained target coverage of both CDK2 and CDK4. And at upcoming scientific meetings, we look forward to sharing our ongoing work and plans for this program. As I alluded, our strategy in HR-positive breast cancer focuses on 3 fundamental pillars: next-generation endocrine therapies and CDKs and novel targeted therapies. Within these 3 pillars, endocrine therapy, as you know, remains the backbone of treatment for HR-positive disease across both early and metastatic disease until, of course, resistance develops. Despite progress in endocrine therapy, there remain limitations. In the adjuvant setting, 50% of patients discontinue due to tolerability issues and 30% will go on to develop progressive metastatic disease. Our ambition is to improve the standard of care across all 3 pillars through novel agents that both meaningfully improve efficacy and reduce toxicity. Let me turn now to our next-generation SERD giredestrant as well as our PI3K inhibitor, Itovebi. As compared to other SERDs currently in development, giredestrant demonstrates the highest potency, is combinable at full dose with CDK4/6 inhibitors and has not been associated with ocular toxicity, an important adverse event for patients now seen in up to 20% of patients treated with an alternative SERD in development. Our development plan for giredestrant aims to replace current standard of care endocrine therapies across early and metastatic disease as the next-generation best-in-class endocrine backbone. We expect first results, as you know, from the Phase III persevERA trial in first-line endocrine-sensitive disease in early 2026. We anticipate an additional readout in the first-line endocrine-resistant setting in 2027, which, by the way, allows physician choice of CDK4/6 inhibitors. Additionally, we are the leading SERD trial in early disease with a head-to-head comparison in the lidERA trial comparing giredestrant to an aromatase inhibitor in the adjuvant setting. We're also evaluating combinations of giredestrant with CDK4/6 inhibitors as a sub-study in lidERA. Several other studies are ongoing in other lines of treatment, including a Phase I/II study in combination with our CDK4/2 inhibitor and a trial in ER-positive, HER2-positive metastatic disease in combination with Phesgo. This morning, as you heard, we announced the positive results from the Phase III evERA trial in second-line HR-positive metastatic breast cancer, comparing physicians' choice of an AI or fulvestrant plus everolimus to the combination of giredestrant plus everolimus. Of note, a 100% of patients had received a prior endocrine therapy and all had received a prior CDK4/6 inhibitor. The study met its co-primary endpoints with giredestrant and everolimus demonstrating a statistically significant and clinically meaningful improvement in progression-free survival in both the intent-to-treat population and the ESR1 mutated population. Overall survival remains immature at this time, but there is a positive trend in both the ITT and ESR1 mutated cohorts. Consistent with prior studies, treatment was well tolerated, and we did not observe any new safety signals. The evERA results reinforce our confidence in the giredestrant clinical development program and show the potential for this giredestrant combination to improve patient outcomes in the second-line setting. Full data will be presented at an upcoming medical meeting, and we are actively sharing these results now with health authorities. In the wake of these positive results, we're looking forward to the persevERA readout in Q1 of next year, followed by our trials in adjuvant therapy and endocrine-resistant disease. We believe that this compendium of studies will make giredestrant the standard of care across all estrogen-dependent breast cancer indications. Complementing giredestrant is our best-in-class PI3K inhibitor, Itovebi. For decades, we've realized the potential to target PI3K mutated in 40% of HR-positive breast cancer and 30% of HER2-positive breast cancer. Nonetheless, the available molecules previously in development and currently approved demonstrated limited efficacy and poor tolerability with a higher rate of treatment discontinuations due to adverse events. In contrast, Itovebi is differentiated as a highly potent and selective inhibitor of PI3K alpha. A unique feature of the molecule is its selective degradation of the mutant PI3K alpha subunit, conferring greater efficacy and far greater tolerability when compared to the alternative PI3K inhibitors. Moreover, Itovebi can be combined at full doses with endocrine therapies and CDK4/6 inhibitors. In the INAVO120 study, the combination of Itovebi, palbociclib and fulvestrant demonstrated a near 60% improvement in progression-free survival in the first-line endocrine-resistant setting and served as the basis for our approval in the U.S. and EU with additional approvals on the way. At the recent ASCO meeting in June, we shared an update of INAVO120, demonstrating a statistically significant 33% improvement in overall survival for the combination, making Itovebi the first PI3K inhibitor to improve overall survival. At that update, the time to subsequent chemotherapy was delayed by 2 years among patients receiving Itovebi. Importantly, Itovebi continued to be well tolerated with discontinuations in the single-digit range. Based on the strength of these data, we're conducting additional studies in PI3K-mutated breast cancer, including INAVO120 a head-to-head comparison of Itovebi versus palbociclib in the post-CDK setting, INAVO120 in the first-line endocrine-sensitive setting, INAVO122 in the HER2-positive disease. We recently initiated a Phase II trial of Itovebi in combination with ribociclib and letrozole as neoadjuvant therapy for patients with Stage II and III disease, and we have other trials in the adjuvant setting currently in design. As well, we're conducting studies in multiple other tumors that possess PIK3CA-mutations. Turning now to lung cancer and our KRAS G12C inhibitor, divarasib. In preclinical studies, divarasib is 25x more potent and 50x more selective than the current G12C inhibitors on the market. These features translate into robust durable clinical activity. In our Phase Ib studies in second-line metastatic non-small cell lung cancer, divarasib monotherapy achieved an objective response of 56% as compared to 30% to 40% for sotorasib or adagrasib. At the same time, divarasib documented a median progression-free survival of 15.3 months as compared to roughly 6 months for the other molecules currently on the market. Based on these highly encouraging results, we have an ongoing comprehensive Phase III program. First, we have the Phase III KRASCENDO-I trial, which is a head-to-head study comparison of divarasib versus the choice of sotorasib or adagrasib in the second-line non-small cell lung cancer setting. We have FDA breakthrough designation for this indication, and the trial will read out next year. Next, we have the Phase III KRASCENDO-II trial in first-line non-small cell lung cancer, which we're initiating, comparing a chemotherapy-free regimen of divarasib and pembrolizumab as compared to chemotherapy and pembrolizumab. Finally, we're expanding our Phase III program into the early curative setting of non-small cell lung cancer, initiating the KRASCENDO-III trial, which will test divarasib in the adjuvant setting. Moving on, Tecentriq continues to deliver positive results across tumors indications. At ASCO, we shared the results of the IMforte trial, demonstrating a statistically significant and clinically meaningful overall survival benefit for the combination of Tecentriq and lurbinectedin as a first-line maintenance therapy for extensive stage small cell lung cancer, establishing a new standard of care for this difficult-to-treat form of lung cancer. At the ASCO Plenary session this year, we shared the results of the ATOMIC trial in the adjuvant setting of DNA mismatch repair deficient colon cancer, demonstrating that the addition of Tecentriq to postoperative chemotherapy conferred a 50% improvement in disease-free survival. This regimen has now been incorporated into NCCN guidelines in the U.S. Additionally, at next month's ESMO conference, we'll be presenting results from the IMvigor011 trial. In this trial, patients underwent serial ctDNA testing following cystectomy for muscle invasive bladder cancer. Those testing positive and therefore, at a high risk of recurrence were randomized to treatment with either Tecentriq or placebo, whereas those testing negative remained on observation. Among patients with positive ctDNA testing, Tecentriq demonstrated a statistically significant and clinically meaningful improvement in both disease-free survival and overall survival. Additionally, ctDNA-negative patients experienced excellent outcomes without adjuvant therapy. This is the first prospective Phase III trial using a personalized ctDNA-guided approach to identify patients who will benefit from adjuvant therapy with Tecentriq and has the potential to change the postoperative management of bladder cancer. We believe these positive trials of Tecentriq across the three domains of small cell lung cancer, colorectal and bladder cancers will translate into continued stable sales for Tecentriq through the decade. Now turning to hematology. We're advancing novel molecules targeting both malignant and nonmalignant conditions across the spectrum of development, all designed to meaningfully improve the lives of patients with hematologic disorders. Over the past 25 years, Roche has transformed the landscape for patients with non-Hodgkin's lymphoma, which accounts for almost half of all blood cancers. We have a comprehensive program of clinical trials in the range -- across the range of NHL subtypes. The list on the right is not an exhaustive one, but it is a strong representation of the breadth of our clinical program in NHL. Our CD79B antibody drug conjugate, Polivy has had strong uptake in the first-line DLBCL setting with over 50,000 patients treated around the globe. At this year's heme summer congresses, we presented the positive results for the POLARGO study of Polivy and R-GemOx in second-line DLBCL. And prior to that, we shared the 5-year update for the POLARIX trial in the first-line setting of DLBCL. We launched Lunsumio monotherapy in over 60 countries. And last week, the CHMP for the European Medicines Agency recommended approval for subcutaneous Lunsumio for the treatment of follicular lymphoma. We're moving Lunsumio both into the second- and first-line treatments of follicular lymphoma, and we look forward to the readout of the second-line CELESTIMO trial of Lunsumio and lenalidomide in the first quarter of next year. Additionally, the SUNMO trial of Lunsumio and Polivy in second-line DLBCL was reported out this summer, and I'll review those results with you. Similarly, for Columvi, the third-line launch of this highly efficacious CD20/CD3 bispecific is going well with over 6,000 patients treated in 60 countries commercially. STARGLO in the second-line setting of DLBCL has been approved in over 45 countries, including the EU, and is a category 1 recommendation by the U.S. NCCN. And our first-line SKYGLO trial of Columvi is almost fully recruited. In July, we shared the positive results of the SUNMO trial of Lunsumio and Polivy in second-line plus DLBCL. Patients randomized to Lunsumio and Polivy experienced a 59% improvement in progression-free survival with a median PFS of 11.5 months for Lunsumio, Polivy and 3.8 months for R-GemOx. The combination of Lunsumio and Polivy also conferred a robust and statistically significant improvement in objective response with a 30% absolute improvement in ORR, 70% versus 40% and a doubling of complete response, 51% versus 24%. Of note, this chemotherapy-free regimen of Lunsumio, Polivy was delivered entirely as an outpatient and was associated with a manageable safety profile with a low incidence and low severity of cytokine release syndrome. SUNMO is the first positive Phase III study of a chemotherapy-free regimen in DLBCL, providing an important fixed duration, well-tolerated, highly efficacious outpatient regimen suitable for the community care setting, where more than half of patients in the U.S. now currently receive their care. Also this summer, we shared the Phase Ib data for the combination of Columvi with Polivy-R-CHP in first-line DLBCL, demonstrating an unprecedented response, a 100% response rate and a 96% complete response rate. These responses were highly durable and treatment was well tolerated with relatively low rates of cytokine release syndrome. The results further enhance our confidence in the ongoing Phase III SKYGLO trial. SKYGLO is the only Phase III trial in which a bispecific is being added to the more effective Polivy-R-CHP regimen, offering patients the best chance for cure for diffuse large B-cell lymphoma. Of note, recruitment for SKYGLO is now nearly complete, and we're expecting the results from this trial in 2027. Turning to multiple myeloma. We're advancing a unique CD3 engaging bispecific cevostamab into pivotal Phase III investigation. Cevostamab is the first antibody in the clinic that targets FcRh5, which is expressed on essentially 100% of myeloma cells. Cevostamab offers the potential to address an important unmet need in multiple myeloma. Emerging data in myeloma is now moving anti-CD38 antibodies, immunomodulatory agents and proteasomes with dexamethasone, all collectively now into standard first-line therapy, often now referred to as first-line quad therapy as the standard of care. Nonetheless, myeloma remains incurable and virtually all patients will eventually develop refractory disease. This highlights the need for additional safer and efficacious options in the second and later lines of treatment. At the International Myeloma Society meeting last week, we reported the efficacy data from our Phase I trial of cevostamab in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma. The combination with cevostamab demonstrated deep and durable responses with an objective response of 86% to 88% and a VGPR rate of 74% across the two doses tested. Equally notable, the safety profile was quite manageable. On the basis of these exciting results, we're initiating the Phase III CEVOLUTION trial for the combination of cevostamab, pom, dex in second-line patients. Beyond CEVOLUTION, we believe the unique target of cevostamab, FcRH5 and the documented efficacy and safety for the molecule enables this agent to be a partner of choice with a range of multiple myeloma therapies across the industry, and we're now actively exploring those combinations with various potential companies. Further building on our portfolio in heme malignancies is our entry into cell therapy with the acquisition of Poseida Therapeutics. CAR-Ts have transformed the landscape of hematologic malignancies, but current autologous technologies are highly complex and only about 25% of patients are technically eligible -- who are technically eligible for CAR-T actually receive the therapy. Our approach developed with Poseida leverages healthy donor-derived stem cell memory T cells, enabling durable antitumor protection. As well, Poseida's nonviral gene editing technology allows stable integration of multiple CAR-T's as well as high fidelity knock-ins and knockouts to both enhance efficacy and reduce adverse events. 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 relapsed/refractory multi myeloma, demonstrating high response rates in heavily pretreated patients for which the FDA has granted RMAT designation. Beyond BCMA, we have a CD19, CD20 dual CAR program currently in Phase I in B-cell malignancies. We're also leveraging this technology in non-oncology indications, and my colleagues will share some of that work with you this afternoon. Finally, switching gears to nonmalignant hematology, we're initiating Phase III trials of NXT007, our next-generations bispecific that promises to enable patients with hemophilia A for a life-free of bleeding complications. Hemlibra has set a high bar in terms of efficacy, safety and convenience. NXT007 builds on Hemlibra to enhance potency, half-life and allow for low-volume, infrequent subcu injections. NXT007 is 30-fold more potent than Hemlibra. And as you can see on the left side of the slide, an in vitro assay indicates that NXT007 promotes thrombin generation within the range of people without hemophilia. In July, we presented our dose escalation trial of NXT in cohorts B-3 and B-4, patients experienced 0 treated bleeds during the observation period, and there were no safety concerns. These data support the growing body of evidence that NXT007 has the potential to become a new standard of care. We're now initiating three Phase III trials, including a head-to-head comparison of NXT007 to Hemlibra, reflective of our confidence in this program. This ends my presentation. I thank you for the opportunity to share our portfolio in hem/onc and I look forward to your questions later this afternoon. But now let me turn to my colleague, Hideki Garren, to review the work in neuroscience. Hideki?

Thank you, Charlie. Well, I'm super excited to talk to you about our neurology portfolio. It's really -- we're one of the leaders in neurology, both on our on-market medicines as well as in the deep and rich portfolio. In fact, I was a little bit of a misguided soul. I left Roche for 4 years. And one of the main reasons I came back is because of our portfolio. It really is the envy of the industry, as you'll see in a couple of slides here. And how do we get to that portfolio? It's through critical capabilities. One is we are looking at multiple therapeutic modalities. The one you already heard about is Brainshuttle, [ anti- amyloid-beta ] for Alzheimer's disease, which we called trontinemab. We also have a Brainshuttle for multiple sclerosis. It's one of our many modalities we're looking at. As you heard multiple times already, we have this unique collaboration with Pharma and Dia. In fact, neurology is one of the areas where we have really used that to our advantage. One example is this traveler prescreening program for Alzheimer's disease, where we're using a blood-based biomarker to identify patients as early as possible and to roll them into the study. And I'll talk about that in a little bit in more detail. Further, we're taking that one step further, using the same blood-based biomarker, we can identify patients for prevention of Alzheimer's disease. So this is in preclinical Alzheimer's disease. Preclinical meaning there are no signs or symptoms of Alzheimer's. These are patients with biomarker-based amyloid pathology who are walking around, perfectly normal maybe one of us as well. And therefore, we may be able to identify patients and treat them, prevent Alzheimer's disease with a molecule such as trontinemab. Finally, we have -- as you heard earlier this morning, we have made end-to-end investments in both MS and Alzheimer's disease. And so we're doubling down on our R&D capabilities there. So let me show you the pipeline I've been talking about. So here's a pipeline. As you see, there are multiple different modalities. The index is on the right lower corner for nearly every modality you can think of is within our pipeline. And the other thing you should notice is the color coding. The across the board through development, we have neuroimmunological molecules across the board in development in purple. Neurodegenerative disorders, we also have molecules in development across the board in green. And the neuromuscular disorders in orange, we also have molecules throughout development. So a broad and deep pipeline in neurology, industry leaders. One other thing you should note is that this pipeline looks a little bit different from what you saw early in the year because two molecules have moved into Phase III. That's at the bottom on the Phase III column, bottom trontinemab, as you heard, has moved into Phase III as well as prasinezumab for Parkinson's moved to Phase III. We're also looking forward to some exciting Phase III readouts with fenebrutinib in PPMS later this year and relapsing MS next year. The other Phase III molecule Enspryng in MOG antibody disease and autoimmune encephalitis, we expect readouts next year. So let me give you one example of our new immunology pipeline molecule. Fenebrutinib, which you've heard about many times already, but let me dig down into some details about why we're excited about this. It is the only BTK inhibitor that achieves a dramatic CSF concentration greater than IC90 for B-cells and microglia. BTK inhibitors have a dual mechanism of action, as shown on the far left panel in terms of targeting B-cells as well as macrophage and microglia. And therefore, they can reduce relapses as well as disability progression. In the middle panel, our particular BTK inhibitor fenebrutinib has an optimized pharmacokinetic profile. What that means is if you look at that red line in that graph, there is a high bioavailability because of the free plasma AUC. And the reason that's important is that it will lead to increased concentration of fenebrutinib in the periphery as well as within the CSF. And speaking of CNS penetration as in the far right panel, you see that we have a dramatically increased CSF penetration compared to the other BTK inhibitors. So therefore, because of this profile as well as CNS penetration, we have a high confidence in the outcome of fenebrutinib in relapsing and primary progressive MS. The other aspect of fenebrutinib that's unique is that it's very highly selective. And that's shown in the left panel where the selectivity is compared to the other BTK inhibitors in development. And you can see that based on this graph, there's very high selectivity to the appropriate BTKs that we're targeting. And it's a non-covalent molecule, meaning that potentially we could have a beneficial benefit risk profile. It's the only non-covalent BTK inhibitor in development. We've completed the Phase II study called noncovalent in relapsing MS versus placebo, and I'll show you that in the next slide. We will have 2 studies reading out early next year with fenebrutinib versus teriflunomide. And then on the bottom, we have a study called FENtrepid, which is in PPMS versus Ocrevus, which readout toward the end of this year. So let me show you the Phase II study that's been completed. Here, we see a really dramatic decrease in relapses and Gad lesions. So the annualized relapse rate is shown on the left, where during the double-blind period, which is that blue greyed part of the graph, you see really 0 relapses within that double-blind period. Patients roll over into the open-label extension. And you can see that the relapse rate is dramatically low at 0.06 up to week 96. Further, 97% of patients remained in the open-label extension through week 48, speaking to the tolerability of the molecule. On the right panel is the data on Gad lesions. T1Gad lesions are measured by MRI, and it's indicative of active acute relapses and acute disease in the brain. And the double-blind period, again, is that greyed out period in the first part of the graph. You see a rapid and dramatic decrease in Gad lesions with over 90% reduction by week 8. If you follow that out into the open-label extension, we have 0 new lesions at week 96. So no new Gad lesions. So really a dramatic decrease in both relapses and Gad lesions, giving us a lot of confidence in the relapsing MS study. Let me switch gears to our neuromuscular pipeline. The first example is Elevidys, which is a micro-dystrophin gene therapy for Duchenne's muscular dystrophy. And what's the most important message to take away here is that we have a positive benefit risk profile in ambulatory DMD patients. The reason that's important is diagram on the left, these patients over time have a loss of the ambulatory skills and motor skills such that roughly around age 13, most patients are wheelchair bound. So there's a huge unmet medical need for these patients. On the right are data that you've already seen from our EMBARK Phase III study. What you see here is a 2-year extension of that study, where we're comparing to external control because the placebo period is over. But in every instance in every measurement of motor function, the Elevidys is favored and so on the right-hand side of the graph with significance. So we demonstrated a stabilization of disease progression with durable effects in DMD patients. It's important to note that over 850 patients have been treated with Elevidys -- ambulatory DMD patients have been treated with Elevidys across clinical and real-world settings. Another example from our neuromuscular pipeline is Emugrobart, previously known as GYM 329, and we expect Phase II results in both SMA and FSHD later this year. Emugrobart is an anti-latent myostatin inhibitor and has a unique sweeping and recycling technology. And this allows for [Audio Gap] every 4 weeks of [ SC ] dosing. Preclinically, Emugrobart has been shown to have an enhanced benefit in mouse studies compared to other anti-myostatin. As you can see, these are the 2 studies that we're waiting for readouts, Phase II studies we're waiting for readouts, the MANATEE study, which is Emugrobart on top of Evrysdi for SMA and then the MANOEUVRE study, which is Emugrobart and FSHD. Important to note that in FSHD, there are no disease-modifying treatments available. Check this [Technical Difficulty] pipeline. First of all, you've heard a lot about prasinezumab, but let me give you one slide on the Parkinson's disease. In Parkinson's disease, there is a steady progression of neurodegeneration and loss of motor and non-motor signs and symptoms, such that by the time of diagnosis of clinical Parkinson's disease, it's already about 40% to 60% of the dopamine producing neurons within the brain have been lost. This diagram the burden on the health care system with about 1% of the population over 60 affected by Parkinson's disease, resulting in a [Technical Difficulty] we do have symptomatic treatments, primarily L-DOPA, MAO-B inhibitors, but it's important to note that they do not change the course of disease and that there's a wearing off phenomenon as patients stay on these symptomatic treatments over time. So prasinezumab, it is our anti-alpha-synuclein antibody. And as you heard, we have achieved a Phase III Go decision with this monoclonal antibody. The pathophysiology of Parkinson's disease is shown on the left panel where alpha-synuclein, which are the red items diagram in the left panel, causes neuron degeneration by accumulating neurons as well as interferes with synaptic transmission. Prasinezumab, which is shown in green in that cartoon is designed to bind to aggregated alpha-synuclein in order to reduce that cell-to-cell transmission of alpha-synuclein. We've conducted 2 Phase II studies, PASADENA and PADOVA. And these are unique in the sense that they are large Phase II studies and that we have a primary endpoint of a clinical endpoint as opposed to a biomarker endpoint. And the wealth of that data, the clinical data from those 2 studies has led to the Phase III Go decision. PASADENA study -- PASADENA first Phase II study started many years ago. And the advantage of that is that now we have long-term data on patients on prasinezumab. And that's shown in the left panel. And what you see is that whether patients started with prasi from the very beginning, that's the early start in dark blue or they switched from placebo to prasinezumab and that's the delayed start in light blue, you see almost flattening of the measurement, which is called MDSUPDRS Part III. One word about the endpoint it is a clinical and Part III is a motor examination by the clinician. In other words, an objective measure of disease progression. And you see near flattening of that curve over the 4-year course of the open-label extension. So the question is, well, what happens if you were not on prasinezumab? And what you see there is in an external control, the grey line going upwards. And that external control is a robust clinical external control called PPMI, where data were collected very carefully and the same endpoint was collected. And so therefore, is a robust comparator to prasinezumab in the open-label extension. And you see this wide separation of about 65% reduction in progression. More proximal study is PADOVA on the right, the Phase IIb study, where again, its that same endpoint, the same measurement, MDSUPDRS Part III, but we have evolved that into a time to event. The reason we evolved into time to event is because these patients were treated with prasinezumab on top of their symptomatic treatments. What we found there is in the L-DOPA subgroup, we see a separation of the curves in blue and grey in terms of time of event, which achieved a hazard ratio of 0.79 and a p-value of 0.04. Now this is a subgroup that's quite large. About 75% of the patients were on L-DOPA. So it's a large subgroup of a large Phase II study. So that result, along with multiple secondary endpoints, which I'm not showing here, which all favored prasinezumab as well as a biomarker endpoint, which is the MRI endpoint looking at neuromelanin and iron, show that prasinezumab has biological activity and is very robust. So that led to the Phase III Go decision in the context of no disease-modifying treatments available. Another molecule early in the pipeline that we're excited about for Parkinson's disease is NLRP3. The NLRP3 inflammasome has been shown to be associated with inflammation across various therapeutic indications and in particular, Parkinson's disease. So the idea is with an oral molecule called Selnoflast to reduce the activity of NLRP3 and therefore, reduce the brain inflammation and microglia activation and progression of disease. Phase I is completed, and we're waiting and analyzing the data from the Phase I. There's also been studies in coronary artery disease and asthma as this inflammasome has been indicated in those -- implicated in those diseases as well. Moving on to our other neurodegenerative indications, Alzheimer's disease. As you know, there have been 2 molecules approved for Alzheimer's disease, lecanemab and donanemab, but there are limitations with what's available to Alzheimer's patients, those limitations are shown in the left-hand side of this slide. Number one is that there's limited blood-brain barrier penetration of these large monoclonal antibodies. Number two is the rapid and deep reduction in amyloid load has been shown to correlate with clinical response, and that's shown in the right-hand side of the cartoon that we want to reduce that amyloid load much more rapidly in a much deeper manner. The third item down on the left is the overall safety profile. There is a side effect with anti-amyloid therapy called ARIA, amyloid-related imaging abnormalities, and that causes brain edema as well as potentially brain bleeding and in rare cases, death. We want to try to avoid that as much as possible. Biomarkers indicative of change downstream of beta amyloid is another area that we want to look at. So how are we addressing that? We're addressing that with trontinemab. Trontinemab is our Brainshuttle coupled anti-beta monoclonal antibody. And we believe this antibody addresses all the limitations that were outlined in the prior slide. From trontinemab crosses the blood-brain barrier through a TfR receptor mediated transport mechanism and that has been shown in humans to have an eightfold increase in the CSF, plasma ratio versus standard antibodies. On the right-hand side is data that was shown earlier this year at AAIC, where we see a dramatic decrease in amyloid. What you see on the Y-axis is the centiloid scale. Centiloid is a 0 to 100 scale in with [Technical Difficulty] in milligram dose which is the purple line, you see a dramatic reduction such by day 196, roughly 6 months, these [Technical Difficulty] level amyloid, patients below the amyloid positivity threshold at 28 weeks, 6 months. All patients had a reduction in amyloid. In other words, there were no nonresponders. We also had a pronounced effect of fluid biomarkers downstream of amyloid on CSF pTau, which decreased by 27% at 25 weeks. And safety that's shown on the right-hand table, there was less than 5% instance of ARIA-E. It's much lower than what's been shown by the competitor molecules. We're excited to announce that we have started the Phase III study called TRONTIER I and II, and we have achieved first patient enrolled in that study. The TRONTIER 1 and II is diagram on the right-hand side. What I'll point out is what's in the green box, we have a prescreening program called TRAVELLER, where we're using a blood-based biomarker, pTau 217 to identify patients for this study. And in TRAVELLER, we already have in the first 60 days, 3,000 patients enrolled in this prescreening study. So there's clearly a lot of excitement about this study. The study design of TRONTIER I and II is diagram here where there after the prescreening, patients enter a screening period, followed by induction with trontinemab every 4 weeks or 6 months, followed by maintenance merit every 12 weeks. The maintenance period is important because it reduces any pathologic burden that the patients might have within the brain. Amyloid is one thing we can measure amyloid plaques or one thing we measure by PET, but we can't measure the other amyloid species that might be toxic like protofibrils. And so that's why it's important to keep that every 12-week dosing schedule. So TRONTIER I and II have started with first patient in. We also announced that we have a preclinical study, which is in the lower left part of this diagram, and that we plan to start shortly. Again, this is in preclinical Alzheimer's patients with no signs of symptoms of Alzheimer's, but with biological evidence of amyloid pathology. And those patients are also going to come from TRAVELLER. So really robust prescreening program to identify patients. A brief word about our Dia collaboration. Diagnosis of early Alzheimer's is, of course, important and is a major unmet need. 55 million people -- over 55 million people have dementia, majority of those have Alzheimer's disease, but majority of them remain undiagnosed. And PET is not available broadly and measuring CSF A beta is invasive because you have to do a lumbar puncture or spinal tap. And therefore, we're really excited about the developments at Dia with the Elecsys pTau217 assay, which should be launched next year and which is the same assay we're using in the TRAVELLER prescreening study. They result directly of our collaboration with Dia. And my last slide because the timer has now been at 0 for a while, is early-stage molecule called nivegacetor, which is a potential first-in-class gamma-secretase modulator orally administered for Alzheimer's disease. Higher iterations for gamma-secretase inhibitors. And what's unique here is that it's a modulator. And what we've already seen in the Phase I study, which is in the middle panel, a decrease in the pathologic A beta 42 and 40 species and an increase in the non-pathogenic A beta 37 and 38 species, which may also be protective as well. So the Phase I study is complete, and we're looking forward to the Phase IIa GABriella study, which have interim data hopefully by next year. And with that, let me turn it over to my colleague, Larry Tsai, to talk to you about our exciting immunology portfolio.

It would seem I'm being encouraged to use the podium. Is that -- okay, fantastic. Thank you so much, Hideki. Hello, everyone. Good afternoon. I guess this afternoon, my jet lag bodies isn't entirely sure what time of day it is. But I am Larry Tsai. I do know that, and I am the Global Head for Product Development Immunology. Happy to be here this afternoon to give you an update on the immunology strategy and pipeline. Hopefully, you are familiar with the One Roche immunology strategy, which we rolled out last year. And -- which is really an extension of the -- one Pharma strategy, which Teresa rolled out last year, which she spoke about a little bit earlier this morning. Roche has a long legacy of innovation in immunology, dating back more than 2 decades at this point. And the strategy really aims to build on that legacy using 4 strategic levers. First of all, optimizing pathways, both novel and validated pathways that are known to play foundational roles in immune-mediated diseases. Second, looking for rational combinations of novel and validated pathways to raise the efficacy ceiling for immune-mediated diseases. Third, using biomarkers to break down patient heterogeneity and identify endotypes, which may predict a better response to specific therapies. And finally, where the science is mature, seeking functional cures using deeper B-cell depletion and potentially immune reset. The strategy also centers around 2 end-to-end disease areas, inflammatory bowel disease and chronic obstructive pulmonary disease, while recognizing there may be opportunities in other disease areas where there is a potential for breakthrough innovation. This is particularly important in immunology because the immune system tends not to abate anatomic boundaries. And often, you do have to follow the science wherever it leads you to other areas of unmet need. So when we look at our clinical stage pipeline, we can see that there is a good balance between programs that are relevant to our end-to-end disease areas and to areas of potential breakthrough innovation. And I'll spend the rest of my time today taking a little bit of a deeper dive into some of these programs. Okay, microphone is working, but clicker is not. There we go. Okay. So one area of breakthrough innovation is that of immune-mediated kidney diseases. Immune-mediated kidney diseases are a common cause of chronic kidney disease and are, in fact, the third leading cause of end-stage kidney disease. Chronic kidney disease is obviously very common globally, affecting about 1 in 10 people worldwide and is associated with high health care costs, including about 1/4 of U.S. annual -- U.S. Medicare annual budget and about $140 billion annually in Europe in health care-related costs. The Roche development pipeline includes several programs which are relevant. Two choices here for clickers and I'll try this one that are relevant to immune-mediated kidney diseases, including lupus nephritis, membranous nephropathy, idiopathic nephrotic syndrome and IgA nephropathy. Gazyva, of course, is our next-generation anti-CD20 monoclonal antibody, which has been glycoengineered to be less dependent upon complement for cytotoxicity and therefore, making it particularly well suited to diseases where there may be depletion of complement levels such as advanced lupus. And in the Phase III REGENCY study, Gazyva was shown to be associated with a 46.4% complete response rate compared to 33.1% for placebo. Those results have now been published in the New England Journal of Medicine. The results have also been submitted to health authorities earlier this year with a U.S. PDUFA target date set for next month. In addition, international and national lupus nephritis guidelines have already been updated to include Gazyva as part of first-line combination treatment for patients with lupus nephritis. Beyond lupus nephritis, Phase III data in extrarenal lupus in the ALLEGORY study and in idiopathic nephrotic syndrome in the INShore study are expected before the end of the year and Phase III MAJESTY in membranous nephropathy data are expected in 2026. With success in these disease areas, we expect that Gazyva can become the treatment of choice for immune-mediated kidney disease. In addition, Roche is helping to write the next chapter in B-cell depletion with its T cell engaging B-cell-directed bispecifics. Lunsumio is a CD3, CD20 bispecific antibody that's already been approved for relapsed and refractory follicular lymphoma. Lunsumio has been tested in the Phase I study in lupus and lupus nephritis and showed deep B-cell depletion in the top 3 dose cohorts with an acceptable safety profile. And accordingly, Lunsumio has now been entered into a Phase II study in lupus and lupus nephritis as of earlier this year. In addition, our CD19, CD3 bispecific program is in an ongoing Phase I study in lupus and lupus nephritis. And beyond our T cell engaging bispecifics, our CD19CD20-ALLO1 CAR-T cell program filed for an IND in lupus and lupus nephritis and should be entering a Phase I study this year. And so with these treatments and with other B-cell-directed therapies in the pipeline, we believe that Roche can continue to build a leadership position in the emerging field of immune reset for autoimmune diseases. Moving beyond B-cell depletion, sefaxersen is our first-in-class antisense oligonucleotide for selective complement suppression in IgA nephropathy. Globally, IgA nephropathy is the most common primary glomerular nephropathy and can progress to chronic kidney disease and renal failure. High levels of complement factor B have been associated with IgA nephropathy. And so sefaxersen aims to treat IgA nephropathy by down-regulating complement factor B production by inhibiting mRNA translation. And sefaxersen was shown in the Phase II study to have met its primary endpoint of a change in 24-hour urinary protein with a 43% reduction in mean proteinuria at week 29 as well as meeting secondary endpoints and showing stabilization of kidney function. The Phase III imagination study of sefaxersen in IgA nephropathy is ongoing with an interim analysis readout expected in 2026 that could lead to an accelerated approval. Shifting gears to talk about GI and in particular, our end-to-end disease inflammatory bowel disease. IBD is a very serious problem that affects about 8 million patients worldwide. And despite significant advances in treatment over the past decade, still only about 40% of patients respond initially to standard of care therapies and only about 20% achieve a lasting remission. And so afimkibart is our anti-TL1A monoclonal antibody that's now being developed for inflammatory bowel disease, atopic dermatitis, MASH, and as announced this morning, rheumatoid arthritis now as well. TL1A sits upstream of and is a key amplifier of several different inflammatory pathways and tissue remodeling pathways and cells that express TL1A and its receptor DR3 are known to be drivers of different immune-mediated and fibrotic diseases. And so we believe that afimkibart has the potential to become a pan-immunology pipeline in the molecule. We have -- as I mentioned, the studies are underway in inflammatory bowel disease, atopic dermatitis and MASH. We have also initiated as of this year, registrational studies in ulcerative colitis and Crohn's disease. And we are continuing to look at additional indications that could help to realize the full potential of afimkibart as a pan-immunology molecule. The Phase II study that I mentioned in rheumatoid arthritis is expected to begin later this year as well. But of course, afimkibart's lead indication is inflammatory bowel disease. And in the Phase II TUSCANY study, afimkibart was -- demonstrated strong proof of concept in ulcerative colitis and also demonstrated its potential to be a best-in-disease molecule. The Phase III AMETRINE I and II studies in ulcerative colitis are well underway, and we are very pleased to report today that enrollment is about 3 to 6 months ahead of target. And that's due in large part to the fast track designation that Levi spoke about earlier this morning, which has enabled expedited enrollment and execution. In addition, the Phase III SIBERITE studies in Crohn's disease are underway as are the studies in atopic dermatitis in Phase II and MASH in Phase I, as I mentioned earlier. And we continue to collect biomarker data, which will help us to explore the endotypes that I mentioned earlier that may predict better response to treatment. But since IBD is an end-to-end disease area for us, we're already thinking about the next generation of treatments, including bispecifics built on a backbone of TL1A combined with other validated mechanisms of action such as IL-23. And towards that end, we have initiated a Phase II study in ulcerative colitis of our p40 TL1A bispecific molecule, and we have additional bispecifics in preclinical development at this time. But let's not forget, although not technically a part of our immunology strategy, Roche's commitment, Roche's contribution to the fight against global antimicrobial resistance, which is part of our commitment to global health security. Zosurabalpin is a novel macrocyclic peptide molecule that targets the LPS transport system in gram-negative bacteria. Zosurabalpin has been shown to have potent activity against Acinetobacter baumannii, including carbapenem-resistant strains, which are the most -- or the highest threat pathogens according to WHO and CDC from a bacterial pathogen standpoint. And Acinetobacter baumannii, in particular, carbapenem-resistant strains are becoming a more common cause of nosocomial infections, including hospital-acquired bacterial pneumonia and ventilator-associated pneumonia, which are associated with high morbidity and up to 40% mortality. A Phase III study of zosurabalpin in [indiscernible] is getting underway and is expecting to enroll its first patients in 2026. And with that, I will end, and I will pass the baton on to Chris Brittain, who will give us an update on what's going on in ophthalmology.

Okay. So good afternoon. Thanks for the introduction, Larry. So I'm aware that I'm the last person standing between you all and an exciting update on the cardiovascular, renal and metabolism franchise. However, I really want to make sure that you learn a lot about the ophthalmology business because there is so much exciting stuff going on. So give me my 15 minutes, please. Just as a reminder, ophthalmology, our strategy remains threefold. Number one, we continue to treat patients who have suffered vision loss, and we have the great example of Vabysmo, which you heard from Teresa and Levi this morning, which is doing really great work for patients globally. We also want to treat earlier in disease still, and that in order to prevent that vision loss happening in the first place because even though Vabysmo does great, the majority of patients once they have vision loss due to the structural damage cannot achieve the vision which they were used to before that disease impacted them. And thirdly, we aim to have truly restorative therapies for those patients who have more end-stage vision loss. And this is the graph which you see at the bottom right. And examples of these will be our OpRegen cell therapy program. So our critical capabilities remain key to our success. So we have a number of novel mechanisms of action, which you'll hear about. And these include bispecific antibodies, of which we now have 2 in clinic and 2 declared novel MOAs, which you'll hear about. We have a concrete and strategic approach to extended durability and novel technologies. Examples here are the port delivery system implant and also, again, our OpRegen cell therapy, very innovative, very novel technologies. In terms of our digital capabilities, we have, over the years, brought in-house tens of thousands of retinal images on top of thousands of biosamples from patients and hundreds of intraocular fluid samples. We've been using all that data to develop algorithms. We have a remote monitoring system. So we really have this robust digital capabilities system setup. And finally, end-to-end investment. We're really using our end-to-end disease areas, which are geographic atrophy and intermediate AMD and then the retinal vascular disorders, which are group together diabetic macular edema, neovascular AMD, diabetic retinopathy. And we're really investing in those heavily. And what that is enabling us to do is have a seamless transition through the stages. And then at the end, we have the opportunity to reverse and to back translate. So we provide those data from our aqueous humor samples, our ocular samples, which taken the Phase III and to identify new markers of disease and new potential targets for new therapies back to our research groups. So in terms of our pipeline, it's exciting to share. First of all, I'll start on the right-hand side. So satralizumab in thyroid eye disease, you've heard of this program for the last couple of years. We'll be able to share some data at the American Society of Ophthalmic Plastic and Reconstructive surgeons, that's in the middle of October as ESOPRS. I'm not going to be able to share any specific data today. That data just came in-house in the last few days. The vamikibart Phase III program in uveitic macular edema, that data will be presented. Again, the 2 Phase III studies there. I'll talk a little bit more in a moment. That data will be presented at the Scientific Congress, the American Academy of Ophthalmologists in the next few weeks. We'll be sharing that data with the regulators. And those 2 programs together, we'll be discussing, as Bruno mentioned this morning, the Investor Relations call specifically for ophthalmology after the AAO meeting. And thirdly, today, we'll be talking a little bit about showing some first-time data from our vamikibart DME program. And we are proud to say that we now have a new asset in Phase I, which is a VEGF/IL-6 bispecific molecule. So starting with susvimo in neovascular AMD. Just as a reminder, this is an intraocular implant, which is designed to continuously release a customized formulation of the anti-VEGF ranibizumab. And the actual implant enables us to have as infrequently as every 6 monthly refills of that device. Now the exciting data which we've been sharing recently is this on the left-hand side, which shows that over 7 years since the implant, about half of patients maintain driving vision. Now I'll compare that to a previous study, which was 7 years of ranibizumab. And over that 7-year time period, about 1/4 of patients were able to maintain driving vision. So the advantage of having this continuous release of ranibizumab through the implant has really doubled that number. So quite remarkable results. Another -- and sometimes I'd like to share kind of patient, patient anecdotes, which are quite interesting. So we here in the clinic, one of our physicians are talking about a conversation he overheard. And one patient was saying, how often do you come into clinic and one patient saying every 4 weeks. And then the next patient says, oh, I come in every 10 weeks. And then the susvimo patient says, I just come in twice a year. So that is a real strong patient benefit for Susvimo. Next piece is that the port delivery platform itself, the implant, we actually have now 2 bispecific molecules, which are ready to be used in that platform and additional -- a large number of additional preclinical assets. Moving on to vamikibart. Now just as a reminder, IL-6 is a cytokine, which is very pro-inflammatory. You will know from many other systemic diseases, but it's also involved in the pathogenesis of uveitis and a number of retinal diseases. Vamikibart is designed for intraocular use, and it was first used and it's an intravitreally delivered product. I've mentioned that -- I've not mentioned, but we're kind of excited to say that we've now got the uveitic macular edema Phase III data in-house. And they've shown that we have a favorable benefit risk profile in the patients that have undergone treatment, and the data will be shared with the regulators. We'll also, as I said, we'll be sharing the clinical data at the AAO, and we'll be able to discuss more clinical data on the 21st of October in our Investor Relations call. Secondly, I'll talk a little bit about the DME study, but I'm delighted to say that we are moving forward with the VEGF IL-6 bispecific in DME. And dwelling on that for a moment, this is the diabetic macular edema study, Phase II study of vamikibart plus ranibizumab versus ranibizumab alone. So this is a superiority study. And what we see here with this data is that the overall outcomes were a 3.4 letter improvement in visual acuity when vamikibart was given on top of ranibizumab versus ranibizumab monotherapy. And more importantly, which is the FDA approvable endpoint, which is a 15-letter gainers, we saw a 44.7 versus a 28.6 percentage of 15-letter gainers if you take vamikibart on top of anti-VEGF monotherapy. So that's exciting data from the [indiscernible] superiority study. As you note in the second bullet, we did note that there were 2 cases of occlusive retinal vasculitis. But when you take all this data together, we believe that there's a strong and robust proof of concept for the role and the benefit of adding an anti-IL-6 mechanism of action on top of VEGF. And therefore, we will be proceeding and we're in the middle of an expanded Phase I program. We'll be accelerating this VEGF-IL6 bispecific in DME. Additional benefit of this bispecific, obviously, is it's a fab sized molecule based on the DutaFab platform, and therefore, it's compatible with the port delivery implant. And then going back to vamikibart in UME. I've already made the comments that we're excited that we've seen robust improvements in vision and anatomy in the 2 identical Phase III studies, which we've just read out, MEERKAT and SANDCAT. As a reminder, uveitic macular edema is the leading cause of vision loss in patients with uveitis. And despite a plethora of systemic immunosuppressive therapies available for this condition, there are significant unmet need for a safer option for patients. We are looking forward to sharing this data more in the American Academy of Ophthalmology, as I say, about 3 weeks' time. Moving on to zifibancimig in neovascular AMD. This is the second molecule, which went into the port delivery implant. This is currently in the Phase I/II BURGUNDY study. As a reminder, zifibancimig is our bispecific, which targets both anti-VEGF and Ang2 and is much more potent than the -- in terms of both VEGF and Ang2 than the intravitreally delivered faricimab molecule. Therefore, we believe that zifibancimig will be able to provide us with an option in the port delivery implant, which will give us infrequently as once every year dosing. So this is proceeding very rapidly in our Phase I/II study. Then moving on to satralizumab. As a reminder, satralizumab is a subcutaneously delivered IL-6 inhibitor. IL-6, as we know, is a key mediator of disease in thyroid eye disease. There is a significant level of unmet need that remains despite a single available treatment in thyroid eye disease. Thyroid eye disease is kind of a painful, disfiguring and potentially blinding condition, which people often forget about. And although there is an available treatment, there is a need for a treatment which is more safe. The available treatment has issues such as its teratogenic. It causes significant disruptions in the menstrual cycle. It causes deafness. It causes muscle spasms. So there's a significant opportunity there for a safer treatment. We have the data just brought in-house. I'm not going to be able to share any today, but what I can say is that we're looking forward to, again, to sharing the clinical data in the ASOPRS conference in just 2 to 3 weeks' time. Next on is OpRegen, one of my personal favorite programs. This is the allogeneic RPE cell therapy injected under the retina for patients with geographic atrophy. This is delivered, as I say, subretinally. And what we're starting to see is over the years, we've got longer-term data from our Phase I study. And on the left-hand graph, you see the visual acuity remains stable over that 3 years compared to the fellow eye of these patients. Now fellow eye controls aren't always optimal. But what I can say is that in the large trials, what we see consistently is that patients with GA generally lose about 5 letters of vision every year. So what we're seeing is stability of vision. So this is really exciting. And this is replicated in the anatomy on the right-hand side, whereby the size of the geographic atrophy lesion is remaining stable. And we see that is not the case in the fellow eye here, and we know from natural history of geographic atrophy that the lesions do get bigger. So we're excited about this program. It continues in Phase II. And with extended follow-up, we're continuing to see a really robust and acceptable safety profile. Now obviously, this is delivered through a transvitreal approach currently. And therefore, there's an opportunity to improve the delivery. And Teresa talked this morning about a number of devices. And so we're excited that we've acquired 2 additional devices, which have the potential to even further improve how we deliver not just this therapy, not just the cell therapy, but other future cell therapies or other future gene therapies or other technologies that we need to deliver to the eye. The left one is a transvitreal subretinal injector with a dual lumen. This means that instead of injecting, you go through the vitreous through the jelly in the eye, make a hole in the retina and inject your therapy. And instead of pulling out and making a second hole because it's got 2 lumens in that injector, you can just simply inject the drug without taking it out and putting it back in again. So this has a significant advantage. The device on the right-hand side is the Orbit Subretinal Delivery System. It goes through what we call a transchoroidal approach, which is between 2 layers between what we call the retina, which is the seeing part of the eye and the choroid, which is the vascular support of the retina, goes between those 2 layers and then a needle comes and the cells are injected between the retina and the choroid. So you don't need to make a hole in the retina. So that's really important. Again, these have the potential to make the delivery of these technologies easier and safer for patients, and we're excited to report these technologies in-house. And so this program carries on in its Phase II, and we're looking forward to sharing more data in future meetings. And with that, I'm delighted now to hand over to our last act for the day, Manu Chakravarthy, who will talk through our cardiovascular, renal and metabolism pipeline. Thanks, Manu.

Great. Good afternoon. Can I stand here or do I have to -- it's good. Okay. Perfect. It's an honor to go after all of the -- all of my esteemed colleagues. So hopefully, we'll have another 15, 20 minutes of engaging discussion and then open up to questions. So you heard a lot from Teresa this morning about the obesity strategy. In case anybody is still wondering why is Roche in CVRM. Hopefully, this is a slide that can remind us as to why this is so important in a way that there's an obligation in some ways to really address this incredible burden to society. I heard earlier this morning that 51% of the globe is going to be either overweight -- with people with overweight or obesity. And what we know from the epidemiology is that obesity transects and touches the lives of almost -- I wouldn't say everybody, but a great majority of the people in the world. And you can see in this graphic, the incredible overlap with many of the diseases and that's why when we really think about CVRM at Roche, we're thinking about these intersecting highly interdependent diseases. And so we see this as one continuum, whether it's CV, whether it's renal, whether it's MASH, whether it's diabetes, all of that underpinned through a common pathophysiological thread. And so in order to address that level of heterogeneity, we really need to be thinking very broadly and very holistically about how to actually position our portfolio to really try to tackle this challenge. And so it's really around the 4 pillars that we had introduced last year. And just to reiterate some of the forward momentum that we've had since the last year, you can see with the first box, it's not just incretins, it's incretins and beyond. We believe that our portfolio will obviously have a foundational backbone with incretins, but there are other foundational targets, too. And that was one of the reasons why we did the deal with Zealand with amylin. And then most recently, a couple of days ago with 89bio with pegozafermin, which is FGF21. So both amylin, FGF21 are foundational targets just like incretins are. In order to really address that level of heterogeneity you saw on the previous slide, we need combinations. So without combinations, it's nearly impossible to really tackle this multi-pathophysiological spectrum of interdependent diseases. Then you heard a little bit about the comorbidities. We are singularly focused on improving the health of the society. And so in order to bend that trajectory, it's not possible to do that without addressing comorbidities. So the key comorbidities, of course, a lot of people think about are CV and renal, but you can also easily imagine other things like MASH and many other areas where there's a true unique synergy with other therapeutic areas. And you heard from my esteemed colleagues, they presented the work from neuroscience, immunology, oncology, these are potentially transsecting areas where incretins and our portfolio can be synergizing. And the final piece is the end-to-end solutions, which -- without which we cannot really bring all these things together. So holistic solutions, which includes a very close partnership with diagnostics with our devices as well as with our digital apps and then ultimately to monitor, diagnose. And the final piece is very, very important as a physician, I can tell you that patient empowerment, especially in a chronic disease setting is critical. People with chronic disease don't like to be reminded that they have chronic disease. And so how do you really address all of these things? And this is kind of what we have really spent a lot of time and effort and thought thinking through. You heard a little bit from Teresa this morning about how we've taken a more patient-centric approach. We also have taken an approach that we also listen to our KOLs, our key opinion leaders and other thought leaders in the field. And here is a smattering of things. And you can see that many of these things intersect with what Teresa shared with us this morning. Patients really are looking for obviously superior weight loss, but also improved tolerability. They're also looking to improve not only 10%, 15% of their weight loss, but improving their whole -- the comorbidities, better maintenance of their weight loss, better quality of their weight loss. And so these are all things that we actually take very seriously. And this is the reason why when we get asked the question, why do you need so many different things? This is the answer to that because there is an intrinsic heterogeneity and the incredible fragmentation of this marketplace. And so we need to be in a position to really meet patients where they are. And chronic weight loss management is a chronic weight loss journey. So we have to meet patients wherever they are, whether it's in a preventive mode, it's an early treatment mode or in really the high-risk comorbidity mode. And so this is why you need the armamentarium that we have, which is orals, incretins, non-incretins, combinations. So all these things are actually required to really compete and to really be successful in addressing the needs of patients that are living with obesity and its comorbidities. So this is the backdrop in which we have taken a lot of pain and thought and care to construct the portfolio that you'll see today. So I was here a year ago and shared this slide. This is -- actually, 2023, there was only one, right? It was fulvestrant. In 2024, we added 4 more to our pipeline. And so this is what we had showed just approximately a year from now. And I'm really proud and gratified to be able to share with you today the portfolio as it stands in 2025. So this is the forward momentum and the progress that we have tried to articulate by learning about the market, knowing what it takes to compete and to pull together a portfolio that will address these kinds of heterogeneous needs. So what I'll do in the next few minutes is to give you snippets and highlights of the 3 Phase III programs. Very happy to announce that we're moving CT-388 into Phase III. And we'll cover those top 3 Phase III programs. And then I'll give you a quick snippets of the remaining 4 Phase II programs with petrelintide, CT-996, emugrobart and then we'll end with CT-868. So let's start with fulvestrant. So we believe that this is a paradigm-shifting first-in-class opportunity that is truly unique. Why do we believe that? The first is the way that addresses the target. So it's way upstream of the -- what is called the RAAS pathway, that's Renin-angiotensin-aldosterone system. So it really addresses angiotensinogen, which is made in the liver. And with an siRNA approach, you can have near a complete knockdown of this gene. So when I say near knockdown, it's like over 95%. So it's completely flattened out. And we know that the suppression of angiotensinogen directly correlates with blood pressure control. So we know that we definitely hit this target. Then the siRNA approach allows us to silence this for a long duration of time, and that's really critical. So that's one of the core reasons why you see here that we are able to reduce blood pressure, not just for a few hours in the day, but 24 hours in a day, 7 days a week for all the way up to 6 months. So one shot every 2 years will give you 24-hour control and gives you nocturnal control. And we know from epidemiological studies that when you have nocturnal control, you will improve outcomes. So that's been a direct link. And that's one of the core reasons why we've been so focused on getting sustained blood pressure control over a long time. So here are some data to actually prove that, right? So one, it's easy to say, well, we have nocturnal control. So we have a very comprehensive Phase III program. Levi shared with you how robust this program is. It was actually heartening to be quite honest, to see 3 Phase II studies before we actually decided to go to Phase III. And that shows the rigor of the program. So KARDIA-1 and 2 were in mild to moderate hypertension. So they're relatively healthy people with 1 or 2 antihypertensive meds. One could have taken the view that, well, we could have actually gone to Phase III at that point in time. But we actually took a little pause to make sure that we truly understood what is the dose, what is the population and how do we actually want to study this. And that's why KARDIA-3 was actually designed. So KARDIA-3 is a population that is much sicker. So they are all people with established CVD or those with high risk of CVD, the exact population that we wanted to study with at least 2, if not maybe 3 or 4 background med. So these people are actually very poorly controlled, and that's why we call it uncontrolled hypertension. And the majority of them were in a backdrop of diuretics. And so what you see in the middle panel is this very nice reduction about 7 to 9 millimeters of mercury in the population [Technical Difficulty] and diuretics, those that have a CVD risk. Those are the people we want to take forward. And then on the right, you'll see what I've been talking about is the importance of the nighttime control. And there, you can see clearly in the nocturnal period, you are able to really see profound suppression, both doses, 300 and 600 relative to placebo. So this gave us great confidence that we are able to achieve what we set out to do. And so I think we already had made this announcement prior today, but just to reiterate, very happy to announce the initiation of ZENITH, which will be our Phase III 11,000-person cardiovascular outcome study. So this is not a small study. It's as robust as it gets. So a large population with a primary outcome of the composite of the essentially the 4-point -- what we call the 4-point MACE. Right? So CV death, nonfatal MI, nonfatal stroke and then heart failure event. And then many secondary events that we will look at in all the different forms and components, including nighttime control, et cetera. So all in all, very happy that this is advancing forward. We feel very confident that this will then -- given the results that we have, it should translate to outcomes because the one thing that we know about blood pressure control is that, that's a significant predictor of cardiovascular morbidity and mortality. Now let's transition from hypertension CV to more obesity. So really, on the left side of this thing, you had seen some of the work that we had presented last year. So to build on the work from the incretins, which by design, all of our incretin molecules have been what we call signal biased because we believe based on our existing data, both preclinical data as well as early clinical data suggests that having a biased signaling pathway enhances pharmacology. So more efficacy, potentially longer duration of action, and we will see all this borne out, hopefully, in the Phase II studies, but that's our approach to incretins. And on the right side, you'll see now that we've added to this armamentarium, as I said, with petrelintide, which is a long-acting amylin analog. It is suitable for once-weekly dosing. We believe based on the preclinical characteristics and the preclinical data set, this is a molecule that will be differentiated because it has no fibrillation, it's stable at neutral pH, has better potency and stability and has the pharmaceutic properties for potential combinability. So all are important attributes and differentiators. So I'm going to start with 388 because that's in our Phase III now. So again, as I said, very happy to advance this forward. We had shown you a lot of the Phase I data from the weight loss. So I'm not going to repeat that, but just remind us that we had seen up to 19% weight loss in 6 months in a cohort of people that were -- had obesity and nondiabetes. And here, what you're seeing here is the cohort with obesity and type 2 diabetes. And in the middle panel there is the curves of the A1c. So this is just over 12 weeks. Glycemic control on people that are on monotherapy of metformin. So if you treat people on a placebo with metformin, you get that gray line, but you treat people with metformin plus CT-388, you get the blue line. So that's a delta of around 2.8% relative improvement in A1c in as little as 12 weeks. On the right, it basically underscores how potent the metabolic benefits are with CT-388. And this is the same cohort from our -- what we call the Phase Ib study over 24 weeks, obesity, again, nondiabetes, we looked at MRI-PDFF. And what was striking to at least to me, having looked at the MASH sort of field for a while is that almost 85% of people achieved a 30% relative risk reduction in PDFF. And for those that follow the MASH field, you know that 30% reduction in PDFF means that you actually have 1-stage improvement in fibrosis or at least 1- to 2-point improvement in MAFLD activity score. So very potent effect even as little as 6 months. So we are very excited about the metabolic benefits here. So for all those reasons, along with all of the data from -- the totality of the data from Phase I because as I said, we've done it in people with and without diabetes, overweight and obesity and looked at it in all different ways. And consistently, we're seeing a very comparative profile of the weight loss. So from all of that, along with the ongoing safety monitoring with 2 existing ongoing Phase IIs, which are fairly large, between 350 to 450 people across the population, we feel very confident to be able to move this now to Phase III, which is planned to be initiated in the first half of '26. So quickly about pegozafermin because that's our -- the third Phase III asset very quickly. For those that have followed the field, you'll appreciate that not all FGF21s are created equal, okay? Because everybody says, this is another FGF21. But again, having worked in this area for a little while, I can tell you that all FGF21s are definitely not the same. It depends on how and what the receptor potencies are, what receptors they bind to, et cetera. And so we believe that pegozafermin certainly has the characteristics to be best in disease for MASH. And what was really exciting to us is that actually not just in between 2 panels, but the panel on the right. So in the Phase II study, it so happened that there were about 11 people that actually had a diagnosis of cirrhosis. So when we actually look at those 11 people, I know it's 11, but again, the point here is that it's a proof of principle. In nearly half of them in as little as 6 months, we were able to see a fibrosis stage improvement. So that is very hard to see, by the way, in as little as 6 months. And so to see that in an F4 population was, again, further reaffirmation of the properties of the FGF21 molecule. And then in between there, you can see the more formalized analysis from the 24-week study ENLIVEN study, where there's about a 27% response rate for fibrosis improvement and roughly the same between 27% and 37% response rate for MASH resolution. So all in all, very excited about this, and we're looking forward to integrating with the company and then continuing the great momentum with 2 additional ongoing Phase IIIs that's ongoing with data that is to be expected in the first half of 2027. Okay. So then moving on to our Phase II assets. So I'm going to talk about 4 very quickly. So let's start with petrelintide. So many of you have already seen this multiple ascending dose data. So currently, where we are with the program is that we have 2 ongoing Phase II studies, what we call supreme 1, that is in people with obesity nondiabetes and then supreme 2 is people with obesity plus diabetes. So both are going really well, very happy with the progress. And then just a reminder here that in as little as 16 weeks, we see a clinically meaningful weight loss of about 8.5% with petrelintide. And what was, again, very reassuring to see this even though we had hypothesized that the tolerability would be better, always nice to see data that supports it. So you can see no vomiting, in petrelintide, excepting for the one case at 9 milligrams, which is very mild and then very little to no diarrhea, okay? These are the 2 things that really annoy people when they take incretins, for example. The nausea is manageable, but vomiting and diarrhea are really life disturbing kind of events for most people. So we're very excited about this profile. We continue to push forward to get this into completed Phase II so that we can get to the Phase III, again, sometime in 2026. Now very quickly on the 996, just as a quick update. Again, many of this we have already presented last year, especially the exciting data from the multiple ascending dose cohort. So this was just a 4-week study in people with obesity nondiabetes. And you can see up to a 7.3% weight loss in about 4 weeks. And that set of data was the reason why we actually initiated 2 large Phase II studies, which you see on the right. So again, roughly between 250 to 350 participants in both with obesity, with and without diabetes. So these 2 studies are now underway. It's being conducted. And again, the data to be expected in 2026. So very excited about this oral program because this is -- we believe, has the potential, again, to be quite differentiated at least from the oral space. Then you heard a little bit from my colleague, Hideki, about emugrobart. So I'm not going to talk about the biology. He's already covered that really nicely. Just as a reminder that this is a sweeping technology and it removes the, what we call the, anti-latent myostatin. So it's really all of the ligands that bind to the activin A receptor. So just not myostatin per se, but a little bit more of a broader swath of ligands that impact the receptor. And so the overarching hypothesis here is that we would get more significant or more deeper weight loss with a clear preservation of lean mass. So we're excited about what we call the GYMINDA study, which is the study that we're doing in combination with tirzepatide. So these are in people, again, overweight or obesity, a 48-week study with tirzepatide by itself and tirzepatide with the various doses of emugrobart. And then we will have this data again in 2026. So last but not the least, we are also very excited about the ongoing developments and work that's going on with CT-868. So CT-868 has been designed, again, as a once-daily dually biased GLP-1/GIP and specifically for type 1 diabetes, again, a very underserved, high unmet need population. So we had already demonstrated the proof of concept of glycemic control reduction in people with type 2. And you might recall, but again, I'll just quickly remind us that we had seen about a 2.3% reduction in A1c in people with type 2 diabetes. And so we feel really good about the glycemic control potential. And we have done 2 studies with type 1 diabetes, both ongoing, near completion. One was a mechanism of action study and the other is a formal Phase II study, dose range finding study, both of which are ongoing, and we'll have data from the Phase II study actually in the fourth quarter of 2025. But just as a reminder, why are we excited about this is that people with type 1 diabetes need to actually still lose weight, are still insulin resistant, still have a very high insulin burden. So the hyperinsulinemia actually predisposes to a very high cardiovascular risk. So this set of data in type 2, which we fully believe will translate to type 1, indicates that you're able to reduce glucose while also reducing the insulin burden, which is really, in our minds, the proof of principle that improving insulin sensitivity in people with type 1 diabetes will improve their overall outcomes as well. So very excited to see what those results bring us. But again, quite happy with the progress there. So let me conclude with this slide, which is the slide that Teresa showed, which to me is an encapsulation of why it is? What we are doing? So let me end before I hand it off to Teresa to bring us home with 3 things. The first is we've taken a lot of thought and effort to understand what is our market needs, what are our patients' needs and what is the holistic way to approach this extremely complex and very heterogeneous disease. So I hope you at least can leave with the impression that we have that understanding that it is a segmented and fragmented market. The second is we have made significant progress with forward momentum in our pipeline, right? So the way the pipeline has been constructed and designed is really to try to address this intrinsic heterogeneity and the interdependencies of CVRM. And the third, which is what I'm most excited about is the fact that we are confident that we can actually execute this because of our capabilities and what unique opportunities are available at Roche. And that confidence then translates to commitment because we have to do this all in. This is not something where we can just sort of dip our toe in the water and see how it feels. We are all in into this. So we feel confident, we're committed, and I am really excited to see how this will evolve in the coming months and coming years. So with that, let me hand it off to Teresa to bring us home, and I take questions after that.

Wow, what a day. We've covered a lot of information. But if there's one thing I hope you take away from everything we've discussed today, it's actually the word that Manu used a couple of times, momentum. We have spent a considerable amount of time over the last number of years, focusing on what it is going to take in order to change the trajectory of our future, and there's how we go. We have thoroughly embedded the Pharma strategy in our everyday operations. And we are investing and strengthening the capabilities along our enterprise from end-to-end to ensure that we can not only deliver to patients today, but we are setting ourselves up to deliver for patients around the world in the future. We are optimizing our investments in our commercialization capabilities, not only to ensure that we can reach maximum potential with our on-market products, but they're ready to launch into these new disease areas when we get there. And we are maintaining and will maintain a stringent cost discipline to ensure that every dollar, whether it's an R&D dollar or an M&D dollar or an SG&A dollar is going to the thing that will deliver the highest return for the patients, for our people and for business. If there is one thing I'm proud of over the last couple of years, it is the change in our portfolio. We are in a 180-degree different position than we were in a number of years ago. We have a significantly evolved Phase III portfolio and a robust Phase I/II portfolio that really well position us to deliver on our ambition of 20 transformative medicines by the end of the year and beyond. R&D excellence is helping us figure out how to do this more efficiently with more rigor and with higher success rates and partnering supplements our impressive internal activities. I'll leave you today with the same commitment I made to you a year ago. We will continue to operate with rigor in the science and discipline in the business, and we will continue the momentum that we've generated. With that, thank you very much for your time and attention. I'm going to call all my colleagues back up on stage, and we can start grilling Manu with questions.

It's Michael Leuchten from Jefferies. Maybe 2 questions. One on cevostamab, just taking that asset straight in Phase III, given what we know about multiple myeloma is quite a aggressive decision. Just wondering how you feel comfortable about those range and [indiscernible] make a decision? And then second question on vamikibart, why would a bispecific targeting the same targets get around the adverse event...

Your microphone seems to be fading in and out. Can you just repeat the latter part of your question on cevostamab? I'm sorry.

Yes. So you're taking cevostamab straight into Phase III, as I understand it. And we've seen dose range work become more important with recent history on the regulatory side. Just wondering how you feel comfortable with the dose ranges out of the Phase I straight into Phase III.

Yes. Well, I think that as you saw, the 2 doses we focused on both are showing excellent tolerability and deep and durable responses. We are finalizing the choice of dose for the Phase III with health authorities, but we're honestly comfortable with both. With regard to the decision to go from Phase Ib to III, the strength of the data for cevostamab, pom, dex. And just to be aware, we've now treated 700 patients with cevostamab in aggregate. The strength of that triplet data and realizing the opportunity in second line because of the evolution of the field where all the drugs are now moved into first line and patients really need new and different, more effective and safe therapy second line, we see the -- and realize what's now available, we see the -- we believe that our probably of technical success based on these data in second line is worth moving forward on.

Okay. So on the vamikibart question, so we're moving -- we're prioritizing the VEGF-IL6 bispecific over vamikibart for a number of reasons. Safety is not the primary reason. The primary reason is actually because having a single molecule, which is a bispecific is much easier to deliver in clinic. Instead of giving 2 separate injections, you can give one separate injection -- you can just get away with just a single injection. So that's the primary reason why we're moving forward with the bispecific. In terms of is the VEGF-IL-6 bispecific safer than vamikibart, what we've seen in the early stages is that it really improves our confidence that, that specific VEGF-IL-6 molecule is looking really good. So we're very confident with that, yes.

Sarita from Morgan Stanley. Just a quick follow-up on Columvi. Have you had confirmation from the FDA post the negative ODAC that the Phase III SKYGLO trial serves as confirmation for converting the accelerated approval? And then I noticed in the data in the STARGLO trial, the OS benefit in when it's actually detrimental in the U.S. patients. So are you confident that we won't see the same trend in the frontline trial? And has the frontline trial recruited enough patients from the U.S. And then if I could just squeeze in another question, sorry, on the FGF21. Do you expect this to move to a combination market with GLP-1? And if so, are you initiating those trials? And perhaps you could speak to the ease of co-formulation and administration.

Yes, I can start. So the ongoing discussions with the FDA, we have not yet finalized the confirmation. Obviously, the accelerated approval for Columvi remains and we are finishing our discussions with the FDA. With regard to your questions about SKYGLO, that we're completing enrollment. I can tell you without getting into the details, there is robust U.S. enrollment in that trial. So I don't think we should be running into problems in terms of U.S. enrollment within that particular first-line study.

FGF21combinations?

You mean -- so just to clarify, so GLP-1 with just generally or specifically to FGF21, sorry.

So MASH team GLP-1 with FGF21 will you start combination trials.

When -- so we haven't basically provided that level of information yet. But we -- as shown on the slide, we fully anticipate that there will be some kind of combination that we would need to do. But the exact timing, we'll come back to you on.

In terms of coformulation?

So in terms of coformulation, so I can start -- that's been a general topic of importance for us because as you saw, combinations is a critical part of our pillar. So all of our assessments have always included early CMC assessments to see is many of the things that we have in our portfolio combinable. So happy to say that while we're doing our Phase II study in parallel, we are also looking at coformulation, feasibility for petre and CT-388 for example, Similarly, we're looked at early for FGF21 and GLP-1 feasibility studies, for example. So that's part of our thinking in terms of feasibility of coformulations.

It's Luisa Hector from Berenberg. I had a question on the TL1A. Just interested to hear where you see that fitting into the treatment paradigm. And then perhaps for Manu, on obesity, could you talk a little bit around how to mitigate some of the risks of running trials today given potential dropouts on placebo arms and perhaps the expectation around the GI tolerability profile and how that could impact? And then maybe just a comment on the obesity market and how you think pricing might work in terms of maybe an induction price and then a maintenance price, whether that's something you're thinking about?

Yes. Maybe I can start in terms of the TL1A, I'm assuming the question has to do with where it fits into the treatment paradigm for MASH. Is that the question?

No, I'm sorry, in IBD.

In IBD. Okay. Yes. No, we believe that, I think, has the potential to be best in disease for ulcerative colitis and Crohn's disease. And therefore, we fully expect that it will be early in the line of therapy as a best-in-disease therapy.

Yes. So in regards to the trials. Thank you for asking that. We are acutely aware that the world that we live in now is very different than when those trials were designed 5, 6 years ago. So one of the things that we're -- we've been paying a lot of attention to is patient retention because that's one of the core challenges, as you can imagine, right? So you're running against placebo, yes, it's important from a regulatory perspective, but it's not the most patient-friendly perspective. And so for that reason, in our trials, what we have decided is to actually allow for what we call long-term extension, meaning after a certain defined period, you collect your primary endpoint, then you convert all of those that were on placebo to active. So that allows for motivation, for retention, for, again, doing what is right ultimately. So we believe that can be a substantive benefit. The second is partly related to your question, if I understand it is, in order to keep patients in the trial and motivated, ultimately, we fully recognize that we would need to go head-to-head. And differentiation is going to be important, and that is very much something that Morten and I think about every single day. And so I can't get into the details of exactly what a competitor in what trial and what population today. But suffice to say, that is at the forefront of our thinking in the design of our trials is that we would need to differentiate and we would need to go head-to-head against the right and the appropriate competitors. Your third question was to Morten, I think.

Yes. I think this thing about a weight loss and a maintenance phase, I think, is starting to evolve. And of course, the question is, will you use the same agent and the same dose and the same everything to reduce the weight loss and maintain it over time. And if that's the case, then you could also argue the price will be the same for the 2. If you can use 2 different, you can say, agents or doses, then you would have the opportunity to charge a price for the weight loss phase and a different price for a different agent on the maintenance. The jury is still out if that will become the way obesity is treated over time. So I think it's too early to comment on a specific price point there. But I think there are some underlying dynamics that needs to play out to really consider such an approach.

Richard Vosser from JPMorgan. Maybe a question on fenebrutinib to start with, please. There's been discussion on lots of the BTKs about changing the endpoints towards a disability endpoint. So I just wonder whether you've had that discussion in terms of your Phase III. And also wondering on the baseline characteristics because as earlier patients are recruited, it's much more difficult to show a difference to Aubagio. So thoughts there, please. And then second question on 996. Lots of discussion on CT-388, just wondering what's going on with 996. It seemed to have got lost in the presentation.

I can address the feneubutinib question on relapsing MS studies, which is what I assume you're asking about. Yes, we're -- at this point, we're not going to change the -- we don't have plans to change the endpoint from annualized relapse rate. We will, of course, look at disability progression as the secondary endpoint, but we have high confidence that based on the Phase II study that we should be able to show a difference in relapse rates.

Do you have a follow-up?

Sorry, baseline characteristics and how similar are they to Phase II? Are they early patients? Just wondering how that might impact the results?

Yes. It's -- the baseline characteristics are relatively similar to other Phase IIs. But what's happened is over evolution of time, the relapse rates just generally have decreased. Nevertheless, because of what we see in the Phase II study, we still have high confidence that we'll see a difference.

So on 996, I mean, it's true, and there's only so much you can pack into a 15 minutes. So it's -- while it may have been buried, it's certainly not in our mind space. It occupies a significant portion of our energy and time. We believe that 996, as I said in my presentation, has the potential to be differentiated and has the characteristics based on the data that we currently have to support that. So we're currently in 2 Phase II studies. Just to reiterate, again, it's both in people with obesity, with and without diabetes. So all in all, it's about between the 2 studies, roughly 600 to 650 participants. So it's a very robust Phase IIb program. We believe that data from that program will inform on the dose, the regimen and also, of course, trying to really creatively think through what are the other areas we can start to really differentiate from endpoint perspective. And all of that will then inform our Phase III decision, which we, as I said before, anticipate in 2026.

Sachin Jain, Bank of America. Two on CNS and one obesity. On fene, whilst we're focused on efficacy, could you just update on the liver safety in your total package? I think there's been one confirmed case of iso, does that impact your regulatory sort of discussions if you get in efficacy? Secondly, on tronti, I think the primary completion of tronti studies is mid-'28. Have you had any discussions of potentially earlier look in the study on amyloid for a potential earlier filing? And then just one on obesity on 388. Any high-level commentary on the Phase II interim that's driven the Phase III start? Did you sort of get your dose maximization on safety? And have you told us what dose and titration regimen you're going into Phase III with?

So let me start with fene. And yes, we've seen slight elevation in liver function. And it's only in a couple of patients, they're mild to mild plus in nature. They were reversible and did not lead to any consequences. We did have one highest loss case, as you pointed out, but it is not a great concern. And then on the tronti. Tronti, yes, as far as earlier filing, we, of course, open-minded to really get this drug, promising drug to patients as soon as possible. But currently, we don't have plans to accelerate filing of that on that study. Having said that, the FDA has stated that amyloid PET is a validated surrogate biomarker.

So on the 388, firstly, very important for ourself to be reminded that the studies are still ongoing. So the study remains blinded. So what we have made the decision on is the extensive totality of the data. So that's what I was trying to emphasize during the presentation is we've done a fairly long and extensive Phase I/Ib program, that has gone up to 6 months essentially. And many of that data, you've seen it either in previous meetings or at the ADA this year. So that totality of the data gives us a lot of confidence in terms of what do we really think is the trajectory? Where do we really believe are the safety tolerability issues. But we also believe that -- which is a known fact at this point, which is going lower and slower in the titration will actually help us. There is ongoing safety monitoring in any study that you would do, and that further reassures us of the profile that we anticipate. So when you take it all together, that's the totality of the information on which we've made the decision to go to Phase III. It's not because we've looked at the data or anything like that. So again, I want to emphasize the data remains blinded, and we need to keep that so for data integrity.

So is dosing being decided? Are you waiting for the Phase II to decide the dosing in Phase III?

So again, based on the PK data, the PK/PD modeling, again, the information that we already have gives us confidence of what the dose is -- at least the dose limits ought to be. So it's not that we have to specifically wait, but we do want to wait to see what is the final doses, if you will.

Can we start in the midsection? Is there in the back anyone? No, then we go to front.

Colin White, UBS. My first question was on FGF21. In 89bio studies, it seemed the placebo rate was quite low compared to some of the other studies that we've seen. I just wondered if you could comment on your thinking about the reasoning for that and then what gives you confidence when you look at all the data that's been presented that your FGF21 is differentiated from the others? And then the second question I had was on fenebrutinib and the FENtrepid study. So it's designed originally to show superiority. I was just wondering when you look at the data from FENopta on disability and obviously, you know the effect of OCREVUS from your studies, if there's anything you've seen in the clinical data to give you reason to believe that on 12-week disability progression, it might be faster acting.

So I got the first part of your question about the placebo response, so I'm happy to answer that. What was your second part?

On FGF21, I mean, what makes you think your FGF21 is differentiated from the others in development?

Okay. So on the placebo response, so one thing to keep in mind again is that's why it's -- kudos to the 89bio team in terms of how they conducted the study. It was very rigorously done. So it was a biopsy-based study, the biopsy endpoint and the way that the biopsy endpoints were read were very rigorous. And so that rigor allows to basically get to what would be a true treatment effect size. So again, really kudos to them for designing a trial that allowed us to get to that very clear result. So in terms of the differentiation with others, I mean, I cannot get into the nitty-gritty, obviously, for obvious reasons. But on a broadest level, it does matter whether you go take the approach of targeting based on a ligand-based approach or a receptor-based approach. So these are all ligand-based approaches. And so we believe, again, that based on the data that we have seen and the data that's available for -- that's in the public domain, we do think that the data speaks for itself. It does look quite robust. The nausea and the vomiting rates are there, but it's very low, in fact, lower rates of diarrhea than others may have seen. So when you take the totality of the efficacy, the tolerability, the safety, the convenience of dosing, when you put it all together and the targeting modality, it gives us a lot of confidence that this will be differentiated and the potential for best in disease.

And on the question of fenebrutinib and impact on disability progression, because of the mechanism of action where it's a dual mechanism action targeting B cells as well as microglia macrophages and the high CSF concentration we achieved, potentially, this could have a very strong impact on disability, even potentially higher than OCREVUS. Nevertheless, if it is as equal to OCREVUS in terms of impact on disability progression, it's an oral molecule. So we think this will be a benefit to patients.

James Quigley from Goldman Sachs. Two questions. So one on a much later point on the Phase III design or potential Phase III design for CT-388, but one of your competitors has gone down the traditional route in terms of escalating up to the highest dose for maximum weight loss. The other competitor has taken approach in Phase III of a more flexible dosing design. So where are you landing in terms of how you're thinking about that for the Phase III design for 388, and also, are you going to start a cardiovascular outcomes trial straight away as well? And the second question, again, on fenebrutinib. The PK/PD data that you've shown today, again, highlights a stronger profile. But when you look at the Phase II data for evobrutinib, there you also had an annualized relapse rate of 0.08 in -- at the highest dose. So have you interrogated gut analysis to work out, why they can still get such a low relapse rate? And then similarly, given the baseline characteristics are similar or similar as you mentioned, have you run any analysis of where you think the fenebrutinib profile will come versus the placebo or the [ bio ] arms in the failed trials for evobrutinib and tolebrutinib?

I can take the 388 question first. So we haven't, as I said before, disclosed the exact details but we will in the coming months when we actually start the Phase III program. So what we have today disclosed is the fact that we are going to Phase III. So we're finalizing the design. So obviously, I cannot speak to the specificity of what you're asking. But in terms of principle, I can tell you that those are all very much front and center of our minds. Just as I mentioned to Luisa, which is that the long-term extension part of the design, the head-to-head component, the regimen is equally important for us. So providing the appropriate level of flexibility, appropriate level of maximization or optimization, if you will, of the tolerability profile because that's another way we believe we can be differentiated. These are all going to be key considerations in the design. And at this point in time, not able to give you more details than that, but that's the general principle in which we would want to do these designs.

And in terms of fenebrutinib and impact on relapses, as you saw, a really low annualized relapse rate, 0.06 at week 96, translates to one relapse every 17 years or so. And so really dramatic reduction in relapses. The important thing to remember about fenebrutinib is the benefit risk ratio is a highly selective BTK inhibitor, which is the advantage it has over the other BTK inhibitors and that is non-covalent, so potentially a better benefit risk profile.

Can we take question from the right side.

It's Justin with Bernstein. Two, please. Firstly, on zilebesiran, given the outcomes data, you said at 2030, could you just remind us on the LOE? And then the second one on [indiscernible]. I know it's not an exact comp true cap, but can you just help us understand if we should be expecting the sales to inflect? And if so, when?

When we'll see the inflection?

So I mean, as you remember, we have an entire program in the whole PIK3 mutations, and we start with a very small patient population. So that's probably -- for that population is a smaller CHF 100 million. But once the other trials read out, which you're going to have in the course of this decade, we'll see those inflection points and move further into frontline. So we'll see the potential of that hopefully being in that CHF 1 billion to CHF 2 billion range as we have anticipated coming then through once those trials come through.

Would you mind repeating the LOE part. We didn't quite get it.

Yes, sorry. I guess I kind of struggle with why Astra aren't doing an outcomes trial, you're doing an outcomes trial. You said today your outcomes data was 2030. So could you just remind us when the patent exclusivity expires on the drug? Or if I got running to the stick and why you are -- you obviously believe in outcomes and Astra don't, I'd love to understand why...

So I mean, I don't want to speak on what the exact data is, but we can get that information for you. But I think in terms of where we think the data will read out, just given the number of people that we just sort of alluded to, 11,000 people, 4-point MACE, it would have to be -- they would have to be followed for at least 2.5 years, minimum. So that's the earliest, but it's event-driven, right? So we would have to wait to see. So that's kind of the end of the bookend, if you will, that we have provided just to make sure that we have a sufficient number of events. We can get back to you on the exact LOE date.

Yihan Li from Barclays. So first question actually is a general question on Alzheimer's disease. So we saw like the trontinemab showed very promising and differentiated profile in Alzheimer's. But we also know like your competitor is running a trial for GLP-1s in Alzheimer's. So we're just wondering what is your view on GLP-1's potential in Alzheimer's in prospective trials? And do you see a rationale for GLP-1 plus anti-amyloid combo for Alzheimer's disease. And our second question actually is a very quick clarification question in NXT007. So you noted in your slides that you will run the Phase III head-to-head trial with Factor VIII. So we are just wondering like can we know which specific Factor VIII will be used in the trial, like potentially out to? Yes, that's all the question.

Why don't I -- I'll take your last question first while people work through the early ones. So we haven't provided yet the details. As you know, we have 3 Phase III trials for NXT, one in the pediatric population, one comparing to Factor VIII and one comparing to Hemlibra. And obviously, all 3 are critical to establish the basis of evidence for this to become a standard of care. We do look forward to providing those additional details, but that's probably as much as I can say right now.

And maybe while Manu and Hideki are starting through at a high level. We have to see the data on the GLP-1s and Alzheimer's. But if it happens to look good, this is -- we, of course, also believe that we have potentially a competitive set of assets in that space. And certainly, we think trontinemab could be very much competitive in that space. So certainly, it will be interesting, but everything depends on the data and whether this, in fact, plays out.

Yes, I couldn't have said it better. I mean I would only add to that is that it's always good to remind ourselves that sometimes Alzheimer's, what it's called Alzheimer's is also called type 3 diabetes because the pathophysiology is very, very similar. It's insulin resistance, neuroprotection, neuroinflammation. So one of the other things that we had highlighted worth highlighting again is the synergy that we have within our own TAs. It's a very unique opportunity for Roche to be able to mix and match the portfolio to go after the most unmet needs. And I think we'll all agree that Alzheimer's is an unmet need. So having that opportunity in a data-driven way is kind of how we will approach it.

Next question goes to Emmanuel.

Emmaneul Papadakis. Maybe a follow-up on NXT on the safety side, 2 out of 30 patients in Phase II seeing clinically significant antidrug antibodies is a fairly meaningful rate. So could you just talk a little bit about potential impact that could have in the real-world setting? How do you think that will be monitored -- because obviously, the risk of patient losing response could be pretty catastrophic. Second question on SUNMO in light of what's happened with STARGLO. Have you had any agency feedback yet on the lack of OS benefit at the interim analysis and the potential importance of showing that at the final? And indeed, could you comment on the potential for an early readout on SKYGLO at interim?

Sure. So I think your first question was on the antibody drug -- antibodies for NXT. So as you rightly point out, we've seen 2 patients with ADAs that influence PK. One patient was on the lowest dose in the dose escalation study and did go off study. The second actually remained on treatment has had 0 bleeding events. And in fact, we're going to have an additional data cut of more patients to be shared at a future medical meeting. But what I can say is the totality of evidence gives us continued confidence to move into Phase III with that robust portfolio that we think will establish this as a standard of care and best-in-class treatment. With regard to the discussions, you asked about the feedback about STARGLO and the OS. I couldn't quite make...

SUNMO, which I think you planned for...

SUNMO, yes. So you're asking specifically about -- well, the study was designed to look at PFS. That's -- that was its PFS. PFS was the primary endpoint as discussed with health authorities. And obviously, it did achieve that robustly with a 59% improvement and a marked improvement in terms of months. The OS is a secondary endpoint. It's certainly going in the right direction. That's historically been what the health authorities have looked for. I think you asked about U.S. data. One thing that was presented in the presentation in July was the PFS within North America, which was a hazard ratio for PFS of 0.15. So certainly result looks like it's going in the right direction. So we are moving forward with our plans and discussions with health authorities. Your third question was on.

In terms of SKYGLO?

First SKYGLO...

Yes.

So the first one.

I think you said the readout would be '27 anytime sooner earlier interim.

Yes. I don't think -- I'm not really able to share more details other than the fact that the study is finishing enrollment. It's robustly. The feedback we get from TAEs was that they really -- they're very impressed with the Phase Ib data with a 96% CR rate, which gives us greater confidence. And right now, what we can say is we're expecting a readout in '27.

Okay. I think this is already final questions. We have to stop here, but I think all our key management will be available for the upper row, so you have another 30 minutes to drill down on whatever is on your mind. Let me quickly use the occasion also to thank a couple of people because this then would not have been possible with the contribution of many, and just to call out here for the people from the IR team who have been working here since 4, 5 weeks, I think day and night, some of them to make it work. It's [ Jan Philip Schwartz ] and [indiscernible]who were responsible for both morning sessions and also manage the overall slide deck and who were working really, I can say, tirelessly day and night and throughout the last few weekends. It's [ Rafael Pablolowsky ] who was responsible for the oncology deck. It's Loren Kalm, who was responsible for the neurology slide deck and also preparing macro topics and keeping Q&A up to date for speaker preparation. It's [ Anita Tang ] who was responsible for the immunology and ophthalmology slide decks and speaker preparation and also manage the epidemiology slides, which you can find in the appendix. [ Julia Broiler ] and Sabine Borngr ber, who are responsible for the CVRM decks and also all the alignment needed around it with all the external partners as well. This was quite a task. And last but not least, and I want to thank the IR back office team that's Melanie Wolf, Beatrice Hau and Eva Losert for all the excellent organization. And of course, there are many other colleagues from -- within the organization and different departments and who have contributed, which I simply could not all call out by name. This would be a long, long list. But we really want to say a big thank you from our end here as well. And with that, I think we are closing the session. As said, you're welcome to stay for an upper row and get additional answers, whatever is on your mind. Thanks.